System for in vivo sampling and analysis

SYSTEM FOR IN ATVO SAMPLING AMD ANALYSIS

FIELD OF THE ΙΝΛΈΝΤΙΟΝ

The present invention relates to the field of in vivo diagnostics. More specifically, the present invention relates to a system and method for in vivo and m-sitii sampling and analysis of conditions prevailing in a body lumen.

BACKGROUND OF THE INVENTION

An atypical concentration or presence of substances in body fluids or in body lumens may be indicative of the biological condition of the body. For example, *־ presence of elevated concentrations of red blood cells in the gastrointestinal (0¢ tract may indicate different pathologies, depending on the location of the bleeding along the GI W. Likewise, abnormalities in the physical conditions of the body, such as elevated temperas®־, may indicate pathology. Early d^tion, identification and location of abnotmd conditions may be critical for correctly diagnosing and treating various pathologies.

Medical detection, kits are usually based on in vitro testing of body fluid samples for the presence of a suspected substance. A know in vitro test is, for example, an agglutination test. Agglutination tests typically rely on the ability of an antibody to form large cross-linked antibody-antigen complexes that precipitate out of a solution. The process of agglutination normally includes 2 steps: sensitization (involves the attachment of antibodies (Ab) to antigens (Ag)) and lattice formation (cross linking between sensitized particles, which results in visual agglutination). Some factors can enhance these reactions, for example, pH,

PCI7IL2003/000651 template־, incubation tint־, ionic strengfc (salt concentedon) of the suspending solution and. so on.

Agglutination reactions, also referred to as the indirect Coombs test, usually involve precipitation of cells, fluently, indirect cross-ibking is used to form 4־ aggregation. A .^.Wy antibody may be added that binds to the prim־־ ׳!־־«bodies that toe bound to epitope on th־ surface of 4־ c־U. An־4־r far־« group of agitation tests are the Latex Agglutination Tests (LAT). These immunoassay tests toe been in clinical use for more than 50 years. The tests are used to detect the presence of an antibody or antigen in a variety׳ of in tit® sampl״ ־־* ^Mds “־ gastrointestinal secretions or blood. Depending on the sample under investigation, and the specific substance one is looking for. 1־^ ™ ^— (typically, sphene־! beads). When the ־־״־P* ׳ '״ * beads agglutinate, i.e. dw t־g־4־r ™bl־ particles, when mixed or ־־me to contact ta sample. The latex beads may be replaced by ota polymers such as polype or even gold particles.

Agglutination tests are typically P־־־*־^d⁵^ “״^{s sKdBS} ''““*י * for adding Ag and Ab or tubes and ships on which the agglutination exposes the underlying colored markers. .... .

In vitro testing of sampl־־ does not easily enable the localization or identification of 4־ origin of an abnormafiy occurring substance. In many ״stances localizing an abnormally occurring substance in a body lumen greatly contributes to the identification of pathology, and the paper type of treatment and thus contributes to the facile treatment of the identified pathology. For example, bleeding in 4־ stomach may indicate an ulcer wbrle bl־edmgin4e small intestine may indicate 4־ presence of a honor. The detection of some conditions in 4־ GI hacf such as bleeding, is possible by endoscope. How4 ,»־is possMtf is Med to 4־ upper or lower GI tract. Thus, conditions in ote parts ־f th־ GI tact, such as the small intestme, ar־ not easily detected by endoscopy.

There is therefore a need fir a system and method that may enable the localization or identification of the origin of an abnormally occurring substance throughout body lumens.

SUMMARY OF THE INVENTION

Tte-e is thus provided, according to embodiments of the invention, a system and ure&od for in vivo and in sifi sampfirg and analyzing. According to one embodiment a system comprises an image sensor, an iltomation source and agglutinative particles. According tn another embodiment a system comprises an image sensor, an illumination source and a sample chamber fiat contains agglutinative particles. Typically, th־ agglutinative particles may be capable of adhering to an analyte, if it is present in a sample, such that clusters or precipitates of agglutinative particles and analytes are formed. An analjte may be a substance, such as a ohemicalorbiologicalmoiety, that is capable of adhering to an agglutinative particle. According to one embodiment clusters of agglutinative particles are discernible whereas agglutinate particles that are not clustered are typically indiscernible.

