# US 2013/0155499 A1 · Pathology Slide Scanner > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2013/0155499 A1 - Document ID: US20130155499A1 - Status: Published application - Kind: A1 - Application number: 13/699,251 - Filed: 2011-12-23 - Published: 2013-06-20 - Earliest claimed: 2010-12-24 - Assignees: Huron Technologies International Inc. - Inventors: Arthur Edward Dixon - Web page: https://patentgrep.com/patent/US20130155499A1 ## CPC - G02B 21/06: Means for illuminating specimens - G02B 21/002: {Scanning microscopes (scanning near field optical microscopes G01Q60/18)} - G02B 21/367: {providing an output produced by processing a plurality of individual source images, e.g. image tiling, montage, composite images, depth sectioning, image comparison} - G02B: OPTICAL ELEMENTS, SYSTEMS OR APPARATUS ## Abstract An instrument and method for scanning at least a portion of a large specimen preferably causes the specimen to move relative to a two-dimensional detector array at a constant speed. The detector array takes one image of the specimen for each line that the detector moves. A controller controls a shutter of the detector array to open to take images and to pass the images to a processor, which is preferably a computer. The instrument takes one partial image of each part of the specimen that is being scanned and then combines those images with other images to produce a contiguous image. ## Claims ### Claim 1 An instrument for scanning at least a portion of a large specimen, said instrument comprising an imaging system having an optical train to focus light from the specimen onto a two dimensional detector array, said detector array being part of the optical train, said specimen being supported on a specimen holder, said holder being movable relative to said detector array in a direction perpendicular to and edge dimension of said detector array and perpendicular to an optical train of the instrument, said specimen moving with said holder, said detector array being configured to receive data from said specimen through said imaging system when a shutter of said detector array is open and to pass data to a processor when said shutter is closed, said shutter being controllable by a controller to open and close as said holder moves relative to said detector array and said optical train, said detector array having N lines a distance X apart, said stage and said specimen being movable relative to said detector array by successive distances of X on said detector and corresponding distances of Y on said specimen, said shutter being controllable by a controller to open briefly and to close within each incremental distance X said detector array moves relative to said specimen, said shutter being controllable to repeatedly open and close numerous times for each image strip taken of said specimen, there being a sufficient number of image strips taken to enable said specimen to be at least partially scanned so that each part of said specimen being scanned is exposed to said detector array N times resulting in N images being taken for each part of said specimen being scanned, said processor being programmed to add together data for all N exposures for each line in the image strip for each part of said specimen being scanned and to assemble the resulting image strips for all parts of the specimen being scanned in order to produce a contiguous image of said portion of said specimen being scanned. ### Claim 2 (depends on 1) The instrument as claimed in claim 1 wherein the instrument is capable of scanning a large specimen in its entirety. ### Claim 3 (depends on 1) The instrument as claimed in claim 1 wherein said stage and said specimen are movable relative to said detector array by successive distances of MX on said detector and corresponding distances of MY on said specimen, said shutter being controllable by a controller to open briefly and to close within each incremental distance MX that said detector array moves relative to said specimen, there being a sufficient number of image strips taken to enable said specimen to be at least partially scanned so that each part of said specimen being scanned is exposed to said detector array N/M times resulting in N/M images being taken for each pan of said specimen being scanned, where M is a positive integer, the time in which the shutter is open or closed is unchanged, and the velocity of the moving stage has been increased by a factor of M, whereby a high-speed preview scan is accomplished. ### Claim 4 (depends on 1) The instrument as claimed in claim 1 wherein Y/X is a magnification factor of said imaging device. ### Claim 5 (depends on 4) The instrument as claimed in claim 4 wherein the imaging device is selected from a group of a microscope, a digital camera other than a CCD camera and a CCD camera. ### Claim 6 (depends on 1) The instrument as claimed in claim 1 wherein there is more than one two-dimensional detector array. ### Claim 7 (depends on 1) The instrument is claimed in claim 1 wherein said two-dimensional detector array is one of a CCD or CMOS array. ### Claim 8 (depends on 1) The instrument as claimed in claim 1 wherein there is a frame grabber configured to read said data from said detector array and to pass said data to said processor. ### Claim 9 (depends on 7) The instrument as claimed in claim 7 wherein said instrument is capable of adding together as sequence of overlapping images on a line-by-line basis to reduce noise in an image of said specimen. ### Claim 10 (depends on 6) The instrument as claimed in claim 6 wherein said instrument allows simultaneous