Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B2503/00—Evaluating a particular growth phase or type of persons or animals
  • A61B2503/40—Animals
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
  • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
  • G01N21/64—Fluorescence; Phosphorescence
  • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
  • G01N21/76—Chemiluminescence; Bioluminescence
  • G01N21/763—Bioluminescence
• • G—PHYSICS
  • G02—OPTICS
  • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
  • G02B2207/00—Coding scheme for general features or characteristics of optical elements and systems of subclass G02B, but not including elements and systems which would be classified in G02B6/00 and subgroups
  • G02B2207/113—Fluorescence

Definitions

• the present invention relates to optical imaging devices and more particularly but not exclusively those intended for imaging the small animal.
• the invention particularly relates to devices in which the body to be observed receives one or more photoluminescent probes, the detection being effected by means of an optical detection system while the body is optionally illuminated so as to cause the fluorescence of the probes.
• US Pat. No. 6,894,289 discloses an imaging device in which a camera is fixedly mounted on the top of a box inside which the animal is placed.
• WO 2006/033064 discloses a human skull imaging device in which a 3D reconstruction takes place from images acquired by the device.
• the subject of the invention is an optical imaging device for the human or animal body, comprising: a support for receiving the body to be examined, an optical detection system, in particular a camera, a drive system of at least one light collector of the optical detection system, for modifying at least the position and / or orientation thereof, a control system of the drive system, arranged to bring about , in particular automatically, the light collector of the optical detection system in at least one observation situation of at least one selected region of the body, according to data concerning the topology thereof.
• the optical detection system comprises a camera
• it can be entirely mobile and movable by the drive system, being for example carried by an arm of the drive system.
• the light collector of the optical detection system may be defined by an input of light into the detection system, for example an input face of light into a camera lens or an end of at least one guide optical collecting light to analyze.
• the control system may be arranged to cause the optical detection system to cover a surface of the test region of between 1 and 5 cm 2 , for example. Thus, a relatively accurate image of the selected region can be obtained.
• the mobility of the optical detection system can in particular allow the control system to position the light collector relatively close to the body to be observed, for example at a distance of less than 9 cm from it, which is favorable to the point of view of resolution and sensitivity.
• the drive system can have three axes of displacement perpendicular two by two.
• the mobility of the optical detection system can facilitate the observation of regions previously difficult to observe with known imaging devices.
• the control system may be arranged to automatically position the optical detection system with an optical axis thereof substantially perpendicular to the region of the body to be examined. This positioning operation can be carried out thanks to the knowledge of topological data concerning the topology of the body to be observed.
• the control system may be arranged to automatically calculate the position and orientation to be given to the light input into the optical detection system, to observe a selected region of the body.
• the optical detection system may comprise a camera, as mentioned above, or any other photosensitive detector, possibly in association with one or more optical guides and / or light amplifiers.
• the detection system may comprise several juxtaposed light amplifiers.
• the imaging device may comprise at least one filter placed in the path of light between the animal and at least a part of the optical detection system, in particular a plurality of filters, for example a plurality of filters carried by a wheel, this can make it easy to replace one filter with another.
• the wheel can be controlled by the control system, for example by means of a motorized drive.
• the filter (s) may be of the interference type.
• at least one wavelength tunable filter for example tunable liquid crystal (LCTF) or acousto-optic tunable type, is used.
• LCTF tunable liquid crystal
• acousto-optic tunable type is used.
• the filter (s) may be of the lowpass, highpass or bandpass type.
• the filter (s) used may be chosen so as to pass selectively only the light emitted by one or more probes, and not the possible light of fluorescence excitation. If necessary, the detection can be synchronous with the illumination, so as to improve the signal / noise ratio.
• the filter or filters may be placed before the camera lens or between the lens and the camera or be integrated into the lens.
• the filter is placed between the lens and the camera, this can reduce the footprint as well as the distance between the lens and the region of the body to be examined.
• the optical detection system When the optical detection system includes a camera, it can be equipped with a telecentric lens.
• the camera can be equipped with a lens having a greater depth of field than conventional lenses, for example greater than or equal to 0.5 cm, and constant magnification over a wide range of work.
• a telecentric lens may make it possible to combine several sequentially acquired images of adjacent regions of the body of the animal.
• the use of a telecentric lens also makes it possible to favor the collection of parallel rays to the optical axis and limits filter leakage of the filter (s) used.
• the support of the body to be observed may be movable or fixed, preferably being movable along an axis, which may facilitate the construction of the support structure of the optical detection system.