According to an embodiment of the invention a system comprising an image sensor, an illumination source and agglutinative particles, optionally contained ™thin a s־־np>״* ־uber, is inserted in vivo and a body lumen sample, typically a fluid sample, is reacted with the agglutinative particles. According to one embodiment ־ sample is collected into tiie sample chamber. The sample chamber may be ffluminated and imaged while in vivo. Agglutination, should it occur in the sample, oanthus be observed in the images taken of the sample ־tether, thereby providing indication of the presence of an analyte m the sample.

According to one embodiment tee is provided an autonomous device designed to traverse the GI tract. The device includes at least one illumination source and at least one image

PCI7IL2003/000651 sensor for obtaining targes of the GI tract The device, according to one embodiment, may include a emitter fa tiansmittrng data (e.g., image «־) to an external reedtag system. Wonting to one embodiment the device includes a sample chamber., which is typically positioned in the field of illmntation and in the field of taw of the image sensor. The chamber, at least portions of which may be transparent in the illumination wavdengdrs, is typically open to the body lumen environment for receiving sampl־4 ־־־& ־־ W lumen environment According to another embodiment the device comprises an optical window, typically for boating and imaging a body lumen through the window. The agglutinative particles may be immobilized to a ehranber on the external surface of the optical window (the surface facing the body lumen environment), such that an optied chrmge occurring due to agglutination may be imaged. Thus, images of a body lumen may contain additional information regarding the presence of analytes in the body lumen. FuAermore, 4־ appearance of discernible agglutination, which indicates 4־ pres־«־ of an analyte, in specific targes, may be directly associated wi4 a specific location tahin 4־ body lumen as can be deduced from 4־ images of the body Inmen or by other localization methods.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention ־wHl be understood and appreciated more fully from the following detailed description taken in conjunction with the appended drawings in which:

Figure 1 is a schematic illustration of a system according to one embodiment of the mention;

Fig®2 ־A is a schematic illustration of agglutinative particles in accordance with an embodiment of the invention;

Figures 2B-E schematically illustrate a chamber including agglutinative particles in accordance with embodiments of the invention;

Figure 3 is a schematic illustration of an in vivo imaging device according to an embodiment of the invention; and

Figure 4 is a box diagram illustrating a method for in vivo sampling and analyzing, according to an embodiment of the invention.

DF,TAILED DESCRIPTION OF THE INVENTION

In the following description, various aspects of the present invention will be described. For purposes of explanation, specific configurations and details are set forth in order to provide a thorough understanding of 4־ present invention. However, it will also be apparent to one sldfied in the art that the present invention may be practiced without the specific details presented herein. Furthermore, well-known features may be omitted or simplified in order not to obsenre the present invention.

A system, according to embodiments of fhe invention, is typically designed to be inserted in and/or passed through a body lumen for sampling contents of the body lumen. A ״״pl,. _or samples may be collected into one or more sample chamber®. Tire samp«־ which typically contains agglutinative particles, may be illuminated and imaged while it is in a body lumen such that optically discernable indication of the presence of a specific analyte may show up in the images.

An exemplary system, according to one embodiment of tire invention, is illustrated in Fig. 1. The system 20 comprises a sample chamber 22, and an optical detecting unit, e.g., irnnging system 30. Imaging system 30 comprises an iHumination source 32 and an image sensor 34. The iliummation source 32 may illuminate chamber 22 and may also illuminate a body lumen. The image sensor 34 may image chamber 22 and may also image the body lumen. The imaging system 30 may further comprise an optical system (not shown), which may include, for example, lenses and/or collimators for collecting reflected tight and for focusing an image on the imagp. sensor 34. According to other embodiments the system 20 may include a plurality of illmnmation sources and/or a plurality of image sensors. Image sensor 34 may be any sensor suitable for in vivo imaging, for example an imager, such as a CCD, CMOS imaging chip, photodiodes ־etc. The image sensor 34 may process the received light rays for example by forming _m image of the chamber. The image may be stored in 1he imaging system 30 or may be further transmitted to an external receiving system. In alternate embodiments other optical detectors may be used for detecting agglutination in tire chamber 22. Typically, agglutination may cause a change in the optical characteristics of a sample. For example, agglutination may cause a change of color, a change in tire optical density, in scattering, transparency, and so on. A device suitable for receiving and processing light rays that have passed through chamber 22, such as a spectrophotometer, may be used, for example, to detect optical characteristics of a sample in the sample chamber 22.

