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WO2017137350A1 - Source lumineuse à del accordable en longueur d'onde - Google Patents

Source lumineuse à del accordable en longueur d'onde Download PDF

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Publication number
WO2017137350A1
WO2017137350A1 PCT/EP2017/052531 EP2017052531W WO2017137350A1 WO 2017137350 A1 WO2017137350 A1 WO 2017137350A1 EP 2017052531 W EP2017052531 W EP 2017052531W WO 2017137350 A1 WO2017137350 A1 WO 2017137350A1
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WIPO (PCT)
Prior art keywords
light
illumination system
wavelength
led
light source
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2017/052531
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English (en)
Inventor
Lars René LINDVOLD
Gregers G. HERMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FREDERIKSBERG HOSPITAL
Danmarks Tekniske Universitet
Original Assignee
FREDERIKSBERG HOSPITAL
Danmarks Tekniske Universitet
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Publication of WO2017137350A1 publication Critical patent/WO2017137350A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/04—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances
    • A61B1/043—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances for fluorescence imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/00064—Constructional details of the endoscope body
    • A61B1/00071—Insertion part of the endoscope body
    • A61B1/0008—Insertion part of the endoscope body characterised by distal tip features
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    • A61B1/06—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements
    • A61B1/063—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements for monochromatic or narrow-band illumination
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    • A61B1/0638—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements providing two or more wavelengths
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    • A61B1/06—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements
    • A61B1/0646—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements with illumination filters
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    • A61B1/06—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements
    • A61B1/0655—Control therefor
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    • A61B1/06—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements
    • A61B1/0661—Endoscope light sources
    • A61B1/0684—Endoscope light sources using light emitting diodes [LED]
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    • A61B1/07—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor with illuminating arrangements using light-conductive means, e.g. optical fibres
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    • A61B1/307—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor for the urinary organs, e.g. urethroscopes, cystoscopes
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    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
    • A61B18/24—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor with a catheter
    • A—HUMAN NECESSITIES
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    • A61N5/0601—Apparatus for use inside the body
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    • A—HUMAN NECESSITIES
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    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/16—Microscopes adapted for ultraviolet illumination ; Fluorescence microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B23/00—Telescopes, e.g. binoculars; Periscopes; Instruments for viewing the inside of hollow bodies; Viewfinders; Optical aiming or sighting devices
    • G02B23/24—Instruments or systems for viewing the inside of hollow bodies, e.g. fibrescopes
    • G02B23/2407—Optical details
    • G02B23/2461—Illumination
    • G02B23/2469—Illumination using optical fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/00163—Optical arrangements
    • A61B1/00186—Optical arrangements with imaging filters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00625—Vaporization
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B2018/00982—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body combined with or comprising means for visual or photographic inspections inside the body, e.g. endoscopes
    • 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
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • 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
    • A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
    • A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/061—Bladder and/or urethra
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F21—LIGHTING
    • F21V—FUNCTIONAL FEATURES OR DETAILS OF LIGHTING DEVICES OR SYSTEMS THEREOF; STRUCTURAL COMBINATIONS OF LIGHTING DEVICES WITH OTHER ARTICLES, NOT OTHERWISE PROVIDED FOR
    • F21V9/00—Elements for modifying spectral properties, polarisation or intensity of the light emitted, e.g. filters
    • F21V9/08—Elements for modifying spectral properties, polarisation or intensity of the light emitted, e.g. filters for producing coloured light, e.g. monochromatic; for reducing intensity of light
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B26/00—Optical devices or arrangements for the control of light using movable or deformable optical elements
    • G02B26/007—Optical devices or arrangements for the control of light using movable or deformable optical elements the movable or deformable optical element controlling the colour, i.e. a spectral characteristic, of the light
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B5/00—Optical elements other than lenses
    • G02B5/20—Filters
    • G02B5/28—Interference filters

Definitions

  • the invention relates to an easy and inexpensive illumination source for spectral tuning of light sources in fluorescence imaging systems. Background
  • Spectral tuning of light sources in fluorescence imaging is a very convenient method of achieving the optimal contrast by exciting the proper fluorophore.
  • the common denominator of all the LED based light source is that the wavelength selection is done by changing a filter having fixed colour (i.e. a fixed wavelength). Depending on the requirements of the use of the lamp, this filter may be an absorption filter or an interference filter.
  • AOTF Acousto Optic Tuneable Filter
  • the AOTF is, however, very compact compared to that of a monochromator and is the preferred method for rapid change of excitation wavelength in fluorescence microscopy if cost is not an issue.
  • a similar tuneable light source used in high-end fluorescence microscopy and spectroscopy (hyper- and multi spectral imaging) is the variable liquid crystal tuneable filter (LCTF).
  • LCTF variable liquid crystal tuneable filter
  • This device makes use of the electrically controlled birefringence of liquid crystal modulator.
  • the tuning properties of the LCTF and AOTF are comparable, the speed of the two devices differs significantly. Due to the basic physical properties of liquid crystal light modulators (twisted nematic type), a tuning speed on the order of milliseconds versus microseconds for that of an AOTF can be achieved. In either cases these tuneable light source are expensive and targeted at users with a need for spectral control over the entire visible spectrum.