• the latter when the latter includes a camera, it can be part of a vision block also including the lens, the possible filtering system and all or part of a possible illumination system.
• At least the camera and better the entire vision block is movable, for example according to at least two axes of translation substantially perpendicular to each other and about an axis of rotation, for example substantially parallel to the axis of movement of the support on which is placed the animal.
• the optical imaging device may further comprise a topological acquisition system, for providing data describing the observed body topology to the control system of the drive system.
• the topological acquisition system may comprise a camera, which is for example the same as that of the optical imaging device or alternatively a different camera.
• the topological acquisition system comprises drive means for moving the support on which the animal is placed, relative to a topology analysis system.
• These drive means are for example the same as those used by the imaging device, the support on which the animal is placed being for example movable between the topological acquisition system and the imaging system.
• the support on which the animal is placed may comprise at least one detector sensitive to a movement of the animal relative to the support.
• the imaging device can be arranged to warn the user of a movement of the animal relative to the support, for example by generating an audible or visual alarm. If necessary, the imaging device can be arranged to automatically trigger a new acquisition cycle of the topology of the animal. and / or mapping topological data with observed data, if a motion thereof is detected relative to the medium.
• the detector sensitive to the movement of the animal may comprise one or more pads on which the animal rests, provided with at least one pressure sensor.
• the pad or pads may be used, if necessary, to transport a fluid for heating the support.
• the control system may be arranged to allow extended analysis of the observed body, by controlling the optical detection system to perform a reduced field observation sequence, with movement of the optical detection system between each of the observations .
• control system can be arranged to control the camera in order to automatically take several successive views of the body, in order to recompose a more global view.
• the imaging device may include at least one source for illuminating the body with radiation having a predefined spectral characteristic.
• the source (s) used may be monochromatic or polychromatic sources, of the laser, electroluminescence or discharge type, for example xenon-mercury, optionally of adjustable power.
• Light from at least one source may be routed to the body to be examined through at least one optical guide, including one or more optical fibers.
• the source or sources and / or the optical guide or guides may be integral with the aforementioned vision block.
• the light can be injected into the optical guide (s) via a focusing system.
• At least one filter may be placed in the path of light for illuminating the body, for example to remove infrared radiation and / or pass essentially only the light for exciting fluorescence.
• An automated filter wheel comprising a plurality of interference filters may be interposed between the source or sources and the aforementioned focusing system.
• the light at the output of the optical fiber or fibers may be collimated, focused or diverged, as required.
• the body to be observed can be illuminated from several places.
• the body may for example be illuminated from the ends of several optical fibers oriented in different directions, these optical fibers can for example be joined in a common beam illuminated by a common source.
• the illumination system can at least partially accompany the optical detection system in its movement, providing substantially uniform and constant illumination over a given region.
• a mechanical positioning system of the source (s) and / or optical guide (s) can ensure the adaptability of the illumination to the magnification of the camera lens and the repeatability of enlightenment between experiences.
• the imaging device may include a user interface configured to allow the user to select at least one observation region on the body.
• This user interface may include a screen allowing a 3D image of the body to be displayed and selection means for selecting the region to be observed, which can be made apparent on the 3D image of the body.
• the user interface can allow the user to select an operating mode from the following three modes: moving the automatic light collector according to the topology data, - moving the light collector according to manually entered coordinates, moving of the light collector in response to the actuation of a manual control member of the displacement, along at least one axis.
• the device may include a substantially monochromatic illumination source for illuminating the human or animal body, the device being devoid of a sealed, light-tight enclosure disposed between the user and the human or animal body.
• the 3D image can be generated from the topology data of the animal.
• the optical imaging device may, in an exemplary implementation of the invention, exercise at least one of the following functionalities: allow fluorescence imaging by reflectance or bio-luminescence, allow tomographic imaging.
• Another subject of the invention is an imaging method, for example a tomography method, in particular a small animal, comprising the step of: - acquiring at least one image photoluminescence with the optical detection system of the device as defined above.
• the acquisition of the image may be preceded by or be concomitant with the illumination of at least one region of the body so as to cause photoluminescence.
• the body may be that of a small animal such as a rodent, the observation being carried out after injection into it of at least one fluorescent probe or after the expression of a gene encoding a photoluminescent protein, by fluorescent example.