Sample chamber 22, according to some embodiments, comprises a chamber cavity enclosed by two sides 25, a bottom 26 and a membrane 24, the membrane 24 typically constituting a partition between the body lumen environment and the chamber cavity. According to some embodiments at least the bottom 26 of the chamber 22 may be transparent m the wavelength of illumination. According to other embodiments one or two of the sides 25 me transparent in the illumination wavelength. According to yet other embodiments any of bottom 26 or sides 25 may comprise a reflecting surface, for example, for more effectively collecting reflected light. In Uris case, light rays traversing the chamber vxrill be essentially all reflected back to Hie image sensor, bi alternate embodiments chamber 22 may comprise other components and have other shapes, such as a sack - like, rectangular or cylindrical shape.

Chamber 22, which is typically configured for containing endo-luminal samples, such as body lumen fluids, may contain agglutinative particles, such that agglutination may occur in the sample chamber if toe sample contains specific analytes (for example, as further detailed below).

When the system 20 is introduced into a body lumen the lumen environment is sampled. An endo-luminal sample may passively enter toe chamber 22 through membrane 24. Alternatively, the sample may be actively drawn into the chamber, for example, based on osmotic pump technology, wherein flux of fluids into the chamber is typically a function of pore size and the outside to inside concentration gradient. Alternatively, the sampling can be periodic, controlled, for example, by a switch.

Membrane 24 of chamber 22 may be fabricated from any suitable material, for example from silicon materials, polysulphone, aid more. According to one embodiment the membrme may have properties, such as hydrophiliciiy/hydrophobicity or the membrane may be charged to attract or repel certain analytes. According to another embodiment the membrane 24 is a semi permeable membrane. According to one embodiment the membrane is permeable to relatively large molecules such as antibody complexes. According to other embodiments the membrane 24 may have any desired cut off size. For example, toe cut off size may be compatible with the size of a suspected analyte or subside. Typically, membrane 24 may include a mesh having a pore size larger than toe size of a suspected substance so as to enable toe passing of toe substance through the membrane into the chamber cavity. According to other embodiments the cut off size may be designed to retain the agglutinative particles within the chamber cavity. In alternate embodiments agglutinative particles may be immobilized in the chamber 22, such as by being immobilized to a chamber side or bottom or to an appendage that is restricted to the chamber. It should be appreciated by a person skilled in the art that the agglutinative particles, according to embodiments of the invention, require a certain amount of mobility in order to agglutinate. For example, agglutinative particles may be embedded in a gel that coats the inside of the chamber wall or bottom. In alternative embodiments the agglutinative particles may be held agamst a chamber side by electric charge attraction, or magnetic forces.

Imaging system 30 transmits and receives light to and from chamber 22. Chamber 22 may be illuminated by Rumination source 32 such that optical changes, typically as a result of the interaction between agglutinative particles and analytes, which may occur in the chamber 22, may be detected by image sensor 34.

An optical change may include any change, typically in an m vivo sample, that may be detected by an optical detector, such as an image sensor. Examples of possible optical changes may include a change in color, hue, brightness, intensity, optical density, transparency, light scattering etc., or a combination of optical changes.

It will be appreciated that chamber 22 may be made of any suitable material such as plastic, glass etc. Parameters to be considered while assessing if a material is suitable may be, for example, the material’s transparency, its safety for internal use, its durability under endo-luminal conditions and so on.

The system 20 may comprise one or more chambers such that the presence and/or concentration of one or more substaces may be detected simultaneously or at different ־teas of the lumen.

