WO2019212472A1 - Systèmes d'imagerie endoscopique par imagerie chimique moléculaire - Google Patents

Systèmes d'imagerie endoscopique par imagerie chimique moléculaire Download PDF

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Publication number
WO2019212472A1
WO2019212472A1 PCT/US2018/030155 US2018030155W WO2019212472A1 WO 2019212472 A1 WO2019212472 A1 WO 2019212472A1 US 2018030155 W US2018030155 W US 2018030155W WO 2019212472 A1 WO2019212472 A1 WO 2019212472A1
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Prior art keywords
analysis
detector
image data
data set
optical component
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PCT/US2018/030155
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English (en)
Inventor
Patrick Treado
Matthew Nelson
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Chemimage Corporation
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Application filed by Chemimage Corporation filed Critical Chemimage Corporation
Priority to PCT/US2018/030155 priority Critical patent/WO2019212472A1/fr
Priority to CN201880092935.3A priority patent/CN112105283A/zh
Priority to EP18917268.7A priority patent/EP3787469A4/fr
Priority to JP2020545579A priority patent/JP7357931B2/ja
Publication of WO2019212472A1 publication Critical patent/WO2019212472A1/fr

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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
    • A61B1/00002—Operational features of endoscopes
    • A61B1/00004—Operational features of endoscopes characterised by electronic signal processing
    • A61B1/00009—Operational features of endoscopes characterised by electronic signal processing of image signals during a use of endoscope
    • A61B1/000094—Operational features of endoscopes characterised by electronic signal processing of image signals during a use of endoscope extracting biological structures
    • 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
    • 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
    • A61B1/05—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 characterised by the image sensor, e.g. camera, being in the distal end portion
    • 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
    • A61B1/06—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
    • A61B1/0607—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 annular illumination
    • 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
    • A61B1/06—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
    • 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
    • A61B1/06—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
    • A61B1/0669—Endoscope light sources at proximal end of an endoscope
    • 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
    • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
    • 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

Definitions

  • the instant disclosure provides medical imaging systems.
  • the medical imaging systems may be used in conjunction with an endoscope.
  • the medical imaging system includes an illumination source configured to generate illuminating photons.
  • the illuminating photons are transmitted to one or more filters configured to filter a first plurality of illuminating photons and generate a first plurality of filtered photons comprising a first passband wavelength and a second plurality of filtered photons comprising a second passband wavelength.
  • a sample is then illuminated with the first plurality of filtered photons and the second plurality of filtered photons to generate a first plurality of interacted photons and a second plurality of interacted photons.
  • One or more detectors are configured to detect the first plurality of interacted photons and the second plurality of interacted photons and generate one or more image data sets.
  • the imaging system includes an illumination source configured to illuminate a sample and generate interacted photons.
  • One or more filters are configured to filter one or more of a first plurality of the interacted photons and transmit a first passband wavelength and a second plurality of the interacted photons and transmit a second passband wavelength.
  • the first and second passband wavelengths are transmitted to one or more detectors configured to detect the first passband wavelength and the second passband wavelength and generate one or more image data sets.
  • the imaging system features an illumination source configured to illuminate a sample with one or more of a first plurality of illuminating photons having a first wavelength to generate a first plurality of interacted photons and a second plurality of illuminating photons having a second wavelength to generate a second plurality of interacted photons.
  • One or more detectors are configured to detect the first plurality of interacted photons and the second plurality of interacted photons to generate one or more image data sets.
  • FIG. 1 illustrates an endoscope comprising an imaging system having a plurality of conformal filters in a dual polarization configuration, according to an embodiment
  • FIG. 1 A is an end-on view of the endoscope according to the embodiment in Fig. 1;
  • FIG. 1B illustrates a patterned conformal filter configuration with a CCD detector, according to an embodiment
  • FIG. 2 illustrates an endoscope comprising an imaging system having a plurality of multivariate optical element (MOE) filters, according to an embodiment
  • FIG. 2A is an end-on view of the endoscope according to the embodiment in FIG. 2;
  • FIG. 2B is a cross-sectional view of the distal end of the endoscope according to the embodiment in FIG. 2;
  • FIG. 3 illustrates an endoscope comprising an imaging system having a conformal filter, according to an embodiment
  • FIG. 3A is an end-on view of the endoscope according to the embodiment in FIG. 3;
  • FIG. 4 illustrates an endoscope comprising an imaging system having a plurality of conformal filters in a dual polarization configuration for source illumination modulation, according to an embodiment
  • FIG. 4A is an end-on view of the endoscope according to the embodiment in FIG. 4;
  • FIG. 4B is an end-on view of an alternate embodiment of the endoscope according to the embodiment in FIG. 4;
  • FIG. 5 illustrates an endoscope comprising an imaging system having an acousto-optic filter, according to an embodiment
  • FIG. 5A is an end-on view of the endoscope according the embodiment in
  • FIG. 5
  • FIG.6 illustrates an endoscope comprising an imaging system having a MOE filter wheel, according to an embodiment
  • FIG. 6A is an end-on view of the endoscope according to the embodiment in Fig. 6; and [0020]
  • FIG. 7 illustrates an endoscope comprising an imaging system having a patterned etalon filter arrangements, according to an embodiment.
