US20150230696A1 - Fibrescope for optical imaging of radiopharmaceuticals - Google Patents

Fibrescope for optical imaging of radiopharmaceuticals Download PDF

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US20150230696A1
US20150230696A1 US14/419,183 US201314419183A US2015230696A1 US 20150230696 A1 US20150230696 A1 US 20150230696A1 US 201314419183 A US201314419183 A US 201314419183A US 2015230696 A1 US2015230696 A1 US 2015230696A1
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image
light
subject
shroud
imaging means
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David Tuch
Nicholas Collier
Kunal Vyas
Euan Morrison
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Lightpoint Medical Ltd
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Lightpoint Medical Ltd
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Publication of US20150230696A1 publication Critical patent/US20150230696A1/en
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Definitions

  • This invention has to do with methods and apparatus for optical imaging of radiopharmaceuticals, in particular Cerenkov Luminescence imaging using a fibrescope.
  • Radiopharmaceuticals that emit charged particles e.g., alpha and beta particles
  • Cerenkov photons are due to the deceleration of the charged particle in tissue.
  • Optical imaging of charged particle-emitting radiopharmaceuticals is termed Cerenkov Luminescence Imaging (CLI).
  • CLI combines the advantages of optical imaging (including high spatiotemporal resolution and low cost and form factor) with the advantages of nuclear imaging (including molecular specificity and widespread commercial availability of radiopharmaceuticals).
  • Optical imaging will be understood to include ultraviolet to near infra-red wavelengths.
  • CLI Cerenkov spectrum for commonly used diagnostic radioisotopes (particularly those labeled with Fluorine-18) is in the visible spectrum between 400-800 nm.
  • the background illumination in the room would interfere and dominate the Cerenkov spectrum.
  • the illumination would induce tissue auto-fluorescence in the visible spectrum which would overlap with the Cerenkov signal.
  • the present invention is concerned with methods and apparatus for optical imaging of radiopharmaceuticals that are practical for clinical settings, for example, in an operating theatre.
  • the inventors have identified a need for imaging tissue in situ at an open surgical site or other clinical site on a patient.
  • abnormal e.g. cancerous
  • a proposal of the present invention is therefore to provide a imaging system and method that use Cerenkov luminescence imaging to inspect the tissue at a clinical site such as an open surgical site to check that the all abnormal tissue (e.g. cancerous cells) has been removed.
  • the invention provides an apparatus for optical imaging of Cerenkov luminescence from a region on a subject subsequent to the subject receiving a dose of a radiopharmaceutical, the apparatus comprising:
  • the optical shroud is capable of at least substantially (and preferably completely) blocking the passage of ambient light.
  • the shroud is designed to attenuate ambient light by at least 10 to 14 orders of magnitude.
  • the ambient light level received by the imaging means should result in a photon flux less than 10 times the photon flux from the radiopharmaceutical, otherwise it may be very difficult or impossible to see the Cerenkov image. More preferably the photon flux resulting from ambient light is no more than 10 times less than the radiopharmaceutical flux.
  • the flux from the radiopharmaceutical e.g. F18
  • a region of interest for example, a surgical site
  • a bottom edge of the shroud forms a seal against the subject's skin around the region of interest (either directly or using additional sealing parts, for example as discussed below)
  • a light tight enclosure is formed to enable Cerenkov imaging of the region of interest.
  • the shroud may be formed of any of a number of suitable materials or combinations of materials that prevent penetration of ambient light to an adequate degree to enable successful Cerenkov imaging. It may for example be a rubberised black-out fabric, a rubber sponge material such as closed cell expanded neoprene, metalised films, opaque moulded polymers.
  • an opaque drape is first placed over the subject, the drape having an opening such that it does not cover the region of interest. A bottom edge of the shroud can then be brought into contact with the drape around the region of interest.
  • sealing means are provided to secure the shroud to the drape.
  • the sealing means may, for example, be physical (e.g. VelcroTM), magnetic, vacuum or electrostatic seals.
  • the shroud and seal may be physically joined to one another by a connector, such as a rigid ring that is engaged by the shroud and the drape.
  • a connector such as a rigid ring that is engaged by the shroud and the drape.
  • Another alternative is to engage the seal using an external power source, such as a vacuum line.
  • a light sensor within the shroud that can be used to confirm whether or not a light tight enclosure has been created.
  • images collected by the imaging means can be used for this confirmation (especially where the imaging means is configurable to collect illuminated images, as discussed below).
  • the imaging means may be a charge coupled device (CCD) camera.
  • CCD charge coupled device
  • emCCD electron-multiplying CCD
  • Possible alternative imaging means include intensified CCD, photon multiplier tube (PMT) array, or micro-channel plates with electron collection by one or more electrodes.
  • the EM gain When using an emCCD camera to image Cerenkov photons, the EM gain will typically be set to at least 100, preferably at least 200 and more preferably to about 300. Higher EM gains may be used. For example, for photon counting a gain of as much as 1000 might be used.
  • the emCCD camera When acquiring the Cerenkov images the emCCD camera will be cooled, typically to ⁇ 80 to ⁇ 100 degrees C.