The reaction between an agglutinative particle and an analyte may be reversible in which, case the agglutinative particles may be used to detect a plurality of analyte sources, each source showing as a single event of an optical change. Also, the reaction kinetics maybe such that the extent of the agglutination (which can be directly proportional to the intensify of the optical change) is proportional to the analyte concentration. According to certain embodiments a system may be calibrated for different agglutinative particles and analytes such that the concentration of an analyte in a sample may be deduced, as !mown in the ait For example, concentrations of analytes in agglutination reactions may be tested by a known system in which reactions are graded ftom 0 to 4 as follows: 0 = no agglutination; 1+ - barely detectable agglutination; 2+ = agglutination with 50% dealing; 3+ = agglutination with 75% clearing; 4+ = visible cluster ־with suspending fluid totally cleared. In order to evaluate accurately the actual concentration of the analyte in the sample, a series of dilutions is made and the “titer” is determined, wherein titer is the reciprocal of the highest dilution giving any positive reaction. Alternatively, samples may be graded by an internal calibration system provided, for example, in one or more chambers in system 20.

The system, according to embodiments of the invention may thus enable to deduce not only the presence of a specific analyte at a specific in vivo location, but also its concentration at that location. Alternatively, particles specific for different analytes may be mixed or placed in separate chambers. Chamber 22 is illuminated by illumination source 32 which may be any illumination source compatible with chamber 22 and image sensor 34. Light sources such as light emitting diodes (LEDs) can be used. Optionally, a collimator or reflector (not shown) may be used for collecting/ directing light rays from the illumination source 32 to chamber 22 and through them to the image sensor 34.

Anc-nTding to one embodiment the system 20 may be set up such that illumination source 32 and image sensor 34 are in front of chamber 22 such that light transmitted from

WO 2(104/014227

Ration source. 32 transmits ttaou^ the transparent bottom 26 of *amber 22 and is reflected to image sensor 34. According to one embodiment U^t rays (represented by arrow 11) .־ emitted from 4־ !!tarnation source 32 and ar־ directed at 4־ tasparent bottom 26 of chamber 22. The light rays (represented by anew 11) pass through the transparent bottom and according to one embodiment, may heat the sample. Light rays (represented by arrow 12) reflected from the chamber 22 ־'1־ received on the image sensor 34. Alternatively, the system 2° may be set up such that chamber 22 is positioned in between an illumination some32 ־ on one side and an image sensor 34 on the other (not show).

Differently designed components and differently set up systems may also be utilized according to embodiments of 4־ invention. For example. *־ ^{tetads a chamte} “ plurality of chambers that do not have a membrane but rather each chamber. comprises two openings to allow collecting and discharge and replatement of the sample in 4e chamber as 4־ system samples new ־״as of the body lumen environment. According to some embodiments the chambers may be toed as capillaries etched, for example, into a slab of glass, or toed in between two glass slabs one of which contains preformed slots or channels.

Tic components of 4־ system according to embodiments of the invention may be specifically designed for 4־ system, or te system may uito some components from other systems 4at operate in body taens, *is ־eonandcally taring advantage of existing components. For example, 4־ system of 4־ invention may be incorporated into or affixed onto medical devices meant for being inserted into body lumens, such as needles, stents, endoscope־, catheters or capsules 4at can pass *־ugh 4e GI tract Endoscopes utilize a tight source and sometimes an imagng device while operating. Thus, 4־ s^em of 4־ invention can be incoiporated into a suitable medical device, such as an endoscope, and utilize tire device’s tight source mid imaging device for detecting 4־ presence ״*־־' concentration of analytes.

Reference is now made to Fig. 2A, which illustrates agglutinative particles according to an embodiment of the invention. Agglutinative particles, according to one embodiment ־re capable of aggregating analytes, typify by adhering to an analyte and/or by cross linking to other particles. Typically an agglutinative particle includes a microscopic particle which is coated with (or otewise adhered to) typically chemical or biological molecules such as antibodies (Ab) or antigens (Ag). According to one embodiment microscopic particles may be latex or magnetic panicles. According to one embodiment agglutinative particle־ may include primary and secondary Abs such as homo-specific Abs or monoclonal Abs. Typically. ־mtib״d־־־may record agglutinate antigenic determinants « may be present in a sampl־. F- example, tumor antigens are expected to be found in a higher concentration in th־ vicinity of a tumor than in remote areas or in the blood stream. Thus, antibodies that may recognize and agglutinate in the presence of tumor antigens may additionally contribute to the diagnosis by enabling te localization of these tumor antigens, as furflier described in the specification. The localization may be important for an accurate diagnosis as most known GI tumor antigenic markers are not specific to a single tumor type and may represent, for example gastric, pancreatic and colon tumors.

