WO2011098458A2 - Procédé pour reconstituer un volume histologique et dispositif de mesure - Google Patents

Procédé pour reconstituer un volume histologique et dispositif de mesure Download PDF

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Publication number
WO2011098458A2
WO2011098458A2 PCT/EP2011/051839 EP2011051839W WO2011098458A2 WO 2011098458 A2 WO2011098458 A2 WO 2011098458A2 EP 2011051839 W EP2011051839 W EP 2011051839W WO 2011098458 A2 WO2011098458 A2 WO 2011098458A2
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WO
WIPO (PCT)
Prior art keywords
tissue sample
histological
camera
image
bottom plate
Prior art date
Application number
PCT/EP2011/051839
Other languages
German (de)
English (en)
Other versions
WO2011098458A3 (fr
Inventor
Martin Groher
Jose Gardiazabal-Schilling
Marco Feuerstein
Tim Hauke Heibel
Original Assignee
Technische Universität München
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Technische Universität München filed Critical Technische Universität München
Publication of WO2011098458A2 publication Critical patent/WO2011098458A2/fr
Publication of WO2011098458A3 publication Critical patent/WO2011098458A3/fr

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Classifications

    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T19/00—Manipulating 3D models or images for computer graphics
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T7/00—Image analysis
    • G06T7/30—Determination of transform parameters for the alignment of images, i.e. image registration
    • G06T7/33—Determination of transform parameters for the alignment of images, i.e. image registration using feature-based methods
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2200/00—Indexing scheme for image data processing or generation, in general
    • G06T2200/08—Indexing scheme for image data processing or generation, in general involving all processing steps from image acquisition to 3D model generation
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/10—Image acquisition modality
    • G06T2207/10016—Video; Image sequence
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/10—Image acquisition modality
    • G06T2207/10056—Microscopic image
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2207/00—Indexing scheme for image analysis or image enhancement
    • G06T2207/30—Subject of image; Context of image processing
    • G06T2207/30004—Biomedical image processing
    • G06T2207/30024—Cell structures in vitro; Tissue sections in vitro
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T2210/00—Indexing scheme for image generation or computer graphics
    • G06T2210/41—Medical