• the invention further relates, in another of its aspects, independently or in combination with the foregoing, to an imaging device of the human or animal body, comprising:
• a camera for example a camera belonging to a vision block also comprising an objective, a filtering system and possibly an illumination system,
• a drive system making it possible to modify at least the position and / or the orientation of the body relative to the camera, either by a displacement of the support, or of the camera, or both, a system of control of the system of 'training,
• a user interface comprising a screen on which a 3D image can be displayed at least partially representing the animal, the interface allowing selection of a region on this image, and the control device being arranged to automatically bring the camera to observe the selected region on the image.
• the selected region may be highlighted or other color in the image.
• an optical detection system in particular comprising a camera, the optical detection system being associated with a system for filtering the light coming from the body to be examined; a drive system making it possible to modify at least the position and / or the orientation of the body with respect to at least a part of the optical detection system,
• a user interface arranged to display simultaneously on the same screen:
• Such a display helps the interpretation of the results by allowing the user to have a global vision of the spectral conditions of image acquisition.
• the invention further relates, in another of its aspects, independently or in combination with the above, to an imaging device of the human or animal body, comprising: a support for receiving the body to be examined,
• an optical detection system in particular comprising a camera
• a drive system for modifying at least the position and / or the orientation of the body relative to at least a part of the optical detection system, a control system of the drive system, an illumination system of the observed region, comprising a focusing system, which may be automatic, of the light on the observed region as a function of an observation field of the optical detection system.
• the illumination system comprises at least one light projection head whose orientation is automatically controlled as a function, for example, of a selected magnification or the distance to the observed region of an entry of light into the light. optical detection system.
• FIG. 1 is a view schematic overview of an example of a device according to the invention
• FIG. 2 partially represents an example of an illumination system
• FIG. 3 represents, in isolation, an example of a topological acquisition system
• FIGS. 4 to 8 are examples. of pages displayed by the screen of the user interface
• Figure 9 is a diagram to illustrate the calculation of the collected light flux
• - Figure 10 shows a detail of a variant of the device.
• FIG. 1 shows an imaging device 1 according to an exemplary implementation of the invention.
• This device 1 comprises an imaging system 20 and a computer system
• microcomputer 6 which comprises, in the illustrated example, a microcomputer, for example PC-type, but which could include other means of data processing, for example one or more specialized electronic cards, possibly integrated into the imaging system 20.
• the device 1 may require working in a dark environment or including a safelight, which does not disturb the acquisition of photoluminescence.
• the device may comprise a blue LED lighting, wavelength 470 nm, the room in which is placed the system imaging 20, the latter being devoid of light-tight box in which the animal would be placed. This can facilitate the connection of animal A to instruments.
• the device 1 is intended for imaging a small animal A, for example a rodent, and the latter can be arranged, as shown in FIG. 1, on a support 10, which can be mobile. in translation along an axis X. Its movement can be controlled by the computer system 6.
• the animal A may be connected to unrepresented instruments, assistance of the respirator type, to a gas anesthesia system, to a catheter, or to sensors of the thermometer, electrocardiograph type ...
• the support 10 may optionally comprise a heating system to be maintained at a predetermined temperature, for example close to that of the animal A, in the case where the latter is alive.
• the support 10 may comprise at least one detector for detecting a movement of the animal A, for example one or more pads provided with at least one pressure sensor and on which the animal A rests. A movement of the animal A relative to the support can thus be detected and the imaging device can warn the user and / or perform an update of the topological data and / or proceed to a new mapping of the topological data. and imaging data.
• the imaging system 20 comprises, in the example considered, a vertical column 11 of Z axis, carried by a carriage 15 which can slide horizontally along a Y axis perpendicular to the aforementioned X axis.
• the imaging system 20 also comprises an optical detection system composed in the example in question by a vision block carried by an arm 24 which can rotate about a horizontal axis of rotation R, carried by a mobile carriage 26 according to the invention. Z axis on the column 11.
• the axis of rotation R is advantageously parallel to the axis X of displacement of the support 10.
• the imaging system 20 could, without departing from the scope of the present invention, provide more degrees of freedom of movement and / or orientation.
• the support 10 could be fixed and the column be carried by an additional carriage, movable along the X axis. Displacements along the X, Y and Z axes and in rotation about the R axis are motorized and controlled by the computer system 6. Thus, the latter can know the relative positions of the support 10 and the vision block.
• This comprises, in the example considered, a camera 21, a lens 23 and a filtering system 22.
• the position and orientation of the camera 21 are known to the computer system 6 and the movements of the camera 21 can be controlled by it.
• the filtering system 22 comprises, for example, a filter wheel 27 which makes it possible to selectively place a filter chosen from among several on the path of the light analyzed by the camera 21.
