HK1101754B

HK1101754B - Intra-lumen polyp detection device

Info

Publication number: HK1101754B
Application number: HK07106616.4A
Authority: HK
Inventors: 约阿夫．基姆希
Original assignee: Check-Cap Ltd.
Priority date: 2003-12-17
Filing date: 2004-12-16
Publication date: 2010-12-03

Description

Inner cavity polyp detection device

Cross Reference to Related Applications

This application claims priority to the following applications: (a) U.S. provisional patent application 60/531,690 entitled "lumen polyp detection" filed on 17.12.2003; and (b) U.S. provisional patent application 60/559,695 entitled "lumen polyp detection" filed 3/31/2004. Both of which are assigned to the assignee of the present application and are incorporated herein by reference.

Technical Field

The present invention relates generally to the field of detection of conditions in a body lumen, and more particularly to a swallowable device that travels in the colon and detects anatomical (or tissue) abnormalities.

Background

Colorectal cancer is one of the leading causes of death in the western world. Clinical evidence suggests that early detection of primary colorectal cancer results in a 5-year survival rate of 90% or greater, while disease detection when cancer has metastasized results in a 5-year survival rate of 50% or less and a poor prognosis with a 30% repetition rate. Colorectal cancer screening and early detection have important positive effects on the prognosis of the malignant tumor.

The following references (all of which are incorporated herein by reference) may be of interest:

shanks U.S. Pat. No. 5,721,462

Trebes et al, U.S. Pat. Nos. 6,134,300 and 6,353,658

U.S. patent application publication 2002/0099310 to Kimchy et al

PCT publication WO02/058531 to Kimchy et al

Brochard J et al, "estimation of motion parameters of 3D constructed surfaces using autocorrelation functions", Pattern Recognition Letters 24 (12): 2031-2045(2003)

Camilleri M et al, "New method for characterizing gastric emptying in humans and filling of solids in the colon", Am J Physiol 257(2Pt 1): G284-G290(1989)

Caner BE et al, "functional evaluation of gastrointestinal tract of human body using 99 Tcm-latex particles", Nucl Med Commun 12 (6): 539-544(1991)

Compton，Arthur H.，Phys.Rev.21，483；22，409(1923)

Cmtman G et al, "new needle-based micro x-ray generation system", Phys Med Biol 49: 4677-4688(2004)

Haga A et al, "miniature x-ray tube", Applied Physics Letters 84 (12): 2208-2210(2004)

Madsen JL et al, "gastrointestinal delivery of technetium-99 m-labeled cellulose fibers and indium-111-labeled plastic particles", J nuclear Med 30 (3): 402-406(1989)

Pais, Abraham, 'predominantly sensitive …': the Science and The Life of Albert Einstein, Oxford (1982)

Proano M et al, "solid transport through the human colon: regional quantification in the intestine was not prepared ", Am J Physiol 258(6Pt 1): -G862(1990)

Tartari A et al, "deep Compton Scattering base imaging by principal Components analysis", conference book of the 15 th non-destructive survey of world meetings, protection and repair of arts and buildings, Roman (10 months, 15-21 days, 2000)

"X-ray contrast medium" Medcyclopaedia^TM(www.medcyclopaedia.com)，The Encyclopaedia of Medical Imaging Volume I

Disclosure of Invention

Embodiments of the present invention are directed to the detection of polyps and other clinically relevant features that may conceal the potential for Gastrointestinal (GI) tract cancer, particularly colorectal cancer.

In some embodiments of the invention, a subject/patient swallows or swallows (swallows) a contrast agent (contrast agent), typically after a waiting period, followed by a capsule containing one or more sources of gamma and/or X-ray radiation and a radiation detector. As the capsule passes through the gastrointestinal tract, the radiation source "illuminates" the vicinity of the capsule. Gastrointestinal contents (including contrast agents), gastrointestinal walls, and tissues outside the gastrointestinal tract typically act as a dispersion medium for the emitted radiation primarily through the compton scattering process. The scattered photons then return through the gastrointestinal contents including the contrast agent. The radiation detector correctly counts compton backscattered photons and transmits count rate information to an external recording unit worn by the subject.

The count rates acquired by each detector per unit time interval are typically only analyzed for a predetermined photon energy window. These data are presented to the physician in a manner that enables him to estimate the likelihood of polyps or other tissue aberrations being present in the gastrointestinal tract. In some embodiments, the data is also analyzed to show the total area of the colon where such a distortion may be present. These polyps or tissue abnormalities may be the result of tumors beginning to grow in the gastrointestinal tract. If the physician suspects that the emerging polyp or other tissue abnormality may be cancerous or precancerous, the subject will generally need to undergo further diagnostic testing, such as colonoscopy.

There is therefore provided, in accordance with an embodiment of the present invention, apparatus, including:

a capsule adapted to be swallowed by a subject and comprising:

at least one radiation source adapted to emit radiation having an energy of at least 10 kev; and

at least one photon detector adapted to detect photons generated in response to the emitted radiation, the photons having an energy of at least 10 kev; and

a control unit adapted to analyze data associated with the photons so as to generate information useful for identifying clinically relevant features of the Gastrointestinal (GI) tract of the subject.

In one embodiment of the invention, the device includes an oral contrast agent adapted to be administered by the subject. Alternatively or additionally, the device comprises an oral formulation (agent) having a high atomic number (high Z) suitable for administration by a subject.

For some applications, the device includes an oral formulation adapted to be swallowed by a subject, the formulation selected from the list consisting of a contrast agent and a high atomic number formulation, the formulation including ferromagnetic particles, and the capsule including a magnet adapted to attract the ferromagnetic particles to the capsule.

In one embodiment of the invention, the radiation source comprises a miniature X-ray generator. In an embodiment, the radiation source comprises a radioisotope. For some applications, the radiation source is adapted to emit gamma rays. Alternatively or additionally, the radiation source is adapted to emit X-rays.

For some applications, the control unit is adapted to analyze the time derivative of the data in order to generate the information.

For some applications, the photon detector comprises at least one collimator adapted to collimate photons detected by the photon detector.

For some applications, the control unit is adapted to distinguish between gases in the gastrointestinal tract and clinically relevant features.

In an embodiment, the control unit is adapted to analyze X-ray fluorescence (XRF) photons generated in response to the emitted radiation. In an embodiment, the control unit is adapted to analyze XRF photons generated in response to the emitted radiation and compton backscattered photons generated in response to the emitted radiation.

For some applications, the capsule includes an acceleration sensor.

For some applications, the device includes an external data recording unit adapted to be maintained outside the body of the subject, and the capsule is adapted to wirelessly transmit information to the data recording unit when it is located in the gastrointestinal tract.

For some applications, the capsule includes a formulation selected from the list consisting of a contrast agent and a high atomic number formulation, and the capsule is adapted to store the formulation and release the formulation into a clinically significant area of the gastrointestinal tract. Alternatively or additionally, the apparatus further comprises an agent storage capsule comprising an agent selected from the list consisting of a contrast agent and a high atomic number agent, the agent storage capsule being adapted to store the agent and release the agent to a clinically significant area of the gastrointestinal tract.

For some applications, the capsule includes a pressure sensor.

For some applications, the data relating to photons comprises data of one or more predetermined photon energy windows, and the control unit is adapted to analyze the energy window data.

In an embodiment, the data relating to photons comprises the number of photons per time interval, the photon detector is adapted to count detected photons, and the control unit is adapted to analyze a statistical number of photons.

In an embodiment, the control unit is adapted to estimate a distance from a location of the capsule to a wall of the gastrointestinal tract. For some applications, the control unit is adapted to estimate the distance using an algorithm in which there is an inverse correlation between the distance and the number of detected photons. For some applications, the control unit is adapted to analyze compton backscattered photons generated in response to the emitted radiation. For some applications, the device comprises an oral contrast agent adapted to be administered by the subject, and the control unit is adapted to estimate the distance by estimating a position of the capsule and a contrast agent depth between walls of the gastrointestinal tract in response to an analysis of compton backscattered photons.

For some applications, the control unit is adapted to estimate the distance using an algorithm in which there is a positive correlation between the distance and the number of detected photons. For some applications, the control unit is adapted to analyze XRF photons generated in response to the emitted radiation. For some applications, the apparatus comprises an oral formulation having a high atomic number adapted to be taken by the subject, the XRF photons being generated by the oral formulation in response to the emitted radiation, and the control unit is adapted to estimate the distance by estimating a location of the capsule and a contrast agent depth between walls of the gastrointestinal tract in response to an analysis of the XRF photons.

In an embodiment, the radiation source is adapted to emit radiation only during a period of time in which the capsule is in the gastrointestinal tract. For some applications, the capsule includes a sensor adapted to sense a parameter indicative of possible impending (imminent) motion of the capsule in the gastrointestinal tract, and the radiation source emits radiation from the capsule in response to the sensor-sensed parameter. For some applications, the radiation source includes a miniature X-ray generator configured to emit radiation only during the period of time.

For some applications, the capsule includes a stem, the radiation source is coupled to the stem, and the actuator is adapted to move the stem so as to move the radiation source.

In one embodiment, the capsule comprises an inflatable balloon adapted to be inflated around the capsule. For some applications, the balloon is configured such that the capsule moves toward the center of the balloon when the balloon is inflated. For some applications, the balloon is configured to expand when the capsule reaches a clinically significant area within the gastrointestinal tract. For some applications, the balloon includes a valve adapted to open for a specified period of time after the capsule reaches the area of clinical attention, thereby deflating the balloon.

For some applications, the control unit is adapted to estimate a wall distance from the capsule position of the capsule to the wall of the gastrointestinal tract by calculating a sum of (a) a first distance within the balloon from the position of the capsule to the position of the balloon on the surface of the balloon and (b) a second distance from the position of the balloon to the wall of the gastrointestinal tract. For some applications, the control unit is adapted to calculate the first distance by measuring and analyzing a change in the number of compton backscattered photons detected by the photon detector. For some applications, the control unit is adapted to calculate the first distance in response to a compton backscatter projection size detected by the photon detector. For some applications, the balloon surface comprises a high density of point particles of a material, and the control unit is adapted to calculate the first distance by measuring and analyzing XRF photons detected by the photon detector. For some applications, the balloon surface comprises a radiation point source, and the control unit is adapted to calculate the first distance by measuring and analyzing radiation emitted from the point source detected by the photon detector. For some applications, the control unit is adapted to calculate the second distance by analyzing the number of XRF photons detected by the photon detector.

In an embodiment, the gastrointestinal tract comprises a colon of the subject, and the control unit is adapted to analyze the data so as to generate information useful for identifying clinically relevant features of the colon. For some applications, the capsule comprises: an electrode attached to an outer surface of the capsule; a pulse generator, and the control unit is adapted to drive the pulse generator to apply an electrical signal to the colon capable of causing movement of a mass within the colon. For some applications, the control unit is adapted to generate information about the geometry of the muscles of the colon.

In an embodiment, the control unit is adapted to generate a graphical representation of the information. For some applications, the control unit is adapted to generate the graphical representation by generating a series of temporal surface morphologies (morphologies). For some applications, the control unit is adapted to generate the graphical representation by generating a first surface having subdivisions representing respective distances between respective locations of the capsule and respective locations of a wall of the gastrointestinal tract and generating a second surface having pixels, each of the pixels representing a respective difference between one of the subdivisions of the first surface and a plurality of subdivisions adjacent to the subdivision.

For some applications, the control unit is adapted to produce the graphical representation by repeatedly generating a second surface at a plurality of points in time and displaying an animation of the second surface corresponding to the plurality of points in time.

For some applications, the control unit is adapted to generate a graphical representation of a reference subject coordinate system. Optionally, the control unit is adapted to generate a graphical representation referring to the coordinate system of the capsule.

In an embodiment, the at least one photon detector comprises a plurality of photon detectors arranged to detect photons from a plurality of respective detection directions. For some applications, the at least one radiation source comprises a plurality of collimators arranged to emit radiation along a plurality of respective emission directions corresponding to the detection directions.

In one embodiment, the capsule includes at least one radiation shield. For some applications, the at least one shield is configured to prevent radiation from exiting the radiation source in a direction other than a single enclosed sector associated with a sphere surrounding the capsule.

In an embodiment the radiation source is adapted to emit radiation having a plurality of primary energy levels, and the control unit is adapted to analyze the number of photons having a plurality of secondary energy levels different from said plurality of primary energy levels, for some applications, the radiation source is adapted to emit radiation having first and second energy levels, and the control unit is adapted to analyze a mathematical relationship between (a) the number of photons having a third energy level detected by the photon detector and (b) the number of photons having a fourth energy level detected by the photon detector, for some applications, the relationship comprises a ratio of (a) the number of photons having the third energy level and (b) the number of photons having the fourth energy level, and the control unit is adapted to analyze the ratio. The control unit is adapted to analyze said relation to determine the actual calibrated distance between the position of the capsule and the wall of the gastrointestinal tract.

In one embodiment, the clinically relevant feature comprises a pathological abnormality of the gastrointestinal tract. In one embodiment, the pathological abnormality includes a polyp.

In an embodiment, the control unit is adapted to analyze compton backscattered photons generated in response to the emitted radiation. For some applications, the control unit is adapted to analyze compton backscattered photons having an energy level indicated by the backscattering angle of the range parameter of angles of 180 degrees +/-less than 30 degrees, for example less than 20 degrees, or less than 10 degrees.

