WO2020093034A1 - Système d'imagerie par fluorescence et d'imagerie par contraste de granularité laser combinées et ses applications - Google Patents

Système d'imagerie par fluorescence et d'imagerie par contraste de granularité laser combinées et ses applications Download PDF

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Publication number
WO2020093034A1
WO2020093034A1 PCT/US2019/059610 US2019059610W WO2020093034A1 WO 2020093034 A1 WO2020093034 A1 WO 2020093034A1 US 2019059610 W US2019059610 W US 2019059610W WO 2020093034 A1 WO2020093034 A1 WO 2020093034A1
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images
fluorescence
auto
lens
speckle contrast
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PCT/US2019/059610
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English (en)
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Emmanuel A. Mannoh
Anita Mahadevan-Jansen
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Vanderbilt University
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Priority to US17/289,323 priority Critical patent/US20220007997A1/en
Publication of WO2020093034A1 publication Critical patent/WO2020093034A1/fr
Priority to US18/379,251 priority patent/US20240041388A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/50—Supports for surgical instruments, e.g. articulated arms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room
    • A61B5/004—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for image acquisition of a particular organ or body part
    • 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
    • A61B5/42—Detecting, measuring or recording for evaluating the gastrointestinal, the endocrine or the exocrine systems
    • A61B5/4222—Evaluating particular parts, e.g. particular organs
    • A61B5/4227—Evaluating particular parts, e.g. particular organs endocrine glands, i.e. thyroid, adrenals, hypothalamic, pituitary
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/10—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges for stereotaxic surgery, e.g. frame-based stereotaxis
    • A61B90/11—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges for stereotaxic surgery, e.g. frame-based stereotaxis with guides for needles or instruments, e.g. arcuate slides or ball joints
    • A61B90/13—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges for stereotaxic surgery, e.g. frame-based stereotaxis with guides for needles or instruments, e.g. arcuate slides or ball joints guided by light, e.g. laser pointers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/30—Devices for illuminating a surgical field, the devices having an interrelation with other surgical devices or with a surgical procedure
    • A61B2090/306—Devices for illuminating a surgical field, the devices having an interrelation with other surgical devices or with a surgical procedure using optical fibres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/36—Image-producing devices or illumination devices not otherwise provided for
    • A61B90/37—Surgical systems with images on a monitor during operation
    • A61B2090/371—Surgical systems with images on a monitor during operation with simultaneous use of two cameras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B50/00—Containers, covers, furniture or holders specially adapted for surgical or diagnostic appliances or instruments, e.g. sterile covers
    • A61B50/10—Furniture specially adapted for surgical or diagnostic appliances or instruments
    • A61B50/13—Trolleys, e.g. carts
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4788—Diffraction
    • G01N2021/479—Speckle
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells

Definitions

  • the invention relates generally to optical assessments of bio-objects, and more particularly, to a combined auto-fluorescence imaging and laser speckle contrast imaging (LSCI) system to enable intra-operative parathyroid identification and viability assessment with the same tool and applications of the same.
  • LSCI laser speckle contrast imaging
  • the endocrine system is a complex system of organs and glands which includes the thyroid and parathyroid.
  • the anatomy of the neck is illustrated in FIG. 1.
  • the thyroid gland regulates many developmental and metabolic processes. Common diseases of the thyroid include goiters, hyperthyroidism, hypothyroidism, benign and malignant nodules, and autoimmune diseases such as Graves' disease. Surgery is the most common treatment for Graves's disease, goiters, benign thyroid nodules, and thyroid cancers.
  • the parathyroid normally lies within the same region as the thyroid in the neck and functions to control calcium levels in the blood.
  • the most common parathyroid disorder is primary hyperparathyroidism, in which one or more of the parathyroid glands become enlarged and hyperactive. This causes excess secretion of parathyroid hormone and a disruption in normal bone and mineral metabolism.
  • the prevalence of primary hyperparathyroidism has been estimated at 21 cases per 100,000 person-years. In 80% of cases, primary hyperparathyroidism is caused by a single overactive parathyroid gland and surgical removal of the diseased parathyroid gland is the only definitive treatment. Typically, there are four tan parathyroid glands, each approximately 6 to 8 mm in size.
  • the parathyroid glands are often difficult to distinguish from surrounding tissue and thyroid in the neck.
  • the parathyroid visually resembles its surrounding tissue and this can extend surgical time during a
  • parathyroidectomy during which the surgeon is simply searching for the small organ.
  • Accidental removal or damage to healthy parathyroids during parathyroid or thyroid surgery can result in serious complications such as hypocalcemia or hypoparathyroidism.
  • Hypoparathyroidism may result from direct injury, devascularization, and/or disruption of the parathyroid glands.
  • the current surgical procedure for thyroid and parathyroid surgeries involves a systematic search within the neck in which the surgeon is mainly relying on visual inspection to identify target tissues.
  • the incidence of complications occurring due to this subjective method is directly proportional to the extent of thyroidectomy and inversely proportional to the experience of the surgeon.
  • the disadvantages to the current method include the lengthy duration of the surgery, the exploratory nature of the surgery, and the lack of sensitive and applicable preoperative and intra operative imaging. Confirmation of removal of the diseased parathyroid relies on histopathology or post-operative diagnosis of symptoms. There is a need for reliable methods for identifying the parathyroid glands intraoperatively.