  • This kind of light source is a white light source.
  • the white light (super-continuum) is generated by exciting optical non-linear effects in a photonic crystal fibre with pico- or femtosecond laser.
  • the core size of the optical fibre is around 40 microns, the light emitted from the light source will be partially spatial coherent (laser like).
  • the aforementioned acousto-optic tuneable filter (AOTF) is used to select the appropriate wavelength form the super-continuum light source. It is apparent that this light source is a high-end product intended for challenging applications in the field of fluorescence microscopy and spectral imaging in biomedicine.
  • the light source disclosed in this patent application is aiming at light sources for use in fluorescence assisted imaging such as e.g. cystoscopy for photodynamic diagnosis and autofluorescence imaging where only a selected spectral tuning range is required.
  • the fluorescence imaging applications may be endoscopic applications in a body cavity comprising bodily fluids or microscopic applications.
  • the illumination system comprises:
  • LED light emitting diode
  • o has an initial half width full maximum (FWHM)
  • o has an initial central wavelength between 500 and 900 nm
  • an optical transmission path adapted to guide the tuned LED light to a region of interest being e.g. an endoscopic region of examination or a microscopic imaging plane;
  • an optical collection path adapted to guide light emitted and/or reflected light from the region of interest
  • an additional filter adapted for blocking light below 500 nm, the additional filter being positioned before or after the bandpass filter.
  • the wavelength of the excitation light can be tuned easily within a range of approximately 15-50 nm using inexpensive equipment.
  • This is highly advantageous as e.g. autofluorescence inside a cavity in a patient studied with endoscopes or from human samples studied with fluorescence microscopy, will vary from patient to patient.
  • the optimum excitation wavelength for one patient / sample giving the best contrast for that specific patient may not be the best wavelength for another patient / sample.
  • the autofluorescence inside the bladder e.g. varies from patient to patient, and tuning of the LED in the illumination system ensures that the optimal contrast between the different fluorescence colors can be obtain individually for each patient without changing any filters or using expensive equipment.
  • the initial central wavelength is between 500 and 550 nm.
  • the initial central wavelength is between 550 and 600 nm. In one or more embodiments, the initial central wavelength is between 600 and 650 nm. In one or more embodiments, the initial central wavelength is between 650 and 700 nm. In one or more embodiments, the initial central wavelength is between 700 and 750 nm. In one or more embodiments, the initial central wavelength is between 750 and 800 nm. In one or more embodiments, the initial central wavelength is between 800 and 850 nm.
  • the initial central wavelength is between 850 and 900 nm.
  • the blue-shifted central wavelength is up to 50 nm lower than the initial central wavelength.
  • the blue-shifted central wavelength is between 15-50 nm lower than the initial central wavelength.
  • the optical bandpass filter is an interference filter.
  • the additional filter is a cut-off filter.
  • the illumination system further comprises a first hybrid aspheric lens and a second hybrid aspheric lens both positioned between the bandpass filter and the LED.
  • the means for tilting the optical bandpass filter is a mechanical piezo or electronic adjustments means.
  • the means for tilting the optical bandpass filter can tilt the optical bandpass filter around a first axis and/or a second axis, wherein both the first axis and the second axis extend through the middle of the bandpass filter along directions being perpendicular to the direction in which the LED light propagates, the second axis being perpendicular to the first axis.
  • the optical transmission path and the optical collection path are fibres extending inside an endoscopic tube, the endoscopic tube having a proximal end where tuned LED light enters the optical transmission path, and light emitted and/or reflected light from the endoscopic region of examination exits by the optical collection path, and a distal end where tuned LED light exits the optical transmission path and light emitted and/or reflected light from the endoscopic region of examination is collected by the optical collection path.
  • the fibres are multimode fibres.
  • the band-rejection filter is adapted to attenuate the predefined wavelength by more than 10 dB, preferably by more than 20 dB, preferably by more than 30 dB, preferably by more than 40 dB, preferably by more than 50 dB, most preferably by more than 60 dB.
  • a solid state imaging device is located at a distal end of the illumination system.
  • the solid state imaging device is a CCD (charge-coupled device) camera. In one or more embodiments, the solid state imaging device is a CMOS (complementary metal-oxide-semiconductor) camera.
  • the illumination system includes a digital solution for a digital endoscope.
  • a camera e.g. in the form of a camera chip, is located at the distal end of the illumination system.
  • the camera comprises an integral colour filter, e.g. in the form of a so-called Bayer mosaic colour filter. This filter makes it possible for the camera to see light in three spectral regions - red, green and blue commonly referred to as RGB. This means that the image transmitted from the distal part of the illumination system subsequently can further be electronically processed to suppress excitation light from the light source and enhance the fluorescence image of tumours and healthy tissue.
  • the integral colour filter acts as the band-rejection filter as it attenuates the tuned LED wavelength.
  • an endoscope comprising an illumination system according to the above.
  • the endoscope may be a digital endoscope.
  • a solid state imaging device such as e.g. a CCD or CMOS camera, may be located at a distal end of the endoscope.
  • Disclosed herein is also a method for tuning the wavelength of a light source for use in endoscopic photodynamic diagnostic in the cavity of a patient, the method comprising the steps of providing an illumination system according to the above and tilting the bandpass filter around a first and/or a second axis, thereby tuning the light from the LED towards shorter wavelengths, wherein both the first axis and the second axis extend through the middle of the bandpass filter along directions being perpendicular to the direction in which the LED light propagates, the second axis being perpendicular to the first axis.