In an embodiment, the control unit is adapted to detect that the capsule has reached a region of clinical interest in the gastrointestinal tract. In an embodiment, the region comprises a colon, and the control unit is adapted to detect that the capsule has reached the colon. For some applications, the control unit is adapted to detect that the capsule has reached the area by detecting and analyzing XRF photons. Alternatively or additionally, the capsule comprises a pH sensitive element, and the control unit detects that the capsule has reached the region in response to a pH change in the region affecting the pH sensitive element. Further alternatively or additionally, the device comprises a tag (tag) adapted to be attached to an outer surface of the body of the subject located in the vicinity of the entrance to the zone, and the control unit is responsive to a signal emitted by the tag to detect that the capsule has reached the zone. Still further alternatively or additionally, the capsule comprises a pressure sensor, and the control unit detects that the capsule has reached the zone in response to a pressure change detected by the pressure sensor. For some applications, the device includes a tag adapted to be attached to an outer surface of the body of the subject in the vicinity of the entrance to the zone, and the control unit detects that the capsule has reached the zone in response to (a) a signal emitted by the tag in combination with (b) a change in pressure. For some applications, the control unit is adapted to detect that the capsule has reached the area by detecting and analyzing XRF photons and in response to pressure changes.

In an embodiment, the control unit is adapted to detect density variations in tissue of the wall of the gastrointestinal tract, which variations are indicative of the presence of a clinically relevant feature. For some applications, the control unit is adapted to detect the change when the control unit detects that at least a portion of the capsule is in physical contact with a wall of the gastrointestinal tract. For some applications, the at least one photon detector comprises a plurality of photon detectors, and the control unit is adapted to analyze the compton backscattered photon count from the location of the wall detected by more than one photon detector. For some applications, the control unit is adapted to analyze the compton backscattered photon number using Principal Component Analysis (PCA). For some applications, the control unit is adapted to detect density variations in response to a determination that a significant portion of the data variance cannot be described by a single Principal Component (PC).

In an embodiment, the capsule comprises at least one extension element adapted to keep the capsule at least a certain distance from the wall of the gastrointestinal tract when extended. For some applications, the extension element is configured to extend when the capsule reaches a region of clinical interest within the gastrointestinal tract. For some applications, the extension element includes at least one leg element, an expandable loop structure, and/or a deployment element.

In an embodiment, the capsule comprises at least one extension element adapted to orient a long axis of the capsule generally parallel to a longitudinal axis of the gastrointestinal tract when extended. For some applications, the extension element includes an inflatable flexible chamber. For some applications, the flexible chamber includes a superabsorbent hydrogel, and the flexible chamber is adapted to swell as the hydrogel absorbs fluid from the gastrointestinal tract.

According to an embodiment of the present invention, there is also provided an apparatus, including:

a capsule adapted to be swallowed by a subject and comprising at least one photon detector adapted to detect photons having a detector energy of at least 10 kev; and

In an embodiment, the apparatus comprises a radio isotope labeled material adapted to be taken down by the subject and to emit radiation having a radio isotope labeled energy, and the control unit is adapted to analyze data related to photons having the radio isotope labeled energy.

In an embodiment, the photon detector is collimated.

In an embodiment, the control unit is adapted to estimate a distance from a location of the capsule to a wall of the gastrointestinal tract. For some applications, the control unit is adapted to estimate the distance using an algorithm in which there is a positive correlation between the distance and the number of detected photons.

a capsule adapted to be swallowed by a subject and comprising at least one radiation source adapted to emit radiation having an energy of at least 10 kev;

at least one photon detector not physically connected to the capsule, adapted to detect photons having an energy of at least 10 kev; and

In an embodiment, the radiation source comprises at least one collimator adapted to collimate the radiation emitted by the radiation source. In one embodiment, the radiation source comprises a miniature X-ray generator. Optionally, the radiation source comprises a radioisotope.

a capsule adapted to be swallowed by a subject and comprising a plurality of photon detectors;

a balloon (bladder) adapted to surround at least a portion of the capsule when inflated and comprising a plurality of radiation sources located on a surface thereof and adapted to emit radiation having an energy of at least 10 kev, wherein the photon detector is adapted to detect photons generated in response to the radiation, the photons having an energy of at least 10 kev; and

In an embodiment, the control unit is adapted to analyze XRF photons detected by the photon detector in order to estimate a position on the balloon surface and a distance between the walls of the gastrointestinal tract.

In an embodiment the control unit is adapted to analyze compton backscattered photons having an energy level indicated by the backscattering angle of the range parameter at an angle of 180 degrees +/-less than 30 degrees.

In an embodiment, the control unit is adapted to analyze incident photons having the same energy as the radiation emitted by the radiation source. For some applications, the control unit is adapted to analyze the incident photons and compton backscattered photons with energy levels indicated by the backscatter angle having a range parameter of angles of 180 degrees +/-less than 30 degrees. For some applications, the apparatus includes more photon detectors than radiation sources.

For some applications, the control unit is adapted to map the feature by comprehensively analyzing the number of incident photons and the number of Compton backscattered photons measured by the plurality of photon detectors.

an expandable structure adapted to surround at least a portion of the capsule when expanded and shaped when expanded so as to define a plurality of locations thereof not in direct physical contact with the capsule, the locations including respective radiation sources adapted to emit radiation having an energy of at least 10 kev, wherein the photon detector is adapted to detect photons generated in response to the emitted radiation, the photons having an energy of at least 10 kev; and

There is also provided, in accordance with an embodiment of the present invention, apparatus for use with an object of interest, including:

at least one radiation source adapted to emit radiation having an energy of at least 10 kev;

at least one photon detector adapted to detect photons having an energy of at least 10 kev;

a high atomic number agent adapted to be positioned between the radiation source and the target; and

a control unit adapted to analyze XRF photons detected by the at least one photon detector and emitted by the high atomic number agent in response to the emitted radiation in order to estimate the distance between the radiation source and the object.

a contrast agent adapted to be placed between the radiation source and the object; and

a control unit adapted to analyze compton backscattered photons detected by the at least one photon detector and emitted by the contrast agent in response to the emitted radiation in order to estimate a distance between the radiation source and the object.

There is further provided, in accordance with an embodiment of the present invention, apparatus for use with an object of interest, including:

a radioisotope labelled material adapted to emit radiation having an energy of at least 10 kilo-electron volts and disposed between the photon detector and the target; and

a control unit adapted to analyze detected photons emitted by the radioisotope labelled material in order to estimate a distance between the photon detector and the target.

According to an embodiment of the present invention, there is further provided a method, including:

emitting radiation having an energy of at least 10 kilo-electron volts from a Gastrointestinal (GI) tract of a subject;

detecting photons from within the gastrointestinal tract that are generated in response to the emitted radiation, the photons having an energy of at least 10 kev; and

data relating to the detected photons is analyzed to produce information useful for identifying clinically relevant features of the gastrointestinal tract.

In one embodiment, the method includes administering to the subject an oral contrast agent. In one embodiment of the invention, emitting radiation includes orally administering to the subject a radioactively labeled material that emits radiation.

In one embodiment, the detecting comprises causing the subject to take the swallowable capsule and detecting from the capsule.

The present invention additionally provides, according to an embodiment of the present invention, a method, including:

detecting photons having an energy of at least 10 kilo-electron volts from within a Gastrointestinal (GI) tract of a subject: and

The present invention additionally provides, according to an embodiment of the present invention, a method, including: emitting radiation having an energy of at least 10 kilo-electron volts from a Gastrointestinal (GI) tract of a subject;

detecting photons having an energy of at least 10 kev; and

According to an embodiment of the present invention, there is also provided a method including:

detecting photons from a plurality of first points within a Gastrointestinal (GI) tract of a subject;

emitting radiation having an energy of at least 10 kev from a plurality of second points within the gastrointestinal tract surrounding the plurality of first points, wherein the photon is generated in response to the emitted radiation and has an energy of at least 10 kev; and

The present invention further provides, according to an embodiment of the present invention, a method, including:

placing a high atomic number agent between a first location and a second location;

emitting radiation having an energy of at least 10 kev from a first location;

detecting photons having an energy of at least 10 kev; and

the distance between the first location and the second location is estimated by analyzing detected XRF photons emitted by the high atomic number agent in response to the emitted radiation.

placing a contrast agent between the first location and the second location;

emitting radiation having an energy of at least 10 kev from a first location;

detecting photons having an energy of at least 10 kev; and

the distance between the first location and the second location is estimated by analyzing detected compton backscattered photons emitted by the contrast agent in response to the emitted radiation.

positioning a radioisotope tagging material between a first location and a second location, adapted to emit radiation having an energy of at least 10 kilo-electron volts;

detecting photons having an energy of at least 10 kev; and

the distance between the first location and the second location is estimated by analyzing detected photons emitted by the radiolabelled material.

The invention will be more completely understood in consideration of the following detailed description of embodiments of the invention in connection with the accompanying drawings, in which:

drawings

FIG. 1A is a schematic diagram of a screening system according to an embodiment of the present invention;

FIG. 1B is a schematic view of a capsule of the system of FIG. 1A according to one embodiment of the present invention;

FIG. 1C is a schematic diagram of an external data recording unit of the system of FIG. 1A, according to one embodiment of the present invention;

FIG. 1D is a schematic diagram of a schematic graphical representation of a cross-sectional reconstruction of a colon in accordance with an embodiment of the present invention;

2A-D are schematic illustrations of an apparatus according to an embodiment of the present invention for performing exemplary experiments illustrating the physical principles upon which some embodiments of the present invention are based;

FIG. 2E is a graph illustrating exemplary experimental results of the experiments shown in FIGS. 2A-D, according to one embodiment of the present disclosure;

FIG. 3 is a graph showing exemplary experimental results similar to the experiment of FIGS. 2A-E in accordance with an embodiment of the present invention;

FIG. 4 is a schematic view of one configuration of a capsule of the system of FIG. 1A according to one embodiment of the present invention;

FIG. 5 is a schematic diagram of a time division multiplexing configuration of the capsule of the system of FIG. 1A according to one embodiment of the present invention;

FIGS. 6A-E are schematic illustrations of a capsule of the system of FIG. 1A coupled to an inflatable balloon in accordance with various embodiments of the invention;

FIGS. 7A and 7B are schematic views of an extension element according to an embodiment of the present invention;

FIGS. 8A-C are schematic illustrations of additional extension elements according to an embodiment of the present invention;

FIG. 9A is a block diagram schematically illustrating different functional blocks of a capsule of the system shown in FIG. 1A, according to an embodiment of the invention;

FIG. 9B is a block diagram that schematically illustrates different functional blocks of a data recording unit of the system shown in FIG. 1A, in accordance with an embodiment of the present invention;

FIG. 10A is a graph illustrating a simulation result using an algorithm for estimating a distance according to an embodiment of the present invention;

FIG. 10B is a graph illustrating the accuracy of the algorithm shown in FIG. 10A with varying Poisson noise percentages, according to an embodiment of the present invention;

11A-C are graphs showing experimental results determined according to one embodiment of the present invention;

FIG. 11D is a plot of X-ray fluorescence count rate versus contrast agent depth in accordance with an embodiment of the present invention;

FIG. 12 is a schematic view of a tank according to an embodiment of the present invention used in experiments conducted by the present inventors;

FIGS. 13A-C show actual experimental results of experiments conducted using the container of FIG. 12, in accordance with an embodiment of the present invention; and

FIGS. 14A-C and 15A-C are schematic representations of surfaces representing surface morphologies of the gastrointestinal tract produced according to an embodiment of the present invention.

Detailed Description

Fig. 2A-D are schematic diagrams of an apparatus according to an embodiment of the invention for carrying out an exemplary experiment illustrating the physical principles upon which some embodiments of the invention are based, container 12 filled with radiopaque contrast agent 10 in liquid or low viscosity gel form, and reservoir 17 placed below the container and filled with water 11, water-filled capsule 18 placed at the bottom of the container, in this experiment, container 12 filled with contrast agent 10 simulates a colon filled with contrast agent, water-filled reservoir 17 simulates tissue and organs outside the colon, and water-filled capsule 18 simulates tissue anomalies such as polyps.

In this experiment, the radiation source 14 and the radiation detector 16 were placed adjacent to each other. The open ends of the collimator 13 for the radiation source 14 and the collimator 19 for the detector 16 face the liquid container. The radiation source 14 typically emits radiation at (a) a single emission level or (b) multiple emission levels, at least one of which is lower and at least one of which is higher. Radiation detector 16 is configured to detect and count photons having an energy level (or levels, in the case of multi-energy level emission) characterized by approximately 180 degrees compton back-scattering by contrast agent 10, water of water bladder 18, and water of liquid reservoir 17.

The source 14 and detector 16 pass over the vessel 12 and are maintained at a constant distance from the bottom of the vessel. At a plurality of points along the source and detector, as shown sequentially in fig. 2A to 2D, the gamma or X-ray count rates in one or more particular gamma or X-ray energy windows are recorded (the count rates are shown on the recording display 15 in the figure).

Fig. 2E is a graph showing exemplary experimental results of the experiment described above in relation to fig. 2A-D according to an embodiment of the present invention. When the radiation source 14 emits radiation at only a single energy level, the count rate at the detector increases as the radiation source 14 and detector 16 pass over the capsule 18 (fig. 2C) because the path of compton backscattered photons interacts with the volume that is readily transparent to radiation. (in other words, water pocket 18 is more radiolucent than the contrast agent, thus allowing more photons to be transmitted.)