  • surgical guidance systems have been developed and utilized for brain surgery and other organ surgery procedures, none is available for thyroid and parathyroid surgeries.
  • One of the objectives of the invention is to provide a combined auto-fluorescence imaging and laser speckle contrast imaging (LSCI) system to enable intra-operative parathyroid
  • the invention relates to a system for intraoperative assessment of parathyroid gland viability of a living subject for guidance in a surgery.
  • the system includes a light source for emitting a beam of light to illuminate a target of interest; and an imaging head positioned over the target of interest for acquiring auto-fluorescence images and laser speckle contrast imaging (LSCI) images of light from the illuminated target of interest responsive to the illumination.
  • LSCI laser speckle contrast imaging
  • the light source comprises a near-infrared laser. In one embodiment, the light source comprises a diode laser emitting the beam of light at a wavelength of about 785 nm.
  • the imaging head comprises a detector disposed in a top portion of the image head for individually acquiring the auto-fluorescence images and the LSCI images; and a first lens and a second lens positioned in an optical path, wherein the first lens is adapted for collecting the light from the illuminated target of interest in a surgical field, and the second lens is adapted focusing the collected light to the detector.
  • a ratio of a focal length of the first lens to that of the second lens is about 80/17.
  • the imaging head further comprises a movable switching plate accommodating filters and an iris, being located between the first lens and the second lens, and operably moving between a first position and a second position, such that when the movable switching plate is in the first position, the filters are positioned in the optical path and the detector operably acquires the auto-fluorescence images, and when the movable switching plate is in the second position, the iris is positioned in the optical path and the detector acquires the LSCI images.
  • a movable switching plate accommodating filters and an iris, being located between the first lens and the second lens, and operably moving between a first position and a second position, such that when the movable switching plate is in the first position, the filters are positioned in the optical path and the detector operably acquires the auto-fluorescence images, and when the movable switching plate is in the second position, the iris is positioned in the optical path and the detector acquires the LSCI images.
  • the filters comprise a combination of first and second long-pass filters between a range of about 800 nm to about 830 nm, and wherein the iris comprises an iris with a diameter equal to or less than about 15 mm diameter.
  • the imaging head further comprises a linear actuator configured to move the movable switching plate between the first position and the second position.
  • the imaging head further comprises a beamsplitter positioned between the first lens and the second lens in the optical path for reflecting and transmitting the collected light into a first path and a second path, respectively, and a third lens positioned in the first path, wherein the reflected light in the first path is focused by the third lens to a first camera of the detector for acquiring the LSCI images, and the transmitted light in the second path is focused by the second lens to a second camera of the detector for acquiring the auto-fluorescence images.
  • two cameras the first and second cameras placed in the first and second paths, are used to individually acquire the LSCI images and the auto-fluorescence images, respectively.
  • the imaging head further comprises a linear polarizer positioned between the beamsplitter and the third lens in the first path, and configured to have its axis of polarization oriented perpendicular to that on the illumination reducing specular reflections.
  • the imaging head further comprises a mirror positioned between the linear polarizer and the third lens in the first path for achieving compactness.
  • the imaging head further comprises an 808 nm long-pass filter positioned between the beamsplitter and the second lens in the second path, and a neutral density filter positioned between the beamsplitter and the third lens in the first path.
  • the imaging head further comprises a focus tunable lens disposed in a bottom portion of the image head and positioned between the target of interest and the first lens in the optical path for focusing light from the illuminated target of interest in a surgical field.
  • the imaging head further comprises a first linear polarizer positioned in front of the illumination.
  • the detector comprises at least one camera.
  • the at least one camera comprises at least one charge-coupled device (CCD) camera and/or at least one complementary metal oxide semiconductor (CMOS) camera.
  • CMOS complementary metal oxide semiconductor
  • the at least one camera comprises at least one infrared camera and/or at least one camera near-infrared (NIR) camera.
  • the system further comprises at least one laser pointer arranged in relation to the detector such that its beam is co-localized with a center of the field of view of the detector at a distance.
  • the system further comprises a lens tube containing at least one lens arranged in relation to the target of interest, wherein the light source is optically coupled to the lens tube for illuminating a spot having a diameter at a distance on the target of interest.
  • the system further comprises a controller configured to control operations of the imaging head for acquiring the auto-fluorescence and LSCI images of the illuminated target of interest, receiving the acquired auto-fluorescence and LSCI images from the detector, and processing the acquired auto-fluorescence and LSCI images to obtain speckle contrast images for the intraoperative assessment of parathyroid gland viability.
  • a controller configured to control operations of the imaging head for acquiring the auto-fluorescence and LSCI images of the illuminated target of interest, receiving the acquired auto-fluorescence and LSCI images from the detector, and processing the acquired auto-fluorescence and LSCI images to obtain speckle contrast images for the intraoperative assessment of parathyroid gland viability.
  • a perfused parathyroid gland has low speckle contrast
  • a devascularized parathyroid gland has high speckle contrast
  • system further comprises a display for displaying the speckle contrast images of the parathyroid gland in real-time.
  • the invention in another aspect, relates to a method for intraoperative guidance in a surgery.
  • the methods includes providing a beam of light to illuminate a target of interest; acquiring auto-fluorescence images and laser speckle contrast imaging (LSCI) images of light from the illuminated target of interest responsive to the illumination; and processing the acquired auto-fluorescence and LSCI images for intraoperative guidance in a surgery.