  • the present disclosure features intraoperative medical imaging systems which can assist surgeons in various medical procedures.
  • the systems disclosed herein are suitable for use as stand-alone devices, or may be incorporated into other medical imaging devices such as a robotic platform.
  • the systems disclosed herein may be used in conjunction with an endoscope.
  • the medical imaging systems disclosed herein may provide real-time detection of tumors and anatomic structures during endoscopic procedures.
  • the systems disclosed herein provide illuminating a biological sample, collecting photons that have interacted with the sample, detecting the interacted photons to generate an image data set of the sample, and analyzing the image data set.
  • Interacted photons may comprise one or more of photons absorbed by a sample, photons reflected by a sample, photons scattered by a sample, and photons emitted by a sample.
  • the medical imaging system provides multivariate imaging. Multivariate imaging features generating two or more wavelengths corresponding to a first image data set (Tl) and a second image data set (T2). These first and second image data sets may be analyzed using an optical computation. Multivariate imaging creates enhanced image contrast and increased discrimination between a target and background.
  • the first image data set and the second image data set feature hyperspectral image data.
  • the medical imaging systems feature imaging frame rates of > 10 Hz (hyper cubes/second).
  • the systems disclosed herein may be used on various biological samples, such as tissues, organs, anatomical structures, physiological systems, cells, blood, fat, nerves, muscle and the like.
  • the systems may be employed in various areas of the body, which would be apparent to one of skill in the art in view of this disclosure.
  • the systems might be employed to investigate and/or perform surgery in the gastrointestinal tract.
  • the systems may be employed in any of the esophagus, the stomach, the duodenum, the small intestine, the large intestine/colon, the bile duct, the rectum, the anus and the like.
  • the systems may further be employed on structures of the respiratory tract including, without limitation, the nose, the sinuses and the lower respiratory tract.
  • the systems disclosed herein may be used to investigate and/or perform surgery on structures comprising the urinary tract, such as the bladder, ureter, kidneys and so forth.
  • the systems may be employed on structures comprising the female reproductive system, such as the cervix, uterus, fallopian tubes and the like.
  • the systems may be employed in medical procedures performed during pregnancy, such as to investigate and/or perform medical procedures on the amnion and fetus.
  • the systems described herein may be employed to investigate and/or perform surgery on the structures involving the musculoskeletal system, i.e., orthopaedics, including the structures of the hand, the knee, the elbow, the shoulder, the spine, including the epidural cavity, bursae, muscles, ligaments, connective tissues and the like.
  • orthopaedics including the structures of the hand, the knee, the elbow, the shoulder, the spine, including the epidural cavity, bursae, muscles, ligaments, connective tissues and the like.
  • the systems may be configured to discriminate between two or more different biological samples.
  • the systems disclosed herein may be configured to discriminate between a ureter and surrounding tissue and fat.
  • the systems disclosed herein may be employed to differentiate cancer from normal tissue, determine one or more of a cancer stage, cancer progression and cancer grade.
  • the systems may be employed during surgical procedures to remove cancer tissue or tumors found on the biological sample.
  • the systems described herein may be employed to differentiate anatomical structures by identifying a bodily fluid associated with such anatomic structures.
  • Bodily fluids may include, for example, urine, saliva, sputum, blood, feces, mucus, pus, semen, lymph, wound exudate, mammary fluid, vaginal fluid and the like.
  • Anatomical structures having an associated bodily fluid would be apparent to those of ordinary skill in the art.
  • the systems of the present disclosure provide illumination to a biological tissue. It is known that such illumination may penetrate a biological sample up to several centimeters, depending on wavelength and tissue type. Thus, such illumination penetration permits the imaging of bodily fluids contained inside an anatomical structure. Further, the bodily fluids may be directly imaged where their presence resides outside of the anatomical structure or other biological sample In another embodiment, the systems disclosed herein may be employed to identify a ureter by detecting urine in or around the ureter.
  • the instant systems may be employed with the use of one or more contrasting-enhancing agents.
  • Contrast-enhancing agents may include one or more stains or dyes. When only one stain or dye is used, the procedure is referred to as staining. Multiple staining comprises the use of more than one stain or dye.
  • a“stain” or“dye” is any chemical or biological compound that can bind to a substance in a biological sample, to induce a color.
  • a stain or dye can bind to a particular cellular or biochemical structure (e.g., cell membrane, organelles, nucleic acid, protein) to induce contrasts when viewed using the systems described herein.
  • the stain or dye can induce a color by emitting electromagnetic radiation at one or more wavelengths when excited (i.e., fluoresce).
  • the one or more stains or dyes can be used, for example, in vivo or ex vivo.