When the radiation source 14 emits radiation at low and high energy levels, the count rate of compton backscattered photons from each radiation energy level changes as the radiation source and detector pass over the balloon. In addition, the mathematical relationship (e.g., ratio or difference) of the count rates between the low energy window and the high energy window changes. After the radiation source and detector have passed the water pocket (fig. 2D), the count rate returns to the level measured before encountering the water pocket. The counting is typically only performed within a predetermined energy window corresponding to the energy level of compton backscattered photons returned at about 180 degrees with respect to the emitted radiation of each photon energy peak.

Fig. 12 is a schematic view of a tank 184 according to an embodiment of the present invention used in experiments conducted by the present inventors. The experiment is similar to that described above with reference to figures 2A-E. The tank 184 is divided into four compartments 186A, 186B, 186C and 186D. Each of compartments 186A, 186B, and 186C has a depth of 2 centimeters, while compartment 186D has a depth of 5 centimeters. A collimated radiation source 188 and an adjacent collimated radiation detector 190 are positioned adjacent the cabinet 184 on the side of the compartment 186A.

Fig. 13A-C show results of experiments performed using a tank 184 according to an embodiment of the invention. The radiation source 188 includes the radioisotope technetium 99 m. Fig. 13A is a graph showing a typical spectrum detected by a radiation detector, wherein the spectral line 35 is a 180 degree backscatter spectrum at 90keV caused by photons emitted from technetium Tc99m (141 keV). (spectral lines 34 are X-ray fluorescence (XRF) of lead used as detector collimation.) two experiments were performed using Telebrix and barium sulfate (BaS04), respectively, as contrast agents fig. 13B and 13C show the backscatter numbers measured using Telebrix and BaS04, respectively, during the performance of each experiment, the initial measurements were taken with all four chambers filled with water (i.e., no contrast agent.) the measurements are represented by the bars labeled "background" in fig. 13B and 13℃ chamber 186A was filled with contrast agent and the second measurement (represented by the bar labeled "2 cm.") was measured, then chamber 186B was also filled with contrast agent and the third measurement (represented by the bar labeled "4 cm.") was measured. And shows that the compton backscattered photon count is related to the round trip distance of the photons through the contrast agent.

Reference is again made to fig. 2A-E. As mentioned above, the number of photons depends on the depth of the contrast agent through which the photons are passed. This variability can be explained by a combination of three physical principles:

compton scattered photons have lower energy than the incident photons, and the scattered photon energy depends on the scattering angle. See, for example, the above-mentioned Compton paper. Typically, only photons scattered at a particular angle based on their energy are selected and counted.

The water bladder 18 occupies the volume that would otherwise be occupied by the contrast agent 10. Thus, reduced radiation absorption occurs. The absorption of radiation by the photovoltaic process is deeply influenced by photon energy. Thus, fewer photons with higher energies are absorbed than lower energies. The compton scattering process therefore depends on the electron density which is linearly related to the total density, which is similar for contrast agents and water pockets. Photon absorption by photoelectric processing depends on Z ^5 (the 5 th power of the atomic number). Thus, where there is less contrast agent present due to the displaced volume of the water pocket, the photon flux detected by the radiation detector increases significantly. With multiple emission energies, the relationship (e.g., ratio or difference) between high-energy photons and low-energy photons becomes larger as the path length through the contrast agent increases.

Because the medium is a liquid or a low viscosity gel, after the contrast agent has flowed in for a sufficiently long time, the concentration of contrast agent in a particular region can be assumed to be generally uniformly distributed within the given medium.

Thus, for a single energy photon radiation source, the relative flux of backscattered photons is inversely related (e.g., inversely proportional) to the distance of the photons through the contrast medium during the entire journey out of the radiation source and back to the radiation detector as compton backscattered photons. For a multi-energy photon radiation source, this method can also be used to calculate the photon propagation distance in the contrast agent. In addition, the relationship (e.g., ratio or difference) between the high and low energy photons received at the detector also indicates the distance the photon traveled in the contrast agent. Since the relationship of the incident radiation generated by the radiation source is constant, any change in this relationship is due to an unbalanced effect of the photoelectric absorption of the protrusions in the contrast agent, which has a significantly greater effect on the low energy than on the high energy. By recording this relationship, the presence of the water pocket can be detected. This photoelectric absorption affects the photons emitted by the radiation source and the backscattered photons.

Some embodiments of the present invention use the above principles and methods to detect polyps and other tissue aberrations within the colon. Polyps that form within the colon sometimes hide the sprouting of colon cancer. It is therefore desirable to detect and remove polyps before they can spread deeply from the inner surface to the colon muscle structure and subsequently migrate to other parts of the body. (including the claims, as used herein the "wall" of the colon or gastrointestinal tract is to be understood to include such polyps or other tissue aberrations as may be present.)

According to one embodiment of the present invention, the system described herein is used as the most important screening procedure for early detection of colorectal cancer.

Reference is made to FIG. 1A, which is a schematic illustration of a screening system 40 in accordance with an embodiment of the present invention. System 40 typically includes an ingestible capsule 50 and an external data recording unit 52. For some applications, the data recording unit 52 is worn on the waist of the subject 54 (as shown in fig. 1) or other part of the subject's body, such as the wrist (structure not shown). Alternatively, for some applications, capsule 50 includes an internal data recording unit and no external data recording unit 52 is provided. In these applications, the data recorded by capsule 50 is retrieved after the capsule leaves the body.

Reference is made to fig. 1B, which is a schematic illustration of a capsule 50 according to an embodiment of the present invention. Capsule 50 includes at least one radiation source adapted to emit gamma and/or X-rays (i.e., rays having an energy of at least 10 kev), at least one gamma and/or X-ray radiation detector 62, and typically at least one collimator 63 adapted to collimate the rays produced by radiation source 60. For some applications, radiation source 60 includes a radioisotope. Optionally, radiation source 60 comprises a micro-radiation generator such as described below. Capsule 50 also typically includes circuitry 64 (which for some applications includes a pressure sensor), a power source 66 such as a battery, a wireless communication device (communication device not shown) for communicating with external data recording unit 52, and a radiation shield 68.

Referring now to fig. 1a, during a typical detection procedure using system 40, subject 54 ingests an oral contrast agent 70. contrast agent 70 is typically adapted to flow through the Gastrointestinal (GI) tract 72 and be expelled with fecal matter, which is not substantially absorbed into the bloodstream.

Capsule 50 passes through gastrointestinal tract 72 and emits gamma and/or X-ray radiation. From a particular point in time, capsule 50 records compton scattered gamma and/or X-ray photons that strike radiation detector 62. The count rate information received by each radiation detector is typically stored together with a time stamp for the measurement value. In a time period typically less than 1 second (e.g., tens to hundreds of milliseconds), the capsule, surrounding colon wall and contrast agent are assumed to be in a quasi-steady state. Choosing a sufficiently small time period and integrating the number across the cells allows the assumption of quasi-steady state. The data may be stored in the capsule and transmitted to the external recording device from time to time by the capsule or after data acquisition has been completed.

In one embodiment of the invention, the radiation source 60 and detector 62 are arranged to "view" the entire 4 pi (pi) square sphere (or a portion thereof) around the capsule.

Referring to fig. 1C, a schematic diagram of an external data recording unit 52 according to an embodiment of the invention is shown. The data recording unit 52 includes a receiving/memory unit 55, a supply electronics/battery pack 56, an antenna 57 and a user control 58. Unit 52 also typically includes a strap 59, such as a belt or wrist/arm strap, for connecting the unit to subject 54.

Reference is made to fig. 4, which is a schematic illustration of one configuration of a capsule 50 according to an embodiment of the present invention. In this embodiment, capsule 50 includes one or more radiation sources 60; one or more collimators 63 adapted to collimate the radiation produced by radiation source 60; and one or more radiation detectors 62, which are typically only slightly collimated or not collimated at all. The radiation source 60 thus illuminates the closed sector (with respect to the capsule). This is typically accomplished by providing a respective shield 68 for radiation sources 60 that prevents photons from being emitted in directions other than the preferred sector for each radiation source. The shield 68 typically comprises a material having a large atomic weight and a large specific gravity, such as lead, tungsten, or gold. Other means for the radiation source, detector and collimator may also be used as appropriate, such as a cylindrical, spherical or other shield covering the radiation source or sources.

In an embodiment of the invention, a single radiation source is placed within a spherical capsule, and the capsule housing is shaped such that a plurality of corresponding photon columns emitted by the radiation source are detected by one or more detectors on the surface of the capsule. In this embodiment, the detector is typically not collimated.

In one embodiment of the present invention, radiation source 60 comprises a miniature X-ray generator such as described in the following references:

trebes et al, U.S. Pat. Nos. 6,134,300 and 6,353,658

Gutnan G et al, "novel needle-based miniature x-ray generation system", Phys Med Biol 49: 4677-4688(2004)

Such a miniature X-ray generator or X-ray tube may be used in place of the radioactive isotope source 60 to illuminate the colon contents with X-ray photons. Turning such generators on and off as needed typically reduces exposure of the subject to radiation. In addition, the energy range can be better controlled and the flux over the on-time can be greater without increasing the overall exposure of the subject.

In an embodiment of the present invention, an apparatus is provided, including:

oral contrast agents such as barium sulfate or iodine-based water-soluble compounds (such as Gastrografin, Telebrix or others described in the above-mentioned paper entitled "X-ray contrast media");

a capsule, such as the capsule described above with reference to fig. 1B, 4 and/or 5, adapted to emit gamma and/or X-ray radiation and to detect compton scattered photons and other gamma and/or X-ray radiation. The capsule typically comprises: (a) one or more sources of gamma and/or X-ray radiation and/or beta (β) electrons, such as thallium 201, xenon 133, mercury 197, ytterbium 169, gallium 67, technetium 99, indium 11, or palladium 100, or (b) an X-ray generator such as the one mentioned above;

a recording unit, such as described above with reference to fig. 1A and 1C, adapted to receive RF signals from the capsule propagating within the gastrointestinal tract; and

data analysis and display software such as that described below with reference to FIGS. 1D, 14A-C, and 15A-C. The software is adapted to receive data from the recording device and analyze the data and display the processed data received from the capsule in a manner that allows the physician to assess the likelihood of polyps or other tissue aberrations being present in the interior cavity of the test individual. The software may be run on a general purpose computer such as a personal computer, which is programmed in the software to perform the functions described herein. The software may be downloaded to the computer in electronic form, over a network, for example, or it may alternatively be supplied to the computer in tangible media, such as CD-ROM. Alternatively, the functionality of software may be implemented using dedicated hardware logic or using a combination of hardware and software elements.

Reference is made to fig. 9A, which is a block diagram schematically illustrating different functional blocks of a capsule 50, according to an embodiment of the present invention. In this embodiment, capsule 50 includes one or more of the following components: (a) gamma and/or X-ray radiation detectors 62, which may include, for example, CZT crystals or scintillation crystals connected to photodiodes; (b) an analog signal amplifying circuit; (c) a digital signal processing circuit; (d) a digital storage circuit; (e) RF transmit, receive and hold circuitry; (f) a calibration hold circuit; (g) an internal timing circuit; (h) MEMS acceleration sensor chip and holding circuit; (i) a pressure sensor and a holding circuit; (j) a supply circuit including a HV bias for the radiation detector and a voltage for the MEMS; (k) an RF transmitter; (l) An RF receiver; (m) an analog circuit; (n) a digital circuit; and (o) a battery or other power source located inside or outside the capsule.

Reference is made to fig. 9B, which is a block diagram that schematically illustrates different functional blocks of the data recording unit 52, in accordance with an embodiment of the present invention. In this embodiment, the data recording unit 52 typically includes one or more of the following components: (a) an RF communication circuit; (b) a stable digital memory or other recording medium adapted for the secure storage and reception of data; (d) a communication circuit for transmitting data to a computer; and (e) a power supply device and a holding circuit.

In an embodiment of the present invention, a method for detecting polyps and other tissue aberrations within the gastrointestinal tract comprises: (a) placing a contrast agent in an interior space of a gastrointestinal tract of a subject; (b) administering a capsule, such as capsule 50, to a subject; (c) the detection capsule has reached a region of clinical interest within the gastrointestinal tract. For example, to detect polyps or other tissue aberrations within the colon, the region of clinical interest is typically the colon or lower ileum; and (d) activating the capsule in response to the detecting.

As the capsule flows through the contrast-filled colon, the radiation source 60 emits gamma and/or X-ray photons, and each of the radiation detectors 62 within the capsule detects Compton backscattered (approximately 180 degrees) photons located at opposite quadrants as viewed by the detector. Each detector receives photons backscattered from a plurality of collimated radiation sources and the photon flux is dependent on the relative geometry between the particular detector and the photon emission collimator. The backscattered photon flux also depends on the volume of contrast agent encountered by the backscattered photons on their way to the detector, and the flux is in turn inversely related, e.g. inversely proportional, to the relative distance separating the outer edge of the collimator and the colon wall.

Assuming that there are enough gamma/X-ray radiation detectors related to the number of collimators, the distances from the outer edge of the collimator to the colon wall perpendicular thereto can be estimated, since the relative geometry between the collimator and the gamma ray detectors is known, for some applications the following algorithm is used to estimate these distances.

C X ═ d (equation 1)

Where C, X and d are real numbers and X and d are positive values, and where the vector d represents the estimated distance from each radiation collimator to the colon wall perpendicular thereto. There are some known methods to solve the equation C X d, for example to minimize C X d. Other methods are known and can be applied to this problem.

Fig. 10A is a graph illustrating the result of a simulation using the algorithm according to an embodiment of the present invention. The vertical bars 100 represent the estimated distances from the simulation determined using the algorithm, and the vertical bars 102 represent the respective actual distances. FIG. 10B is a graph illustrating the accuracy of the algorithm according to an embodiment of the present invention with varying Poisson noise percentages.