  • LSCI laser speckle contrast imaging
  • said processing the acquired auto-fluorescence and LSCI images comprises cropping a background- subtracted auto-fluorescence image to remove first pixels on each edge; thresholding the cropped auto-fluorescence image into first, second and third intensity levels using a multiple thresholding scheme, wherein the first intensity level is corresponding to a low intensity background; setting the second intensity level equal to the low intensity background, resulting in an image having a distinction between the parathyroid gland of interest and everything else; filtering the resulted image using a two-dimensional Gaussian to locate a dominant cluster of points, wherein the dominant cluster of points is corresponding to the parathyroid gland;
  • said processing the acquired auto-fluorescence and LSCI images further comprises, prior to said the background- subtracted auto-fluorescence image filtering an acquired auto-fluorescence image with a Gaussian profile; and registering the filtered auto fluorescence image to a first speckle contrast image.
  • said processing the acquired auto-fluorescence and LSCI images further comprises imaging an irregular grid by two cameras to determine a rigid transformation that aligns the fields of the two cameras together, wherein one of the two cameras is adapted for acquiring the auto-fluorescence images and the other of two cameras is adapted for acquiring the LSCI images.
  • the rigid transformation is determined using an intensity-based image registration.
  • said processing the acquired auto-fluorescence and LSCI images comprises after obtaining the contour, applying the rigid transformation to demarcate the parathyroid gland in the first speckle contrast image of the acquired series of speckle contrast images; registering the remaining subsequent speckle contrast images of the acquired series of speckle contrast images into the first speckle contrast image using a discrete Fourier transform registration that only accounts for translation; averaging the acquired series of speckle contrast images to obtain the average speckle contrast of the parathyroid area within the transformed contour so as to improve spatial resolution; and converting the value to a percent likelihood of parathyroid devascularization using a logistic regression model.
  • the method further comprises for displaying the speckle contrast images of the parathyroid gland in real-time.
  • the invention relates to a non-transitory tangible computer-readable medium storing instructions which, when executed by one or more processors, cause the above- disclosed method for processing auto-fluorescence and LSCI images for intraoperative guidance in a surgery to be performed.
  • FIG. 1 shows a general view of the anatomy of human thyroid/parathyroid glands.
  • FIGS. 2A-2G shows schematically a combined auto-fluorescence and laser speckle contrast imaging (LSCI) system (alternatively, device or apparatus) for intraoperative assessment of parathyroid gland vascularity of a living subject according to one embodiment of the invention.
  • FIG. 2A shows a view of the device in the operating room.
  • FIG. 2B is a view of an imaging head of the system.
  • FIGS. 2C-2D show perspective and cross-sectional views of the imaging head, respectively.
  • FIGS. 2E-2F are two perspective views showing optical paths inside the imaging head for acquiring auto-fluorescence images and LSCI images, respectively.
  • FIG. 2G is an optical layout of the system.
  • FIGS. 3A-3B show schematically a combined auto-fluorescence and laser speckle contrast imaging (LSCI) system for intraoperative assessment of parathyroid gland vascularity of a living subject according to one embodiment of the invention.
  • FIG. 3A shows a view of the device in the operating room.
  • FIG. 3B is an optical layout of the system, where DBS represents a dichroic beamsplitter, Ll represents a first lens, L2 represents a second lens, L3 represents a third lens, LP represents a linear polarizer, LPF represents a long-pass filter, M represents a mirror, NDF represents a neutral density filter, respectively.
  • DBS represents a dichroic beamsplitter
  • Ll represents a first lens
  • L2 represents a second lens
  • L3 represents a third lens
  • LP represents a linear polarizer
  • LPF represents a long-pass filter
  • M represents a mirror
  • NDF represents a neutral density filter, respectively.
  • FIG. 4 shows a flowchart of automated image processing according to one embodiment of the invention.
  • FIGS. 5A-5F shows parathyroid localization steps according to one embodiment of the invention: starting with background- subtracted fluorescence image (FIG. 5A), threshold into 3 levels ((FIG. 5B); setting a second intensity level equal to background ((FIG. 5C), then locating the dominant cluster of points ((FIG. 5D); creating edge map based on this cluster of points (FIG. 5E) and fitting an active contour model to the edge ((FIG. 5F).
  • FIGS. 6A-6B show processed images illustrating segmented fluorescence images of parathyroid glands according to embodiments of the invention.
  • FIGS. 7A-7B show an in vivo example of a fluorescence image (FIG. 7 A) and probability of parathyroid devascularization (FIG. 7B) according to one embodiment of the invention.
  • FIG. 8 shows white light, auto-fluorescence and speckle contrast images of a diseased parathyroid gland before and after blood supply ligation, according to one embodiment of the invention.
  • the parathyroid is more fluorescent than surrounding tissue and an increase in speckle contrast after ligation shows devascularization of the gland.
  • first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below can be termed a second element, component, region, layer or section without departing from the teachings of the present invention.
  • relative terms are intended to encompass different orientations of the device in addition to the orientation shown in the figures. For example, if the device in one of the figures is turned over, elements described as being on the“lower” side of other elements would then be oriented on the“upper” sides of the other elements. The exemplary term“lower” can, therefore, encompass both an orientation of lower and upper, depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as“below” or“beneath” other elements would then be oriented“above” the other elements. The exemplary terms“below” or“beneath” can, therefore, encompass both an orientation of above and below.