  • the stain or dye is any stain or dye suitable for use in a living organism/individual that does not kill cells, i.e,. a biological stain.
  • biological stains include, but are not limited to, azo dyes, arylmethane dyes, cyanine dyes, thiazine dyes, xanthene dyes (e.g., eosin), natural stains (e.g., alizarin red), steroids, trypan blue, janus green, indocyanine green, alizarin red, propidium iodide, erythrosine, 7-aminotinomycin D, and Nile blue.
  • the contrasting-enhancing agent is a fluorescent contrast- enhancing agent.
  • the contrast-enhancing agent may include a Flourophor.
  • Suitable Fluorophores include an immuno-fluorescent compound, a basophilic compound, an acidophilic compound, neutral stains and naturally occurring luminescent molecules.
  • a user e.g., a surgeon
  • some (one or more) biological stains can identify cancerous cells so that the surgeon can resect the tumor.
  • Other biological stains can also identify living cells (tissue) versus non-living cells.
  • the contrast-enhancing agent may be ingested by a subject, where the contrast-enhancing agent will appear in a bodily fluid.
  • the contrast-enhancing agent may be taken orally, through an IV or through other means as would be apparent to one of skill in the art in view of this disclosure.
  • the target biological sample may be examined by the systems disclosed herein.
  • the systems may be configured to detect the contrast-enhancing agent in the bodily fluid to provide contrast between structures comprising the bodily fluid and surrounding biological samples, such as surrounding tissue.
  • a patient may orally ingest a solution comprising a contrast-enhancing agent where the contrast-enhancing agent at a certain time thereafter appears in the patient’s urine.
  • a endoscopic procedure may be performed on the kidney area of the patient with a system according to the instant disclosure.
  • the system is configured to detect the contrast-enhancing agent present in the urine located in an ureter to differentiate the ureter and other surrounding tissues.
  • a biological tissue may be imaged with a system according to the instant disclosure ex vivo.
  • the biological sample may be removed and analyzed outside of the surgical site.
  • Traditional staining methods may be applied to the resected tissue to determine one or more biological characteristics of the sample. Ex vivo techniques are known in the art and would be apparent to one of skill in the art in view of this disclosure.
  • the biological sample may be enhanced by applying a digital stain to the sample.
  • Digital stains are applied to an image data set by using an algorithm.
  • the use of a digital stain eliminates the need to apply a physical and/or chemical stain to the biological sample.
  • Digital stains may be applied to any of the image data sets obtained through the systems disclosed herein.
  • One example of the application of a digital stain to a Raman data set may be found in U.S. Patent Application Publication Number 2012/0083678, filed as application number 13/200,779 on September 30, 2011 to Drauch et al. and entitled SYSTEM AND METHOD FOR RAMAN CHEMICAL ANALYSIS OF LUNG CANCER WITH DIGITAL STAINING, assigned to Chemlmage Corporation, Pittsburgh, PA, the entirety of which is incorporated herein by reference.
  • the instant disclosure is directed to analyzing a ureter via an endoscope.
  • Other medical imaging instrumentation and the detection of other types of biological samples is further contemplated by the instant disclosure and would be apparent to those of skill in the art in view of the instant disclosure.
  • the medical imaging instalments disclosed herein provide real-time multivariate imaging by generating a multivariate signal using one or more detectors. The detectors detect the multivariate signal to produce one or more image data sets. Provided herein are two ways to achieve this result. One such method includes illuminating a sample, collecting interacted photons that have interacted with the sample, and modulating the collected signal prior to passing the signal on to a detector.
  • a second method includes modulating the illumination source signal prior to interaction with a sample, collecting interacted photons of the modulated signal, and detecting the interacted photons of the signal.
  • Both processes provide a modulated signal to produce a multivariate chemical image in real- time with enhanced contrast to assist surgeons with delicate medical procedures.
  • the embodiments contained herein can further be configured to provide real-time images displayed in stereo vision. Such a configuration would be apparent to those of skill in the art in view of this disclosure. Stereo vision further assists a surgeon by providing the depth perception needed in medical procedures employing medical imaging techniques, such as in endoscopic procedures.
  • the following embodiment features modulating an optical signal after the collection of photons that have interacted with a sample.
  • a biological sample 100 may be illuminated and/or excited by an illumination source 103.
  • the illumination source 103 may comprise a quartz tungsten halogen light source.
  • the illumination source may comprise a metal halide light source, a light emitting diode (LED), a LED array having a uniform selection of emitters which emit over a constant wavelength range or a plurality of emitters which emit over a diversity of wavelength ranges, a pulsed LED, a pulsed LED array, a laser, a pulsed laser, a broadband illumination source and/or the like.
  • LED light emitting diode
  • the illumination source 103 generates illuminating photons that are directed from the illumination source 103 to the distal end of an endoscope 102 through a fiber optic bundle 104.
  • the endoscope 102 is configured to direct interacted photons 101 that have interacted with the biological sample 100 to a polarizing beam splitter 107.