  • the Cerenkov imaging means (e.g. emCCD camera) is housed within a radiation shield to help avoid interference from unwanted radiation, such as gamma rays, or beta particles.
  • a radiation shield to help avoid interference from unwanted radiation, such as gamma rays, or beta particles.
  • Suitable forms of shielding include lead shielding and Boron-filled high density polyethylene for example. Other materials or composite structures that can block the unwanted radiation can also be used.
  • the fibrescope comprises a lens mounted on the distal end of a light conduit for conveying an optical signal from the lens to the imaging means.
  • the light conduit will typically be a coherent fibre optic bundle, with the lens mounted on its distal end.
  • the fibrescope may have a conventional construction and will normally be flexible to allow it to be easily manipulated by the operator.
  • the diameter of the lens may be about 1.5 cm.
  • the focus of the lens can be varied.
  • the adjustment of the lens focus is motorised so that controls can be provided outside the shroud to facilitate focusing the lens when the shroud is in position over a region of interest.
  • the fibre optic bundle within the fibrescope is shielded by a radiation shield.
  • a radiation shield Similarly to the shield for the imaging means, this is to help avoid interference from unwanted radiation, such as gamma rays, or beta particles in the fibreglass of the fibrescope.
  • Suitable flexible radiation-shielding materials include, for example, metal-impregnated elastomers.
  • an illuminated image e.g. a white light image
  • an illuminated image e.g. a white light image
  • the Cerenkov image Prior to acquisition of the Cerenkov image this may be useful, for example, to ensure correct positioning of the fibrescope and correct focus of the lens.
  • acquisition it may be useful in order to monitor movement of the fibrescope relative to the region of interest and/or to provide sequences of illuminated and Cerenkov images that can be overlaid upon one another e.g. to ensure correct registration of sequential Cerenkov images.
  • This registration of images may be particularly important in some embodiments, where for example the fibrescope is held by a person who is liable to move.
  • the Cerenkov image is typically averaged from multiple frames and if the subsequent frames are not spatially registered with one another then there will be a loss of resolution. Any change in position of the fibrescope relative to the region of interest can be identified in the illuminated image and the registration of the Cerenkov frames corrected accordingly with suitable image processing procedures (e.g. using image processing software).
  • a surgeon may also want an illuminated image in order that they can conduct a procedure (e.g. excision of tissue) using instruments within the shroud.
  • a procedure e.g. excision of tissue
  • the image may conveniently be a video image.
  • the preferred approach to illuminate the enclosure is to employ a separate illumination channel in the fibrescope through which light from an illuminated source (e.g. white light source or R/G/B light source, which may be one or more LEDs) can be transmitted from the proximal end to the distal end of the fibrescope to provide an illumination source at the tip of the fibrescope within the shroud.
  • an illuminated source e.g. white light source or R/G/B light source, which may be one or more LEDs
  • one of more LEDs may be mounted within the shroud, for example on the distal end of the fibrescope.
  • Some embodiments may include a third mode for simultaneous illuminated image capture and CLI.
  • the mechanical shutter will be synchronised to the image acquisition sequence.
  • the shutter may, for example, be a rotating disc with regularly spaced cut outs round its circumference so that the disc can intermittently cover and uncover the light source(s). The rotation of the disc can then be controlled to give the desired periods of light and dark within the shroud, with which the illuminated and Cerenkov image acquisitions can be synchronised.
  • a mechanical shutter may also be used for the CLI imaging means (to avoid damage to the imaging means during periods of illuminated image acquisition).
  • the shutter for the CLI imaging means may also be a rotating disc.
  • the CLI imaging means and the light source for illuminating the chamber can be arranged so that a single rotating disc can serve as a shutter for the imaging means and the light source.
  • the duration on CLI acquisition periods will be longer than illuminated image acquisition periods to allow time to capture an adequate Cerenkov image, given the much lower light intensity levels.
  • the CLI acquisition period may be many times as long as the illuminated periods, for instance about 3 to 20 times as long. For example, for a 10 Hz illuminated video rate, the illuminated period would take 17 ms, with 75 ms of CLI acquisition in-between frames. 8 ms are lost every cycle due to the shutter transition times.
  • the CLI imaging is only enabled whilst the light shutter is firmly closed and not in transition.
  • the CLI acquisition does not commence immediately after the light is ‘switched off’ (e.g. covered by the shutter) to give time for any residual light in the chamber to disperse.
  • the imaging means In the case where a single imaging means is used it will normally be desirable to switch the imaging means between an illuminated level image mode and a low light level image mode for capture of the illuminated and CLI images respectively. This is because the types of camera that are sensitive enough to detect Cerenkov photons are likely to be damaged if the same sensitivity settings are used for an illuminated image.
  • the level of light for the illuminated image is preferably low and may be achieved, for example, by using neutral density filters and pulse width modulation of LEDs.
  • the camera in the case of an emCCD camera, whilst it will be cooled significantly and the EM gain set to a relatively high level for CLI, the camera will typically be operated in a conventional CCD mode, with no EM gain when capturing illuminated images. Furthermore, in order to avoid ghosting it would be necessary to raise the temperature of the sensor to ambient before cooling it down once more for the next CLI image.