According to other embodiments agglutinative particles may include antigenic a^inonts or epitopes that may be recognized by antibodies present in a sample. According to yet further embodiments agglutinative particles may include a particle having linkers attached to it, for binding an analyte and/or for binding another particle. According to other embodiments ־putative particles may include Ab or Ag te are chemically attached to particles, such as to latex or magnetic particles. In yet other embodiments Ab or Ag are attached to specially shaped particles, optionally, to enhance sensitivity of the reaction (for example, by avoiding steric hindrance of the binding process), h ote embodiments the agglutinative particles may include cells, such as bacteria (e.g., H. pylori). Accenting to

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WO 200-1/014227 additional embodiments, any combination of agglutinative particles may be used. Correspondingly _ה an analyte may include an antigenic determinant, such as antigen bearing cells, for example, cancerous cells, viruses, bacteria, fungi and otiier parasites etc. Alternatively, an analyte may be an antibody that is present in a body lumen, such as antibodies produced in response to a viral or bacterial attack or in response to the presence of a tumor or other pathologies. An analyte may further include substances, such as chemical or biological determinants having affinity to agglutinative particles.

According to one embodiment, in sample 40 an analyte 46 may bind to a particle 42 through linkers 44 that are attached to particles 42. Linkers 44 may include, for example, Morpholino ethane sulphonic acid available as MES/Protein Solution (by Merk or Sigma) or WSC: 1 3) ־-dimethylaminoprophyl) -3־ ethylcarbdlimide (by Aldrich-Sigma). Particles with linkers may include, for example, OptiBind™ Polysterene microparticles or OptiLink™ Carboxylate-Modified Microparticles.

According to some embodiments analyte 446, which may be an antigen, may agglutinate particles, for example, by binding to one aim 442’ of Ab 442 wherein another aim 442” of Ab 442 is bound by another analyte particle (for purposes of illustration 446’). Thus, when an analyte (such as 446 and 446’) is present in a sample 40 particles, such as particles whidiinctade Ab 442 will agglutinate, typically forming a visible structure.

According to some embodiments, a secondary particle 412 having aims 414 may be present in the sampl־־™ <* ־ ™s Mang of Ab 442. Typically, binding of Ab 442 to an analyte may cause a change in &־ Ab (e.g. a chemical or a configuration change). Secondary particle 412 will bind to Ab 442 only in the Ab’s bound configuration (i.e״ when Ab 442 is bound to an analyte). Thus, agglutination of Ab 442 by secondary particles 412, which will occur only in the presence of an analyte (e.g., 446 and 446’), may enhance foumfion of visible structures.

Agglutinative particles 42, Ab 442 and/or secondary particles 412 may be colored. According to one embodiment, agglutinative particles (such as agglutinative particles 42, Ab 442 and/or secondary particles 412) may have different shapes and may have a diameter m the range of 0.1 to 300 micron; other diameters are also possible. Typically, the agglutinative particles are indiscernible when 1hey are dispersed in a sample, however, when agglutination occurs, the gathering or precipitate of the particles becomes discernable. According to one embodiment the agglutinative particle 42 or the Ab 442 are colored such that when agglutination occurs a color becomes visible in tire sample. Typically, tight absorption and scattering may be dependent on particle size together with wavelength of illumination and relative viewing angle and therefore changes in light absorption and/or scattering with agglutination, may follow generally known functions. According to another embodiment the secondary particle 412 is colored such that when agglutination occurs a color becomes visible in the sample. According to yet another embodiment an optically discernable reaction (such as a clouding or a color reaction) occurs once an agglutinative particle binds, or is bound by an analyte. This optical reaction may typically be discernable only when agglutination occurs. For example, precipitates or conglomerates may become visible when they a large enough. Alternatively, large particles may cease to scatter light effectively relatively to smaller particles. It should be appreciated by a person skilled in the art that although the analyte illustrated in Fig. 2A is an antigen and the agglutinative particle illustrated in Fig. 2A includes an antibody, the analyte may be an antibody or any other suitable particle or substance and 1he agglutinative particle may include an antigen or any other suitable particle or substance.