imaging of multiple fluorophores, even where there is a large difference in signal strength of the different fluorophores. ### Claim 11 (depends on 1) The instrument as claimed in claim 1 wherein a dynamic range of the instrument is larger than a dynamic range of the detector array. ### Claim 12 (depends on 10) The instrument as claimed in claim 10 wherein said large specimen is a microscope specimen and said instrument is capable of detecting multiple fluorophores in said large microscope specimen. ### Claim 13 (depends on 1) The instrument as claimed in claim 1 wherein said instrument is capable of acquiring fluorescence images in which image data from each fluorophore substantially fills a dynamic range available in a final image file by acquiring and storing image data in files with larger dynamic range, then contracting the image data to fill the dynamic range in the final image files. ### Claim 14 (depends on 3) The instrument as claimed in claim 3 wherein the instrument is a fluorescence imaging system for macroscopic specimens in which a correct gain setting for fluorescence imaging can be estimated from a preview scan of the entire specimen or part thereof before a final scan is commenced. ### Claim 15 (depends on 3) The instrument as claimed in claim 3 wherein there is a fluorescence imaging system for macroscopic specimens in which a correct gain setting for each fluorophore detection channel when simultaneously imaging multiple fluorophores can be estimated from a preview scan of the entire specimen or part thereof before the final scan is commenced. ### Claim 16 (depends on 3) The instrument as claimed in claim 3 wherein an imaging system is provided for imaging specimens containing fluorescence nanoparticles in which a correct gain setting for fluorescence imaging can be estimated from a preview scan of the entire specimen or part thereof before the final scan is commenced. ### Claim 17 (depends on 1) The instrument as claimed in claim 1 wherein a means is provided for acquiring an image of an entire specimen which can be used as an index image, followed by acquisition of single field-of-view images at one or several positions on the specimen, said instrument being capable of acquiring said single field-of-view images while said stage is stationary, said images being one of brightfield or fluorescence images. ### Claim 18 A method of scanning at least as portion of a hinge specimen using an instrument comprising an imaging device having at least one lens, a holder to support said specimen, a two dimensional area detector array and a processor, said holder and said specimen being movable relative to said detector array, said method comprising moving said holder and said specimen relative to said detector array in a direction perpendicular to an edge dimension of said detector array and perpendicular to an optical train of the instrument, configuring said detector array to receive data from said specimen through said imaging device when a shutter of said detector array is open and to pass data to said processor when said shutter is closed, said detector array having N lines a distance X apart moving said holder and said specimen relative to said detector array by successive distances of X on said detector array and distances of Y on said specimen for each line of said detector array, operating a controller to briefly open and close said shutter within each incremental distance X that said detector array moves relative to said specimen and corresponding incremental distance Y on said specimen, controlling said shutter to repeatedly open and close numerous times for each image strip of said specimen, taking a sufficient number of image strips to enable said specimen to be at least partially scanned so that each part of said specimen that is being scanned is exposed to said detector array N times resulting its N images being taken for each part of said specimen, programming said processor to add together data for all N exposures of each line in the image strip for each part of said specimen being scanned and to assemble the resulting image strips for all of the parts of at least said portion of the specimen being scanned in order to produce a contiguous image of at least said portion of said specimen being scanned. ### Claim 19 (depends on 18) The method as claimed in claim 18 including the step of taking a sufficient number of image strips to enable the specimen's to be entirely scanned. ### Claim 20 (depends on 18) The method as claimed in claim 18 including the steps of moving the specimen relative to the detector array by successive distances of MX on the detector and corresponding distances of MY on the specimen, where M is a positive integer, operating the controller to open briefly and to close the shutter within each incremental distance MX that the detector array moves relative to the specimen, storing image data in said processor and using the image data stored in an image histogram during scanning to direct contractions of the dynamic range of the image data file after scanning is complete, performing such contraction by one of automatically or manually. ### Claim 21 (depends on 18) The method as claimed in claim 18 including the steps of moving said specimen relative to said detector array by successive distances of MX on said detector and corresponding distances of MY on said specimen, operating the controller to open briefly and to close the shutter within each incremental distance MX that said detector array moves relative to said specimen, taking a sufficient number of image strips