Definitions

  • the present invention relates to a measuring device for the examination of tissue samples, and in particular relates to a device for reconstructing a histological volume from a stack of successive sectional images of a tissue sample. Furthermore, the present invention relates to a histological volume reconstruction method.
  • Microscopes examined. In the so-called morphological diagnosis is based on the appearance and the
  • Histological tissue samples include u.a. Surgical preparations, such as
  • microtome used.
  • Such a microtome can as a
  • Carriage microtome or a rotary microtome are performed.
  • the preparations obtained with the microtome are then examined microscopically.
  • the object of the present invention is an improved reconstruction method and a corresponding measuring device for the reconstruction of a histological
  • the above object is achieved by a camera support for mounting a camera for receiving a reference image with the features of claim 13.
  • the above task is accomplished by a
  • An essential idea of the invention is reference images from a cut surface of the tissue sample
  • Tissue sample on the basis of stored reference images associated with each other, then the associated and
  • the present invention provides a method for reconstructing a histological
  • Volume from a stack of consecutive sectional images a tissue sample having at least one cut surface comprising the steps of: providing the
  • Sectional view of a histological layer and assembling the aligned and aligned slice images to the histological volume.
  • the present invention provides a camera support including a bottom plate and a positioning device attached to the bottom plate, which is designed for the spatial positioning of a camera with respect to the bottom plate, wherein the
  • Attachment of the camera and at least one actuating unit which is designed to set a spatial position of the fastener along at least one axis.
  • the positioning device can also be located on the microtome or on the table on which the microtome is located.
  • FIG. 1 shows a perspective view of a measuring system for the reconstruction of a histological volume, wherein the measuring system comprises a carriage microtome, according to a typical embodiment; a detailed view of that shown in Fig. 1
  • the measuring system comprises a rotary microtome, according to another typical embodiment; another perspective view of the measuring system shown in Figure 3; a detailed view of a deflecting mirror for
  • FIG. 1 Deflection of an optical beam path for recording reference images in the in Figs. 3 and 4 measuring system shown; a perspective view of a camera support, which can be used with a microtome of Figures 1 to 5; another perspective view of the camera support shown in Figure 6; Yet another perspective view of the camera support shown in Figures 6 and 7. Yet another perspective view of the camera support shown in Figures 6 to 8. and a flowchart for illustrating a
  • FIG. 1 is a perspective view of a measurement system for reconstructing a histological volume from a stack of successive sectional images of a tissue sample according to a first embodiment.
  • a cutting device 300 which is designed as a carriage microtome (see also below description with reference to FIG. 2).
  • the carriage microtome has a sample holder 302 in which a tissue sample, for example, embedded in paraffin or similar material, can be introduced.
  • a guide carriage see Fig. 2
  • a tissue sample for example, embedded in paraffin or similar material
  • Microtome blade 301 is mounted, which is moved over the sample holder 302 and a thin histological layer of the
  • Tissue sample (not shown in FIG. 1) by movement of the microtome blade 301 relative to the tissue sample ablates.
  • This histological layer is then removed, placed in a liquid, such as water, and mounted on a substrate, such as a glass support. Subsequently, the histological layer can be examined by, for example, staining it with an HE stain (hematoxylin-eosin stain) and digitizing it with an image digitizing device such that a sectional image of the wounded on the substrate histological layer is obtained.
  • HE stain hematoxylin-eosin stain
  • Brightfield microscopy also fluorescence microscopy, confocal microscopy, multiphoton microscopy, electron microscopy, or any combination thereof can be used for image digitization.
  • the measuring system shown in Fig. 1 further has a
  • Carrier frame 104 includes. On the support frame 104, a camera 102 is mounted, on which a cut surface of the tissue sample can be imaged. The cut surface of the tissue sample is before ablating a respective
  • histological layer taken with the camera and stored as a reference image.
  • a histological volume can be
  • the previously digitized histological sectional images are thus brought into a local, geometric reference relationship to corresponding reference images recorded during the cutting process.
  • the reference images are generated by the camera 102, which is at the
  • Support frame 104 is attached.
  • the camera 102 arranged such that the optical axis of the camera 106 is approximately orthogonal to the cutting direction.
  • the reference image is generated at the exact moment that the sample is not obscured by the blade or other parts of the cutting device 300 (microtome). For example, it is possible to automatically perform cuts by the cutting device 300, such that image acquisition by an algorithm is automatic
  • Tissue sample can thus be determined depending on one
  • Position of the microtome blade in relation to the tissue sample or in dependence on a detected position of the tissue sample are performed automatically. For example, taking the reference image of the cut surface of the tissue sample may be performed in response to the detected position of the microtome blade relative to the tissue sample or in response to a sensed position of the tissue sample after an elapse of a predetermined latency period.
  • the image acquisition during the transition to the next cut is triggered, for example, by a sensor attached to the measuring system (see FIG. 2) or manually.
  • Reconstruction of the histological volume then takes place a spatial orientation of corresponding images or subvolumes of these image stacks.
  • a subvolume for example, a three-dimensional structure becomes
  • Reference image can be an alignment of 2D coordinates or alignment of 3D coordinates of at least one
  • the quality of an alignment can be checked or optimized with iterative methods.
  • the alignment can be done by a (semi-) automatic
  • Image registration algorithm which global (eg perspective, affine, isometric with or without
  • Such coordinate transformations form coordinates of the histological slice stack in coordinates of the
  • a global transformation is a transformation that treats each pixel coordinate in the same way, e.g.
  • a nonrigid transformation is a change of spatial