  • Two independently tunable conformal filters 105a, 105b are situated along distinct orthogonal beam paths to filter orthogonal polarization components emerging from polarizing beam splitter 107.
  • Suitable conformal filters for use in the instant disclosure may include those disclosed in U.S. Patent Application Publication Number 2013/0176568 to Priore et al., filed January 4, 2013, assigned to Chemimage Corporation and entitled CONFORMAL FILTER AND METHOD OF USE TITEREOF, the entirety of which is hereby incorporated by reference.
  • the paths of the filtered beams are not parallel through the conformal filters 105a, 105b, but are directed by appropriate reflectors, i.e., mirrors, 109a, 109b to a beam combiner 111.
  • the beam combiner may be a polarizing cube or polarizing beam splitter.
  • the orthogonal components may comprise the same or different multi-passband wavelengths Sli and ⁇ l 2.
  • the conformal filter 105a is configured to generate a polarized multi-passband wavelengths Sli and conformal filter 105b is configured to generate a polarized multi-passband wavelengths ⁇ l 2.
  • multi-passband wavelengths Sli and ⁇ l 2 are directed to a detector 115 through a lens assembly (not shown).
  • the multi-passband wavelengths Sli and ⁇ l 2 may be combined as they are directed to the detector 115.
  • beam paths from the polarizing beam splitter 107 to the beam combiner 111 may be made symmetrical to avoid, for example, a need for infinitely-corrected optics.
  • the detector 115 as illustrated comprises a CCD detector.
  • the detector 115 may comprise other suitable detectors including, for example, a complementary metal-oxide-semiconductor, a (CMOS) detector, an indium gallium arsenide (InGaAs) detector, a platinum silicide (PtSi) detector, an indium antimonide (“InSb”) detector, a mercury cadmium telluride (“HgCdTe”) detector, or combinations thereof.
  • CMOS complementary metal-oxide-semiconductor
  • InGaAs indium gallium arsenide
  • PtSi platinum silicide
  • InSb indium antimonide
  • HgCdTe mercury cadmium telluride
  • the controller 117 may be configured to independently tune each multi-passband wavelengths Sli and ⁇ l 2 to respectively process orthogonal components of the input. Therefore, by appropriate control, the conformal filters 105a and 105b may be tuned to the same multi-passband wavelengths or to two different multi-passband wavelengths ( ⁇ l
  • the controller 117 may be programmable or software-implemented to allow a user to selectively tune each conformal filter as desired.
  • a fast switching mechanism (not shown) may be provided to switch between the two views (or spectral images) corresponding to spectral data collected by the detector 117 from each of the conformal filters 105a and 105b.
  • FIG. 1 comprises a single CCD detector 115 to capture the filtered signals received from the conformal filters 105a and 105b.
  • FIG. 1B illustrates an alternative embodiment of the instant disclosure.
  • the beam combiner 111 and mirror 109a may be removed and two detectors may be used.
  • the first conformal filter 105a is configured to filter and transmit first multi- passband wavelengths corresponding to a Tl state to a first detector 115a where the first detector 115a detects the first multi-passband wavelengths and generates a first image data set (Tl).
  • the second conformal filter 105b is configured to filter and transmit second multi-passband wavelengths corresponding to a T2 state to a second detector 115b where the second detector 115b detects the second multi-passband wavelengths and generate a second image data set (T2)..
  • Fig. 1A illustrates an end-on view of the distal end of the endoscope 102.
  • the distal end features a lens 119 for collecting interacted photons 101 and fiber ends 121 of the fiber optic bundle 103 which illuminate the biological sample 100 to generate the interacted photons 101.
  • the detector 115 detects the multi-passband wavelength from the conformal filters 105a and 105b and is configured to generate one or more image data sets.
  • the image data set may comprise a Tl image corresponding to the first multi-passband wavelengths Sli and a T2 image corresponding to the second multi-passband wavelengths ⁇ l 2.
  • the image data set comprises a Raman image data set.
  • the one or more image data sets generated by the detector 115 may be further analyzed as set forth below.
  • FIG. 2 illustrates another embodiment featuring modulating the collected optical signal.
  • an illumination source 103 generates illuminating photons which traverse along a fiber optic bundle 104 through an endoscope 102 and terminate at a series of fiber ends 121 on the distal end of the endoscope 102 (shown in FIG 2A).
  • the fiber ends 121 emit illuminating photons to illuminate a sample 100 to produce a plurality of interacted photons 101.
  • the interacted photons are collected by a first collection optic 231 and a second collection optic 233.
  • the first collection optic 231 collects a first portion of the interacted photons 101 and passes these photons on to a first Multivariate Optical Element“MOE” filter 237 which filters the first portion of the interacted photons 101 to generate a first portion of filtered photons.
  • the first portion of filtered photons is detected by a first detector 241.
  • the second collection optic 233 collects a second portion of the interacted photons 101 and passes these photons on to a second MOE filter 238 to generate a second portion of filtered photons.