to enable said specimen to be at least partially scanned so that each part of said specimen being scanned is exposed to said detector array N/M times resulting in N/M images being taken for each part of said specimen being scanned, where M is a positive integer, the time in which the shutter is open or closed is unchanged, and the velocity of the moving stage has been increased by a factor of M, whereby a high-speed preview scan is accomplished. ### Claim 22 (depends on 18) The method as claimed in claim 18 including the steps of using CCD or CMOS technology in said two dimensional detector array, creating a preview image histogram of said portion of said specimen being scanned, using the preview image histogram to perform dynamic range contraction and other image processing operations, if required, on the data from said two dimensional detector array during scanning to contract a dynamic range of the image data file after scanning is complete, performing the same contraction on stored images of scanned strips before the final image is assembled. ### Claim 23 (depends on 21) The method as claimed in claim 21 including the steps of using the instrument for fluorescence imaging of genetic, protein or tissue microarrays. ### Claim 24 (depends on 21) The method as claimed in claim 21 including the steps of using the instrument for fluorescence imaging, estimating the correct gain setting and/or dark current offset from a high speed preview scan of or part of said specimen. ### Claim 25 (depends on 24) The method as claimed in claim 24 including the steps of using a CCD or CMOS two dimensional array, acquiring an image of the entire large specimen which can be used as an index image, subsequently acquiring single field of view images at one or several positions on the large specimen while said specimen is stationary, allowing an operator to view changes in the specimen as a function of time or to increase an exposure of an image. ### Claim 26 (depends on 21) The method as claimed in claim 21 including the steps of using a CCD or CMOS two dimensional array, operating, the instrument to conduct brightfield imaging, of the large specimen, dividing the two dimensional array into thirds, covering one third with a red transmission filter, covering another third with a green transmission filter and covering a remaining third with a blue transmission filter, operating the instrument so that each one third of the detector array acquires an image strip and combining the three images digitally to produce a RGB brightfield image of said large specimen. ### Claim 27 (depends on 21) The method as claimed in claim 21 including the steps of using a CCD or CMOS two dimensional detector array, conducting fluorescence imaging of said large specimen, the specimen containing multiple fluorescent dyes or other sources of fluorescence, dividing the detector array into fractions, one fraction for each fluorescence source, covering each fraction with a transmission filter that transmits the emission peak of one of the fluorescent dyes or sources, in which each fraction of the detector acquires a image strip image and combining the multiple strip images digitally to produce a single fluorescence image. ### Claim 28 (depends on 21) The method as claimed in claim 21 including the steps of using a CCD or CMOS two dimensional detector array and a tunable litter to provide a multi-spectral fluorescence slide scanner and method for imaging large specimens mounted on microscope slides on said stage. ### Claim 29 (depends on 21) The method as claimed in claim 21 including the step of creating a sparse image of said at least a portion of the large image being scanned. ### Claim 30 (depends on 21) The method as claimed in claim 21 including the step of scanning the specimen at a proper exposure. ### Claim 31 (depends on 9) The method as claimed in claim 9 including the step of using a frame grabber to capture the image. ### Claim 32 (depends on 1) The instrument as claimed in claim 1 wherein the specimen holder is a movable stage, the stage being movable at relative to the two dimensional detector array in a direction perpendicular to the edge dimension of the detector array, the detector array remaining in a fixed position. ### Claim 33 (depends on 1) The instrument as claimed in claim 1 wherein the holder is movable relative to the two dimensional detector array in a direction perpendicular to the edge dimension of the detector array by moving an optical train, including the detector array, laterally in a direction that is perpendicular to the edge dimension of the detector array, the holder remaining in a fixed position. ### Claim 34 (depends on 32) The instrument as claimed in claim 32 wherein the stage is movable at a constant velocity relative to the two-dimensional detector array. ### Claim 35 (depends on 33) The instrument as claimed in claim 33 wherein the holder is movable at a constant velocity relative to the two-dimensional detector array by moving the optical train including the detector array laterally at a constant speed. ### Claim 36 (depends on 18) The method as claimed in claim 18 wherein the specimen holder is a movable stage, the method including the steps of moving the stage relative to the two dimensional detector array in a direction perpendicular to the edge dimension of the detector array while the detector array remains fixed. ### Claim 37 (depends on 18) The method as claimed in claim 18 including the steps of moving an optical train, including the detector array, laterally in a direction that is perpendicular to the edge