In one embodiment of the invention, detecting that the capsule has reached the region of clinical interest includes detecting X-ray fluorescence (XRF) photons, which are significantly different for the stomach, small intestine and colon. The XRF count rate is measured and estimated every time period when the capsule enters the gastrointestinal tract. In the stomach, XRF count rates are expected to be at moderate levels, since a portion of the oral contrast agent administered several hours ago remains. The XRF count is significantly reduced when the capsule enters the small intestine, because the capsule is in contact or nearly in contact with the small intestine wall, so there is not enough space between the detector and the wall for a significant amount of fluorescing contrast agent. Subsequently, as the capsule enters the colon, the XRF number increases because the colon is filled with well-mixed contrast agent along its length. (it should be noted that some segments of the small intestine are in close proximity to the colon portion, such that when the capsule is in these segments, the XRF number may increase for some detectors due to contrast agent located in the adjacent colon portion (and not due to local contrast agent in the small intestine.) this increased XRF number continues until the capsule continues its travel and enters a portion of the small intestine in close proximity to the colon.)

Optionally, detecting that the capsule has reached an area of clinical attention comprises using a pH sensor and/or a pH sensitive coating for the capsule. For applications where the clinically interesting area includes the colon, the pH sensor is typically configured to detect a decrease in acidity, and the pH sensitive coating is configured to dissolve in the characteristic pH value of the colon.

Further optionally, for detecting that the capsule has reached the colon, the capsule includes a trigger configured to turn the capsule on once the capsule is proximate an externally-affixed patch placed on the lower abdomen near the entrance to the colon. Such a trigger may for example comprise an active oscillator circuit on the patch. When the capsule approaches the patch, a passive resonant circuit within the capsule absorbs energy from the oscillations on the patch, and this triggers the capsule to start running. Similar devices are commonly used in anti-theft systems in stores and libraries.

Still further optionally, in order to detect that the capsule has reached the colon, the capsule comprises a pressure sensor adapted to measure pressure changes in the gastrointestinal tract. The pressure sensor is continuously monitored as the capsule flows through the gastrointestinal tract. In the stomach, pressure changes are usually infrequent, for example every few minutes. As the pressure changes become more frequent and regular, this may indicate that the capsule has entered the small intestine, at which time the capsule is expected to travel an average of 2-5 hours. Once the regular pressure changes cease and the lack of regular pressure waves and less frequent pressure waves are monitored, the capsule is likely to have entered the large intestine where it is expected to stay for an average of 24-72 hours.

These methods for detecting that the capsule has reached the region of interest may be used separately or in combination. When used in combination, information from multiple independent sensors as described above is typically correlated and analyzed to determine that the capsule has reached a region of interest, such as the colon. (optionally, the capsule is in substantially continuous operation in the gastrointestinal tract.)

In one embodiment of the invention, the rationale for polyp detection in the colon is based on the physical principles described in the experiments described above with reference to FIGS. 2A-E and 13A-C, and the use of the generally symmetric nature of colon muscle contraction and the generally regular characteristics of the colon lumen for polyp detection, the capsule measures the relative distance from the outer edge of each collimator to the surface of the colon wall. This corresponds to the solid angle pointing to the short axis of the colon at each point in time, the algorithm then begins to estimate the disk described by the different range measurements by simulating 2D elliptical splines that best fit these measurements, which in turn are a prediction of the colon cross-section at the capsule location, typically it reconstructs the appearance of the internal colon distance as the capsule passes through the colon, for some applications the calculation is performed within the coordinate system of the subject, for these applications the MEMS acceleration sensor chip in the capsule 50 typically provides a reference to the direction of gravitational force, and a second MEMS acceleration sensor chip attached to the outer surface of the target (e.g., band 59 described above with reference to FIG. 1C) provides a second reference for correcting for target motion. No reference is required and the output includes the distance relative to the capsule coordinate system.

Typically, after the capsule is expelled, the data is post-processed and presented to an observing specialist. For some applications, the data is presented to the viewer as a series of cross-sectional reconstructions. Observers can identify irregular features that are not normally found in the lumen of the colon during contraction of the colon muscles. In particular, the system is capable of detecting "bumps" and irregular bumps in the colon wall that may be polyps or other suspected tissue aberrations.

Reference is made to fig. 1D, which is a schematic illustration of an exemplary graphical representation of such a colon cross-section reconstruction, in accordance with an embodiment of the present invention.

In an embodiment of the invention, the time derivative of the data can be used for reconstruction of the path traveled by the capsule in the colon. The use of time derivatives in place of the data itself or in combination with the data enables the observer to better identify the irregular features on the inner surface of the colon as the capsule passes through the colon. In particular, this manner of analyzing the data enables detection and differentiation of polyps and other features (such as baglet loops) on the colon wall. Polyps appear as narrower traces in the time derivative plot, while the pockets appear as wide traces, which typically cover the full 360 degrees around the capsule as it approaches them. (see FIGS. 14A-C and 15A-C, described below.)

In one embodiment of the invention, data from the capsule may be presented to the physician in a chart format (see FIGS. 14A-C and 15A-C described below) that does not give image information, but instead displays information in a graphical representation that helps the physician determine whether there is a possibility of polyps or other tissue distortions that may conceal the cancer and require colonoscopy.

For applications where radiation source 60 emits photons having two or more different energies, the elementary analysis data unit may be the relationship (e.g., ratio or difference) between the high energy number and the low energy number. Alternatively or additionally, the basic analysis data unit is a count for each energy window.

In an embodiment of the invention, the proportional relationship between high and low energy count rates backscattered from the colon contents and far is used to calibrate the actual distance of the capsule from the colon wall. This is possible because the ratio of photon fluxes at different energies is related to, e.g. proportional to, the actual distance. This feature is particularly useful because the concentration of contrast agent changes as the capsule travels from the right colon (where the colon contents are mobile) to the left colon and rectum (where the colon contents are typically less mobile, or even semi-rigid). Thus, the average flux of photons per cm depth of contrast agent decreases with increasing contrast agent concentration. (Water flows out of the colon; thus the concentration of contrast agent in the colon increases because the contrast agent does not leave the colon.)

In one embodiment of the present invention, a capsule such as capsule 50 is adapted to detect Compton backscattered photons, typically photons formed by a 180(+/-20 to 30) degree backscattering process with respect to incident photons, depending on detector energy resolution and detector collimation (if difficult to collimate). For multiple energy window applications, the count rates for different energy windows are used as the primary data for the imaging process. In particular, for each detector, electronics associated with its dedicated channel calculate the sum of the number of photons striking the detector at each predetermined energy window according to the Compton backscattered energy principle. (other energy windows to detect XRF photons from illuminated contrast agents.)

In this embodiment, capsule 50 implements an algorithm that can be understood to resemble insect compound eyes. Such eyes do not have a single focusing lens but instead have a large number of optical sensors arranged on a portion of the hemisphere. Insects with compound eyes are extremely myopic, seeing something just a few millimeters in front of them. Their eyes are well suited to detect motion at larger distances and to detect vector direction and morphology of moving objects. For example, these capabilities allow an in-flight mosquito to detect mosquitoes away from it by more than a few meters, and insects such as bees to fly at high speed through dense forests without hitting branches.

For capsules adapted to travel in the gastrointestinal tract, it is often difficult to mount large arrays of detectors and appropriate collimation devices to reconstruct high resolution images. This situation is therefore similar to the situation where insects have to "resolve" the morphology using a limited detector source. In an embodiment of the invention, the probe is arranged in the capsule to "view" the hemisphere or a part of the hemisphere surrounding the capsule. However, the number of detectors is typically limited to less than 100, for example less than 40, with the upper limit on the number being set in accordance with (a) the minimum size of any given detector that still provides a suitable signal-to-noise ratio, and (b) the maximum number of independent signal channels that can be reasonably accommodated in the available small space of the capsule. In addition, to fully exploit the fewer photons that can be obtained from compton backscatter processing and the lack of space on the capsule, the detectors are typically arranged to be either not collimated or very slightly collimated. Thus, each detector "sees" a relatively wide-angle image, and the overall static spatial resolution is compromised to some extent, similar to the case of insect compound eyes. Unlike the insect case, where the resolution is set by the viewing angle of a single optical detector, in the case of the capsule, the "image" resolution of the capsule is determined by the collimation of the radiation source.

As in the case of insects, the capsule is also "myopic", which can only constitute a static image from a distance of a few millimetres. However, similar to insects with their compound eyes, the capsule is able to detect bends, baglets and polyps as it moves through the colon. Typically, but not necessarily, detection of polyps and other forms is accomplished off-line by using data acquired by the capsule as it passes through the colon.

Reference is made to fig. 14A-C and 15A-C, which are schematic illustrations of surfaces representing surface morphology of the gastrointestinal tract produced in accordance with an embodiment of the present invention. A dynamic tracking algorithm is provided for detecting polyps in the gastrointestinal tract, such as in the colon, and distinguishing them from morphologies normally found in the colon, such as curved colon walls, baglet loops and colon folds. The algorithm exploits the motion of the capsule within the colon to detect polyp morphology and separate them from the morphology of other normal structures in the colon.

In this embodiment, the emitted radiation is typically configured to "illuminate" all or a portion of the volume surrounding the capsule. Optionally, the collimation of the emitted radiation is configured to preferentially illuminate a particular sector of the volume surrounding the capsule, while leaving other sectors unlit. The latter configuration can be used to better detect the constituent shapes within the colon as the capsule moves, detecting the object of interest as it moves from "dark" to "bright".

In the following description of the dynamic tracking algorithm, for simplicity, it is assumed that the radiation detectors are distributed on a 2D rectangular surface. It is also assumed that the data from the detector is mapped on a 2D rectangular surface, where the data of the detector is represented by measured readings of a property such as the count rate per integration time in a particular energy window corresponding to the energy window of the compton backscattered photon. In this way, the 3D colon lumen is mapped on a 2D rectangular surface.

In the first step of the dynamic tracking algorithm, for each subdivision on the 2D representation surface, the relative distance each collimator "sees" is calculated, for example, using a matrix algorithm such as equation 1 described above. Surfaces 120A, 120B, and 120C of fig. 14A, 14B, and 14C, respectively, and surfaces 122A, 122B, and 122C of fig. 15A, 15B, and 15C, respectively, represent exemplary representations of such relative distances at respective points in time.

In the second step of the algorithm, the difference between the reading representing a subdivision and the respective reading representing all adjacent subdivisions is calculated (up to 6 adjacent segments on the 2D surface).

In a third step, a threshold value is calculated from the poisson distribution, e.g., +/-o with respect to the fine value. For example, if Nij is the reading at subdivision ij (after the analysis described in the first step), the threshold would be one Σ (i.e., the square root of +/-Nij). Only the reading of at least one sigma of the fine value is used in the fourth step described immediately below.

In a fourth step, a new 2D surface is rendered, where the pixels represent the differences between the subdivisions of the first 2D map (i.e., surfaces 120A-C and 122A-C of FIGS. 14A-C and 15A-C, respectively). The result of this representation is a series of 2D time morphologies representing the time derivative, which depicts the motion of the capsule within the colon and shows the different morphologies as the capsule travels. Surfaces 124A, 124B, and 124C of fig. 14A, 14B, and 14C, respectively, and surfaces 126A, 126B, and 126C of fig. 15A, 15B, and 15C, respectively, are exemplary curved surface representations representing such differences at respective points in time. For example:

the form of the moving front (consisting of several related paths) is a line, such as line 128 of fig. 15A-C.

The morphology of the moving front with cylindrical symmetry (in 3D capsule space) appears as a linear ridge intersecting with a 2D distinct space, such as the ridge 130 in fig. 15A-C. Such a moving front may be associated with a wall movement or a capsule movement associated with a wall.

Moving objects with independent morphology may be associated with polyps or other tissue aberrations, as shown in fig. 14A-C.

In a fifth step of the algorithm, these 2D different maps are displayed as an animated series to the viewing expert in order to help him assess possible anomalies, such as polyps.

For some applications, the algorithm uses an autocorrelation function based on readings from a detector to estimate the current 3D motion of the capsule. The use of such an autocorrelation function generally improves the signal-to-noise ratio. This information can then be used to correlate readings from adjacent subdivisions and thus increase the integration time by estimating the readings from multiple integration periods rather than using a single integration time. The increase in integration time caused by averaging the associated readings generally reduces noise. Data from the MEMS acceleration sensor chip (fig. 9A) can also be used for this correlation, or as a verification measurement.

The dynamic resolution provided by the algorithm generally allows polyps to be resolved from greater distances from the capsule, even with a smaller number of detectors. Although a smaller number of detectors are not or slightly collimated (and therefore their fields of view overlap), not using this algorithm will generally result in a lower static resolution (which is determined by the collimation of the radiation source).

Other algorithms utilizing dynamic analysis may be used to detect polyps or other tissue abnormalities within the colon and distinguish them from normal colon wall motion (e.g., colon muscle contraction) and capsule motion within the colon. In particular, the use of dynamic analysis algorithms similar to those described may be adapted for use with the above-described embodiments to enhance and improve robustness and immunity to spatial and temporal variations. In particular, dynamic analysis may be used in conjunction with static analysis to improve detection and assessment of abnormalities such as polyps.