  • the imaging means is switched between operating modes (Cerenkov image capture and illuminated image capture modes) during operation, this switching being synchronised with the switching on and off (e.g. by the mechanical shutter) of the light(s) in the chamber as the apparatus switches back and forth between Cerenkov image capture and illuminated image capture.
  • the apparatus is to be used during a procedure for removing abnormal tissue
  • examination of the margins, especially the surface of the open region of interest can be important (as noted above).
  • the inventors have recognised that there the sensitivity is reduced by the charged particles at the surface that escape the tissue and therefore cease generating Cerenkov photons.
  • the sensivity of CLI can be increased by placing a Cerenkov radiator on the surface of the tissue so that the escaping charged particles generate Cerenkov light.
  • the Cerenkov radiator should have high refractive index (1.5 ⁇ RI ⁇ 2.4), high transmission at short wavelengths ( ⁇ 500 nm), and sufficiently thin to minimize scattering of the charged particles.
  • a Cerenkov radiator consisting of a cover slip or mesh with the properties indicated above.
  • the Cernekov radiator can be placed over the tissue surface at the region of interest. The interaction with the cover slip or mesh of charged particles from the tissue surface generates Cerenkov photons and/or scintillation photons that can then be imaged by the imaging means.
  • Suitable high refractive index materials for the cover slip or mesh include lead glass, zirconium glass, or tellurite glass.
  • a mesh is advantageous because it can better conform to an irregular-shape tissue surface.
  • the mesh may be formed, for example, using discrete sections of high refractive index material held together by a flexible mesh lattice, for example of polyurethane.
  • the fibrescope is housed within a sterile casing.
  • the casing may be connected to the shroud.
  • the sterile casing is made of a flexible material (e.g., silicone) with a transparent window (for example, made of glass) on the distal end.
  • the sterile casing consists of a hard material (for example, metal) with a transparent window on the distal end, and the casing is sterilisable (for example, by autoclave or ethylene oxide gas).
  • the invention provides a method for optical imaging of Cerenkov luminescence from a region of interest on an object subsequent to the object receiving a dose of a radiopharmaceutical, the apparatus comprising:
  • the method further comprises illuminating the interior of the shroud with light and capturing an illuminated image of the region of interest whilst the interior of the enclosure is illuminated, the Cerenkov luminescence image being captured when the interior of the enclosure is not illuminated.
  • the method may employ the apparatus of the first aspect above, including any one or more of its preferred and optional features discussed above.
  • the object is a subject such as a patient undergoing a clinical (e.g. surgical) procedure.
  • the object is a sample or specimen.
  • the shroud may be a flexible light tight shield that is held over the sample, for example on a table top or a tray (e.g. a surgical tray).
  • the shroud may be a light tight container such as a sample dish with a lid having opaque walls to exclude ambient light from the inside of the container.
  • the container may be disposable.
  • the distal end of the fibrescope may be exposed to the interior of the container for example through a sealed opening in a wall of the container or the container lid.
  • a third aspect of the invention provides a method for optical imaging of Cerenkov luminescence from a subject subsequent to the subject receiving a dose of a radiopharmaceutical, the method comprising the steps of:
  • a fourth aspect of the invention provides an apparatus to perform the third aspect.
  • the first and second images may comprise a sequence of images (e.g. a video).
  • the steps of capturing the first image and the second image are repeated rapidly in sequence, or more preferably simultaneously, so that a video of the subject formed from the overlaid or superimposed images is created.
  • the video rate of the first and second images may vary significantly, for example with the CLI image being semi-static at 0.2 Hz, and the white light image being dynamic at 10 Hz.
  • a fifth aspect of the invention provides a method for optical imaging of Cerenkov luminescence from a subject subsequent to the subject receiving a dose of a radiopharmaceutical, the method comprising the steps of:
  • the methods of the invention include placing an optical shroud or opaque drape to shield the region to be imaged. In this way, it is not necessary to interfere with the lighting in an operating theatre.
  • the method includes use of a light detector and indicator to determine the light level within the shroud or drape. This makes it possible to check that the surgical site is sufficiently shrouded to perform CLI.
  • the method includes the step of applying strobed or spectrally separated lighting.
  • the strobed or spectrally separated lighting may be applied within the optical shroud or drape.
  • the strobe or spectrally separated lighting may be applied by a light source within the room.
  • a sixth aspect of the invention provides an apparatus for optical imaging of Cerenkov luminescence from a subject subsequent to the subject receiving a dose of a radiopharmaceutical, the apparatus comprising a first imaging means for capturing a first image of the subject, and a second imaging means for capturing a second image of the subject, wherein said second image is captured at wavelengths of light distinct from that of the illuminating light.
  • the first imaging means images the subject over wavelengths ranging from the ultra-violet to visible to infra-red.
  • the two images from the first and second imaging means are superimposed to produce a single image for use e.g. by a surgeon performing surgery to remove cancerous tissue that has taken up the radiopharmaceutical.
  • the steps of capturing the first image and the second image are repeated rapidly in sequence, or more preferably simultaneously, so that a video of the subject formed from the overlaid or superimposed images is created.