dimension of the detector array and parallel to a plane through the holder and perpendicular to the optical train of the instrument, while the detector holder remains fixed. ### Claim 38 (depends on 36) The method as claimed in claim 36 including the step of moving the stage at a constant velocity relative, to the two-dimensional detector array. ### Claim 39 (depends on 37) The method as claimed in claim 37 including the step of moving the optical train laterally at a constant speed. ### Claim 40 (depends on 1) The instrument as claimed in claim 1 wherein scanning is used to obtain an image of at least a part of the specimen which is then used as an index image, the instrument taking one or more single field-of-view images at one or more positions of interest respectively in the index image where such single field-of-view images are acquired while there is no relative movement between the holder and the detector array. ### Claim 41 (depends on 40) The instrument as claimed in claim 40 wherein the one or more single field-of-view images are one of brightfield and fluorescence images. ### Claim 42 (depends on 40) The instrument as claimed in claim 40 wherein several single field-of-view images are taken to allow an operator to view changes in the specimen as a function of time. ### Claim 43 (depends on 40) The instrument as claimed in claim 40 wherein exposure of the single field of view fluorescence images is increased by increasing the time that the shutter is open. ### Claim 44 (depends on 40) The instrument as claimed in claim 40 wherein exposure is increased by adding a series of images of the same field of view which allows a dynamic range of an image to be larger than that of the detector array. ### Claim 45 (depends on 40) The instrument as claimed in claim 40 wherein increased optical resolution can be achieved in the single field of view images using structured illumination. ### Claim 46 (depends on 40) The instrument as claimed in claim 40 wherein optical sectioning can be accomplished in the single field of view images by injecting a laser beam into a tube of the microscope through a diffuser plate, which is image onto a back aperture of the objective. ### Claim 47 (depends on 40) The instrument as claimed in claim 40 wherein optical sectioning can be accomplished in a single field of view images by illuminating the specimen directly. ### Claim 48 (depends on 40) The instrument as claimed in claim 40 wherein two images can be acquired, one illuminated by speckle when a diffuser plate is stationary and a second uniform-illumination image when the diffuser plate in rapid motion. ### Claim 49 (depends on 48) The instrument as claimed in claim 48 wherein the two images can be processed and combined to give a final optically-sectioned high resolution image. ### Claim 50 (depends on 48) The instrument as claimed in claim 48 wherein optical sectioning can be accomplished in the stationary images by injecting a laser beam into a tube of the microscope through a diffuser plate, which is imaged onto a back aperture of the objective. ### Claim 51 An instrument for alternatively scanning and stationary imaging of at least part of a specimen in combination, the instrument comprising an optical train to focus light from the specimen onto a two-dimensional area detector array, the detector array being part of the optical train, there being a holder for the specimen, the holder moving relative to the detector array during scanning and being perpendicular to the optical train of the instrument during scanning, the holder being fixed relative to the detector array during stationary imaging of the specimen. ### Claim 52 (depends on 51) The instrument as claimed in claim 51 wherein the detector array has a shutter, the detector array being configured to receive data from the specimen when the shutter is open and to pass data from the detector array to a processor when the shutter closed, the scanning images being images taken during scanning being added together by a processor to produce a contiguous image of at least part of said specimen being scanned. ### Claim 53 (depends on 51) The instrument as claimed in claim 51 wherein stationary images, being images taken when the holder is fixed relative to the detector array are single field of view images. ### Claim 54 (depends on 51) The instrument as claimed in claim 51 wherein the stationary images, being single field of view images taken when the holder is fixed relative to the detector array are either bright field or fluorescence images. ### Claim 55 (depends on 53) The instrument as claimed in claim 53 wherein the stationary images are taken to provide video array acquisition for viewing in real time. ### Claim 56 (depends on 54) The instrument as claimed in claim 54 wherein increased exposure of single field of view fluorescence images can be accomplished by increasing a time that the shutter is open or by adding a serious of images of the same field of view, which allows a dynamic range in the image to be larger than that of the detector array. ### Claim 57 (depends on 52) The instrument as claimed in claim 52 wherein increased optical resolution can be achieved in the single field of view images using structured illumination. ### Claim 58 (depends on 57) The instrument as claimed in claim 57 wherein the specimen is illuminated by speckle when the diffuser plate is stationary and a second uniform-illumination image when the diffuser plate is in rapid motion, the two images being processed and combined to produce a final optically-sectioned high resolution image.