  • the second portion of filtered photons is detected by a second detector 239.
  • the first detector 239 and the second detector 241 are CCD detectors.
  • the detectors 239 and 241 may comprise other suitable detectors including, for example, a complementary metal-oxide-semiconductor, a (CMOS) detector, an indium gallium arsenide (InGaAs) detector, a platinum silicide (PtSi) detector, an indium antimonide (“InSb”) detector, a mercury cadmium telluride (“HgCdTe”) detector, or combinations thereof.
  • CMOS complementary metal-oxide-semiconductor
  • InGaAs indium gallium arsenide
  • PtSi platinum silicide
  • InSb indium antimonide
  • HgCdTe mercury cadmium telluride
  • the first MOE filter 237 may be configured to generate a first filtered passband. In one embodiment, the first MOE filter 237 is configured to generate a first filtered passband consistent with a randomized target or background. In one embodiment, the second MOE filter 238 may be configured to generate a second filtered passband consistent with the target or sample 100. In embodiments where the first MOE filter 231 is configured to generate a first filtered passband corresponding to a randomized target or background, the second MOE filter 238 may be configured to generate a second filtered passband corresponding to a target or sample. This type of embodiment permits discrimination of both a target and a background.
  • MOEs are typically known in the art.
  • An MOE features wide-band, optical interference filters encoded with an application-specific regression (or pattern) specific to a target.
  • MOEs provide multivariate optical computing by performing the optical computation based on the pattern of the filter.
  • MOEs are uniquely tuned to the pattern that needs to be measured using multivariate analysis on the filter as opposed to capturing multiple measurements at different wavelengths to estimate the full spectrum of a target and processing this information by applying multivariate statistics to the spectrum.
  • MOEs increase throughput and efficiency over conventional filters, which can increase the speed of analysis. Suitable MOEs would be apparent to those of skill in the art in view of this disclosure.
  • the first detector 241 is configured to detect the first filtered passband from the first MOE filter 237 to generate a first image data set (Tl), and the second detector 239 is configured to detect the second filtered passband from the second MOE filter 238 to generate a second image data set (T2).
  • Tl first image data set
  • T2 second image data set
  • the first image data set and the second image data set may be further analyzed, as set forth below.
  • the following embodiments feature modulating the illumination source signal prior to interaction with a sample.
  • FIG. 3 illustrates an illumination source 103 configured to generate illuminating photons which are transmitted through a filter 305.
  • the filter 305 comprises a conformal filter, as disclosed herein.
  • the filter 305 may comprise other filters, such as a liquid crystal tunable filter (“LCTF”), or filters as would be apparent to those of skill in the art in view of this disclosure.
  • the filter 305 may include a multi-conjugate filter. The filter 305 is controlled by a controller (not shown) that is configured to switch the filter configuration to pass first multi-passband wavelengths (Sli) and subsequently be switched to configure the filter to pass a second multi-passband wavelengths ( ⁇ l 2 ).
  • a controller not shown
  • the rate at which the controller switches between the two states is on a millisecond order of magnitude.
  • the filter 305 transmits each multi-passband wavelengths, Sli and ⁇ l 2 , through a fiber optic bundle 309 to the distal end of an endoscope 102 where each multi- passband wavelengths exits the distal end of the endoscope 102 via fiber ends 321, as shown in FIG. 3A, to illuminate the sample 100 and produce interacted photons 329.
  • the interacted photons 329 are collected by a first detector 331 and a second detector 335 located on the distal end of the endoscope 102.
  • the detectors 331 and 335 of the illustrated embodiment comprise CCD detectors. However, other detectors, such as disclosed herein, may be employed.
  • the first detector 331 may be configured to detect substantially only the first multi-passband wavelengths. In one embodiment, the first detector 331 may be timed, i.e., turned off and on, to detect the first multi-passband wavelengths concurrent with the filter 305 transmitting the first multi- passband wavelengths. Likewise, the second detector 335 may be configured to detect substantially only the second multi-passband wavelengths. In one embodiment, the second detector 335 may be timed, i.e., turned off and on, to detect the second multi-passband wavelengths concurrent with the filter 305 transmitting the second multi-passband wavelengths.
  • the timing sequence of the modulation between the first multi-passband wavelengths and the second multi-passband wavelengths and the detection of the first multi-passband wavelengths and the second multi-passband wavelengths with the corresponding detector may be controlled by the controller (not shown).
  • the first detector 231 detects the first multi-passband wavelengths and generates a first image data set (Tl) and the second detector detects the second multi-passband wavelengths and generates a second image data set (T2).
  • the first image data set and the second image data set may be further analyzed as set forth below.
  • FIG. 4 illustrates another embodiment of illumination source modulation.
  • an illumination source 103 generates an optical signal that is transmitted through a polarizing beam splitter 405 which splits the optical signal into a first polarization signal and a second polarization signal.
  • the first polarization signal is transmitted to a first filter 409
  • the second polarization signal is transmitted to a second filter 411.