  • “around”,“about”,“approximately” or“substantially” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term“around”,“about”,“approximately” or“substantially” can be inferred if not expressly stated.
  • the phrase“at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR.
  • the term“and/or” includes any and all combinations of one or more of the associated listed items.
  • the term“living subject” refers to a human being such as a patient, or a mammal animal such as a monkey.
  • auto-fluorescence refers to the fluorescence produced by a molecule of interest without the use of exogenous markers. Auto-fluorescence may serve as a useful diagnostic indicator such as in the case of“biological auto-fluorescence”, which refers to the fact that cells contain molecules, which become fluorescent when excited by UV/VIS (typically 400 - 700 nm) radiation of suitable wavelength. This fluorescence emission, arising from endogenous fluorophores, is an intrinsic property of cells and is called auto-fluorescence to be distinguished from fluorescence signals obtained by adding exogenous markers. The majority of cell auto-fluorescence originates from mitochondria and lysosomes.
  • the most important endogenous fluorophores are pyridinic (NADPH) and flavin coenzymes.
  • NADPH pyridinic
  • flavin coenzymes In tissues, the extracellular matrix often contributes to the auto- fluorescence emission more than the cellular component, because collagen and elastin have, among the endogenous fluorophores, a relatively high quantum yield. Changes occurring in the cell and tissue state during physiological and/or pathological processes result in modifications of the amount and distribution of endogenous fluorophores and chemical-physical properties of their microenvironment. Therefore, analytical techniques based on auto-fluorescence monitoring may be utilized in order to obtain information about morphological and physiological state of cells and tissues. Moreover, auto-fluorescence analysis can be performed in real time because it does not require any treatment of fixing or staining of the specimens.
  • laser speckle contrast imaging or its abbreviation “LSCI” refers to a technique for imaging flow for assessment of parathyroid gland vascularity during endocrine surgery, which utilizes intrinsic tissue contrast from dynamic light scattering and provides a relatively simple technique for visualizing detailed spatiotemporal dynamics of blood flow changes in real-time.
  • Laser speckle is the rando interference pattern produced when coherent light scatters from a random medium and can be imaged onto a detector. Motion from scattering particles, such as red blood cells in the vasculature, leads to spatial and temporal variations in the speckle pattern. Speckle contrast analysis quantifies the local spatial variance, or blurring, of the speckle pattern that results from blood flow. Areas with greater motion have more rapid intensity fluctuations and therefore have more blurring of the speckles during the camera exposure time LSCI can be used to quantify relative changes in blood flow.
  • the LSCI technique analyzes the interference pattern produced when coherent light is incident on a surface. Minute differences in path length created by the light waves scattering from different regions of the surface produce bright and dark spots of constructive and destructive interference respectively, termed as a speckle pattern. This speckle pattern fluctuates depending on how fast particles are moving within a few microns of the surface. Blurring of the speckle pattern occurs when the motion is fast relative to the integration time of the detector. Analyzing this spatial blurring provides contrast between regions of faster versus slower motion and forms the basis of LSCI. This technique is sensitive to microvascular perfusion and has been employed in a variety of tissues where the vessels of interest are generally superficial, such as the retina, skin and brain.
  • Parathyroid glands are densely packed with blood vessels, given that they secrete PTH to the entire body. Furthermore, their small size (3-8 mm) makes many of these vessels superficial, making these glands suitable targets for assessment using LSCI. Certain aspects of this invention disclose a combined auto-fluorescence and LSCI system for assessment of parathyroid gland vascularity during endocrine surgery.
  • charge-coupled device or“CCD” refers to an analog shift register that enables the transportation of analog signals (electric charges) through successive stages (capacitors), controlled by a clock signal.
  • Charge-coupled devices can be used as a form of memory or for delaying samples of analog signals.
  • a CCD for capturing images there is a photoactive region (an epitaxial layer of silicon), and a transmission region made out of a shift register (the CCD, properly speaking).
  • An image is projected through a lens onto the capacitor array (the photoactive region), causing each capacitor to accumulate an electric charge proportional to the light intensity at that location.
  • a one-dimensional array used in line- scan cameras, captures a single slice of the image, while a two-dimensional array, used in video and still cameras, captures a two-dimensional picture corresponding to the scene projected onto the focal plane of the sensor.
  • a control circuit causes each capacitor to transfer its contents to its neighbor (operating as a shift register).
  • the last capacitor in the array dumps its charge into a charge amplifier, which converts the charge into a voltage.
  • the controlling circuit converts the entire semiconductor contents of the array to a sequence of voltages, which it samples, digitizes and stores in some form of memory.
  • the invention in one aspect discloses an imaging system capable of performing both auto-fluorescence and laser speckle contrast imaging (LSCI) intraoperatively for guidance in a surgery.
  • This system is developed to guide surgeons performing thyroid and parathyroid surgeries, which allows a surgeon to objectively identify a parathyroid gland during surgery and assess its viability.
  • Auto-fluorescence imaging helps identify the parathyroid, while LSCI helps assess its viability.
  • the system includes a light source for emitting a beam of light to illuminate a target of interest 105; and an imaging head 100 positioned over the target of interest 105 for acquiring auto-fluorescence images and LSCI images of light from the illuminated target of interest 105 responsive to the illumination.