Referring to FIG. 5, a schematic diagram of a time-multiplexed configuration of a capsule 50 according to an embodiment of the invention is shown, in which the capsule 50 includes at least one radiation shield 68, the capsule is configured such that the shield 68 blocks radiation from the radiation source 60 for a period of time during which the capsule is in the GI tract, for some applications, this partial blocking is accomplished by moving the shield 68. alternatively or additionally, this blocking is accomplished by moving the radiation source 60. for some applications, the radiation source 60 is coupled to a moving rod 80. during a resting phase, when the capsule is not acquiring data, the radiation source 60 is positioned behind the shield 68 to minimize the amount of radiation escaping toward the body of the subject. during a use phase, when the capsule 50 is acquiring data, the rod 80 is reciprocated, such as by a low power actuator 84 (e.g., a voice coil linear actuator or a piezoelectric linear motor). movement of the rod 80 exposes the radiation source 60 to different collimators 63 Causing the radiation source 60 to illuminate at different times different angular sectors of the spherical region surrounding the capsule the detector 62 detects compton backscattered photons or X-ray fluorescence photons from the colon contents including the medium in time synchronism with the radiation source position.

For some applications, radiation source 60 includes isotopes, such as tritium 1201, iodine 111, iodine 131, gallium 67, technetium 99m, or palladium 100. For some applications, the rod 80 includes a heavy metal, such as tungsten, lead, or tantalum. For some applications, the shield 68 comprises a high atomic number material, such as tungsten, gold, or tantalum.

With these techniques, the system resolution can be controlled by adjusting the "illumination" volume. For example, a higher intensity radiation source may be placed in the capsule and a very narrow high resolution observation volume can be obtained by controlling the collimation angle of the radiation source. In this configuration, the total radiation exposure for the subject is still small.

The physiology and anatomy of the human colon is such that the colon contents are mostly immobile (during an average of 24-72 hours) and do not mix a little in time rather than move forward. Every few hours, contraction begins, which creates pressure within the colon (up to an average of 200 mmhg) squeezing the material forward towards the anus. To minimize subject radiation exposure, the motorized back and forth movement of radiation source 60 is typically only activated when the capsule senses an increase in lumen pressure indicative of impending mass motion within the colon and/or when the capsule senses a change in angle indicative of possible impending motion of the capsule using a MEMS acceleration sensor chip. The radiation source 60 is stabilized in the center of the shield 68 during periods when the capsule does not sense any change in pressure or inclination and the XRF readings of the detectors near the colon wall are at steady state.

The motorized reciprocating movement of the radiation source 60 causes the radiation source to emit gamma or X-ray radiation through the collimator 63 as it reciprocates behind the shield 68. The collimator 63 is arranged such that at any given time only a predetermined sub-portion of the collimator emits radiation. Exposing the radiation source only when it is desired that the capsule acquire data generally reduces the amount of radiation to which the subject is exposed.

In an embodiment of the invention, the actuator 84 and the rod 80 are arranged such that the rod 80 moves according to the dynamics of the forced mechanical oscillator. In this arrangement, the rod 80 is connected to at least one spring (spring not shown) such that the combination of the rod and spring constitutes a mechanical oscillator having a particular resonant frequency. At or near this frequency, the energy required to move the rod 80 is minimized. The actuator 84 provides the energy lost due to friction. At both ends of the rod movement, the rod slows down. The rod, spring and collimator are typically arranged such that the radiation source is exposed to the opening of the collimator at the location where the rod decelerates.

In an embodiment of the invention, the processing unit is integrated in the capsule so that limited data analysis can be performed in real time within the capsule. In particular, the capsule may calculate an autocorrelation function of the measurement data and incorporate this information in order to determine whether the capsule is moving within the colon due to gravity or other external forces other than mass motion induced pressure. In particular, the combination of the MEMS accelerometer and the autocorrelation function can help determine whether the capsule is stable or moving within the colon. The capsule thus continues to move the radiation source until the capsule comes to rest.

In an embodiment of the invention, the shield 68 may at least partially comprise a magnetic material such that the shield functions as part of the actuator 84 (e.g., when the actuator comprises a voice coil actuator). In this embodiment, no dedicated magnet is generally required.

In one embodiment of the invention, the contrast agent is mixed with ferromagnetic particles, such as spherical particles. When the capsule enters the colon, these particles are magnetically attracted to the capsule and form an increased mass that is transmitted with the capsule, slowing the capsule and increasing the probability of polyp detection. For some applications, the shield 68 includes an electromagnet that can be turned on or off to allow or force the ferromagnetic particles to separate from the capsule.

Reference is now made to fig. 6A-E, which are schematic illustrations of capsule 50 with inflatable balloon 140 attached thereto, in accordance with various embodiments of the present invention. Inflation of balloon 140 surrounding capsule 50 typically moves the capsule away from the outer surface of the balloon toward the center of the balloon. Thus, the capsule is positioned near the center of the colon lumen. Such localization generally improves the system resolution of the capsule in various aspects for detection of polyps and other tissue abnormalities. The method of detecting tissue abnormalities and polyps using balloon structures is substantially the same as those embodiments that do not include a balloon.

In these embodiments, balloon 140 is adapted to expand when capsule 50 reaches a region of clinical interest, typically the colon. Capsule 50 typically detects its arrival in the colon using the methods described herein. For some applications, for inflation, balloon 140 contains or is connected to a gas (e.g., CO) that is released when it comes into contact with water in the colon contents₂) Or a gel material. For example, balloon 140 may include a compound 142 positioned on the outer surface of the balloon. Compound 142 is exposed to the colon contents and the balloon interior. Other methods for inflating a balloon will be apparent to those skilled in the art having read the present application and are within the scope of the present invention.

For some applications, balloon 140 includes a release valve 144 configured to slowly dissolve when the valve comes into contact with water in the colon contents. The valve 144 is typically configured to dissolve after a predetermined period of time that is slightly longer than the desired time required for the capsule to pass through the colon. The dissolution of the valve 144 allows the gas contained within the balloon 140 to escape from the balloon, thereby deflating the balloon. This mechanism ensures that the capsule and air bag do not undesirably block the passage of objects in the colon.

Refer to fig. 6C and 6D. In one embodiment of the invention, capsule 50 is coated with a pH sensitive coating 150 adapted to dissolve at pH, such as about 7, which may occur in the distal small intestine and colon. Alternatively or additionally, other structures are used to detect the capsule's arrival in the colon, such as a mechanism that binds to a polymer that reacts with and dissolves enzymes released by bacteria in the colon. These bacteria have a significant presence in the colon relative to other parts of the gastrointestinal tract. For example, a combination of a pH sensitive coating and a bacterial dissolution undercoating such as those sold by aicello chemical co., Ltd. (Aichi, Japan) may be used.

Reference is again made to fig. 6C and 6D. In one embodiment of the invention, the entry of capsule 50 into the colon is determined by detecting changes in the pressure wave pattern and/or the presence of XRF due to contrast agents. These indicators may also be used to trigger mechanical or chemical action to release the outer coating or to enable water from the colon contents to enter the layer below the first coating. In these embodiments, the outer surface of balloon 140 includes a semi-permeable membrane 152 that allows water and contrast media to enter balloon 140. For some applications, bladder 140 includes a layer 153 of superabsorbent hydrogel that expands as water flows through semi-permeable membrane 152. For some applications, capsule 50 is attached to semi-permeable membrane 152, such as by long flexible attachment elements 154, such that capsule 50 is retained within balloon 140. For these applications, balloon 140 typically has a length greater than capsule 50 and a width greater than the colon, such that the capsule tends to orient along the length of the colon. Additionally, for some applications, bladder 140 includes one or more support elements 156 adapted to extend the bladder around the capsule. The element 156 may, for example, comprise a material such as Memory-formed nitinol (e.g., sold by Memory-metal GmbH (Weil amRhein, Germany)).

In one embodiment of the present invention, the expansion of balloon 140 beyond the confines of capsule 50 creates an inflation medium in which there is negligible compton scattering. Thus, compton backscattering begins at the boundary of balloon 140 and the colon contents, typically between about 0.5 and 1.5 centimeters from the outer surface of capsule 50. In this configuration, to measure the total distance from the outer surface of capsule 50 to the colon wall, capsule 50 calculates the sum of two separate distances: (a) the distance from the capsule to the balloon exterior surface inside the balloon and (b) the distance from the balloon exterior surface to the colon wall.

For some applications, the measurement of the distance from the capsule to the outer surface of the balloon is performed using one or more of the following methods:

compton backscattering is used to measure the change in distance from the capsule to the balloon surface, since these changes are reflected by large changes in the total number of backscattered Compton photons. This is due to the fact that there is substantially no backscattering inside the balloon. Thus, the change in distance from the balloon surface reflects a change in backscattering ratio, such as 1/R ^2, where R is the distance to the balloon surface. The change in compton backscattering due to changes outside the balloon is small. Alternatively, for some applications, these changes are associated with changes in XRF external to the balloon.

Estimate the distance from the capsule to the balloon surface from the backscatter projection size. This is known because the collimation geometry is known and compton scattering is essentially negligible within the inflated balloon and therefore only starts at the interface of the balloon and colon contents.

As shown in fig. 6B, the balloon surface is filled with dot particles 158 of a high density material such as tungsten or tantalum. When particles 158 are illuminated with gamma and/or X-ray photons from radiation source 60 inside capsule 50, some XRF (having a particular spectral line) is detected by radiation detector 62 on the capsule. The distance to these point sources can be calculated using the count rate for a particular energy window from some detectors, using the following equation:

(equation 2)

The distance depends on the range r and angle to the point source.

The surface of balloon 140 includes (e.g., is filled with) a small point source 160 of gamma and/or X-ray radiation, as shown in fig. 6E. Point source 160 typically includes a short-lived gamma radiation source, such as tritium 1201, indium 111, or other material that emits gamma rays having one or more energy levels. The distance from the balloon surface to these point sources is typically determined using the method described immediately above with reference to equation 2, mutatis mutandis.

To estimate the distance from the balloon surface to the colon wall, the capsule typically analyzes the XRF emitted from the contrast agent (or other orally administered high atomic number material in the gastrointestinal tract). The XRF count rate is related, e.g., proportional, to the volume of colon contents mixed with contrast agent located between the colon and the balloon surface.

Refer again to fig. 6E. As described above, in one embodiment of the present invention, the surface of balloon 140 includes a radiation point source 160. In this embodiment, capsule 50 typically includes a radiation source 60. In this embodiment, the capsule 50 and/or external data analysis software maps: (a) the geometry of the outer surface of balloon 140, and (b) the anatomy of the colon (i) in contact with balloon 140 or (ii) in the vicinity of balloon 140. Typically, balloon 140 includes less than 40 point sources 160 and capsule 50 includes less than 40 radiation detectors 62. Photons emanating from point source 160 travel in all directions. Photons traveling toward the radiation detector 62 are detected by detectors in their respective energy windows. A portion of the photons traveling toward the colon contents undergo compton scattering, causing some of the photons to return to the detector at about 180 degrees from the incident photons. These scattered photons are registered at the appropriate energy window by the capsule radiation detector and associated electronics. Capsule 50 and/or external data analysis software use (a) positional information of point sources 160 relative to each other on the surface of the balloon and (b) detection of the primary and scattered photons by detectors arranged on the capsule to map the anatomy of the colon, regardless of whether these parts are in contact with the balloon. Typically, the location of each point source and the backscatter component from each point source is determined by solving a linear equation describing the detection of the point source by a plurality of detectors. Solving the equation is possible because the capsule typically includes a plurality of detectors and a lesser number of point sources.

For some applications, the following algorithm is used to perform the mapping:

the capsule 50 records the number of photons at each integration time interval for each initial (i.e., incident) energy window at which the point source 160 produces photons.

Capsule 50 records the number of photons at each integration time interval for each compton approximately 180 degree back-scattered energy window corresponding to the initial energy window at which the point source produced the photons.

For each detector size d (Ek) i, the count of each initial energy window Ek is set equal to the sum of the photons arriving from all possible "observed" sources, i.e.:

(equation 3)

Where Sij is the known intensity of a point source (or a matrix representing the relationship between a plurality of known point sources) for a particular energy window, andis an unknown functional relationship between the geometry of the point source Sij and the detector detection number d (ek) i. For example, the following equation can be usedIs represented by:

(equation 4)

Using a matrix form, the linear transformation can be written as follows:

d ═ S phi (equation 5)

The relationship between the intensity of the point sources is typically measured and stored in the capsule memory during capsule manufacture or at the beginning of the step prior to balloon inflation. These relationships remain unchanged throughout the lifetime of the radioisotope tagging material of point source 160.

Since the measurement matrix D and the point source matrix S are known, it is possible to transform S, since S is benign and invertible, and the values of Φ are calculated as:

φ＝S^-1d (equation 6)

Where phi is a weighting function whose value is related to the spatial geometry of the balloon surface relative to the probe surface, e.g. proportional, where the dominant rule of the weighting matrix is the inverse square rule. In other words, the intensity of a radiation source detected from a distance is inversely proportional to the square of the distance between the point source and the radiation detector. It may further be stated that for solving for the position of the point sources, the number of radiation detectors should be at least three times the number of point sources.

Other methods for calculating the position of the radiation source on the balloon and extrapolating the shape of the balloon surface are also within the scope of the invention.

For some applications, analysis of XRF photons is used to estimate the distance from the balloon surface to the colon wall, either alone or in combination with the ranging methods described above. For some applications, structures other than balloons are used to effectively produce a balloon-like effect, e.g., the extension of the radiation source to the outer boundary is close to the colon wall. When such other structures are used, the method for rendering the colon anatomy (such as the algorithm described above) is suitably adapted to include such other structures.