  • the subject is illuminated only with light at the red end of the spectrum e.g. from monochromatic red or monochromatic blue LED lighting.
  • the subject is illuminated only with light in the range of 500-740 nm, preferably in the range 625-740 nm, or in the range 435-500 nm.
  • other predetermined ranges of wavelengths of light may be used to illuminate the subject, e.g. red light, or non-contiguous ranges of light (e.g. red light and blue light). It is beneficial for the subject to be illuminated to allow e.g. a surgeon to be able to operate on the subject.
  • Red illumination may be preferable to blue illumination since green-to-violet light induces tissue autofluorescence in the visible range.
  • the second imaging means images Cerenkov luminescence to perform CLI.
  • the second imaging means is ultra-sensitive and is optimised to perform CLI.
  • the second imaging means is cooled to eliminate background noise (commonly called “dark noise”).
  • the first and second images are calibrated.
  • the light paths feeding the two imaging means pass through a beam-splitter, so that they both image the same region of the subject.
  • the beam-splitter is preferably a dichroic prism.
  • the second imaging means has a band pass filter to block any residual light and to aid in selecting the discrete and distinct wavelengths of light to be imaged.
  • the need for the band pass filter may depend on the performance of the beam-splitter.
  • the light source may also use a filter to further minimize spectral overlap.
  • the first and second imaging means can be contained within the same apparatus.
  • the imaging means is a camera.
  • the imaging means could be a charge-coupled apparatus (CCD) contained within a camera.
  • the first imaging means and the second imaging means may be two different CCDs contained within the same unit. Using two imaging means is preferable because it allows for the spectral response and dynamic range to be selected separately for each image.
  • strong illumination of a sensitive camera increases the dark noise for a period after illumination.
  • the CCD for the Cerenkov camera could have high quantum efficiency in the near infra-red range.
  • the chip could comprise, for example, an electron multiplying CCD, intensified CCD, photon multiplier tube (PMT) array, or micro-channel plates with electron collection by one or more electrodes.
  • the second imaging means is also enclosed within a radiation shield (e.g. lead shielding or Boron-filled high density polyethylene) to block any interference from unwanted radiation, such as gamma rays, or beta particles.
  • a radiation shield e.g. lead shielding or Boron-filled high density polyethylene
  • the plane of the imaging means (e.g. CCD) within the second imaging means may also be placed parallel to the incoming light to minimize the cross-section exposed to unwanted radiation, such as gamma rays, or beta particles.
  • image processing is applied to the two images obtained from the first and second imaging means to calibrate the intensity windowing and apply image registration if required.
  • additional imaging processing may be performed on this image including both spectral and spatial information.
  • the image from the second imaging means only comes from a restricted field-of-view (e.g. the surgical site) within the image.
  • the signal within a pixel should fit the expected spectrum emitted from the radiopharmaceutical (e.g. the Cerenkov spectrum).
  • an optical shroud or opaque drape is placed to shield the region to be imaged. In this way, it is not necessary to interfere with the lighting in an operating theatre, which is advantageous in case of emergencies.
  • a light detector and indicator may be used to check that the region to be imaged (e.g. clinical site) is sufficiently shrouded to perform CLI.
  • a seventh aspect of the invention provides a method for optical imaging of Cerenkov luminescence from a subject subsequent to the subject receiving a dose of a radiopharmaceutical, the method comprising the steps of:
  • the region of interest is illuminated with light from the light source for the majority of the time.
  • the light from the light source is emitted in repeated pulses.
  • strobe illumination should be >100 Hz and the pulses should be 10-1000 microseconds in duration.
  • Strobe illumination at >100 Hz is typically imperceptible e.g. by a surgeon performing on the subject. Whilst the subject is illuminated with this light from the light source, a first image, or series of first images, is obtained of the subject. Then, for short intervals between the pulses of illumination, the light source is switched off so that the subject is not illuminated with light from the light source. Preferably during this interval, the subject is in the dark.
  • the second image, or series of second images, of the subject may be obtained.
  • the second image may detect Cerenkov luminescence during this interval.
  • This sequence may be repeated resulting in repetitions or pulses of imaging with light from the light source and imaging Cerenkov luminescence with no light from the light source.
  • the first and second images or sequences of images are then preferably overlaid or superimposed.
  • Preferably a video of sequences of overlaid or superimposed first and second images is produced.
  • An eighth aspect of the invention provides an apparatus for optical imaging of Cerenkov luminescence from a subject subsequent to the subject receiving a dose of a radiopharmaceutical, the apparatus comprising a first imaging means for capturing a first image of the subject, and a second imaging means for capturing a second image of the subject, wherein the first and second imaging means are connected to a stroboscopic illuminating apparatus, and said second image is captured when the subject is not illuminated by the stroboscopic illuminating apparatus.
  • the first image is obtained with a first imaging means and the second image obtained with a second imaging means.
  • the first and second images may be obtained with the same imaging means. This is important as it may reduce costs, as imaging means suitable for these applications can be expensive.
  • the time offset or gating offset between the strobe pulse and the acquisition of the second image is sufficiently long to allow for the decay of any induced tissue autofluorescence, and also for any charge on the imaging means (e.g. CCD) to be cleared.