  • the light source is, but not limited to, an infrared laser.
  • the infrared laser is a diode laser emitting the beam of light at a wavelength of about 785 nm.
  • the imaging head 100 comprises a detector 120 disposed in a top portion 112 of the image head 100 for individually acquiring the auto-fluorescence images and the LSCI images; and a first lens 150 and a second lens 130 positioned in an optical path 182.
  • the first lens 150 is adapted for collecting the light from the illuminated target of interest 105 in a surgical field
  • the second lens is adapted focusing the collected light to the detector.
  • a ratio of a focal length of the first lens to that of the second lens is about 80/17.
  • the first lens is, but not limited to, a 400 mm lens
  • the second lens is, but not limited to, an 85 mm lens. It should be appreciated that any set of lenses with a similar ratio of focal lengths can be utilized to practice the invention, for example, a 500 mm lens and a 100 mm lens.
  • the choice of the 400 mm and 85 mm lenses was mainly to have a large working distance (400 mm) while keeping the imaging head relatively compact.
  • the imaging head 100 also has a movable switching plate accommodating filters 140 and an iris 145, as shown in FIGS. 2E-2G, being located between the first lens 150 and the second lens 130.
  • the movable switching plate operably moves between a first position and a second position.
  • the filters 140 are positioned in the optical path 182 (FIG. 2E) and the detector operably acquires the auto-fluorescence images.
  • the iris 145 is positioned in the optical path (FIG. 2F) and the detector acquires the LSCI images.
  • the filters includes, but are not limited to, a combination of an 808 nm long-pass filter and an 800 nm long-pass filter
  • the iris comprises, but is not limited to, a 15 mm diameter iris. It should be appreciated that any long-pass or band-pass filters between the range of about 800 nm to about 830 nm can be utilized to practice the invention. In addition, for this configuration, any iris size less than 15 mm also works provided there is enough light. The 15 mm diameter of an iris is the limit to satisfy an equation regarding speckle size.
  • the imaging head 100 includes a linear actuator (not shown) configured to move the movable switching plate between the first position and the second position.
  • the imaging head 100 further comprises a focus tunable lens 152 disposed in a bottom portion 114 of the image head 100 and positioned between the target of interest 105 and the first lens 150 in the optical path 182 for focusing light 180 from the illuminated target of interest 105 in a surgical field.
  • a focus tunable lens 152 disposed in a bottom portion 114 of the image head 100 and positioned between the target of interest 105 and the first lens 150 in the optical path 182 for focusing light 180 from the illuminated target of interest 105 in a surgical field.
  • the imaging head 100 comprises a first linear polarizer 154 positioned in the optical path between the focus tunable lens 152 and the target of interest 105.
  • the detector 120 comprises at least one camera.
  • the at least one camera comprises at least one charge-coupled device (CCD) camera and/or at least one complementary metal oxide semiconductor (CMOS) camera.
  • CMOS complementary metal oxide semiconductor
  • the at least one camera comprises at least one infrared camera and/or at least one camera near-infrared (NIR) camera.
  • the system further comprises at least one laser pointer 170 arranged in relation to the detector 120 such that its beaml72 is co-localized with a center of the field of view of the detector 120 at a distance.
  • at least one laser pointer 170 arranged in relation to the detector 120 such that its beaml72 is co-localized with a center of the field of view of the detector 120 at a distance.
  • two laser pointers, 532 nm and 650 nm, (output power ⁇ 5 mW) attached on the sides of the imaging head 100 guide a surgeon in positioning the imaging head 100 so that the target of interest 105 in roughly in the center of the field of view and in focus when imaging, as shown in FIG. 2G.
  • the system also has a lens tube 160 containing at least one lens arranged in relation to the target of interest 105.
  • the light source is optically coupled to the lens tube 160 for illuminating a spot 165 having a diameter D at a distance H on the target of interest 105.
  • the system further comprises a controller (alternatively computer) configured to control operations of the imaging head for acquiring the auto- fluorescence and LSCI images of the illuminated target of interest, receiving the acquired auto- fluorescence and LSCI images from the detector, and processing the acquired auto-fluorescence and LSCI images to obtain speckle contrast images for the intraoperative assessment of parathyroid gland viability.
  • a controller alternatively computer configured to control operations of the imaging head for acquiring the auto- fluorescence and LSCI images of the illuminated target of interest, receiving the acquired auto- fluorescence and LSCI images from the detector, and processing the acquired auto-fluorescence and LSCI images to obtain speckle contrast images for the intraoperative assessment of parathyroid gland viability.
  • speckle contrast images a perfused parathyroid gland has low speckle contrast, and a devascularized parathyroid gland has high speckle contrast.
  • the system further comprises a display for displaying the speckle contrast images of the parathyroid gland in real-time, as shown in FIG. 2A.
  • the LSCI and auto-fluorescence imaging system is generally similar to LSCI and auto-fluorescence imaging system shown in FIG. 2A. Except that an alternative design of the imaging head, which includes two cameras 221 and 222, instead of a single camera 120 in the embodiment shown in FIGS. 2A-2G, and places a
  • beamsplitter DBS in the optical/detection path to simultaneously collect fluorescence (by camera 222) and laser speckle images (by camera 221).