  • the first filter 409 and the second filter 411 each comprise conformal filter, as described herein.
  • the first filter 409 and second filter 411 comprise an LCTF.
  • the first filter 409 and the second filter 411 each may comprise a multi-conjugate filter.
  • the first filter 409 is configured to filter the first polarization signal and transmit a first multi-passband wavelengths (Sli)
  • the second filter 411 is configured to filter the second polarization signal and transmit second multi- passband wavelengths ( ⁇ l 2 ).
  • the first multi-passband wavelengths and the second multi- passband wavelengths are transmitted from their respective filters 409, 411 to the distal end of an endoscope 102 via a first fiber optic bundle 417 and second fiber optic bundle 419.
  • the first fiber optic bundle 417 and the second fiber optic bundle 419 comprise a polarization-maintaining fiber optic bundle.
  • FIG. 4A and FIG. 4B illustrate different embodiments of the distal end of the endoscope 102.
  • the first fiber bundle 417 and a the second fiber bundle 419 traverse through the endoscope 102 to the distal end.
  • the first fiber bundle 417 terminates at first fiber ends 423 and the second fiber bundle 417 terminates at second fiber ends 425.
  • FIG. 4A illustrates one exemplary arrangement of the first fiber ends 423 with respect to the second fiber ends 425.
  • the first fiber ends 423 are distributed together on one side of the distal end of the endoscope 102 and the second fiber ends 425 are distributed together on the other side of the distal end of the endoscope 102.
  • first fiber ends 423 and the second fiber ends 425 alternate around the distal end of the endoscope 102. Suitable arrangements of the fiber ends would be apparent to those of skill in the art in view of this disclosure.
  • the sample 100 is illuminated from the multi-first passband wavelengths and the second multi-passband wavelengths emitting from the first fiber ends 423 and the second fiber ends 425, respectively, to generate interacted photons 435.
  • the interacted photons 435 are detected by a first detector 437 and a second detector 441 disposed on the distal end of the endoscope 102.
  • the first detector 437 and the second detector 441 are CCD detectors.
  • the first fiber bundle 417 and the second fiber bundle 419 comprise polarization maintaining fiber bundles.
  • polarizers may be disposed in front of the detectors 437 and 441, which are arranged for stereovision, and configured to differentiate between a Tl state and a T2 state on the basis of polarization.
  • the first detector 437 is configured to detect substantially only interacted photons generated from the first multi-passband wavelengths
  • the second detector 441 is configured to detect substantially only interacted photons generated from the second multi-passband wavelengths.
  • the location of the first fiber ends 423 and second fiber ends 425 with respect to the first detector 437 and the second detector 441 can be arranged to optimize the detection of the interacted photons corresponding to the first multi-passband wavelengths by the first detector 437 and the interacted photons corresponding to second multi-passband wavelengths by the second detector 441.
  • the first detector 437 and the second detector 441 detect the interacted photons 435, the first detector 437 is configured to generate a first image data set (Tl), and the second detector 441 is configured to generate a second image data set (T2).
  • the first image data set and the second image data set may be further analyzed.
  • FIG. 5 illustrates an embodiment of the instant disclosure employing an acousto-optic tunable filter (AOTF).
  • This embodiment features an illumination source 103 to generate illuminating photons for illuminating a sample 100.
  • a filter 507 is configured to filter photons emitted from the illumination source 103.
  • the filter 507 comprises an AOTF in which the AOTF transmits a single passband wavelength. To achieve a >10 fps sampling rate, the AOTF is rapidly switched between target vs background passband wavelengths.
  • the filter comprises a conformal filter based on AOTF technology in which the AOTF transmits multi-passband wavelengths simultaneously.
  • the conformal filter AOTF is switched in series with microsecond switching speeds.
  • multiple conformal AOTFs may be employed in which the Tl and T2 states are selected simultaneously.
  • each filter may be tuned to various wavelengths where each filter transmits different multi-passband wavelengths simultaneously.
  • Acousto-optic filters are known in the art and, generally, operate by passing a beam of source light through a substrate, typically quartz.
  • the substrate is vibrated by a piezoelectric transducer modulator.
  • An RF frequency is applied to the modulator, causing the substrate to vibrate.
  • Source light or radiation is passed through the vibrating substrate, which causes the source light passing through the substrate to diffract, thus creating a filter gradient for the source light.
  • the source light emitted from the acousto-optic filter can be filtered to a desired passband wavelength by the RF frequency applied to the piezoelectric transducer. Details on the operation of an acousto-optic filter are described in more detail in Turner, John F.
  • the passband wavelength transmitted from the filter 507 is transmitted to the distal end of an endoscope 102 through a fiber optic bundle 515.
  • Fig. 5A illustrates the distal end of the endoscope 102 and features a plurality of fiber ends 519 from the fiber optic bundle 515.