  • Image registration is the process by which a transformation can be automatically calculated from given images or from information extracted from images, so that the
  • corresponding structures of the images can be superimposed.
  • an optimization can be carried out, the distance of corresponding markers and anatomical landmarks, which for this purpose in a
  • Labeling are introduced, minimized; Further, an optimization can be carried out, the distance of the color ⁇ or intensity values of corresponding image or
  • Volume elements (pixels or voxels) are minimized.
  • the correspondence of the landmarks and landmarks is within the registration algorithm either via a next-point criterion, or by matching
  • Landmarks is determined by a distance standard
  • the Euclid 's standard (L2 standard) or the Ll standard is calculated.
  • the distance of color or intensity values of corresponding image or volume elements is determined by comparative measures (for example, sum of squared values)
  • Cuts are piled to a volume.
  • Providing the tissue sample may include at least one
  • a tissue sample in a paraffin block including the tissue sample in resin, and any combination thereof.
  • Histological sectional images are digitized sections produced in a histological process, which are located on substrates or on the substrate. Digitization is typically done with a scanner by microscope camera and illumination system
  • An image stack is a collection of consecutive images from the same tissue sample.
  • a microtome may be employed which may be embodied as a carriage microtome or a rotary microtome. The tissue sample is added
  • Carrier frame 104 is mounted at an angle of approximately 45 °, which makes it possible to attach the camera facing downward and to record the tissue sample facing the front.
  • Carrier frame 104 both
  • Microtome types may also be provided with a stabilization stage on which the assembly together with the microtome
  • the local resolution of the scanned images which is generally known by a separate calibration of the histological scanner, may be related to the local resolution of the image
  • Camera images may also be determined by a camera calibration algorithm within the image plane that relates to the histological tissue sample.
  • image processing techniques are used to improve structural similarities. Such a pre-processing step takes place before the actual registration. To do this
  • Embedding material such as paraffin
  • a method is used to analyze the histological sections
  • Render three-dimensional reconstructed volumes This rendering creates an image on the computer screen, either by "flipping through” the image stack via a user interaction or by computing a new virtual one
  • the volumes reconstructed from the histological sections will eventually allow volumetric measurements to be performed semi-automatically or fully automatically by performing geometric extraction of landmarks or anatomical landmarks. For example, a tumor region can be extracted from the volume, and its volumetric spread can be calculated.
  • the extraction can be manual, semi-automatic or automatic via a software user interface
  • histological layer provided.
  • An overview staining for example a hematoxylin-eosin stain or an azan stain, a connective tissue or supporting tissue depiction, for example a Van Gieson stain, a
  • Lipid representation for example, a Sudan-I I-staining, a carbohydrate representation, for example, a Alcianblau- staining, an amyloid representation, for example a
  • Congo red stain a pigment representation, for example a Berlin blue reaction stain, a microorganism representation, for example a Gram stain, for example by safranin-O, a representation of neurological structures, for example a crescent-fast stain, a
  • Fluorescence staining for example DAPI, cyanide (Cy3, Cy5) or Fitc staining, immunohistochemical staining, staining for electron microscopy, in situ hybridization staining (ISH), fluorescence in situ Hybridization stains (FISH), and any
  • Microtome 301 of the microtome 300 is removed, is typically in a range of 2 pm to 15 pm.
  • FIG. 2 is a detail view of a portion of the microtome 300 shown in FIG. 1, with the microtome blade 301 and the sample holder 302 shown in more detail.
  • the microtome 300 is attached to the bottom plate 101 or to the support frame 104 to which a camera to be described later for capturing reference images can be attached.
  • the attachment of the microtome 300 to the bottom plate 101 or to the support frame 104 can be done by screwing by means of a screw connection. Further, the microtome 300 can be placed without screwing only on the bottom plates 101 or on the support frame 104.
  • the microtome blade 301 is attached to a guide carriage 304 which is used to move the microtome blade 301 along the surface of the sample (not shown) into the sample holder 302 is einbringbar, is suitable. In this way, a histological layer of the tissue sample through the
  • Microtome 301 are removed. Before removing the histological layer, as below
  • a reference image of the cut surface of the tissue sample is taken.
  • the surface of the tissue sample must be optically accessible, i. the microtome blade 301 is in a retracted state as shown in FIG.
  • Imaging process is a sensor unit 303, which detects when the guide carriage 304 of the microtome 300 is retracted, such that the microtome blade 301, the surface of the tissue sample releases.
  • the sensor unit 303 may include a sensor selected from the
  • Group which consists of a limit switch, a button, an ultrasonic sensor, a laser sensor, a
  • Infrared sensor and any combination thereof.
  • Sensor unit 303 thus provides a signal which indicates when the surface of the tissue sample for a recording of a reference image is optically freely accessible. That shown in the typical embodiment of Figs. 1 and 2
  • the microtome is shown as a slide microtome such that removal of the tissue sample from the sample holder 302 is provided by displacement of the guide carriage 304.
  • FIG. 3 is a perspective view of a measuring system according to another typical embodiment.
  • a microtome 300 shown in Fig. 3 is formed as a rotary microtome.
  • the sample holder 302 is such
  • a surface i. a cut surface of the tissue sample is oriented perpendicular to the bottom plate 101.
  • a vertical linkage 204th On the bottom plate 101 is a vertical linkage 204th
  • a camera 102 is mounted, which from above, ie with an optical axis aligned perpendicular to the bottom plate 101st
  • a camera assembly is provided in connection with a cryostat.
  • a cryostat is a cutting device that contains a sample and a blade in an upwardly open, cooled chamber, and with which manual or motorized thin layers can be removed from a sample. The structure of the cryostat is different from the above
  • said carriage microtome and rotary microtome such that typically a substructure identifies the cryostat as a ground-based device that can not be mounted on a table.