Reference is now made to Figures 2B-E illustrating a sample *amber including agglutinative particles in which die sample does not contain an analyte suitable for reacting wife the agglutinative particles (e.g, Fig. ZB) and a sample chamber including agglutinative particles in which the sample ־״־tains ^m *^{ble for reacti!ls pricleS} (e.g., Fig. 2C), according to embodiments of the invention. Figs. 2D and 2E show a chamber including agglutinative, paiticles in which the sample contains an analyte suitable for reacting with the agglutinative particles, before and after agglutination, according to embodiments of the invention. Chamber 22 may be incorporated in a device that is capable of being inserted into and passing through body lumens, such as the GI tact, blood vessels, the reproductive tract, the urinary tract etc. For example, the chamber 22 may be incorporated in a swallowbale capsule, as will be described below.

According to one embodiment sample chamber 22 includes a membrane 24 and a bottom wall 26 that may be at least partially transparent In one embodiment the membrane 24 has a mesh size which allows an analyte 28 enter the chamber but does not allow agglutinative particles 42 exit the chamber. In one embodiment the membrane cut off size is in the range of 0.05 to 10 microns. Antibodies typically range in size between 100A to 200A, thus' they may penetrate through membrane 24 while other particles, such as particles 42, having a size in the _ΓΗη£Ρ, _of 0.1 to 300 microns are entrapped in the chamber 22. Fig. 2B illustrates a sample chamber 22 containing a sample 40 that does not have an analyte present in the sample. In this case particles 42 are randomly dispersed in sample 40 and are typically indiscernible. Fig. 2C illustrates a sample chamber 22 containing a sample 40 hating an analyte. 28 present in ±e sample. Sample 40 including the analyte 28 may flow through membrane 24 into chamber 22 from a body lumen environment. The presence of an analyte in sample 40 causes agglutination of particles 42 (such as described above) and a colored (or otherwise discernible) precipitate 42 becomes discernible. Alternatively, sample 40 may become cloudy or clear or may go through any oilier optical change following agglutination. As discussed above, the intensity of the optical change may indicate the concentration of an analyte, hi an alternate embodiment, for example as illustrated in Fig. 2D, membrane 24 may be colored or contain visible marks. Agglutinative particles 42 are present in such a concentration so as to render sample 40 cloudy or otherwise obscure when they are randomly dispersed in the sample 40 (e.g., top left comer of Fig. 2D and in an ovendew , bottom left comer of Fig. 2D). However, if sample 40 contains an analyte the particles 42 will agglutinate (e.g., top right comer of Fig. 2D), the cloudiness of the sample 40 will be alleviated due to the agglutination and the membrane 24 may be exposed. The appearance of a visible membrane (e.g., as illustrated in the bottom left comer of Fig. 2D) 24 indicates that there is an analyte in the sample 40

According to another embodiment, exemplified in Fig. 2E, agglutinative particles 42 are immobilized within a sample chamber 22 (e.g., in two lines as illustrated in the top left comer of Fig. 2E). Before agglutination sample 40 may seem clear, cloudy or otherwise obscure (illustrated, for example, as an overview in the bottom left comer of Fig. 2E). After agglutination occurs, analyte 28, which is present in sample 40, agglutinates according to the immobilized agglutinative particles 42, e.g., in two lines (top right comer of Fig. 2E). An overview of toe visible agglutination is illustrated in toe bottom right comer of Fig. 2EReference is now made to Fig. 3, which schematically illustrates a device comprising a system, according to embodiments of toe invention. According to one embodiment toe device 100 is capable of being inserted into and passing autonomously through body lumens, such as toe GI tract.