  • the imaging head includes a beamsplitter DBS positioned between the first lens Ll and the second lens L2 in the optical path for reflecting and transmitting the collected light into a first path and a second path, respectively, and a third lens L3 positioned in the first path.
  • the reflected light in the first path is focused by the third lens L3 to a first camera 221 of the detector for acquiring the LSCI images
  • the transmitted light in the second path is focused by the second lens L2 to a second camera 222 of the detector for acquiring the auto-fluorescence images.
  • the imaging head further has a linear polarizer LP positioned between the beamsplitter DBS and the third lens L3 in the first path, and configured to have its axis of polarization oriented perpendicular to that on the illumination reducing specular reflections.
  • a linear polarizer LP positioned between the beamsplitter DBS and the third lens L3 in the first path, and configured to have its axis of polarization oriented perpendicular to that on the illumination reducing specular reflections.
  • the imaging head further comprises a mirror M positioned between the linear polarizer LP and the third lens L3 in the first path for achieving compactness.
  • the imaging head has an 808 nm long-pass filter LPF positioned between the beamsplitter DBS and the second lens L2 in the second path, and a neutral density filter NDF positioned between the beamsplitter DBS and the third lens L3 in the first path.
  • the neutral density filter is configured to reduce the intensity of the laser light so it does not saturate the camera.
  • the neutral density filter is a 1.3 O.D. neutral density filter.
  • the laser is not so powerful it may not be needed, or a lower optical density may work, e.g. 0.5 O.D.
  • the method for intraoperative assessment of parathyroid gland viability of a living subject for guidance in a surgery includes providing a beam of light to illuminate a target of interest; acquiring auto-fluorescence images and laser speckle contrast imaging (LSCI) images of light from the illuminated target of interest responsive to the illumination; and processing the acquired auto-fluorescence and LSCI images for intraoperative guidance in a surgery.
  • LSCI laser speckle contrast imaging
  • said processing the acquired auto-fluorescence and LSCI images comprises cropping a background- subtracted auto-fluorescence image (FIG. 5A) to remove first pixels on each edge; thresholding the cropped auto-fluorescence image into first, second and third intensity levels using a multiple thresholding scheme (FIG. 5B), wherein the first intensity level is corresponding to a low intensity background; setting the second intensity level equal to the low intensity background, resulting in an image (FIG. 5C) having a distinction between the parathyroid gland of interest and everything else; filtering the resulted image using a two-dimensional Gaussian to locate a dominant cluster of points, wherein the dominant cluster of points is corresponding to the parathyroid gland (FIG. 5D); converting the filtered image to an edge map (FIG. 5E); and fitting an active contour model to the edge map to obtain the contour demarcating the parathyroid gland (FIG. 5F).
  • FIG. 5A background- subtracted auto-fluorescence image
  • FIG. 5B multiple thresholding scheme
  • said processing the acquired auto-fluorescence and LSCI images comprises, prior to said the background- subtracted auto-fluorescence image, filtering an acquired auto- fluorescence image with a Gaussian profile; and registering the filtered auto-fluorescence image to a first speckle contrast image.
  • said processing the acquired auto-fluorescence and LSCI images comprises imaging an irregular grid by two cameras to determine a rigid transformation that aligns the fields of the two cameras together, wherein one of the two cameras is adapted for acquiring the auto fluorescence images and the other of two cameras is adapted for acquiring the LSCI images.
  • the rigid transformation is determined using an intensity-based image registration.
  • said processing the acquired auto-fluorescence and LSCI images comprises after obtaining the contour, applying the rigid transformation to demarcate the parathyroid gland in the first speckle contrast image of the acquired series of speckle contrast images; registering the remaining subsequent speckle contrast images of the acquired series of speckle contrast images into the first speckle contrast image using a discrete Fourier transform registration that only accounts for translation; averaging the acquired series of speckle contrast images to obtain the average speckle contrast of the parathyroid area within the transformed contour so as to improve spatial resolution; and converting the value to a percent likelihood of parathyroid
  • the method includes for displaying the speckle contrast images of the parathyroid gland in real-time.
  • Yet another aspect of the invention provides a non-transitory computer readable storage medium/memory that stores computer executable instructions or program codes.
  • the computer executable instructions or program codes enable a computer or a similar computing apparatus to complete various operations of the above-disclosed method for processing auto-fluorescence and LSCI images for intraoperative guidance in a surgery.
  • the storage medium/memory may include, but is not limited to, high-speed random access medium/memory such as DRAM, SRAM, DDR RAM or other random access solid state memory devices, and non-volatile memory such as one or more magnetic disk storage devices, optical disk storage devices, flash memory devices, or other non-volatile solid state storage devices.
  • Embodiment 1 In this exemplary embodiment as shown in FIGS. 2A-2G, the imaging system is disposed on a cart (FIG. 2A) that can be wheeled into and out of the operating room. On the cart sits the computer that controls the instrument (home-built machine with six 3.7 GHz cores - Intel OEM Core ⁇ 7-8700K), as well as a single mode 785 nm diode laser with 80 mW power output (Innovative Photonics Solutions, Monmouth Junction, NJ). Attached to the cart is an articulated arm (ICWUSA, Medford, OR) capable of extending about 4 feet from the edge of the cart, and having an attachment for a sterile handle to allow maneuvering by a surgeon.