  • the structure of the camera is not used together with the camera mount 100, but in
  • an alternative camera carrier can be provided, which is mounted on a surface located above and behind or next to the cutting chamber and in turn deflects the observation beam path of the camera onto the sample by means of a deflection mirror.
  • the alternative camera carrier may have actuators, one
  • a positioning device 200 which includes a first actuator (not shown) and the second and third actuators 202 and 203, serves to adjust the camera in three axes (x, y, z) with respect to the bottom plate 101 so that the intersection of the Tissue sample is imaged on the camera 102.
  • FIG. 4 is another perspective view of the measurement system shown in FIG. 3 for reconstructing a histological volume from a stack of successive slice images of a tissue sample.
  • FIG. The microtome 300 is in turn mounted on the bottom plate 101, with the bottom plate
  • the 101 may have positioning recesses for placing the microtome 300 such that a reproducible positioning of the microtome 300 is provided on the bottom plate 101.
  • a camera carrier 100 for holding the camera 102 includes the bottom plate 101, the positioning unit 201 consisting of the first setting unit 201, the second setting unit 202, and the third setting unit 203, the vertical linkage 204, and the horizontal linkage 205.
  • the camera carrier 100 is described below with reference to FIGS. 6 to 9 explained in more detail.
  • first, second and third actuators 201, 202 and 203 may be formed as a linear stage.
  • Actuator 201 is attached to the bottom plate 101. In a direction shown by a double arrow x, the vertical linkage 204 is moved by the first actuator unit 201 with respect to the bottom plate 101. On the vertical linkage 201, the second actuator 202 is mounted, which a
  • the second actuator 202 is connected to the third actuator 203, which has a
  • a mounting unit 206 is attached to which the camera 102 is attached. In this way it is possible for the camera 102 to be in three
  • FIG. 5 is a perspective detail view of the measuring system shown in FIG. 4, to illustrate the deflection of the optical camera axis 106 in a direction perpendicular to the cut surface of the tissue sample.
  • Deflection mirror 103 attached to a mirror holder 107 at an angle of approximately 45 ° to the bottom plate 101, such that the optical beam path 105 is deflected by approximately 90 °. In this way, the optical camera axis 106 can be perpendicular to the bottom plate 101.
  • the camera 102 includes a lighting ring configured to illuminate the tissue sample.
  • the Fign. Figures 6, 7, 8 and 9 show a camera carrier 100 according to a typical embodiment in different perspective views, respectively.
  • the camera carrier 100 includes the bottom plate 101 and the first, second and third actuators 201, 202 and 203
  • a free surface of the bottom plate 101 which is shown on the left in FIG. 6, serves to receive a microtome.
  • the optical camera axis 106 of the camera 102 is substantially perpendicular to the bottom plate 101
  • the optical camera axis 106 hits the
  • Deflection mirror 103 which is attached to the mirror holder 107 at an angle of approximately 45 ° to the bottom plate 101.
  • first, second and third actuators 201, 202 and 203 may be configured as a phaser having a predetermined stroke, i. have a predetermined adjustment.
  • the first actuator 201 provides a stroke in a range of 2 cm to 6 cm, and even more
  • This stroke corresponds to the adjustment path length x shown in FIG. 4
  • Actuator 203 is designed to set a
  • the second actuator 202 provides a stroke in a range of 30 cm to 50 cm, and more typically a 40 cm stroke. This stroke corresponds to a displacement z in the vertical direction, i. approximately orthogonal to
  • the stroke that the third actuator 203 provides corresponds to an adjustment length z shown in FIG.
  • At least one of the actuators 201, 202, 203 may be electrically operated.
  • FIG. 7 is another perspective view of FIG.
  • Deflection mirror 103 is shown obliquely from behind. Of the
  • Camera carrier 100 may further include vibration damping
  • vibration damping feet on the bottom plate 101 a weight of the bottom plate 101, active damping elements, or any combination thereof.
  • Fig. 8 corresponds to a perspective view of Fig. 4, wherein in Fig. 8, the camera carrier 100 without the
  • Microtome 300 is shown.
  • Deflection mirror 103 is shown obliquely from behind.
  • FIG. 10 is a flow chart illustrating a method of reconstructing a histological volume from a stack of successive slice images of a tissue sample, wherein the tissue sample includes at least one of a tissue sample
  • the camera carrier as a modular unit. As a result, this may e.g. to existing ones
  • the camera carrier is not firmly connected to the cutting device.
  • the measuring device according to embodiments of the invention may be used together with a cryostat because the camera carrier is modular. According to others typical embodiments described with here
  • the camera is a macroscopic camera, so for example, is not connected to a microscope or has no magnifying optics analogous to that of a microscope or an enlargement of less than 10.
  • Block 401 the procedure starts.
  • Block 402 serves to provide the tissue sample whose histological volume is to be reconstructed from the stack of successive slice images of the tissue sample.
  • a reference image of the cut surface of the tissue sample is taken. This cut surface is a cut surface, which arises after a removal of a
  • the recorded reference image is displayed in a block 404
  • a histological layer is removed from the cut surface of the tissue sample with the aid of the microtome, as described above with reference to FIGS. 1 to 3.
  • the histological layer is mounted on a substrate. Such a process step is necessary to be able to digitize the typically very thin tissue sample. After putting up the
  • step 406 a sectional image of the histological layer grown on the substrate is taken in step 407.
  • Such recording of the sectional image can in one
  • Image digitizing device take place. This will not be described in detail here, since it is not required for understanding the invention.
  • the recorded slice image can now be aligned geometrically with the stored reference image.
  • Such geometric alignment can be performed by a transformation model.
  • the transformation can be considered a global transformation
  • Transformation corresponds to a local orientation of the recorded slice image with the stored
  • stored reference image is a pair of images
  • the aligned slice image is assigned to at least one further recorded slice image of the histological slice.
  • the histological volume is reconstructed from a stack of successive sectional images of the tissue sample.
  • the procedure ends in a block 411.