  • the tilting of the bandpass filter is done automatically based on an optimization for obtaining the most contrast in the fluorescence signal.
  • the endoscope is made from a material which can be reused.
  • a system comprising an illumination system according to the above, and a high intensity treatment light source adapted for photo induced denaturation of tumour tissue inside the bladder in connection with treatment of bladder tumours, wherein the high intensity treatment light source is a solid state light source emitting light at a wavelength between 800-1000 nm or between 350-500 nm.
  • Figure 1 schematically illustrates an illumination system according to the invention used in connection with endoscopic applications.
  • Figure 2 is a close-up of the LED light source system with a tiltable bandpass filter.
  • Figure 3 shows a tuning curve for spectrally tuning a bandpass filter.
  • Figure 4A schematically illustrates a bladder as an example of a cavity inside a patient
  • Figure 4B shows an image of the bladder before tuning the LED wavelength and 4C shows an image of the bladder after tuning the LED wavelength to obtain a maximum contrast signal for the viewer.
  • Figure 5 schematically illustrates an illumination system according to the invention in combination with a high intensity treatment light source adapted for photo induced denaturation of tumour tissue inside a patient's cavity.
  • Figures 6a-c show in vitro results for diode laser treatment on chicken breast meat.
  • Figures 7a-e show in vivo results for diode laser treatment on a tumour in the bladder of a patient from the before treatment (figure 7a), during treatment (figure 7b), immediately after end treatment (figure 7c) and after end treatment (figures 7c-d). Description of preferred embodiments
  • the illumination system 200 may be adapted for inducing fluorescence in exogenous or endogenous fluorophores for performing photodynamic diagnosis (PDD).
  • PDD photodynamic diagnosis
  • the illumination system is shown schematically in figure 1 for the application of endoscopic use.
  • the illumination system 200 comprises a light source in the form of an LED 202 emitting substantially monochromatic LED light 204.
  • the LED is the single light source in the illumination system 200, and the LED light has an initial half width full maximum (FWHM), and an initial central wavelength between 500 and 900 nm.
  • FWHM half width full maximum
  • the LED light 204 typically have an emission spectrum with a FWHM of between 15 and 100 nm. In one or more embodiments, the LED light have an emission spectrum with a FWHM of between 20 and 75 nm, or between 30 and 50 nm or between 35 and 45 nm.
  • the predefined central wavelength of the LED may be between 500 and 550 nm, or between 550 and 600 nm, or between 600 and 650 nm, or between 650 and 700 nm, or between 700 and 750 nm, or between 750 and 800 nm, or between 800 and 850 nm, or between 850 and 900 nm.
  • the predefined central wavelength of the LED may be between 500 and 505 nm, or between 505 and 510 nm, or between 510 and 515 nm, or between 515 and 520 nm, or between 520 and 530 nm, or approx.
  • the illumination system 200 also comprise an optical bandpass filter 205 adapted to reduce the initial FWHM, whereby LED light with a reduced FWHM is obtained.
  • the FWHM of the unfiltered LED light is approx. 40 nm, whereas the spectrum of the LED light covers a span from 450 nm to 600 nm.
  • this is not desirable because the "blue" 450-500 nm range is unwanted due to stimulation of green fluorescence from urine.
  • the "red" 550-600 nm range will confound the native fluorescence of the tissue.
  • the bandpass filter 205 is inserted in the optical path between the LED and an optical transmission path 208.
  • Figure 2 shows a close up of the setup 206 around the bandpass filter 205 and the LED 204.
  • the bandpass filter 205 reduces the FWHM to approx. 25 nm thereby reducing the lower wavelength light that may induce fluorescence in e.g. urine and also reducing the longer wavelength light that may be allowed through the band-rejection filter, i.e. the filter maximizes the desired sensitized fluorescence from cancerous tissue as well as the native autofluorescence of the healthy tissue.
  • the illumination system also comprises means 212 for tilting the optical bandpass filter 205 thereby tuning the initial central wavelength of the LED light such that tuned LED light 208 with a blue-shifted central wavelength is obtained.
  • the means for tilting the optical bandpass filter is illustrated as a box 212 around the filter 205.
  • the means for tilting the optical bandpass filter may tilt the optical bandpass filter around a first axis and/or a second axis, wherein both the first axis and the second axis extend through the middle of the bandpass filter along directions being perpendicular to the direction in which the LED light propagates.
  • the second axis being perpendicular to the first axis.
  • Figure 3 shows a tuning curve for spectrally tuning the bandpass filter, where the spectral transmission curve of a bandpass filter is blue-shifted when the bandpass filter is tilted 10 or 20 degrees in the plane of incidence.
  • plane of incidence is meant the plane defined by the first and the second axis, i.e. the optical plane.
  • the tilting of the bandpass filter is done with respect to the optical axis.
  • the means for tilting the optical bandpass filter may be purely mechanical mounts allowing for rotation about the plane of incidence or similar mechanical mounts driven by actuators based on either electromagnetic means or piezo-based devices.