  • the acquisition of the second image is gated off of a signal from the illumination system.
  • the gated acquisition can be performed using, for example, a digital micro-mirror apparatus (DMD), a liquid crystal shutter or a spatial light modulator.
  • DMD digital micro-mirror apparatus
  • liquid crystal shutter or a spatial light modulator.
  • the subject is illuminated by an automatic stroboscopic illumination.
  • the automatic stroboscopic illumination is white-light illumination with a gated shutter, for example, using a Pockels cell or digital micro-mirror apparatus (DMD).
  • DMD digital micro-mirror apparatus
  • the first image is a structural image and the second image is a Cerenkov image.
  • the gated acquisition can be performed by treating segments of the signal as the Cerenkov image.
  • the plane of the imaging means may be placed parallel to the incoming light to minimize the cross-section exposed to other sources of radiation such as gamma rays or beta-particles.
  • the first and second images are calibrated.
  • image processing is applied to the first and second images to calibrate the intensity windowing and apply image registration, if required.
  • additional imaging processing may be performed on this image including both spectral and spatial information. For example, it can be specified that the signal within a pixel should fit the expected spectrum emitted from the radiopharmaceutical (e.g. the Cerenkov spectrum).
  • the second imaging means is ultra-sensitive and is optimised to perform CLI.
  • the second imaging means is a cooled, electron-multiplying CCD camera.
  • the light paths feeding the two imaging means pass through a beam-splitter, so that they both image the same region of the subject.
  • the beam-splitter is preferably a dichroic prism.
  • the second imaging means has a band pass filter to block any residual light and to aid in selecting the discrete and distinct wavelengths of light to be imaged.
  • the need for the band pass filter may depend on the performance of the beam-splitter.
  • the first and second imaging means can be contained within the same apparatus.
  • the imaging means is a camera.
  • the imaging means could be a charge-coupled apparatus (CCD) contained within a camera.
  • the first imaging means and the second imaging means may be two different CCDs contained within the same unit. Using two imaging means is preferable because it allows for the spectral response and dynamic range to be selected separately for each image.
  • the CCD for the Cerenkov camera could have high quantum efficiency in the near infra-red range.
  • the chip could comprise, for example, an electron multiplying CCD, intensified CCD, PMT array, or micro-channel plates with electron collection by one or more electrodes.
  • the second imaging means is also enclosed within a radiation shield (e.g. lead shielding or Boron-filled high density polyethylene) to block any interference from gamma rays, or beta-particles.
  • a radiation shield e.g. lead shielding or Boron-filled high density polyethylene
  • the above aspects are such that they could also be applied in other diagnostic imaging procedures such as endoscopy, capsule endoscopy, imaging for robotic surgery, whole-body imaging, and basic research.
  • a further aspect of the invention provides a phantom, or testing replica, for ultra-weak light.
  • the phantom may use a light emitting diode (LED) with one or more, for example a stack or layers of, neutral density filters through which light from the LED is emitted.
  • a wavelength selective attenuator may be used in the LED. Reduction of intensity may alternatively or additionally be achieved using pulse width modulation, which may be varied using electronics or software techniques.
  • the phantom may be used to calibrate the light system, and may also or alternatively be useful for maintenance and/or quality control.
  • FIG. 1 shows an example embodiment of the invention
  • FIG. 2 shows an example embodiment of the invention that uses stroboscopic illumination
  • FIG. 3 shows an example sequence of stroboscopic illumination, Cerenkov image acquisition and illuminated structural image (e.g. anatomical image) acquisition of an example embodiment of the invention
  • FIG. 4 a schematically shows an example embodiment of the first aspect of the invention using a fiberscope for Cerenkov luminescence imaging
  • FIGS. 4 b to 4 d show variations of the shroud arrangement for the fibrescope embodiment of FIG. 4 a.
  • FIG. 5 schematically shows an alternative embodiment that employs two cameras and an optical coupler and shutter to direct light to the two cameras;
  • FIGS. 6 a and 6 b show two alternative arrangements for the optical coupler used in the embodiment of FIG. 5 ;
  • FIG. 7 a shows a plan view and FIG. 7 b a cross-section of a rotating disc shutter that can be used to shutter a light source and an emCCD camera.
  • FIG. 8 is a schematic view of an optical light shield and camera setup used in experiments to illustrate the principles of embodiments of the invention.
  • FIG. 9 shows the layout of sample wells used in the experiments.
  • FIGS. 10 a and 10 b show Cerenkov images captured during the experiments.
  • FIG. 11 is a graph of signal photon rate for each of the experimental wells.
  • FIG. 1 An example embodiment of the invention is shown in FIG. 1 .
  • This example embodiment allows CLI to be performed under lit conditions.
  • the background lighting is completely eliminated, and monochromatic red LED lighting is used to illuminate the subject.
  • the exemplary set-up of the camera and other components of the imaging system may also be used for embodiments with regular ambient lighting where the part of the subject being imaged is shrouded to exclude the ambient light, as discussed further below.
  • a subject is injected with 18 F-Fluorodeoxyglucose (FDG) (a common beta-emitting radiopharmaceutical).