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  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Theoretical Computer Science (AREA)
  • Computer Graphics (AREA)
  • Computer Hardware Design (AREA)
  • General Engineering & Computer Science (AREA)
  • Software Systems (AREA)
  • Computer Vision & Pattern Recognition (AREA)
  • Sampling And Sample Adjustment (AREA)

Abstract

L'invention concerne un système de mesure et un procédé pour reconstituer un volume histologique à partir d'un empilement de vues en coupe superposées d'un échantillon tissulaire. Un échantillon tissulaire est préparé, puis une image de référence de la surface coupée de l'échantillon tissulaire est acquise et enregistrée. Une couche histologique est prélevée sur la surface coupée de l'échantillon tissulaire au moyen d'un microtome puis est positionnée sur un substrat. Une vue en coupe de la couche histologique positionnée sur le substrat est acquise. La vue en coupe acquise est alignée géométriquement avec l'image de référence enregistrée, et la vue en coupe alignée est associée à au moins une autre vue en coupe acquise d'une couche histologique, pour combiner les vues en coupe associées et alignées afin de former le volume histologique.
PCT/EP2011/051839 2010-02-09 2011-02-08 Procédé pour reconstituer un volume histologique et dispositif de mesure WO2011098458A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102010007264.8 2010-02-09
DE102010007264 2010-02-09
DE102010037059 2010-08-18
DE102010037059.2 2010-08-18

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WO2011098458A2 true WO2011098458A2 (fr) 2011-08-18
WO2011098458A3 WO2011098458A3 (fr) 2012-09-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113848085A (zh) * 2021-08-12 2021-12-28 澎立检测技术(上海)有限公司 一种病理硬组织切片系统

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113848085A (zh) * 2021-08-12 2021-12-28 澎立检测技术(上海)有限公司 一种病理硬组织切片系统
CN113848085B (zh) * 2021-08-12 2024-05-31 澎立检测技术(上海)有限公司 一种病理硬组织切片系统

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