  • the means for tilting the optical bandpass filter is an opto- mechnical component like a gimbal mount allowing the filter to be tilted in the
  • the optical bandpass filter is an interference filter.
  • the blue-shifted central wavelength is up to 50 nm lower than the initial central wavelength. In one or more embodiments, the blue-shifted central wavelength is up to 40 nm lower than the initial central wavelength.
  • the blue-shifted central wavelength is up to 30 nm lower than the initial central wavelength.
  • the blue-shifted central wavelength is up to 20 nm lower than the initial central wavelength.
  • the blue-shifted central wavelength is between 15-50 nm lower than the initial central wavelength.
  • the blue-shifted central wavelength is between 15-40 nm lower than the initial central wavelength. In one or more embodiments, the blue-shifted central wavelength is between 15-30 nm lower than the initial central wavelength.
  • the blue-shifted central wavelength is between 15-20 nm lower than the initial central wavelength.
  • the tilting of the bandpass filter may be done automatically based on an optimization for obtaining the most contrast in the fluorescence signal.
  • the optimization will normally be an iterative process based on an algorithm included in a computer connected to the illumination system.
  • the system will normally use region of interest (ROI) data from the imaging system to evaluate optimal contrast based on a look up table (LUT).
  • the illumination system may in one or more embodiments further comprises an additional filter 216 adapted for blocking light below a specific wavelength, the additional filter being positioned before or after the bandpass filter. In figure 2 the additional filter 216 is positioned before the bandpass filter 205. In connection with bladder cancer detection, a filter, which blocks light below 500 nm is normally used.
  • the additional filter 216 is a cut-off filter.
  • the illumination system further comprises a first hybrid aspheric lens 213 and a second hybrid aspheric lens 214 both positioned between the bandpass filter 205 and the LED 202 .
  • a third hybrid aspheric lens 215 may also be found in the system being positioned between the bandpass filter 205 and the optical transmission path 208.
  • the first and second hybrid aspheric lenses 213, 214 may form a refractive-diffractive pair.
  • a condensate system is formed.
  • An optical transmission path 208 adapted to guide the tuned LED light 210 to either an endoscopic region of examination, e.g. the bladder, or to an optical illumination plane in a microscope is also part of the illumination system 200.
  • An example of such is shown in figure 2 illustrated by the entrance to a fibre.
  • a first fibre is connected to or part of the LED.
  • the first fibre may be the optical transmission path 208.
  • the fibre may further by extending through an endoscopic tube 226 as shown in figure 1 when an endoscope and the LED light source 202 are connected.
  • the fibre may be a multimode fibre.
  • Light 218 emitted and/or reflected light from the region of interest is collected in an optical collection path 220 and guided to an electronic imaging device 222 allowing the practitioner or surgeon to observe the region of interest or the sample.
  • a CCD camera may be used in this context.
  • An example of an optical collection path is a second fibre connected to or part of the LED.
  • the second fibre may further by extending through an endoscopic tube 226 as shown in figure 1 when an endoscope and the LED light source 202 are connected.
  • the second fibre may be a multimode fibre.
  • a coherent optical fibre bundle may also be used as the optical transmission path 208 and the optical collection path 220.
  • the light illuminating the region of interest and the light reflected from this region is in this case normally separated by a mirror, e.g. a dichroic mirror.
  • the illumination system 200 may also comprise a band-rejection filter 224 adapted to attenuate at least a part of the tuned LED wavelength 208 for the viewer.
  • the band-rejection filter 224 attenuates the majority of the tuned LED wavelength 208 for the viewer.
  • the band-rejection filter 224 may be a narrow band rejection filter, such as a notch filter, preferably a Raman notch filter, also known as a rugate filter. Another example of a narrow band rejection filter that can be used is a Fabry-Perot etalon.
  • the rejection band of the band-rejection filter 224 comprises the tuned LED wavelength 208.
  • the rejection band of the band-rejection filter is centred closed to the tuned central LED wavelength 208.
  • the band-rejection filter 224 may be designed such that it blocks wavelengths below around the central wavelength of the monochromatic tuned LED 210 and allows wavelengths above this wavelength to pass through.
  • the illumination system includes a digital solution for a digital endoscope.
  • a camera e.g. in the form of a camera chip
  • the camera comprises an integral colour filter, e.g. in the form of a so-called Bayer mosaic colour filter. This filter makes it possible for the camera to see light in three spectral regions - red, green and blue commonly referred to as RGB. This means that the image transmitted from the distal part of the illumination system subsequently can further be electronically processed to suppress excitation light from the light source and enhance the fluorescence image of tumours and healthy tissue.
  • the integral colour filter acts as the band-rejection filter as it attenuates the tuned LED wavelength.
  • the band-rejection filter is preferably adapted to attenuate the tuned LED wavelength by more than 10 dB, preferably by more than 20 dB, preferably by more than 30 dB, preferably by more than 40 dB, preferably by more than 50 dB, most preferably by more than 60 dB.
  • the optical transmission path and the optical collection path are fibres extending inside an endoscopic tube, the endoscopic tube having:
  • the endoscope further comprises biopsy extracting means adapted for extraction a biopsy sample from e.g. the bladder, wherein the biopsy extracting means extends into the patient's bladder through an auxiliary channel in the endoscopic tube.