• the implementation of the selected filter is done automatically, the wheel 27 being rotated by a stepper motor 31 controlled by the computer system 6, a sensor for informing the computer system on the angular position of the wheel 27.
• the filtering system 22 may comprise, for example, five filters having for example 5 cm in diameter. In the case where the wheel is placed between the lens and the camera, it may comprise, for example, 7 filters 2.5 cm in diameter.
• the invention is not limited to a particular filtering system and the filter wheel illustrated by a wavelength tunable filter can be replaced.
• the camera 21 may be a CCD camera, preferably "back thinned", having a resolution greater than or equal to one million pixels and pixels larger than 10 microns.
• the camera 21 may be equipped with a thermoregulation system, for example Peltier effect.
• the objective 23 has for example a magnification ranging from x1 to x ⁇ .5 and a focal length, for example equal to 50 mm, so as to make it possible to place in the field of view a relatively small region of the animal A, by example of surface between 1 and 2.3 cm side.
• the objective 23 is advantageously a telecentric objective.
• the imaging system 20 may also include an illumination system to illuminate the animal A to allow detection of fluorescence from one or more fluorescent probes therein.
• the wavelength of the light illuminating the animal A as well as the spectral characteristics of the filtering system will be chosen according to the probe to be detected.
• the animal A is illuminated for example in at least two directions from optical guides, for example optical fibers, which can receive light from a single source.
• optical guides lead for example to heads 60 and 61 carried by the arm 24 as illustrated in FIG. 2, and which can be oriented by the user in order to illuminate the animal at a particular incidence ⁇ with a possibility, the if necessary, adjusting the orientation to change the angle of incidence ⁇ and focus the light on the region observed.
• the angle of incidence ⁇ is changed according to the distance of the observed region and / or magnification, automatically by the computer system 6, through a motorization of the lighting heads 60 and 61. This can allow, in an automated way, to concentrate the light on the observed region.
• a light filtering system may be associated with the source (s) of the illumination system to control the spectral characteristics of the light illuminating animal A.
• the imaging device may also include, where appropriate, several light sources which are selectively switched on depending on the position of the camera relative to the animal, for example to not illuminate the animal with sources that could interfere the detection of luminescence.
• the positioning of the camera 21 can be performed automatically using topological data of the animal A, in order to place the region to be observed in the field thereof.
• topological data can be obtained in various ways and for example by means of the topological acquisition system 30 illustrated in FIG. 3.
• This system 30 comprises a device 31 for projecting a structured light onto the animal A and at least one camera 32 to proceed to the acquisition of the relief of the animal thus lit.
• the latter can be mounted during the acquisition of the topological data on the same support 10 as that used for imaging.
• the support 10 is moved in a controlled manner along the X axis and the projection system 31 makes it possible to project on the animal a luminous ray oriented transversely to the axis X.
• an image of the profile illuminated by the projected line is acquired and the topology of the animal can then be reconstructed by software, for example by the computer system 6 which then directly at least one file containing the topological data of the animal.
• the topological acquisition system 30 is distinct from the imaging system 20, the support 10 passing from one to the other by a displacement along the axis X, but in a variant not illustrated, the same camera is used for both the acquisition of the topology and the imaging, a structured light projection device being then added to the imaging system 20.
• the acquisition of the topological data takes place while the support 10 has been removed from the imaging device 20 and placed in a topological acquisition system which has support drive means 10 distinct from those of the imaging device 20.
• the support 10 can be made with at least one mark that can be identified by the camera 21 to facilitate, for example, the matching of the topology data with that from the imaging system.
• Topological acquisition can still be done by laser triangulation.
• the computer system 6 is advantageously provided with a user interface that allows the latter to control the positioning of the camera 21 in order to observe a predefined region of the animal A.
• the user interface may include a screen 50 and at least one information input system that may include a mouse 52, a joystick, a keyboard 51, a graphics tablet, a stylus or a touch screen.
• the computer system 6 may be arranged to allow the opening of one or more windows on the screen 50, for example a window 42 for controlling the camera and a window 44 for the images acquired during the imaging, as shown in Figure 4,
• a window 43 may still be displayed concerning the topology of the animal A, as illustrated in FIGS. 7 and 8, and a window, not shown, in which a drop-down menu concerning the history of the images acquired may appear.
• the aforementioned window 42 may contain fields for entering coordinates that can be filled by the user, and the computer system 6 can be arranged to automatically cause the camera 21 to observe the region centered on the point whose coordinates have been entered, the optical axis of the camera being for example substantially perpendicular to this point.