  • ICWUSA Medford, OR
  • the imaging head 100 On the end of the arm is the imaging head 100, see FIGS. 2B-2G, particularly FIG. 2G, which acquires both LSCI and fluorescence images by a detector 120 disposed on an optical/detection path 182.
  • the laser source is coupled through a single mode fiber optic patch cable 162 (Thorlabs, Newton, NJ) to a lens tube 150 containing a 75 mm focal length lens (Edmund Optics, Barrington, NJ), illuminating a spot 165 having a diameter D of about 45 mm at a distance H of about 450 mm.
  • a linear polarizer 164 (Thorlabs, Newton, NJ) - together with another linear polarizer 154 attached to the front end of the detection path 180, this enables reduction of specular reflections in images.
  • the illumination has a Gaussian profile and the maximum power across the spot 165 was measured to be 4 mW.
  • a 532 nm and 650 nm laser pointer 170 (output power less than 5 mW) attached on either side of a body portion 110 of the imaging head 100 (FIGS. 2D and 2G) guide the surgeon in positioning the system so that the tissue of interest in roughly in the center 105 of the field of view at the object 101 and in focus when imaging, as shown FIG. 2G.
  • the detection path 182 basically includes two lenses: a 400 mm lens 150 to collect light 180 scattered from the tissue of interest responsive to the illumination from the imaging plane, and an 85 mm lens 130 (Edmund Optics, Barrington, NJ) to focus this light 180 onto the detector (camera sensor) 120.
  • the camera 120 is a near-infrared optimized Basler acAl300-60gmNIR (Basler AG, Ahrensburg, Germany).
  • the imaging head 100 is designed to use one camera 120 to acquire both fluorescence and laser speckle images.
  • a focus tunable lens 152 In front of the 400 mm lens 150 is a focus tunable lens 152 (Optotune, Dietikon, Switzerland), the purpose of which is to enable remote image focusing, and attached to the front of the focus tunable lens 152 is the another linear polarizer 154.
  • This system is developed to guide surgeons performing thyroid and parathyroid surgeries, which allows a surgeon to objectively identify a parathyroid gland during surgery and assess its viability.
  • Auto-fluorescence imaging helps identify the parathyroid, while LSCI helps assess its viability.
  • Embodiment 2 is an alternative design of the imaging head that includes two cameras, instead of a single camera 120 in the embodiment shown in FIGS. 2A- 2G, and places a beam splitter in the optical/detection path to simultaneously collect fluorescence (by camera 222) and laser speckle images (by camera 221), as shown in FIGS. 3A-3B.
  • the LSCI and auto-fluorescence imaging system is developed in-house for the purpose of thyroid and parathyroid surgical guidance, as depicted in FIGS. 3A-3B, is generally similar to LSCI and auto-fluorescence imaging system shown in FIG. 2A.
  • the device is constructed on a cart that can be wheeled into and out of the operating room. As shown in FIG. 3A, on the cart sits a computer that controls the instrument (home-built machine with six 3.7 GHz cores - Intel OEM Core ⁇ 7-8700K), as well as a single mode 785 nm diode laser with 60 mW power output
  • an articulated arm (ICWUSA, Medford, OR) capable of extending about 4 feet from the edge of the cart, and having an attachment for a sterile handle to allow maneuvering by the surgeon.
  • the imaging head On the end of the arm is the imaging head that acquires both LSCI and auto-fluorescence images.
  • the laser source is coupled through a single mode fiber optic patch cable (Thorlabs, Newton, NJ) to a lens tube attached on the exterior of the imaging head.
  • This lens tube contains a 75 mm focal length lens (Edmund Optics, Barrington, NJ), illuminating a -30 mm diameter spot at a distance of 400 mm.
  • a linear polarizer (Thorlabs, Newton, NJ).
  • the illumination has an approximately Gaussian profile and the maximum power across the spot was measured to be 4.8 mW.
  • Two laser pointers, 532 nm and 650 nm, (output power ⁇ 5 mW) attached on the sides of the imaging head guide the surgeon in positioning the device so that the tissue of interest in roughly in the center of the field of view and in focus when imaging.
  • Light scattered from the tissue is detected in the imaging head through one of two similar optical paths, depending on the wavelength. As shown in FIG. 3B, both paths share a 400 mm focal length lens Ll (Edmund Optics, Barrington, NJ) which collects the scattered light from the imaging plane and collimates it onto an 801 nm dichroic beamsplitter DBS (Semrock, Rochester, NY). The light scattered from the tissue (resulting in speckle images) reflects off the dichroic beamsplitter DBS and is focused by an 85 mm lens L3 (Edmund Optics, Barrington, NJ) onto a near-infrared-optimized camera 222 (Basler AG, Ahrensburg, Germany).
  • Ll Exposure Optics, Barrington, NJ
  • a second linear polarizer LP that has its axis of polarization oriented perpendicular to that on the illumination in order to reduce specular reflections.
  • NDF neutral density filter
  • the first optical path is folded to achieve compactness by inserting a silver mirror M (Thorlabs, Newton, NJ) after the polarizer LP. Modeling in Zemax 13 (Zemax, Kirkland, Washington) showed that this
  • the longer wavelength fluorescence is transmitted through the dichroic beamsplitter DBS and is further filtered by an 808 nm long-pass filter LPF (Semrock, Rochester, NY). It is then focused by another 85 mm lens L2 onto a second near-infrared- optimized camera 222.