  • the endoscope is a digital endoscope.
  • a miniature CCD camera may be located at the distal end 228 of the endoscope 200 whereby the digital image formed in the CCD camera can be transmitted via an electrical connection to the proximal end, thereby eliminating the need for an optical relay system for transmitting images from the distal to the proximal end.
  • the CCD camera comprises an integral colour filter, e.g. in the form of a so-called Bayer mosaic colour filter. This filter makes it possible for the camera to see light in three spectral regions - red, green and blue commonly referred to as RGB. This means that the image transmitted from the distal part of the illumination system subsequently can further be electronically processed to suppress excitation light from the light source and enhance the fluorescence image of tumours and healthy tissue.
  • the endoscope is made from a material which can be reused.
  • the illumination system may e.g. be used for photodynamic diagnostic of bladder cancer.
  • Figure 4A schematically illustrates a bladder 100 with three tumours 102, 104 inside the bladder wall and the urethra 106 leading into the bladder cavity 100.
  • means for guiding the movement of the endoscopic tube when inserting the distal end 228 of the endoscopic tube 226 into the patient's bladder 100 through the patient's urethra 106 is also included in the illumination system.
  • a common problem encountered in endoscopic examination of bladders is that urine has a relatively strong absorption in the UV-blue region.
  • Many commercial monochromatic light sources, used for photodynamic diagnosis or other methods for visualizing malignant tissue emit light in the UV-blue region and thus cause strong green fluorescence in urine that confounds the sensitized fluorescence of the malignant tissue. As urine enters the bladder constantly during examination this problem cannot be avoided and prevents the use of photodynamic diagnosis for bladder cancer to be used in the outpatient department (OPD).
  • OPD outpatient department
  • an endoscope utilizes two wavelength bands, one bright white light source used for illuminating the bladder with white light and a narrow band of light obtained by optically filtering the white light source for exciting the fluorophore of the photosensitizer.
  • the physician locates the pre-cancerous tissue with the fluorescent light and switches to white light in order to remove the pre-cancerous tissue surgically. Thus, the physician has to switch between the two light sources during examination.
  • Photobleaching is primarily caused by bright blue light sources used for illuminating the bladder. The consequence is that some precancerous tissues may remain undetected by the physician.
  • Bladder cancer is identified and resected during endoscopic examination of the bladder through the urethra.
  • a new kind of photodynamic diagnosis (PDD) of bladder cancer (BC) was developed in 2001 where hexaminolevulinate or 5-aminolevulinic acid (5- ALA) is used as precursor to the dye.
  • the aminoacid 5-ALA is metabolized to protoporphyrin IX (PPIX) in the malignant cells which fluoresces at approx. 635 nm when excited with blue light.
  • the illumination system is for endoscopic applications in the bladder, where the LED light has an initial central wavelength between 500 and 550 nm.
  • the photosensitive compound used in that embodiment is preferably selected from the group of porphyrins, such as haematoporphyrin or protoporphyrin, preferably protoporphyrin IX (PPIX).
  • the photosensitive compound is preferably delivered to malignant cells by means of a precursor based on levulinic acid, such as hexaminolevulinate (e.g. Hexvix(R)), 5- aminolevulinic acid (ALA or 5-ALA) or methyl aminolaevulinate (MAL, e.g. Metvix).
  • Levulinic acid are metabolized to photosensitive PPIX in cells through the intrinsic cellular haem biosynthetic pathway.
  • the combination of the tuned monochromatic LED light 208 and the band rejection filter 224 allows the surgeon to use the autofluorescence of the surrounding (healthy) tissue as normal examination light, because the irradiated tissue fluoresces and thereby becomes visible.
  • a 525 nm LED was used resulting in an autofluorescence spectrum from surrounding tissue of approx. 550-700 nm, i.e. only the green, yellow and red part of the visible spectrum, but still adequate for discerning the morphology of the tissue.
  • Using the monochromatic light source generated autofluorescence light from the healthy tissue as normal examination light allows the surgeon to skip the use of bulky liquid core light guides and power consuming metal halide lamps or discharge lamps, like xenon lamps, normally used in many endoscopic procedures.
  • Use of an LED as examination light source greatly reduces the footprint of the optical transmission path, because the light may be transmitted to the region of examination via a thin optical fiber with a diameter of 0.5 mm. And the power consumption of the excitation light source may also be reduced.
  • tuning of the LED in the illumination system is highly advantageous, as the contrast between the different fluorescence colors can be optimized individually for each patient without changing filters or using expensive optics.
  • Figure 4B shows an image of the bladder before tuning the LED wavelength and 4C shows an image of the bladder after tuning the LED wavelength to obtain a maximum contrast signal for the viewer.
  • the system and the method of the present disclosure need only have one light source for illuminating the bladder, since the monochromatic LED generates sufficient autofluorescence in the bladder to allow an observer, e.g. a physician, to view the tissue irradiated by the light from the monochromatic LED because the irradiated tissue is being illuminated by the autofluorescence generated in the irradiated tissue, i.e. the tissue fluoresces whereby it becomes visible.
  • the possibility to perform photodynamic diagnosis of bladder cancer in the outpatient department combined with photo induced denaturation of tumour tissue inside the bladder of the patient greatly reduces the cost of bladder cancer / tumor diagnosis and treatment.