In one embodiment of the present invention, an algorithm is provided for identifying polyps, colorectal cancers, or other abnormalities from within a colon lumen based on the difference in density between abnormal and normal colon tissue. The algorithm also helps detect cancerous tissue and flat polyps that do not bulge into the lumen of the colon (approximately 5% of polyps in the western world, and more than 10% in japan). Other methods of processing the data set and using the correlation between measurements to improve signal-to-noise ratio may also be used. (the subsequent description relates to single backscatter energy and the relationship (e.g., ratio or difference) between multiple backscatter energies and high and low backscatter energies.)

Using this algorithm when at least a portion of the capsule 50 or balloon 140 is in contact with the colon wall or other internal structure generally yields optimal results such that there is substantially no contrast agent between the one or more radiation detectors 62 and the colon wall or other structure. The capsule 50 typically travels in close contact with the colon wall, as the capsule typically advances in the colon due to peristaltic squeezing of the colon wall.

The algorithm is typically performed upon determining that at least a portion of the swallowable device has contacted the colon wall or other internal structure. For example, the determination may be made by detecting a reduction in XRF photons to substantially zero at the contact portion of the device, which indicates that there is substantially no contrast agent present between the device and the colon wall or other structure.

The algorithm analyzes the number of approximately 180 degrees compton backscattered photons produced in response to incident photons emitted by radiation source 60 and/or point source 160 (fig. 6E) on the surface of balloon 140.

Y ═ UX (equation 7)

Where X is a matrix of the number of backscattered photons (or some relationship between backscattered photons of different energy windows, e.g., a ratio or difference, such as a high energy window divided by a low energy window). Associated with each pixel Y is a principal component matrix. U is an nxn identity matrix derived from the variance-covariance matrix of X,

C_X＝X^Tx (equation 8)

Wherein, variablej (j ═ 1 to N), N being bisected by the center. The rows of the matrix U are Cx_xThe standard feature vector of (2). The covariance matrix of the principal components is then

(equation 9)

And the variable of the Principal Components (PCs) is C_xIs ordered such that

λ₁＞λ₂…＞λ_N。

Since U is a unitary transform, the total data variance is preserved, i.e.,

(equation 10)

Wherein sigma_x ²Is the original variable x_jThe variance of (c). A redistribution of the variance is useful in information recovery. Because the principal components are uncorrelated, and each Yj has a variance less than the preceding components, some principal components will contain a large percentage of the total variance. In other words, it is expected that for common homogeneous tissue layers such as the colon muscle wall, a large portion of the total data variance can be described by a single principal component. On the other hand, the presence of polyps and/or cancerous tissue will induce a change in the ratio of the number of backscattered photons from the colon wall (compared to the uniform colon muscle composition). The composite structure of Cx will result in the presence of two associated terms (i.e., two principal components) that describe the total variance of a significant fraction of more than one principal component.

In one embodiment of the invention, in addition to static analysis of data from adjacent detector pixels, as described above, the same mathematical formula is performed at successive locations of the capsule as it traverses the colon. The autocorrelation function of the data acquired from the different detectors is used to estimate the local motion. (this technique is somewhat analogous to estimating the location of changes in an optical computer mouse using optical analysis techniques.)

In one embodiment of the present invention, a method for detecting and discriminating gas and tissue anomalies such as polyps within the colon is provided. Gas bubbles are formed in the colorectal lumen from time to time. These bubbles may be erroneously identified as possible polyps or other tissue aberrations in the colon. In this embodiment, a set of algorithmic tools and supporting hardware are implemented to help distinguish between bubbles and polyps or other tissue distortions within the colon. These algorithmic tools include, but are not limited to:

the compton scattering from the gas is significantly lower (typically, almost non-existent) than the compton scattering from the tissue (normal and abnormal). Thus, the bubble appears as a reduced compton scattering in all energy windows. In addition, the relationship (e.g., ratio or difference) between high and low energies does not vary greatly in the presence of bubbles. Thus, the identification of reduced compton scattering in all energy windows and smaller changes in the above relationship is an indication of the presence of gas, as photons pass through less contrast agent.

Because of the lower atomic number and primarily because of the lower density, air and other gases within the colon do not emit xrf.

As formed, the bubbles tend to rise to the top of the lumen due to gravity. Thus, using the tilt angle from the MEMS chip with respect to the center of gravity information, it can be determined whether a possible bubble has been detected. With information about the direction of gravity, it is possible to determine the position of the bubble relative to any solid angle sector where a change in count rate associated with the bubble may be detected.

The bubble has a flat surface at its bottom when stable. Thus, they achieve tissue abnormalities other than polyps or other bulges within the colon.

The bubble is pulled away from gravity to travel when unstable. Thus, using information from the MEMS chip, it can be determined whether a possible bubble is close to the capsule.

In the final part of the colon and in the rectum, gas can form and subsequently be expelled from the anus. This is manifested as a gradual decrease in the XRF radiation count and compton scattering count over seconds and minutes, followed by a sudden return to a high value once the gas is released.

To reduce the amount of gas in the colorectal lumen, other absorbents such as carbon compounds or compounds used in civilian products to absorb gas in the gastrointestinal tract may be mixed with or taken along with the contrast agent.

For some applications, the presence of bubbles is detected using acoustic waves (e.g., ultrasound). The air bubbles have significantly different sound emission properties compared to polyps and other tissue anomalies in the colon lumen.

In one embodiment of the present invention, wherein the radiation source 60 comprises a radioisotope, the radioisotope emits beta rays. Such beta emitters may include, for example, phosphorus 32, sulfur 35, or xenon 133. The radioisotope is placed in a high atomic number metal housing such as gold, lead, tungsten or other high atomic number metal. The selected material typically has higher energy XRF lines (e.g., tungsten, with an XRF of 67 keV). The device produces XRF sub-photon radiation as a result of the excitation of the beta electrons.

In one embodiment of the invention, an energy saving protocol is used to conserve battery power when the capsule travels in the gastrointestinal tract before entering the colon. According to this protocol, one or more of the methods described above for detecting that the capsule has reached the colon are used. Once arrival in the colon has been detected, the capsule begins data acquisition to detect polyps within the colon. The data acquisition typically lasts an average of between 24 and 72 hours. In order to minimize radiation exposure from the capsule, the capsule is designed to emit radiation only when it is about to move. Such impending movement may be detected, for example, by sensing pressure changes in colon contents; the capsule activates when the gradient of pressure with respect to time passes a certain threshold. Alternatively or additionally, the capsule may be activated if it changes its inclination with respect to the earth's gravitational force vector, which can be detected using a MEMS accelerometer chip. A change in this relative inclination above a certain threshold may indicate that the capsule is about to move. Alternatively or additionally, the capsule may use a combination of these indicators for determining when to activate the radiation source.

Alternatively or additionally, for applications where the capsule includes a bladder 140, as described above with reference to fig. 6A-E, the trigger for activating the probe may include a pressure gauge that measures the pressure of the gas within the bladder. When the colon wall begins to move, pressure builds up in the balloon, activating the capsule to switch on the probe channel and other electronics circuits that have previously been disabled to conserve power. After the pressure reduction, optionally after a delay, the capsule returns to the resting operating state.

For some applications, the measurement of pressure on the balloon is performed by monitoring compton backscattering numbers from different detectors with high-energy photons escaping the shield when the capsule is in its rest operating state. Changes in the readings from these detectors may indicate that the bladder is at a higher pressure and therefore the capsule should transition to a fully active state in anticipation of possible movement.

In one embodiment of the invention, the subject takes a specially prepared diet prior to taking the capsule, which includes a contrast agent as described above and a mild purgative to soften the intestinal contents and promote large bowel movement, thereby reducing the average transit time of the capsule.

In one embodiment of the invention, a radiation detector placed on the subject's body is used to track the location of the capsule. Measuring the relative intensity of the detected radiation from a number of detectors having known relative positions to each other enables the position of the capsule to be tracked in real time. The position of the detector may be tracked by a magnetic position marker system or other position tracking system known in the art.

In one embodiment of the invention, a subject is administered an oral formulation having a high atomic number (i.e., an atomic number of at least 50, typically between 60 and 100) and emitting relatively bright X-ray fluorescence in response to incident gamma and/or X-ray radiation. Such agents may include, for example, barium sulfate, iodine-based compounds, or gadolinium-based compounds, which are commonly used as gastrointestinal contrast agents, or other compounds that emit X-ray fluorescence with higher energy (barium at 32 keV). The material is generally confined within the gastrointestinal lumen. The high atomic number agent fills the volume of the colon lumen and assists in the detection of polyps and other tissue aberrations by showing where the volume is not occupied by the high atomic number agent.

The principle of operation of this embodiment is similar to that of the embodiment described above, except as described below. As in these other embodiments, the capsule emits gamma and/or X-ray radiation to illuminate the vicinity of the capsule. However, unlike other embodiments, the purpose of the illumination is to excite high atomic number agents to emit X-ray fluorescence (XRF). The X-ray radiation emitted by the XRF process is then detected and processed by the capsule.

Reference is made to fig. 11A-D, which are graphs showing experimental results measured in accordance with an embodiment of the present invention. 11A, 11B, and 11C are energy spectrum charts showing the use of a high atomic number 2% barium sulfate formulation having a thickness of 1 cm, 2 cm, and 3 cm, respectively, in accordance with an embodiment of the present invention. Each graph shows a barium sulfate XRF spectral line 180 and a Compton backscattered light spectral line 182 measured at a backscattering angle of 180 degrees. As can be seen from the graph, the XRF photon count rate is dependent on the high atomic number agent (BaSO)₄) Is measured. FIG. 11D is a graphical representation of an XRF spectrum of barium sulfate versus the thickness of a high atomic number formulation in accordance with an embodiment of the present invention, also illustratingThe correlation of photon counting rate to high atomic number agent is shown. (the solid line shows the average count rate and the dashed line shows plus or minus one standard deviation.)

Analysis of XRF data received by the capsule is generally similar to that performed in the embodiments described above. However, the XRF photon count decreases in the presence of polyps or other tissue abnormalities, while the compton scattered photon count increases in the presence of polyps or other tissue abnormalities.

According to one embodiment of the invention, the compton scattered photon and XRF photon counts are measured and the combined information is utilized to identify the presence of a polyp or other tissue abnormality. In this XRF/compton embodiment, the two different types of radiation are calculated separately, evaluated through different energy windows corresponding to two separate energies. Typically, the photon energy of the radiation source is selected such that the incident photons from the capsule have a sufficiently high energy such that approximately 180 degrees compton scattered energy is sufficiently separated from the XRF of the contrast agent. The use of XRF photon counts and compton scattered photon counts typically improves the statistics derived from received photons.

In one embodiment of the invention, a combination of compton scattered photons and XRF photons is used to estimate the absolute distance from each detector on the capsule to the wall of the colon lumen. This information is then used (typically retrospectively, when analyzing data from the capsule) to reconstruct the colon inner wall surface curvature as a function of time (or as a function of another parameter, such as distance traveled in the colon, typically determined using information from MEMS sensors or autocorrelation functions based on count rates from different detectors).

For some applications, the following absorption equation is used to estimate the distance from the colon wall to the capsule at any given time:

I＝φ(C，D)I₀exp (- μ x) (equation 11)

Wherein:

i is the photon intensity measured by the detector (for a particular energy window);

phi (C, D) is a function describing the efficiency of the measurement, which depends on the geometry of the collimation and the detector efficiency;

·I₀is the photon intensity at the radiation source (for the same specific energy window);

μ is the absorption coefficient of colon contents, which depends on the total chemical composition and the specific density;

x is the length in centimeters.

For some applications, a method of estimating the absorption coefficient μ is provided. The following experiments will help to understand the description of the method below;

the probability that compton scattering will affect each other depends on the electron density and is therefore linearly proportional to the density of the colon contents.

Most of the photon absorption in the contrast agent (both in the way out of the capsule and in the way back into the capsule after Compton scattering) is due to photoelectric interactions, which vary with function Z ^ 5; and is

The density of material within the colon is similar to that outside the colon and usually inside the body (as far as the probability of compton scattering interactions is concerned).

The method for estimating the absorption coefficient μ of colon contents (including contrast agent) typically comprises:

determine which probe on the capsule is in contact with the small intestine wall at any given time. This determination is typically made by identifying which detector is recording an extremely low level of XRF at any given time, as this is an indication that the detector is in contact with the wall. (XRF is measured at a high level in response to incident photons passing through the contrast agent however, photons striking the detector in contact with the small intestine wall do not substantially pass through the contrast agent.) this determination is typically made by analyzing the data recorded in external recording device 52. The estimate is derived from the average compton scattered photon count for each detector recorded when it is in contact with the small intestine wall. This corresponds to X ═ 0 in the absorption equation shown above;

separating the probe of the capsule from the colon wall by at least a known minimum separation distance. The detector that is recording the minimum distance is therefore located at this known minimum separation distance. For some applications, the separation is accomplished using an extension device such as described below with reference to fig. 7A or 7B. The separation is performed when the capsule enters the colon. Capsule entry into the colon may be detected using a variety of methods such as those described above; and

the absorption coefficient μ of the colon contents including contrast agent is calculated using equation 11 and the compton scattering count rate determined in the first two steps of the method.

Using the calculated value μ, the time-varying distance from any probe to the near wall portion of the colon is calculated over the entire movement cycle of the probe through the colon. In an embodiment, the calculation is according to a model using a semi-logarithmic table, where count rate is on the y-axis and distance is on the x-axis. The slope of the graph is the calculated μ, which is based on the measurements obtained in the first two steps of the μ calculation method.