The device 100 typically comprises a shell 101 which may include an optical .window׳ 210. The device 100 further includes an imaging system, which comprises an illumination unit 230 and an image sensor 240. According to one embodiment toe device 100 includes at least one sampling chamber 102. The sampling chamber 102’ is typically positioned in toe field of illumination and in the field of view of the image sensor 240. According to some embodiments a sampling chamber 102 may be integrated into toe device shell 101, optionally in toe optical window210 ׳. Anuntoing to other embodiments toe device 100 does not include a sample chamber, rather agglutinative particles may be embedded in a medium which may be attached onto the optical vandow 210, such that the agglutinative particles may be in contact with a body lumen environment and may move through the medium to form visible formations (for example a strip of gelatin having agglutinative particles embedded wititin may be attached to the optical window external surface).

The imaging system may obtain images from inside a body cavity or lumen, such as the GI tract TIip. imaging system also obtains images of the sampling chamber 102, such that, according to an embodiment of the invention, a. single image (frame) may contain image data of the body lumen and image data of the agglutination.

The illumination unit 230 may include one or more discrete light sources or may׳ include only one tight source. The one or more light sources may be a planar light source, a white tight emitting diode (LED), or any other suitable tight source, known in the art Optimal parameters may be chosen for a tight source while taking into account, for example, the scattering of light, which is a function of the relationship between the wavelength and particle size. The device 100 includes an image sensor 240, which acquires the images and an optical system 220 which focuses the images onto the image sensor 240. The image sensor 240 may be any suitable in vivo imager, such as a CCD or CMOS image sensor. The optical system 220 may include optical elements, such as one or more lenses (not shown), one or more composite lens assemblies (not shown), one or more suitable optical filters (not shown), or any other suitable optical elements (not shown) adapted for focusing an image on die imaging sensor. According to one embodiment ihe illumination unit 230 illuminates the sampling chamber 102 and inner portions of the body lumen through the optical window 210. In an embodiment of the invention the device. 100 may comprise a plurality of imaging devices and, optionally, their corresponding optical systems, and optionally a plurality of illumination sources. For example, a plurality of imaging devices and optionally a plurality of interaction chambers may be positioned at opposing sides of the device for multi-directional sampling and/or viewing of tire body lumen.

Device 100 further includes a transmitter 260 and an antenna 270 for transmitting data, e.g., image signals of ihe image sensor 240, and one or more power sources 250. Ihe power source(s)250 may be any suitable power sources such as but not limited to silver oxide batteries, Efbium batteries, or other electrochemical cells hairing a high energy density, or the like. Ihe power source(s) 250 may provide power to the electrical elements of the device 100. It is noted that for die sake of clarity of illustration, the connections between tire power source 250 and the circuits or components of the device 100 which receive power therefrom, are not shown in detail.

According to one embodiment, as the device 100 is transported through the body lumen, such as the gastrointestinal (GI) tact, the imager acquires images (frames), which are processed and transmitted to an external receiver/recorder (not shown) worn by the patient for recording and storage. The recorded data may then be downloaded, from the receiver/recorder to a computer or workstation (not shown) for display and analysis. Other systems and methods may also be suitable.

During the movement of the device 100 through the GI tract, the imager may acquire frames at a fixed or at a variable frame acquisition rate. For example, the imager may acquire images at a fixed rate of two frames per second (2 Hz). However, other different frame rates may also be used, depending, inter alia, on the type and characteristics of Ihe specific unagei or camera or sensor array implementation that is used, and on the available transmission bandwidth of the transmitter 260. The downloaded images may be displayed by the workstation by replaying them at a desired frame rate. This way, the expert or physician examining the data is provided with a movie-like video playback, which may enable the physician to review the passage of the device through the GI tract and to observe occurrences of agglutination.

The device 100 may be constructed as an ingestible video capsule, similarly to capsules disclosed in U.S. patent 5,604,531 to Iddan et ״1־ WO 01/65995 to GMchovsky et al., US 6,240,312, to Alfano, or in WO 01/50941 to Refael (all of which are incorporated herein by reference). A capsule optionally utilized according to another embodiment of the invention may be a remote-controllable, micro-scale device having a motion mechanism, such as a mechanical propeller that may be driven by an electric motor or may be turned by a build in gas flow. Another capsule may contain a rotation mechanism that can be charged by external radio waves and that can initiate capsule rotation. In alternate embodiments the system and method may be used in conjunction with other in-vivo devices, such as endoscopes, catheters, needles, stents and the like.