  • FDG F-Fluorodeoxyglucose
  • the radiopharmaceutical may be injected systemically, or locally. Commonly, there is a narrow time window of around 60 minutes to 3 hours post-injection for a scan to be performed. This is a result of the pharmacokinetics and radioactive decay of the radiopharmaceutical at the region of interest.
  • the second camera (C 2 ) is an ultra-sensitive camera such as a cooled emCCD camera.
  • the first camera (C 1 ) one or more monochromatic or colour cameras may be used. By rapidly applying (in any order) sequential red, green and blue illumination and then composing the image, full colour imaging can be provided. The speed at which the illumination is applied is determined by the desired frame rate of the video image.
  • use of very low levels of illumination and a single camera may be used to take advantage of the sensitivity of the CLI camera.
  • This illumination could be flashed red, green and blue if a colour image is required.
  • a large aperture lens with low f number is preferred. This arrangement means that more light can be collected. Usually this is undesirable because it leads to distortions.
  • the spatial resolution is sufficiently maintained for CLI, which generally has a comparatively poor spatial resolution, so that the improvement in light input outweighs the loss of spatial resolution.
  • the light generated by the radiopharmaceuticals is passed through a beam splitter (BS) such as a dichroic prism that directs the red light to the first camera and the non-red light to the second camera.
  • BS beam splitter
  • the second camera is also equipped with a band-pass filter (BP) to block any residual red light.
  • BP band-pass filter
  • the need for the band-pass filter will depend on the performance of the beam-splitter.
  • the role of red and blue may be reversed to allow, for example, a surgeon to see deeper into tissue to direct a portion of the light to the illuminated camera and a portion of the light to the Cerenkov camera.
  • C 2 is also enclosed within a radiation shield (e.g., lead shielding) (RS) to block any interference from gamma rays or beta-particles.
  • RS lead shielding
  • the plane of the camera chip within C 2 may also be placed parallel to the incoming light to minimize the cross-section exposed to gamma rays or beta-particles.
  • Image processing (P) is applied to the two images (I 1 and I 2 ) to calibrate the intensity windowing and apply image registration, if required.
  • additional imaging processing can be performed on I 2 including both spectral and spatial information.
  • the Cerenkov image only comes from a restricted field-of-view (such as the tumour within the surgical site) within I 2 .
  • the signal within a pixel should fit the expected Cerenkov spectrum.
  • the final image (I) is generated by superimposing the calibrated Cerenkov image (I 2 ) on the illuminated image (I 1 ).
  • CLI can be performed in intervals between stroboscopic pulses of light.
  • the subject is illuminated by automatic stroboscopic illumination.
  • the illumination is white-light illumination with a gated shutter using a digital micro-mirror apparatus (DMD).
  • DMD digital micro-mirror apparatus
  • the stroboscopic or spectrally separated, lighting may be provided within an optical shroud.
  • the stroboscopic or spectrally separated, lighting may be provided in the room.
  • This embodiment uses a similar apparatus setup to the embodiment described above.
  • the acquisition of the second image is gated off of a signal from the stroboscopic illumination system, as shown by FIG. 2 .
  • the gated acquisition is performed using a digital micro-mirror apparatus (DMD).
  • DMD digital micro-mirror apparatus
  • a trigger connects the DMD to the light source. Connecting the light source and the DMD by the trigger allows light to be directed to one of two cameras for separate imaging of the Cerenkov or structural images.
  • FIG. 3 shows an example sequence of the stroboscopic pulses and intervals.
  • strobe illumination may be >100 Hz and the pulse duration (PD) may be 10-1000 microseconds in an example embodiment.
  • Structural image acquisition is performed during the stroboscopic pulse duration.
  • the time or gating offset (GO) between the strobe pulse and the acquisition of the second image is sufficiently long to allow for the decay of any induced tissue autofluorescence, and also for any charge on the CCD of the camera to be cleared.
  • the pulse duration (PD) is 1000 microseconds
  • the pulse interval (PI) is 9000 microseconds
  • the gating offset (GO) may be 2000 microseconds and the second (Cerenkov) image acquisition time is 7000 microseconds.
  • the pulse duration (PD) is 10 microseconds
  • the pulse interval (PI) is 9990 microseconds and so the gating offset (GO) may be 1990 microseconds and the second (Cerenkov) image acquisition time is 8000 microseconds.
  • an optical shroud may be used to shield the patient, or the region to be imaged.
  • An optical shroud is a shroud or shield that is capable of substantially preventing the penetration of ambient light through the shroud material, so that CLI measurements are possible without turning off room lights.
  • the optical shroud is capable of conforming to desirable shapes.
  • the optical shroud is made of a material capable of conforming, for example, to the contours of a patient's body.
  • the shroud may comprise fabric or metal foil. Other materials that achieve the desired effects are contemplated.
  • the shroud may make an optically tight seal with the surface of the patient.
  • An optically tight seal may be achieved using, for example, a gel.
  • the gel may be placed around the rim of the shroud that comes into contact with the patient.
  • the seal should reduce in wavelength “passband” light levels inside the shroud to a level comparable to, or lower than, the CLI signal.
  • the shroud may include built-in gloves to allow, for example, a surgeon access to the region of interest during imaging without breaking the optically tight seal.