In one embodiment of the invention, the subject swallows a radiotracer material, which is poorly absorbed and resides only in the gastrointestinal tract. The subject then swallows a capsule provided with gamma ray sensors connected to an external recording device worn on the subject. Except as described herein, the principle of operation of this embodiment is similar to that of the embodiment described above.

This embodiment of the invention is based on the following physical principles described with reference to fig. 3, where fig. 3 is a graph showing exemplary experimental results of an experiment similar to that described above with reference to fig. 2A-E according to an embodiment of the invention, a container similar to container 12 in fig. 2A-D is filled with a radioisotope labeled liquid or low viscosity gel, and a water filled bead similar to balloon 18 in fig. 2A-D is placed at the bottom of the container, a collimated radiation detector similar to detector 16 in fig. 2A-D is passed over the container, maintained at a constant distance from the bottom of the container (no radiation source similar to radiation source 14 in fig. 2A-D is used in the experiment), gamma or X-ray radiation counts per second are recorded at multiple points along the detector path, when the detector passes over the water balloon position (position C), the count rate reading drops as shown in fig. 3, two physical principles combine to produce this effect:

because the medium is a liquid or a low-viscosity gel, the concentration of the radioactive substance is uniformly distributed in the medium, provided that sufficient time has elapsed after introduction of the radioisotope; and

the number of photons detected per unit time is proportional to the volume "seen" by the calibrated detector. In other words, the probability of detecting photons originating from isotopes that decay into more stable nuclei is directly proportional to the volume of the radionuclide that the collimated detector "observes".

The principle of operation of this embodiment is generally similar to that of the embodiments described above, except that the high-energy photons of this embodiment are emitted by the radiolabeled material swallowed by the subject, rather than from the capsule (or point source of the balloon). The radiolabelled material is typically similar to that used to study colon transit time. For example, the radiolabelled material may be an oral tracer such as iodine-131-cellulose, cation exchange resin particles (0.5-1.8 mm in diameter) labelled with indium 111 in a capsule, gallium 67-citrate or other such material which is administered orally and held within the gastrointestinal tract. (see, for example, the above-mentioned paper by Camilleri et al.)

The capsule of this embodiment is similar to capsule 50, such as described above with reference to fig. 4. Unlike capsule 50, however, the capsule of this embodiment typically does not include any radiation source. Furthermore, the radiation detector of the capsule of this embodiment is typically collimated. The radiation detectors are typically arranged within a sphere such that they "see" the entire 4 pi squared sphere (or a portion thereof) around the capsule. The collimation of the detectors enables each detector to "see" a closed (with respect to a sphere) sector.

The capsule passes through the gastrointestinal tract and measures photons that strike its radiation detector. Typically, this measurement is usually made continuously unless the capsule is in an energy saving mode. Count rate information from each radiation detector is stored with a time stamp for each measurement. During the integration time of the device, the capsule and its surrounding colon wall and the radiolabelled material are assumed to be in a quasi-steady state. Choosing a sufficiently small time interval and integrating the counts over these small time periods takes into account the quasi-steady state assumption. These data are stored in the capsule and are typically transmitted from time to time by the capsule to an external recording device.

The analysis of the data from the capsule is substantially similar to that described above. The presence of protruding anatomical structures reduces the gamma count rate received from this region, resulting in smaller count readings as the structures displace the radioisotope labeled colon contents.

Reference is now made to fig. 7A and 7B, which are schematic illustrations of an extension element according to an embodiment of the present invention. These extension elements are deployed when capsule 50 reaches the clinically significant region of the gastrointestinal tract (typically the colon). In their expanded position, the extension elements keep the capsule 50 a small distance from the colon wall. For some applications, capsule 50 includes a material that reacts on the basis of a chemical trigger (such as a pH change) when the capsule reaches the vicinity of the colon (e.g., using the methods described in the Camilleri et al article, supra). The chemical reaction causes the extension element to unfold. Alternatively or additionally, the material used swells upon absorption of gastrointestinal fluids therein, thereby causing the extension element to expand.

The elasticity and flexibility of the expansion elements are such that they are sufficiently soft not to interfere with the normal travel of the capsule in the small intestine, even if the elements are inadvertently fully expanded in the small intestine.

For some applications, as shown in fig. 7A, the extension element includes a leg 200. Optionally, as shown in fig. 7B, the extension element comprises an expandable ring structure 202. The ring structure 202 is initially held tightly surrounding the capsule 50 by a dissolving material, such as a pH sensitive material that dissolves in the colon at a particular pH. When the dissolving material dissolves in the colon, the ring is released and expands around the capsule. More optionally, the extension element comprises another expanded geometry.

Reference is made to fig. 8A and 8B, which are schematic illustrations of additional extension elements, in accordance with an embodiment of the present invention. In these embodiments, capsule 50 typically includes one or two expandable flexible chambers 211 connected to one end of capsule 50 (fig. 8A) or both ends of the capsule (fig. 8B). Each chamber 211 comprises a semi-permeable inflatable membrane 212 enclosing a super absorbent hydrogel 214. Capsule 50 is typically coated with a coating 210 that is pH sensitive to the pH of the colon and/or sensitive to bacterial enzymes found in the colon. When capsule 50 reaches the colon, coating 210 dissolves, allowing colonic liquid (such as water and possibly contrast media) to pass through membrane 212 and be absorbed by hydrogel 214. This absorption of hydrogel 214 expands chamber 211 such that the length of capsule 50 with the chamber is greater than the width of the colon lumen, thereby forcing the length of capsule 50 to be oriented parallel to the longitudinal axis of the colon lumen. The expansion of the chamber 211 also typically minimizes capsule movement in the absence of bulk movement of the colon contents. Even if the chamber 211 unintentionally fully opens in the small intestine, the chamber does not impede the movement of the capsule in the small intestine.

Reference is made to fig. 8C, which is a schematic illustration of yet another extension mechanism, in accordance with an embodiment of the present invention. In this embodiment, the extension element comprises a deployment element 220. Deployment element 220 typically comprises a flexible material that extends as coating 210 dissolves. Other forms and shapes of the extension unit will be apparent to those skilled in the art having read the present application and are within the scope of the present invention.

For some applications, other chemical or non-chemical methods are used to trigger the deployment of the various extension mechanisms described herein. For example, capsule 50 may receive a signal from a location external to the subject, or may detect an electrical signal indicative of a characteristic of the colon, and deploy the extension element mechanically, electrically, chemically, or otherwise in response to the signal.

In one embodiment of the present invention, the contrast agent or the radiolabeled (or labeled) agent and/or the high atomic number agent is encapsulated in capsule 50 or a separate agent storage capsule that dissolves when the ambient pH becomes characteristic of the desired portion of the gastrointestinal tract. In response, the formulation dissolves in or near the colon, thereby increasing the effective concentration of the formulation in the colon.

In one embodiment of the present invention, the capsule 50 is tracked by a navigation system that adds location information to the capsule data. Such a navigation system may include, for example, a set of radio receivers that track the capsule by measuring the relative amplitude of the RF signals transmitted by the capsule at different locations on the subject's body. Other embodiments utilize ultrasound-based localization, wherein the capsule acts as a transponder to signals from some location on the subject's body, and time-of-flight measurements provide localization. Other localization techniques known in the art, such as magnetic field-based position sensing, are used in some applications.

In one embodiment of the invention, capsule 50 includes conductive electrodes attached to its surface and a pulse generator located in the capsule that is controlled by the capsule's microcontroller. In this embodiment, the capsule is adapted to electrically excite the colon, thereby causing controlled bulk motion (or bulk motion). Such an activation method is described, for example, in U.S. patent 6,453,199 to Kobozev, incorporated by reference in the present application, and RU No.936931MKI a 61N 1/36BIR 1982, incorporated by reference in the present application, the capsule typically repeatedly performing the following steps: (a) the capsule may be controlled and data acquired at the corresponding time the subject may also know that the capsule has begun its imaging inside the colon.

In one embodiment of the present invention, the colon muscles are observed during contractions using the observation and analysis techniques described herein. Healthy colon muscle contraction is usually in the form of cylindrical symmetry. The possible presence of tissue anomalies is detected by observing deviations from this cylindrical symmetry. Such abnormalities may be polyps or other tissue abnormalities that may conceal cancer or a tumor preceding cancer. Deviations from one region to another along the path of the colon may also indicate the presence of tissue abnormalities.

In one embodiment of the invention, the power source of the capsule includes a "nuclear battery" that utilizes the radioactive material in the capsule as a beta emitter. For example, the methods and apparatus described in U.S. patent 5,721,462 to Shanks, which is incorporated herein by reference, may be used.

For some applications, the methods and apparatus described in the above-mentioned U.S. provisional patent applications 60/531,690 and/or 60/559,695 are used in conjunction with the methods and apparatus described herein.

It is noted, however, that some embodiments of the invention described herein relate to causing a subject to swallow a contrast agent such as barium (which increases the absorption of photons and thus provides a means of distinguishing between the wall of the gastrointestinal tract and the contents of the lumen), and in other embodiments of the invention, the subject instead swallows a contrast agent having reduced absorption relative to the wall of the gastrointestinal tract. For example, nutritional fibers have less absorption than the absorption of the gastrointestinal and parenteral tissues, and thus, the compton scattered photons recorded will be reduced when the capsule passes polyps and other abnormalities. Including the claims, as used herein "contrast agents" includes both positive and negative attenuation contrast agents.

Although in some embodiments of the present invention capsule 50 and/or data recording unit 52 are described as performing specific calculations and/or analyses, all or a portion of these calculations and/or analyses may be performed instead by external data analysis software and/or hardware. Similarly, for some applications, the calculations and/or analyses described herein performed by external data analysis software and/or hardware may be performed by capsule 50 and/or data recording unit 52.

Although some embodiments of the invention are described in relation to examination of the colon of a subject, some of the methods described herein are also applicable, mutatis mutandis, to other parts of the gastrointestinal tract and/or other body lumens, such as blood vessels.

For simplicity, some embodiments of the invention described herein relate to a scatter angle of 180 degrees, but typically also include ranges around 180 degrees. For example: the range may be 180 degrees +/-a range parameter typically less than 10, 20 or 30 degrees.

It will be apparent to those skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not in the prior art.

Claims

1. An apparatus for lumen probing, comprising:

a capsule adapted to be swallowed by a subject, and comprising:

at least one radiation source adapted to emit radiation having an energy of at least 10 kev, and the radiation source is adapted to emit radiation from the capsule only during a period of time in which the capsule is in the gi tract;

a sensor adapted to detect a parameter indicative of possible impending movement of the capsule in the gastrointestinal tract, and wherein the radiation source is adapted to emit radiation from the capsule in response to a readout of the parameter by the sensor;

an oral contrast agent adapted to be administered by a subject; and

a control unit adapted to analyze data relating to the photons in order to generate information useful for identifying clinically relevant features of the gastrointestinal tract of the subject.

2. The apparatus of claim 1, wherein the oral contrast agent comprises an oral contrast agent having a high atomic number suitable for administration to the subject.

3. The device of claim 1, wherein the oral contrast agent comprises ferromagnetic particles, and wherein the capsule comprises a magnet adapted to attract the ferromagnetic particles to the capsule.

4. The apparatus of claim 1, wherein the radiation source comprises a miniature X-ray generator.

5. The apparatus of claim 1, wherein the radiation source comprises a radioisotope.

6. The apparatus of claim 1, wherein the radiation source is adapted to emit gamma rays.

7. The apparatus of claim 1, wherein the radiation source is adapted to emit X-rays.

8. The apparatus of claim 1, wherein the control unit is adapted to analyze a time derivative of the data to generate the information.

9. The apparatus of claim 1, wherein the radiation source comprises at least one collimator adapted to collimate radiation emitted by the radiation source.

10. The apparatus of claim 1, wherein the photon detector comprises at least one collimator adapted to collimate photons detected by the photon detector.

11. The apparatus according to claim 1, wherein the control unit is adapted to distinguish between the gas in the gastrointestinal tract and the clinically relevant feature.

12. The apparatus of claim 1, wherein the control unit is adapted to analyze X-ray fluorescence photons generated in response to the emitted radiation.

13. The apparatus of claim 1, wherein the control unit is adapted to analyze X-ray fluorescence photons generated in response to the emitted radiation and compton backscattered photons generated in response to the emitted radiation.

14. The device of claim 1, wherein the capsule comprises an acceleration sensor.

15. The apparatus of claim 1, comprising an external data recording unit adapted to be maintained outside the body of the subject, wherein the capsule is adapted to wirelessly transmit information to the data recording unit when the capsule is in the gastrointestinal tract.

16. The apparatus of claim 1, wherein the capsule comprises the oral contrast agent, wherein the capsule is adapted to store the oral contrast agent and release the oral contrast agent to a clinically significant area within the gastrointestinal tract.

17. The apparatus of claim 1, further comprising an agent storage capsule comprising the oral contrast agent, wherein the agent storage capsule is adapted to store the oral contrast agent and release the oral contrast agent to a clinically significant area within the gastrointestinal tract.

18. The device of claim 1, wherein the capsule comprises a pressure sensor.

19. The apparatus of claim 1, wherein the photon-related data comprises data for one or more predetermined photon energy windows, and wherein the control unit is adapted to analyze the energy window data.

20. The apparatus of claim 1,

wherein the photon-dependent data comprises a number of photons per time interval,

wherein the photon detector is adapted to count detected photons, an

Wherein the control unit is adapted to analyze the statistical number of photons.

21. The device according to any of claims 1-11, 14-20, wherein the control unit is adapted to estimate the distance from the location of the capsule to the wall of the gastrointestinal tract.