Acting to one embodiment the chamber 102 is open to the GI tract environment, such that GI tract fluids 370 can enter the chamber 102, typically through a membrane 102’, either passively or actively as described above. The agglutinative particles (not shown) contained within the chamber 102 are typically restricted to the chamber. Ihe particles may be unable to leave the chamber because of the membrane 102’ which enables the entrance of GI tract fluids 370 but does not allow leakage of the particles from the chamber. According to one embodiment th? WTrihra. 102 comprises sides 125 and 125’ and bottom 126. Typically, chamber 102 may be at least partially transparent to enable viewing optical changes within the chamber. According to one embodiment side 125’ is transparent so as to allow illumination from Hie illumination unit 230 enter the chamber for iliummating the sample. According to one embodiment side 125 and/or bottom 126 may be coated by a reflecting surface, for example, a minor, for more effectively collecting reflected tight and for possibly enhancing the image of the sample chamber 102. The reflective surface may have a color contrasting that of the particles.

According to one embodiment device 100 schematically show in Fig. 3 is designed to be inserted into the GI tract and pass through the entire tract. However, tire device 100 is not limited to any specific configuration. For example, in accordance with the specific imager and specific energy requirements, device elements (such as the illumination source and transmitter) may be connected by cable to an external power supply or to an external receiving system. Alternatively, the device may be powered externally (e.g., by an external electromagnetic field that may induce power in a set of coils which may be included in the device 100). Further, the device may be of any shape suitable for being inserted into a body lumen and for passing through the body lumen or for being included in a device that is inserted into a body lumen.

According to one embodiment, as the device 100 proceeds down the GI tract, minute amounts of GI tract fluids 370 may slowly enter the chamber 102. Optionally, GI tract fluids that enter the chamber 102 in one area of the GI tract may be displaced by fluids from a newly reached area in the GI tract. According to some embodiments the device 100 constantly samples the GI tract environment throughout the lumen. Thus, the origin or location of pathologies in the GI tract can be detected. For example, the presence of a tumor or tumor cells in a patient’s GI tract can be detected by inserting a device according to an embodiment of the invention into the patient’s GI tract. The device may comprise a sample chamber, which includes, for example, agglutinative particles that may specifically bind to tumor cells. For example, CAM 17.1, which is an anti-mucin monoclonal.antibody and which has recently been proven as a reagent for serological diagnosis of pancreatic cancer and has been shown to bind to a sialic-acid-containing determinant of mucin, which is an epitope that shows wide distribution throughout the gastro-intestinal tract (Eclleston DW, Milton ID, Hoffman J, Bara J, Rhodes JM, Digestion. 1998 Nov-Dec;59(6):665-70). Another example of a suitable agglutination assay may be the Ca 19-9 Agglutination Assay in which 116-NS-19-9 is monoclonal antibody generated against a colon carcinoma cell line in order to detect a monosialoganglioside (CAI 9-9) found in patients with gastrointestinal adenocarcinoma.

The device 100 passively travels through 1he patient’s GI ttact imaging both the GI tract and the sample chamber. A location of a tumor in the GI tract may be characterized by the presence of antibodies such as mentioned above. GI tract fluids sampled at the location of the tumor will typically contain the antibodies. The antibodies react with the agglutinative particles such that agglutination occurs in tlie sample chamber. The agglutination, typically resulting in an optical change, may be imaged by the image sensor 240. The image of the optical change and of the location in the GI tract may be transmitted to. an external operator who may identify the location of the device 100 at the time the image was produced and thus identify the ongin of the tumor.

Reference, is now made to Fig. 4 winch is a box diagram illustrating a method for in vivo sampling and. analyzing, according to an embodiment of 1he invention. According to one embodiment a body lumen environment is sampled, in vivo, in the presence of agglutinative particles (502), for example, a sample of a body lumen may be combined wtith agglutinative particles. According to one embodiment the sample and agglutinative particles are combined within a chamber. The sample is observed, in vivo, for optical changes (504). Typically, the step of observing the sample includes detecting at least one optical change within the combined sample. According to one embodiment the step of detecting an optical change is done by imaging the combined sample. Optionally, images of 1he sample may be transmitted to an external receiving unit According to one embodiment the method further includes the step of obtaining images of the body lumen.

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