  • Bladder tumour disease is a disease normally experienced by elderly people with a median age of bladder tumours debut at 65 years. Less straining treatment is required, as populations and thus also patients get older and suffer from more comorbidity making them less fit for admittance to hospital and general anaesthesia.
  • Urothelial cancer of the bladder is the second most expensive cancer disease and the one of the most common cancer types detected in Europe. About 75% of the patients suffer from non-muscle invasive bladder cancer (NMIBC) and account for approximately 65% of the cost of bladder cancer treatment.
  • NMIBC non-muscle invasive bladder cancer
  • NMIBC is normally removed in general anesthesia either by admitting the patient for two- three days to a urology ward or in day-surgery settings.
  • the prognosis of NMIBC is good, although 30-80% of cases will recur. In 1-45% of the cases NMIBC will progress to muscle invasion within 5 years. Consequently, NMIBC is a chronic disease with varying oncologic outcomes.
  • the LV technique has traditionally been tested using either a Holmium laser emitting light with a wavelength of 2100 nm or a Thulium laser emitting light with a wavelength of 2013 nm to vaporize the entire tumour.
  • Removal of bladder tumours using the Holmium laser technique may produce less pain than diathermia.
  • the method has mainly been used for patients unfit for general anesthesia, presenting solitary or few small tumours and without routine simultaneous biopsy. Also, when using this technique, the operation procedure normally takes between 15 to 35 minutes, which may be straining for a fragile elderly awaken patient.
  • Laser TUR-BT has mainly been tested in rigid cystoscopes and in the operating theatre in general anesthetic using Holmium or Thulium lasers to vaporize the entire tumour or using vaporizing to do en-bloc tumour resection.
  • the experience is that the operation time may be longer for laser surgery than conventional TUR-BT, but the method is safe, excellent hemostasis is achieved, obturator nerve reflection is not seen and bladder perforation very rare.
  • laser based TUR-BT is more or less equal to TUR-BT using diathermia.
  • Thulium laser TUR-BT of non-invasive urothelial bladder tumours in selected patients was reported showing a recurrence rate at 14.5% during 16 months follow-up and a 2 year over all recurrence rate at 48% after Holmium laser TUR-BT. Similar results may be found after golden standard TUR-BT in general anaesthetic but data comparing laser TUR-BT and conventional TUR-BT are missing.
  • a system for photo induced denaturation of tumour tissue inside e.g. a bladder may be incorporated in a system comprising the illumination system.
  • An example of such a system 400 is shown in figure 5.
  • the illumination system 200 of figure 1 is shown in figure 5 in combination with a high intensity treatment light source 402 adapted for photo induced denaturation of tumour tissue inside the bladder in connection with treatment of bladder tumours.
  • the high intensity treatment light source 402 is in one or more embodiments a solid state light source emitting light 404 at a wavelength between 800-1000 nm. This wavelength range is in particularly suitable for photo induced denaturation of tumour tissue having a cauliflower shape as shown as item 102 in figure 4A.
  • the high intensity treatment light source 402 is in one or more embodiments a solid state light source emitting light at a wavelength between 350-500 nm. This wavelength range is in particularly suitable for photo induced denaturation of tumour tissue having a flat shape as shown as item 104 in figure 4A.
  • the high intensity treatment light source 402 emits light 404 and further comprises a second optical transmission path 406 for guiding light 404 from the high intensity treatment light source 402 to a distal end 228 of the endoscopic tube 226.
  • the first optical transmission path 208 and the second transmission path 406 may be combined or two separate channels extending through the endoscopic tube 406.
  • a third fibre is connected to or part of the high intensity treatment light source 402 the third fibre extending through the endoscopic tube when the cystoscope and the high intensity treatment light source are connected.
  • the system 400 also comprises a cystoscope comprising an endoscopic tube 226 with a distal end 228 adapted for extending through a patient's urethra 106 into the patient's bladder cavity 100 and a second optical transmission path 406 for guiding light 404 from the high intensity treatment light source 402 to the distal end 228 of the endoscopic tube 226.
  • the high intensity treatment light source 402 is adapted for photo induced denaturation of tumour tissue 102, 104 inside the bladder 100 of the patient.
  • the high intensity treatment light source 402 and the LED 202 are the only light sources in the system 400.
  • the high intensity treatment light source 402 is a diode laser, a high power light emitting diode, or a fibre laser. Other laser types may also be imagined. In one or more embodiments, the high intensity treatment light source 402 is a diode laser emitting light at a wavelength of 808 nm, 820 nm, 880 nm, 940 nm or 980 nm. In one or more embodiments, the high intensity treatment light source 402 is a diode laser emitting light at a wavelength of 808 nm.
  • the high intensity treatment light source 402 is a diode laser emitting light at a wavelength of 820 nm.
  • the high intensity treatment light source 402 is a diode laser emitting light at a wavelength of 880 nm.
  • the high intensity treatment light source 402 is a diode laser emitting light at a wavelength of 940 nm.
  • the high intensity treatment light source 402 is a diode laser emitting light at a wavelength of 980 nm.
  • the conventionally used Holmium and Thulium lasers differs from the solid state light source used here as the high intensity treatment light source 402 in that the Holmium and Thulium lasers emit light at 2100 nm and 2013 nm, respectively, and not between 800-1000 nm or between 350-500 nm.