  • instrument ports and/or instruments may be included.
  • an image display may be located on a camera.
  • a flexible fiberscope or endoscope may be used for Cerenkov luminescence imaging.
  • FIG. 4 schematically shows an embodiment in accordance with the first aspect of the invention in which a fibrescope 10 is used to image tissue at a region of interest 18 (for example a surgical site) during a procedure being carried out on a patient 14 .
  • a fibrescope 10 is used to image tissue at a region of interest 18 (for example a surgical site) during a procedure being carried out on a patient 14 .
  • the fiberscope 10 which is preferably flexible for a surgeon's ease of use, extends from an electron multiplying charge coupled device camera (emCCD) 12 to the region of interest 18 on the patient 14 . It is envisaged that the fibrescope 10 will be held in place by the surgeon or an assistant but in other examples a physical support may be provided.
  • the tip 16 of the fiberscope 10 is used for imaging tissue at the region of interest 18 .
  • the emCCD camera is supported by a boom 20 .
  • An optical shroud 22 (or opaque drape) surrounds the distal end 16 of the fibrescope 10 and the region of interest 18 so that little or no external light is present inside the optical shroud 22 and external light is prevented from entering the region of interest 18 .
  • the optical shroud 22 is mounted on the distal end of the fiberscope 10 . Sealing of the optical shroud 22 may be provided in the same way as described above for sealing against a patient, for example. Alternative approaches to achieving a light tight seal around the edges of the shroud are discussed below with reference to FIGS. 5 b to 5 d .
  • the shroud is also sealed tightly against the fibrescope.
  • a skirt or drape 24 may be used to extend over the patient 14 away from the region of interest 18 .
  • the skirt 24 may be attached to the shroud 22 to help block light from entering the region of interest 18 .
  • the drape may be attached to a rigid ring and the lower edge of the shroud formed with clasps that can engage a top edge of the ring to form a light tight seal.
  • a sponge member below the ring prevents the ring from pressing into the patient's skin and also help to ensure a light tight seal against the skin is maintained.
  • FIGS. 4 c and 4 d show alternative arrangements for sealing the shroud to the drape.
  • the shroud is connected to the top surface of the drape by a seal that may, for example, be a hook and loop seal, a magnetic seal or an electrostatic seal.
  • a seal may, for example, be a hook and loop seal, a magnetic seal or an electrostatic seal.
  • the fibrescope rather than the fibrescope extends into the shroud through a light tight port.
  • the seal is created without any physical connection and relies instead on a long overlap between a skirt of the shroud and the drape.
  • a sponge member is also used to enhance the seal.
  • the tip 16 of the fiberscope 10 may be manipulated by, for example, one or more gloves through the optical shroud 22 , by a wire through the optical shroud 22 , or by having a rigid end part of the fiberscope 10 near the tip 16 so that it is possible to manipulate the tip 16 from outside the shroud 22 .
  • Other ways of manipulating the tip 16 of the fiberscope 10 will be apparent to the skilled person.
  • a light detector and indicator may be used to provide feedback to, for example, a surgeon, to provide information about the light tightness of the optical shroud.
  • the light detector is a camera. In some embodiments, this may be the CLI camera.
  • An additional detector may be used to prevent damage to the CLI camera if, for example, the level of illumination is too great.
  • FIG. 5 shows an alternative embodiment.
  • the imaging means comprises two cameras, an emCCD camera for CLI and a colour video camera for illuminated (e.g. anatomical) imaging.
  • This figure also illustrates the white light source at the proximal end of the fibrescope that can be used to illuminate the shrouded region of the patient.
  • An optical coupler and shutter direct light to the two cameras and shutter is emCCD camera during periods when the interior of the shroud is illuminated.
  • the shutter is controlled by a shutter controller to be synchronised with the illumination.
  • FIG. 6 a shows one exemplary configuration for the optical coupler and shutter.
  • a single aspheric lens is used for coupling out of the fibre bundle and focussing on to both cameras.
  • a high transmittance beam splitter option is shown.
  • FIG. 6 b shows another option for the configuration of the optical coupler.
  • a modular setup is used with a collimating lens coupling out of the fibre bundle and a focussing lens attached to each camera.
  • the high transmittance beam splitter option is shown in this example too.
  • FIGS. 7 a and 7 b show an alternative shutter arrangement that can be used to shutter both the light source and the emCCD camera in embodiments where these two components are located adjacent to one another.
  • the shutter is a rotating disc that is configured to cover both the light source and the emCCD lens.
  • the disc is driven by a motor and as it rotates, windows (holes) in the disc, aligned respectively with the light source and the emCCD lens (which are at different radii) mean that the light source and the emCCD camera lens are selectively covered and uncovered.
  • the relative positions of the windows ensure that the emCCD lens is covered when the light source is uncovered.
  • the emCCD windows are longer than the windows for the light source, to give a longer CLI acquisition period compared with the illuminated image acquisition period.
  • FIG. 8 shows a schematic view of an exemplary optical light shield and camera setup in line with the present invention and used for the experiments discussed below.
  • an iXon camera is positioned directly above a sample to be imaged (not shown) on a metal mounting plate b.