• the window 42 may make it possible to modify, if necessary, the resolution of the camera, the exposure time, the filters selected for the source and for the camera, the magnification, the distance to the animal, and may possibly allow the user manually controlling the movement of the camera in at least one direction relative to the observed region.
• the window 44 may include the image observed by the camera in real time and a histogram showing the number of pixels for each gray level.
• the window 43 may be used to trigger a sequence of acquisition of the topology of the animal, and may allow the opening of a window for controlling the positioning of the camera.
• the window 43 may include a 3D synthetic image of the animal.
• the region covered by the field of view of the camera can be materialized on this 3D image, for example by highlighting and / or by showing the contour 48 of the region covered by the observation field of the camera, as illustrated. in Figure 7.
• the computer system 6 may be arranged in such a way as to make it possible, according to a probe, to memorize the matched filter and possibly the characteristics of the source, as illustrated in FIG. 5.
• the spectra of the incident light, of the light emitted by the source and the filter receiving this light can be displayed simultaneously, as shown in Figure 5.
• the topological data can be imported in a predefined format in the computer system 6, as illustrated in FIG. 6, these topological data having for example been obtained using another acquisition system than that illustrated. in Figure 3, in another experiment.
• the computer system 6 can be arranged to perform, if desired, a tomographic reconstruction. This reconstruction can use the optical parameters of the system and rely on one or more models to describe the propagation of luminescence within the animal to its surface.
• the light propagation, in a turbid medium and of a complex geometry can be described in particular by a direct model.
• the reconstruction of the position and intensity of the light source from the acquired data is achieved by solving an inverse problem.
• a photometric calibration can make it possible to make a link between the data acquired by the camera and those resulting from the modeling.
• This calibration can allow a mapping of the local illumination E s (Wm ⁇ ) to the surface of the sample obtained by modeling with the flux detected at the pixel.
• D is the maximum gray level - Doffset
• x and y are the coordinates of the measured pixel.
• the flux measured by a pixel can be considered as equal to the flux emitted by the surface A s (eq.3) and collected by the optical opening system equal toA r .
• u is the size of a pixel
• m is the magnification of the optical system.
• the flux collected at an angle ⁇ r is connected to the luminance of the source L s by:
• G 0 is the geometric extent defined on the optical axis of the system
• T d N (6q - 5) where N is the opening number of the system.
• the measured flux is connected to the local illumination Es by the following formula (eq.6)
• F E s - U 2 - COS 4 ( ⁇ r ) (eq.6) ⁇ r ⁇ - (m - N - cos ( ⁇ r - ⁇ j) 2
• the imaging device can in particular be used to detect a photoluminescence that would not be induced by the illumination of the animal with a particular light.
• the imaging device may optionally include a box for isolating the animal from ambient lighting.
• the imaging device may comprise other means for positioning the camera, for example a manipulator arm.
• the invention can also be applied to the imaging of a larger animal, or even a human.
• the imaging device may include, where appropriate, at least a second camera whose positioning can be controlled by the computer system for example to refine the location of the probe in the body of the animal.
• the motorized axes X and Y are carried by parts 70 and 71 rigidly coupled to one another.
• the X axis is raised relative to the Y axis, so as to approach the acquisition system of the subject A, thus limiting the movements along the Z axis.
• Parts 70 and 71 also make it possible to increase the stability of the device.
• the processing of the images and topology data can be effected delocalised by a server to which the computer system 6 would be connected, the function of the latter being for example limited to controlling the positioning system of the camera and to the acquisition of the images coming from the camera.
• the camera of the imaging device can be replaced by another optical detection system, for example one or more photosensitive detectors possibly associated with one or more light amplifiers.
• the optical detection system may comprise a fixed part and a movable part defining an entrance for the light coming from the animal and whose position and / or orientation can be modified by the drive system.
• the movable portion may comprise an optical guide, for example to one or more optical fibers, the distal end of which defines the aforementioned entry is orientable so as to be positioned in the desired manner relative to the animal and whose proximal portion is for example fixed and connected to a camera or any other optical detection system.
• an optical guide for example to one or more optical fibers, the distal end of which defines the aforementioned entry is orientable so as to be positioned in the desired manner relative to the animal and whose proximal portion is for example fixed and connected to a camera or any other optical detection system.

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• Life Sciences & Earth Sciences (AREA)
• Health & Medical Sciences (AREA)
• Medical Informatics (AREA)
• Biophysics (AREA)
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• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Heart & Thoracic Surgery (AREA)
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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

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