  • the Holmium and Thulium lasers emit light at 2100 nm and 2013 nm, respectively, and not between 800-1000 nm or between 350-500 nm.
  • a strong optical absorption in water is present, which lead to a penetration depth of only 0.1 mm in water.
  • the Holmium laser being a pulsed laser, this leads to adiabatic heating of water and subsequent formation of steam bubbles, which ablate tissue mechanically but do not coagulate blood vessels.
  • the continuous wave Thulium laser can coagulate blood vessels, but only if the fibre tip is in intimate contact with the blood vessel due to the strong absorbance of water at 2013 nm.
  • An advantage of using a solid state light source in the form of e.g. a diode laser is the lack of steam bubble effect. Both the Holmium and the Thulium laser (however to less extent) creates steam bubbles, when their energy destructs the tissue which may affect visibility during the operation.
  • Another advantages of solid state light sources in comparison with Holmium and Thulium lasers are a smaller box size and a much higher wall-plug efficiency i.e., how much of the main supply is converted into laser power and a lower price.
  • photo induced denaturation / de-vascularization of the tumour by illuminating the blood vessels in the tumour base / root 108 with a wavelength between 800- 1000 nm, which is absorbed in haemoglobin, results in a heating of haemoglobin.
  • the accumulated heat in the haemoglobin and surrounding tissue cause clotting of the vessels and subsequent tumour ischemia.
  • the tumour 102, 104 is not removed from the bladder 100 during the procedure, but exfoliates during the following days due to ischemia. Patients tell that they pass small tissue clots in the urine during days after treatment.
  • haemoglobin absorbs light efficiently, which results in an occluded vessels in the tumour base.
  • the optical absorption coefficient in hemoglobin is 50 cm "1 , which is sufficient to heat and ensure coagulation of blood vessels in tumour.
  • a low absorption coefficient of 0,3 cm "1 in water makes deep tissue penetration possible. Shorter wavelengths absorbed more strongly by haemoglobin could also be used to treat carcinoma in situ of the bladder wall in order to prevent unintended heating of healthy tissue below which may cause pain.
  • wavelengths in blue spectral region are avoided for photocoagulation in medical treatments of the retina and skin diseases like telangiectasia and haemangioma.
  • the retina In the case of the retina it is to avoid absorption in xanthophyll (pigment of the macula).
  • the blue light would be scattered too strongly (due to Rayleigh and Lorenz-Mie scattering).
  • the use of blue light for photocoagulation of blood vessels in tumour 102, 104 of the bladder may therefore be unique to the bladder.
  • the high intensity treatment light source 402 may therefore emit light 404 at a wavelength of between 350-500 nm.
  • the high intensity treatment light source 402 is a laser emitting a pulse with a duration of approximately 1 millisecond.
  • the high intensity treatment light source 402 is a laser emitting a pulse in intervals of 1 milliseconds.
  • the high intensity treatment light source 402 is a laser emitting a pulse with a duration of approximately 1 millisecond and in intervals of 1 milliseconds. In one or more embodiments, the high intensity treatment light source 402 is a laser emitting pulses for an exposure treatment time of between 10-240 seconds, or between 10-120 seconds, or between 30-120 seconds, or between 30-60 seconds is used.
  • tumour 102, 104 Normally, only the base 108 of the tumour 102, 104, and not the entire tumour is denaturized.
  • a tumour up to a size of about 2 centimetres may be de-vascularize using a solid state light source between 800-1000 nm or 350-500 nm according to this invention.
  • the de-vascularized tumour 102, 104 is left in the bladder 100 after treatment. As the tumour 102, 104 is left in situ but without blood supply, it will dye and fall off after some weeks. The tumour 102 , 104 then exfoliates due to ischemia.
  • Most suitable for removing cauliflower-shaped tumours 102 using photo denaturisation is a solid state light source between 800-1000 nm, whereas the flat tumours 104 are best removed used photo denaturisation with a solid state light source between 350-500 nm.
  • the procedure is almost pain free and do not include the use of pain killers. Normally, the patients can leave the outpatient department immediately after the cystoscope has been removed.
  • the high intensity treatment light source 402 is used in combination with a system comprising a cystoscope comprising an endoscopic tube 226 with a distal end 228 adapted for extending through a patient's urethra into the patient's bladder cavity, the endoscopic tube 406 being adapted to hold a first optical transmission path 410 for guiding light from the solid state light source, i.e. the high intensity treatment light source 226, to the distal end 228 of the endoscopic tube 226, and means for guiding the movement of the endoscopic tube when inserting the distal end of the endoscopic tube into the patient's bladder through the patient's urethra.
  • the cystoscope is a flexible cystoscope.
  • the high intensity treatment light source is a laser.
  • the impact of varying laser illumination time, laser power and distance between fibre and target tissue were investigated.
  • the laser treatment with a diode laser emitting light at 980 nm in 1 millisecond pulses at intervals of 1 millisecond was conducted for 10 seconds, 15 seconds, 30 seconds and 45 seconds.
  • the 980 nm diode laser was set to an average power of 12 W.