  • An f/1.8 lens c is located beneath the camera and metal mounting plate b.
  • a plastic (PVC) tube d extends between the metal mounting plate b and the sample to be imaged.
  • the plastic tube d is lined with a low reflectance flock lining e.
  • the sample is surrounded by packing foam g, which is covered with a neoprene rubber sponge lining g, in turn covered with stretched elastic h.
  • a phantom, or testing replica, for ultra-weak light may be used to calibrate the light system.
  • the phantom may use a light emitting diode (LED) with a stack or layers of neutral density filters. If necessary, the LED may be driven with a modulated waveform to further and controllably reduce the output of the LED.
  • LED light emitting diode
  • Such a phantom may also or alternatively be useful for maintenance and quality control of the light system.
  • An iXon Ultra 897 emCCD camera was used to detect the extremely low light levels expected in CLI.
  • the source was simulated using a duty cycled LED with neutral density filters and a diffuser.
  • An f/2.8 lens was used, though the light levels were scaled to simulate an f/1 lens.
  • the target irradiance was 0.013 photons/pixel/s.
  • the number of photons produced by the LED was scaled by the duty cycle (proportion of time the LED was on in 1 s) distributed by the collimator into a circular beam with a 25 mm diameter. Once attenuated by neutral density filters it encountered the heavy diffuser. This randomised the direction of each photon resulting in half the photons being emitted at the other side. These photons were now divergent and were spread over 2 ⁇ sr (a hemisphere). This provided radiance in photons/s/sr/cm 2 , and allowed prediction of the irradiance of the detector.
  • the OD4 and OD2 filters were used with a 1/10 duty cycle.
  • the camera was used in photon counting mode, which digitized each pixel using a photon threshold in counts, removing the impact of the excess noise factor.
  • the camera setup was as follows:
  • the signal for a 1 s exposure with the room lights off was 0.0048 photons/pixel. This corresponded to S:N for a 32 ⁇ 32 binned pixel of 1.7.
  • OD4 and OD2 filters were used with a 1/10 duty cycle.
  • Signal for a 1 s exposure with the room lights off was found to be 0.0015 photons/pixel, corresponding to a S:N for a 32 ⁇ 32 binned pixel of 2.1.
  • the silicone cone shroud provided a good quality seal on the flat surface, but was not sufficiently opaque and allowed light to be transmitted into the shielded area.
  • the OD4 and OD2 filter was used with a 1.10 and 1.100 duty cycle.
  • the camera setup was as follows:
  • the signal for a 1 s exposure with the room lights on was 0.0016 photons/pixel, corresponding to S:N for a 32 ⁇ 32 binned pixel of 3.1.
  • an appropriate shroud such as a silicone cone with rubber sponge layers around the outside, can be used to shield ambient light to such a level that it is possible to employ CLI with room lights on.
  • the camera was set up so that the experiment could be conducted inside a lead enclosure with the operation of the laptop on the other side of a room.
  • the camera had the following settings:
  • F18 was diluted and distributed into six 0.2 mL experimental wells inside a PerspexTM (PMMA) block. Three control wells with inactive material were also prepared.
  • FIG. 7 illustrates the layout of the experimental wells.
  • the liquid volume and initial activity concentration in the active wells is shown in the table below.
  • One control well and one active well with activity 2 ⁇ Ci were covered with 6 mm thick BK7 glass.
  • One control well and one active well with activity 2 ⁇ Ci were covered with 6 mm thick BK7 glass and black masking tape.
  • the BK7 glass is inset, with the wells under it 6 mm below the level of the other wells as viewed by the camera.
  • the black masking tape was placed between the wells and the glass, leaving the glass open for viewing.
  • the sample block was prepared and placed under the shielded camera, which was then lowered into place and draped to give a light tight enclosure. Images with the following settings were acquired:
  • Signal ⁇ ( photoelectrons ) ( Signal ⁇ ( counts ) - Bias ⁇ ⁇ Offset ) ⁇ Conversion ⁇ ⁇ Factor EM ⁇ ⁇ Gain
  • FIG. 10 a shows a set of images taken approximately 15 minutes into the experiment with the lights on and lights off. The positions of the wells have been circled in the top left image using the same scheme as FIG. 6 . It can be seen that a higher resolution of 32 ⁇ 32 is obtainable in 5 seconds. In addition to the Cherenkov emission interference from high energy rays can be seen as random white pixels that have a signal level beyond the scale used.
  • FIG. 10 b shows set of images taken approximately 180 minutes into the experiment. Even with the lower signal levels there is no discernible difference due to the room lights. The higher activity wells are still easily visible and the lowest activity well is still discernible.
  • FIG. 11 shows the signal photon rate for each active sample well, after correcting for the background by subtracting the corresponding control signal.
  • Each point on the graph represents an image of the sample.
  • the measured decay constant corresponds to a half-life of 108 minutes.
  • the active well covered by glass but not masked produced a similar signal to the open active wells.
  • the masked well showed no visible signal, and was quantified to be 10% of the signal obtained from the unmasked well. Therefore it was concluded that the scintillation in optical BK7 glass was insignificant.

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