  • LPF Long-pass filter
  • a focus tunable lens (Optotune, Dietikon, Switzerland) attached to the front of the imaging head, before the 400 mm lens Ll, which the purpose of focus tunable lens is to enable small remote adjustments in focus to help ensure images acquired in surgery are in focus.
  • the field of view of the imaging system at the working distance of 400 mm is about 26 x 32 mm.
  • the device is controlled with a custom program created using Lab VIEW 2017 (National Instruments, Austin, TX).
  • this transformation can be applied to the identified contour to demarcate the parathyroid in the corresponding speckle contrast image and automatically determine viability.
  • Intraoperative imaging followed one of two procedures depending on the health status of the gland being imaged. For a diseased gland, after locating and exposing the gland, the surgeon positions the device above the surgical field guided by the laser pointers. One set of images (a single fluorescence image and a series of speckle contrast images) is acquired at this point. Generating the fluorescence image involves first acquiring a background frame with the laser off, then acquiring a second image with the laser on and subtracting the former from the latter.
  • Speckle contrast images are generated and displayed simultaneously in real time (about 24 fps) and the first 30 frames after acquiring the raw fluorescence image is saved. After acquiring the images, the surgeon then ligates the blood supply to the diseased parathyroid, which is a part of the standard procedure, and then a second set of images is acquired before excision of the gland. For a healthy gland, only one set of fluorescence and speckle contrast images is acquired and this could occur at any point during the surgery.
  • the camera exposure times for imaging auto-fluorescence and speckle were 300 ms and 5 ms, respectively. During all imaging procedures, the room lights are left on. The surgeon’s headlamp and the operating table lamp however have to be turned off or pointed away from the surgical field.
  • the algorithm developed to automatically segment the parathyroid is described herein according to one embodiment of the invention.
  • the background- subtracted auto-fluorescence image (FIG. 5A) is cropped to remove the first 200 pixels on each edge (original image size is 1024 x 1280 pixels), and then thresholded into three levels using a multiple thresholding scheme based on Otsu’s method (FIG. 5B).
  • the reason for choosing three levels is that, while the parathyroid is generally the strongest auto-fluorescing tissue in the neck at this wavelength, other tissues such as the thyroid also emit significant fluorescence; choosing three levels allows separation of parathyroid, thyroid (and other less fluorescent tissues), and non- fluorescent background.
  • the middle intensity level (thyroid) is set equal to the low intensity background (FIG. 5C).
  • the parathyroid gland By this point there should ideally be a clear distinction between the parathyroid gland of interest and everything else, however noise due to specular reflections and imperfect thresholding may still contaminate the image.
  • the next step is to filter the image using a two-dimensional Gaussian in order to locate the dominant cluster of points, the parathyroid gland (FIG. 5D).
  • This filtered image can then be converted to an edge map (FIG. 5E), and an active contour model or“snake” can be fit to this edge map to obtain the contour demarcating the parathyroid gland (FIG. 5F).
  • the force used to drive the active contour towards the parathyroid boundary is based on gradient vector flow.
  • the transformation that aligns the two cameras is applied to demarcate the parathyroid in the first of the acquired series of speckle contrast images.
  • Nine subsequent speckle contrast images are registered to the first using a discrete Fourier transform registration that only accounts for translation - since these images are acquired at 24 fps, there is not much motion from frame to frame and a transformation that only relies on translation is sufficient to register them.
  • These ten images are then averaged to improve spatial resolution and the average speckle contrast of the parathyroid (area within the transformed contour) is obtained.
  • this value can be converted to a percent likelihood of parathyroid devascularization using a logistic regression model based on data accumulated in a previous study. The entire process described above takes about 5 seconds to run on the current computer.
  • FIGS. 6A-6B show fluorescence images of parathyroid (para) and thyroid (thy) specimens in which the parathyroid has been successfully segmented out by the algorithm (indicated by the cyan contour). There are five parathyroids of different fluorescence intensities, each paired with two thyroid specimens.
  • FIGS. 7A-7B show an in vivo example of a fluorescence image (FIG. 7 A) and probability of parathyroid devascularization (FIG. 7B) according to one embodiment of the invention.
  • Figure 8 shows a set of images obtained with the current iteration in a parathyroidectomy case, where images were obtained before and immediately after blood supply ligation.
  • the parathyroid is clearly distinguished in the fluorescence images.
  • the only observable difference between the before and after images is seen with LSCI where there is an increase in the parathyroid speckle contrast.

Abstract

L'invention concerne un système d'imagerie par auto-fluorescence et d'imagerie par contraste de granularité laser (LSCI) combinées permettant une identification de parathyroïde intra-opératoire et une évaluation de viabilité au moyen du même outil. Le système comprend une source de lumière servant à émettre un faisceau de lumière pour éclairer une cible d'intérêt, et une tête d'imagerie positionnée sur la cible d'intérêt servant à acquérir individuellement des images d'auto-fluorescence et des images de LSCI de lumière provenant de la cible d'intérêt éclairée en réponse à l'éclairement. L'imagerie par auto-fluorescence aide à identifier la parathyroïde, tandis que la LSCI aide à en évaluer la viabilité.
PCT/US2019/059610 2008-07-30 2019-11-04 Système d'imagerie par fluorescence et d'imagerie par contraste de granularité laser combinées et ses applications WO2020093034A1 (fr)

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