  • the fiber ends 519 transmit the passband wavelength from the filter 507 to illuminate the sample 100 to produce interacted photons 521 which are detected by a first detector 525 and a second detector 529 located on the distal end of the endoscope 102.
  • only one detector is used, i.e., the first detector 525, to detect a plurality of the interacted photons 521.
  • the interacted photons 521 are detected by both detectors 525 and 529.
  • a plurality of acousto-optic filters are employed and generate a first passband wavelength and a second passband wavelength.
  • the first detector 525 may be configured to detect the first passband wavelength and generate a first image data set (Tl)
  • the second detector 529 may be configured to detect the second passband wavelength and generate a second image data set (T2).
  • the first image data set and the second image data set may be further analyzed as set forth below.
  • FIG. 6 illustrates another embodiment according to the instant disclosure.
  • An illumination source 103 generates illuminating photons which are transmitted to a filter wheel 605 where the illuminating photons are filtered to generate filtered photons.
  • the filter wheel 605 comprises a plurality of filter elements 609.
  • each filter element 605 comprises an MOE. Suitable MOEs for use in the instant disclosure are known in the art and described herein.
  • Each filter element 609 may be different and each filter element may be configured to filter and transmit a different passband wavelength.
  • filter element 609a may be configured to transmit a wavelength corresponding to a background, such as a specific type of tissue or anatomical structure
  • filter element 609b may be configured to transmit a passband wavelength corresponding to an anomaly in a tissue sample, such as a cancerous tumor on the tissue.
  • the filter wheel 605 can be rotated during a surgical procedure to assist a surgeon in distinguishing normal tissue from cancerous tissue.
  • the filter elements 609 are configured to detect a plurality of different samples.
  • the filter elements 609 are configured to discriminate background tissue from an anatomical structure such as a ureter.
  • the filtered photons are transmitted via a fiber optic bundle 603 to the distal end of the endoscope 102 and exit the distal end of the endoscope through a plurality of fiber ends 621 as shown in FIG. 6A.
  • the filtered photons illuminate the sample 100 and generate a plurality of interacted photons 601.
  • the interacted photons 601 are detected by a one or more detectors 619, and the one or more detectors 619 is configured to generate an image data set (Tl).
  • the image data set may be further analyzed, as set forth below.
  • Fig. 7 illustrates another embodiment of the instant disclosure.
  • Illumination source 103 generates illuminating photons which are transmitted through a fiber optic bundle 104 to the distal end of the endoscope 102 to fiber ends 121.
  • Illuminating photons exit the fiber ends 121 and illuminate the sample 100 and generate interacted photons 101 from the sample 100.
  • the interacted photons 101 are detected by a first detector 705 and a second detector 707 disposed on the distal end of the endoscope 102.
  • the first detector 705 and the second detector 707 comprise hyperspectral cameras.
  • the detectors 705 and 707 comprise a Fabry-Perot interferometric (patterned etalon) filter configuration disposed on each pixel of the detector. Suitable examples of patterned etalon filter arrangements and associated detectors are available from Ximea Corporation.
  • the filter on each pixel is configured to transmit one or more passband wavelengths for each pixel.
  • the first detector 705 comprises a patterned etalon filter arrangement in a mosaic snapshot arrangement.
  • a mosaic snapshot can be acquired over 1088x2048 pixels.
  • the mosaic snapshot comprises a 4x4 mosaic having 16 wavelength bands.
  • the mosaic snapshot comprises a snapshot of the sample from 465-630 nm at 11 nm intervals.
  • the mosaic snapshot may comprise a 5x5 mosaic having 25 bands over a wavelength range from about 600 to 1,000 nm.
  • the mosaic snapshot may include a spatial resolution per band of about 512x272 with up to 2 megapixels with interpolation and may collect up to 170 data- cubes/sec.
  • the first detector 705 and the second detector 707 may comprise a patterned etalon filter arrangement for obtaining a snapshot tiled configuration.
  • the snapshot tiled configuration transmits a passband wavelength at each pixel.
  • the patterned etalon snapshot tiled filter configuration can acquire up to 1088x2048 pixels.
  • the tiled snapshot has a spectral resolution of up to 32 bands and can detect wavelengths ranging from 600-1,000 nm over 12 incremental steps.
  • the spatial resolution per band is about 256x256.
  • the tiled snapshot may detect up to 170 data-cubes/sec.
  • the patterned etalon filter arrangement may also be customized to generate a predetermined response based on the sample to be analyzed and the result desired. Such customization would be apparent to one of skill in the art in view of this disclosure.
  • the first detector 705 and the second detector 707 comprise IMEC mosaic filter arrangements.
  • the patterned etalon mosaic filter arrangements of the first detector 705 and the second detector 707 are configured to transmit one or more different wavelength bands at each pixel.
  • the first detector 705 and the second detector 707 comprise patterned etalon tiled filter arrangements.
  • the patterned etalon tiled filter arrangements of the first detector 705 and the second detector 707 are configured to detect a different wavelength band at each pixel.