22. The device according to claim 12, wherein the control unit is adapted to estimate the distance from the location of the capsule to the wall of the gastrointestinal tract.

23. The device according to claim 13, wherein the control unit is adapted to estimate the distance from the location of the capsule to the wall of the gastrointestinal tract.

24. The apparatus of claim 21, wherein the control unit is adapted to estimate the distance using an algorithm in which an inverse relationship exists between the distance and the number of detected photons.

25. The apparatus of claim 22, wherein the control unit is adapted to estimate the distance using an algorithm in which an inverse relationship exists between the distance and the number of detected photons.

26. The apparatus of claim 23, wherein the control unit is adapted to estimate the distance using an algorithm in which an inverse relationship exists between the distance and the number of detected photons.

27. The apparatus of claim 24, wherein the control unit is adapted to analyze compton backscattered photons generated in response to the emitted radiation.

28. The apparatus of claim 25, wherein the control unit is adapted to analyze compton backscattered photons generated in response to the emitted radiation.

29. The apparatus of claim 27, wherein the control unit is adapted to estimate the distance by estimating a contrast agent depth between a location of the capsule and a wall of the gastrointestinal tract in response to the compton backscattered photons.

30. The apparatus of claim 28, wherein the control unit is adapted to estimate the distance by estimating a contrast agent depth between a location of the capsule and a wall of the gastrointestinal tract in response to the compton backscattered photons.

31. The apparatus of claim 21, wherein the control unit is adapted to estimate the distance using an algorithm in which there is a positive correlation between the distance and the number of photons detected.

32. The device according to claim 22 or 23, wherein the control unit is adapted to estimate the distance using an algorithm in which there is a positive correlation between the distance and the number of detected photons.

33. The apparatus of claim 31, wherein the control unit is adapted to analyze X-ray fluorescence photons generated in response to the emitted radiation.

34. The apparatus of claim 33, wherein the X-ray fluorescence photons are generated by the oral contrast agent in response to emitted radiation, and wherein the control unit is adapted to estimate the distance by estimating a depth of the oral contrast agent between the location of the capsule and a wall of the gastrointestinal tract in response to an analysis of the X-ray fluorescence photons.

35. The apparatus of claim 32, wherein the oral contrast agent has a high atomic number, wherein the X-ray fluorescence photons are generated by the oral contrast agent in response to the emitted radiation, and wherein the control unit is adapted to estimate the distance by estimating a depth of the oral contrast agent between the location of the capsule and the wall of the gastrointestinal tract in response to an analysis of the X-ray fluorescence photons.

36. The apparatus of claim 1, wherein the radiation source comprises a miniature X-ray generator configured to emit radiation only during the period of time.

37. The apparatus of claim 1,

wherein the radiation source comprises a radioactive isotope,

wherein the capsule comprises a radiation shield, an

Wherein the capsule comprises an actuator adapted to move at least one of the radiation source and the shield such that the shield does not obstruct radiation emitted from the radiation source during the period of time.

38. The apparatus of claim 37, wherein the capsule comprises a plurality of collimators, and wherein the plurality of collimators and the shield are configured such that no radiation emitted by the radiation source passes through all of the collimators at any given time.

39. The apparatus of claim 37, wherein the capsule comprises a rod, wherein the radiation source is connected to the rod, and wherein the actuator is adapted to move the rod so as to move the radiation source.

40. The device of claim 39, wherein the capsule comprises at least one spring, and wherein the stem and the spring are configured to form a mechanical oscillator.

41. The device of any one of claims 1-20, wherein the capsule comprises an inflatable balloon adapted to be inflated around the capsule.

42. The device of claim 41, wherein the balloon is configured such that the capsule moves toward the center of the balloon when the balloon is inflated.

43. The apparatus of claim 41, wherein the balloon is configured to expand when the capsule reaches a clinically significant area within the GI tract.

44. The apparatus of claim 41, wherein the balloon comprises a valve adapted to open for a specified period of time after the capsule reaches the clinically significant area, thereby allowing the balloon to deflate.

45. The apparatus according to claim 41, wherein the control unit is adapted to estimate the distance from the capsule position of the capsule to the wall of the gastrointestinal tract by calculating the sum of a first distance from the capsule position to a balloon position on the balloon surface inside the balloon and a second distance from the balloon position to the wall of the gastrointestinal tract.

46. The apparatus of claim 45, wherein the control unit is adapted to calculate the first distance by measuring and analyzing a change in a number of Compton backscattered photons detected by the photon detector.

47. The apparatus of claim 45, wherein the control unit is adapted to calculate the first distance based on a size of a Compton backscatter projection detected by the photon detector.

48. The apparatus of claim 45, wherein the surface of the balloon comprises a high density of point particles of a material, and wherein the control unit is adapted to calculate the first distance by measuring and analyzing the number of X-ray fluorescence photons detected by the photon detector.

49. The apparatus of claim 45, wherein the surface of the balloon comprises a radiation point source, and wherein the control unit is adapted to calculate the first distance by measuring and analyzing radiation emitted from the point source and detected by the photon detector.

50. The apparatus of claim 45, wherein the control unit is adapted to calculate the second distance by analyzing a number of X-ray fluorescence photons detected by the photon detector.

51. The apparatus of any of claims 1-20, wherein the gastrointestinal tract comprises a colon of the subject, and wherein the control unit is adapted to analyze the data to generate information useful for identifying clinically relevant features of the colon.

52. The apparatus of claim 51, wherein the capsule comprises:

an electrode attached to an outer surface of the capsule; and

a pulse generator for generating a pulse of a pulse signal,

wherein the control unit is adapted to drive the pulse generator to apply an electrical signal to the colon capable of causing mass movement within the colon.

53. The apparatus of claim 51, wherein the control unit is adapted to generate information about the geometry of the muscles of the colon.

54. An apparatus according to any one of claims 1-20, characterized in that the control unit is adapted to generate a graphical representation of the information.

55. The apparatus according to claim 54, wherein the control unit is adapted to generate the graphical representation in a series of modalities in time.

56. The apparatus of claim 54, wherein the control unit is adapted to generate the graphical representation by:

generating a first surface having a subdivision representing distances between locations of the capsule and locations of a wall of the gastrointestinal tract, an

A second surface is generated having pixels, each of the pixels representing a respective difference between one of the subdivisions of the first surface and a plurality of subdivisions adjacent to the subdivision.

57. The apparatus of claim 56, wherein the control unit is adapted to generate the graphical representation by:

repeatedly generating the second surface at a plurality of points in time, an

Displaying an animation of the second surface corresponding to the plurality of points in time.

58. The apparatus according to claim 54, wherein the control unit is adapted to generate the graphical representation with reference to a coordinate system of the subject.

59. The apparatus according to claim 54, wherein the control unit is adapted to generate the graphical representation based on a coordinate system of the capsule.

60. The apparatus of any one of claims 1-20, wherein the at least one photon detector comprises a plurality of photon detectors arranged to detect photons from a plurality of detection directions.

61. An apparatus according to claim 60, wherein the at least one radiation source comprises a plurality of collimators arranged to emit radiation in a plurality of respective emission directions corresponding to the detection direction.

62. The device according to any of claims 1-20, wherein the capsule comprises at least one radiation shield.

63. The apparatus of claim 62, wherein the at least one shield is configured to prevent radiation from being emitted from the radiation source in directions other than a single closed sector associated with a sphere surrounding the capsule.

64. The apparatus of any one of claims 1-20, wherein the radiation source is adapted to emit radiation having a plurality of primary energy levels, and wherein the control unit is adapted to analyze the number of photons having a plurality of secondary energy levels different from the plurality of primary energy levels.

65. The apparatus of claim 64, wherein the radiation source is adapted to emit radiation having first and second energy levels, and wherein the control unit is adapted to analyze a mathematical relationship between the number of photons having the third energy level detected by the photon detector and the number of photons having the fourth energy level detected by the photon detector.

66. The apparatus of claim 65, wherein the relationship comprises a ratio of a number of photons having a third energy level to a number of photons having the fourth energy level, and wherein the control unit is adapted to analyze the ratio.

67. The apparatus according to claim 65, wherein the control unit is adapted to analyze the relationship to determine an actual calibrated distance between the location of the capsule and the wall of the gastrointestinal tract.

68. The apparatus of any of claims 1-20, wherein the clinically relevant characteristic comprises a pathological abnormality of the gastrointestinal tract.

69. The apparatus of claim 68, wherein the pathological abnormality comprises a polyp.

70. The apparatus of claim 1, wherein the control unit is adapted to analyze compton backscattered photons generated in response to the emitted radiation.

71. The apparatus of claim 70, wherein the control unit is adapted to analyze compton backscattered photons having an energy level indicative of a backscattering angle for a range of angles from less than 210 degrees to more than 150 degrees.

72. The apparatus of claim 71, wherein the range parameter is less than 200 degrees to greater than 160 degrees.

73. The apparatus of claim 72, wherein the range parameter is less than 190 degrees to greater than 170 degrees.

74. The apparatus according to any of the claims 1-20, wherein the control unit is adapted to detect that the capsule has reached a region of clinical interest in the gastrointestinal tract.

75. The apparatus according to claim 74, wherein the region comprises a colon, and wherein the control unit is adapted to detect that the capsule has reached the colon.

76. The apparatus according to claim 74, wherein the control unit is adapted to detect that the capsule has reached the region by detecting and analyzing X-ray fluorescence photons.

77. The apparatus according to claim 74, wherein the capsule comprises a pH sensitive element, wherein the control unit is adapted to detect that the capsule has reached the region by responding to a change in pH in the region affecting the pH sensitive element.

78. The apparatus of claim 74, comprising a tag adapted to be attached to an outer surface of the body of the subject in the vicinity of the entrance to the zone, and the control unit is responsive to a signal emitted by the tag to detect that the capsule has reached the zone.

79. The apparatus according to claim 74, wherein the capsule comprises a pressure sensor, and wherein the control unit is adapted to detect that the capsule has reached the zone by responding to a pressure change detected by the pressure sensor.

80. The apparatus of claim 79, comprising a tag adapted to be attached to an outer surface of the body of the subject near the entrance to the zone, and the control unit detects that the capsule has reached the zone in response to the signal emitted by the tag and the change in pressure.

81. The apparatus according to claim 79, wherein the control unit is adapted to detect that the capsule has reached the region by detecting and analyzing X-ray fluorescence photons and in response to the pressure change.

82. The device according to any of claims 1-20, wherein the control unit is adapted to detect density variations in the tissue of the wall of the gastrointestinal tract, which variations are indicative of the presence of the clinically relevant feature.

83. The apparatus according to claim 82, wherein the control unit is adapted to detect the change when the control unit detects that at least a portion of the capsule is in physical contact with the wall of the gastrointestinal tract.

84. The apparatus according to claim 82, wherein the at least one photon detector comprises a plurality of photon detectors, and wherein the control unit is adapted to analyze a compton backscattered photon count from the location of the wall detected by more than one photon detector.

85. The apparatus according to claim 84, wherein the control unit is adapted to analyze the compton backscattered photon count using principal component analysis.

86. The device according to any of claims 1-20, wherein the capsule comprises at least one extension element adapted to keep the capsule at least a certain distance from the wall of the gastrointestinal tract when extended.

87. The apparatus of claim 86, wherein the extension element is configured to extend when the capsule reaches a region of clinical interest within the gastrointestinal tract.

88. The device of claim 86, wherein the extension member comprises at least one leg member.

89. The device of claim 86, wherein the extension member comprises an expandable ring-shaped structure.

90. The device of claim 86, wherein the extension element comprises a deployment element.

91. The device according to any of claims 1-20, wherein the capsule comprises at least one extension element adapted to orient a long axis of the capsule substantially parallel to a longitudinal axis of the gastrointestinal tract when extended.

92. The device of claim 91, wherein the extension element comprises an inflatable flexible chamber.

93. The device of claim 92, wherein the flexible chamber comprises a super-absorbent hydrogel, and wherein the flexible chamber is adapted to expand when the hydrogel absorbs fluid from the gastrointestinal tract.

94. The apparatus according to claim 75, wherein the control unit is adapted to inhibit the radiation source from emitting radiation until the capsule has reached an area of clinical attention.

95. The apparatus according to claim 94, wherein the control unit is adapted to inhibit the photon detector from detecting photons and to inhibit the control unit from analyzing data until the capsule has reached an area of clinical attention.

96. The apparatus according to claim 80, wherein the control unit is adapted to inhibit the radiation source from emitting radiation until the capsule has reached an area of clinical attention.

97. The apparatus according to claim 96, wherein the control unit is adapted to inhibit the photon detector from detecting photons and to inhibit the control unit from analyzing data until the capsule has reached an area of clinical attention.

98. An apparatus for lumen probing, comprising:

a capsule adapted to be swallowed by a subject and comprising at least one radiation source adapted to emit radiation having an energy of at least 10 kev, and said radiation source is adapted to emit radiation from said capsule only during a period of time in which said capsule is in the gastrointestinal tract;

at least one photon detector not physically connected to the capsule, adapted to detect photons having an energy of at least 10 kev;

a sensor adapted to detect a parameter indicative of possible impending movement of the capsule in the gastrointestinal tract, and wherein the radiation source is adapted to emit radiation from the capsule in response to a readout of the parameter by the sensor; and

99. The apparatus of claim 98 wherein the radiation source comprises at least one collimator adapted to collimate radiation emitted by the radiation source.

100. The apparatus of claim 98, wherein the radiation source comprises a miniature X-ray generator.

101. The apparatus of claim 98, wherein the radiation source comprises a radioisotope.