  • the diode laser was a 220 V / battery driven laser with a green 532 nm aiming beam and a front firing 400 ⁇ 0,22 numerical aperture bare laser fibre attached (Fox Laser; dimensions: 14 x 16 x 17 cm and 1.2 kilo; A.R.C. Laser GmbH, Nuremberg. Germany).
  • the distance between the chicken meat and a fibre connected to the diode laser for controlling the illumination distance between the laser light and the chicken meat was set to 0 mm, the fibre just touching the meat without applying pressure to the chicken meat.
  • Figure 6a shows the laser induced tissue destruction in chicken meat after 45 seconds of laser illumination.
  • Figure 6b shows the tissue destruction depth as a function of the laser treatment time and figure 6c shows the tissue destruction width as a function of the laser treatment time. From figure 6b it can be seen that the destructive effect in depth appears to reach a maximal effect after between 30 to 45 seconds. Contrary, the width of the tissue destruction as shown in figure 6c seems to have a constant level between 2-3 millimetre.
  • a flexible cystoscope (Karl Storz) was used through which a 400 micron fibre was introduced into the bladder through the urethra.
  • Figure 7a-e show the inside of a bladder in a 62 years old male patient with a previous history of Ta low grade urothelial tumour at different time during treatment of bladder cancer. As can be seen in the before treatment picture in figure 7a, the patient has healthy tissue
  • FIG. 7b is a picture taken during the treatment period and figure 7c is taken directly after the treatment has ended. In figure 7c, it can be seen that the tumour 700 is still attached to the healthy tissue 700.
  • the laser treatment procedure shown in figure 7a-c lasted two minutes and the entire procedure including a washing lasted for about 15 minutes. Afterwards, the patient could leave the OPO for returning to work.
  • the alternative standard treatment would require one to three days of hospitalization and surgery during general anaesthesia.
  • the diode laser in the in vivo studies was used with similar settings as for the in vitro studies.
  • the tumour was given laser treatment for a total of two minutes at different places at tumour basis and the tumour was left in situ. Biopsy and images of the tumour area shown in figure 7a-c was observed again 14 days and 4 months after treatment as shown in figure 7d and figure 7e, respectively. As can be seen in figure 7d no residual tumour was detected after 14 days - only a small reddening 704 of the treated tissue area is observable when comparing figure 7d and figure 7e.
  • Tumours all over the bladder may be treated using the setup described herein, even in the bladder neck when using a flexible cystoscope with endoscopic tubes in the form of smooth and bendable laser fibres.
  • the largest tumour size for treatment normally does not exceed 2-2.5 cm, but the number of tumours to be treated in one patient is less important. We have treated up to 10 tumours in a bladder of one patient may be treated during one treatment session.

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Abstract

L'invention concerne un système d'éclairage (200) permettant un accord spectral dans des applications d'imagerie par fluorescence telles que des applications endoscopiques dans une cavité corporelle comprenant des liquides organiques ou des applications microscopiques.
PCT/EP2017/052531 2016-02-11 2017-02-06 Source lumineuse à del accordable en longueur d'onde Ceased WO2017137350A1 (fr)

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WO2019116947A1 (fr) * 2017-12-15 2019-06-20 Hoya株式会社 Système d'endoscope électronique
JP2021500552A (ja) * 2017-10-20 2021-01-07 ナントバイオ，インコーポレイテッド 膀胱癌免疫療法のモニタリング方法
EP3738511B1 (fr) * 2019-05-16 2023-04-26 inContAlert GmbH Dispositif de mesure non invasif permettant de mesurer une retention liquidienne dans la vessie d'un patient
WO2023126344A1 (fr) * 2021-12-30 2023-07-06 Optheras A/S Appareil de traitement médical à fibre optique permettant de traiter une voie urinaire d'un sujet
CN119279526A (zh) * 2024-12-13 2025-01-10 广东欧谱曼迪科技股份有限公司 一种适用于膀胱光动力诊断的荧光成像方法
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021500552A (ja) * 2017-10-20 2021-01-07 ナントバイオ，インコーポレイテッド 膀胱癌免疫療法のモニタリング方法
WO2019116947A1 (fr) * 2017-12-15 2019-06-20 Hoya株式会社 Système d'endoscope électronique
EP3738511B1 (fr) * 2019-05-16 2023-04-26 inContAlert GmbH Dispositif de mesure non invasif permettant de mesurer une retention liquidienne dans la vessie d'un patient
WO2023126344A1 (fr) * 2021-12-30 2023-07-06 Optheras A/S Appareil de traitement médical à fibre optique permettant de traiter une voie urinaire d'un sujet
CN119279526A (zh) * 2024-12-13 2025-01-10 广东欧谱曼迪科技股份有限公司 一种适用于膀胱光动力诊断的荧光成像方法
CN119279525A (zh) * 2024-12-13 2025-01-10 广东欧谱曼迪科技股份有限公司 一种基于光源通滤的荧光成像方法、装置及存储介质
CN119279526B (zh) * 2024-12-13 2025-03-25 广东欧谱曼迪科技股份有限公司 一种适用于膀胱光动力诊断的荧光成像方法
CN119279525B (zh) * 2024-12-13 2025-03-25 广东欧谱曼迪科技股份有限公司 一种基于光源通滤的荧光成像方法、装置及存储介质

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