  • the second detector is eliminated and the embodiment employs the first detector 705 having either a snapshot mosaic patterned etalon filter arrangement or a snapshot tiled patterned etalon filter arrangement.
  • the detectors 705 and 707 are configured to generate one or more image data sets for each passband wavelength transmitted from the filter arrangements. In one embodiment, the detectors 705 and 707 are configured to generate a first image data set (Tl) and a second image data set (T2). In one embodiment, the image data sets may be further analyzed, as set forth below.
  • an illumination source may be configured to generate illuminating photons at specific wavelengths.
  • the illumination source may comprise a plurality of LEDs where a first portion of the LEDs are configured to generate a first wavelength and a second portion of the LEDs are configured to generate a second wavelength for illuminating a sample.
  • a first detector may be configured to detect interacted photons from the first wavelength and generate a first image data set (Tl)
  • a second detector may be configured to detect interacted photons from the second wavelength and generate a second image data set (T2).
  • Other illumination sources or arrangements may be employed which are capable of producing illuminating photons at a plurality of wavelengths.
  • the illumination source comprises a modulating laser which is capable of generating multiple wavelengths.
  • the image data sets described herein may comprise one or more of an ultraviolet (UV) image data set, fluorescence image data set, a visible (VIS) image data set, a Raman image data set, a near-infrared (NIR) image data set, a short-wave infrared (SWIR) data set, a mid-infrared (MIR) data set, and a long-wave infrared (LWIR) data set.
  • the image data set comprises a hyperspectral image data set.
  • the image data sets of the instant disclosure may further be analyzed.
  • the systems disclosed herein may include a fiber array spectral translator (FAST). Suitable FAST devices are disclosed in U.S.
  • Patent Number 8,098,373 to Nelson et al. entitled SPATIALLY AND SPECTRALLY PARALLELIZED FIBER ARRAY SPECTRAL TRANSLATOR SYSTEM AND METHOD OF USE, filed April 13, 2010 and assigned to Chemimage Corporation, the disclosure of which is incorporated by reference in its entirety.
  • the systems disclosed herein may comprise a processor and a non-transitory processor-readable storage medium in operable communication with the processor.
  • the storage medium may contain one or more programming instructions that, when executed, cause the processor to analyze the image data sets.
  • the analysis may comprise applying an optical computation to the data set.
  • the optical computation may comprise one or more of Tl, and (Tl-T2)/(Tl+T2). Other optical computations known in the art may be applied.
  • the analysis may comprise applying one or more chemometric techniques to the image data sets.
  • the chemometric analysis may comprise one or more of a multivariate curve resolution analysis, a principle component analysis (PCA), a partial least squares discriminant analysis (PLSDA), a k means clustering analysis, a band t entropy analysis, an adaptive subspace detector analysis, a cosine correlation analysis, a Euclidian distance analysis, a partial least squares regression analysis, a spectral mixture resolution analysis, a spectral angle mapper metric analysis, a spectral information divergence metric analysis, a Mahalanobis distance metric analysis, and spectral unmixing analysis.
  • the processor may be configured to control operation of the system.
  • the process may be configured to cause the a controller to apply voltages to the tunable filter to obtain the desired passband transmission.
  • the processor may be configured to control timing of an illumination source and detectors so that the correct detector is in operation for the specific illumination.
  • Other processor configurations are contemplated and would be apparent to one of skill in the art in view of this disclosure.
  • the systems according to the instant disclosure may further include a display.
  • the display may include one or more results from one or more of the detectors.
  • the display may include one or more results from the analysis of the processor.
  • the display may include one or more results from one or more of the detectors and one or more results from the analysis of the processor.

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Abstract

La présente invention concerne des systèmes d'imagerie médicale qui peuvent être utilisés conjointement avec un dispositif médical intra-opératoire, tel qu'un endoscope. De manière générale, les systèmes d'imagerie médicale selon l'invention comprennent une source d'éclairage configurée pour générer des photons d'éclairage afin d'éclairer un échantillon biologique. Un modulateur de signal optique est configuré pour séparer un ou plusieurs des photons d'éclairage et des photons qui ont interagi avec l'échantillon biologique en un premier signal optique ayant des premières longueurs d'onde à bande passante multiples et un second signal optique ayant des secondes longueurs d'onde à bande passante multiple. Au moins un détecteur est configuré pour détecter un ou plusieurs du premier signal optique et du second signal optique et générer au moins un ensemble de données d'image. Un processeur est configuré pour analyser ledit au moins un ensemble de données d'image. Dans certains modes de réalisation, le processeur est configuré pour différencier des structures de l'échantillon biologique, par exemple un uretère des tissus environnants.
PCT/US2018/030155 2018-04-30 2018-04-30 Systèmes d'imagerie endoscopique par imagerie chimique moléculaire WO2019212472A1 (fr)

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EP18917268.7A EP3787469A4 (fr) 2018-04-30 2018-04-30 Systèmes d'imagerie endoscopique par imagerie chimique moléculaire
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