Image analysis – Applications – Biomedical applications
Reexamination Certificate
1998-09-18
2004-02-10
Chang, Jon (Department: 2723)
Image analysis
Applications
Biomedical applications
C382S165000, C382S224000
Reexamination Certificate
active
06690817
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to spectral methods in general and, more particularly, to spectral imaging methods for cell classification, biological research, medical diagnostics and therapy, which methods are referred to hereinbelow as spectral bio-imaging methods. The spectral bio-imaging methods of the present invention can be used to provide automatic and/or semiautomatic spectrally resolved morphometric classification (e.g., detection, grading) of neoplasm, by standardizing the measured spectra of biological material present in biological samples in general, but more specifically when these samples are stained for microscopy imaging, and as a result enabling the building of libraries of spectral signatures for these biological objects, and therefore allowing automatic and semiautomatic analysis of such samples. Also, cytological or tissue section specimen which are generally stained with chromogenic dyes, simultaneously with, or without, specific tagged or marked expressed proteins and/or genes and/or DNA segments, to be measured by bright field light microscopy have the advantages over fluorescently dyed, tagged and/or marked specimen, of being significantly more permanent and therefore of providing means to repeat the tests at later times, of avoiding the background signals due to auto fluorescence of the specimen itself, and in general of being less expensive, at least at present. By helping overcome the signal variations due to drifts in staining colors and concentrations, due to different manufacturing processes of the stains, different origins of the stains, and other environmental reasons, and instabilities of the measuring instrumentation, due to drifts in the illumination spectrum and/or intensity, changes in the optics spectral transmission, and spectral response of the detector array, the methods can be used for the improvement and automatization of the detection of the spatial organization and of the qualification and quantification of cellular and tissue constituents and structures associated with, for example, tumorogenesis, using, for example, light transmission microscopy combined with high spatial and spectral resolutions. Furthermore, the methods of the present invention can be used to improve the detection of cellular spatial organization and the quantification of cellular and tissue natural constituents, domains and structures, including, but not limited to, proteins, genes, DNA sections, subcellular organelles, and the like, using light transmission, reflection, scattering and fluorescence emission strategies, with high spatial and spectral resolutions, and may therefore be employed for classification of cancer cells and/or grading and/or staging the progression of cancer, using, what is referred herein as, spectrally resolved morphometry, mainly for diagnostic and prognostic applications. In particular the methods of the present invention can be used for classification of cells to developmental stages, and to qualify and quantify metabolic processes within cells. The methods can further be used to develop new and more fine tuned indexes for neoplasm classification (including grading), which will eventually replace the existing indexes. Although the explanations and the treatment is shown for full spectral measurements encompassing a large number of wavelengths, it will be recognized on the basis of the description of the method, the assumptions and the provided mathematical modeling, that the method of the present invention is useful and valid for spectral imaging measurements which contain an arbitrary number of wavelengths in the defined spectral range, from one single wavelength to hundreds (the usual maximum number used in this technology), and more.
A spectrometer is an apparatus designed to accept light, to separate (disperse) it into its component wavelengths, and measure the lights spectrum, that is the intensity of the light as a function of its wavelength. An imaging spectrometer is a spectrometer which collects incident light from a scene and measures the spectra of each pixel (i.e., picture element) thereof.
Spectroscopy is a well known analytical tool which has been used for decades in science and industry to characterize materials and processes based on the spectral signatures of chemical constituents therein. The physical basis of spectroscopy is the interaction of light with matter. Traditionally, spectroscopy is the measurement of the light intensity emitted, scattered or reflected from or transmitted through a sample, as a function of wavelength, at high spectral resolution, but without any spatial information.
Spectral imaging, on the other hand, is a combination of high resolution spectroscopy and high resolution imaging (i.e., spatial information). Most of the works so far described concern either obtaining high spatial resolution information from a biological sample, yet providing only limited spectral information, for example, when high spatial resolution imaging is performed with one or several discrete band-pass filters [See, Andersson-Engels et al. (1990) Proceedings of SPIE—Bioimaging and Two-Dimensional Spectroscopy, 1205, pp. 179-189], or alternatively, obtaining high spectral resolution (e.g., a full spectrum), yet limited in spatial resolution to a small number of points of the sample or averaged over the whole sample [See for example, U.S. Pat. No. 4,930,516, to Alfano et al.].
Conceptually, a spectral bio-imaging system consists of (i) a measurement system, and (ii) an analysis software. The measurement system includes all of the optics, electronics and the manner in which the sample is illuminated (e.g., light source selection), the mode of measurement (e.g., fluorescence or transmission), as well as the calibration best suited for extracting the desired results from the measurement. The analysis software includes all of the software and mathematical algorithms necessary to analyze and display important results in a meaningful way.
Spectral imaging has been used for decades in the area of remote sensing to provide important insights in the study of Earth and other planets by identifying characteristic spectral absorption features originating therefrom. However, the high cost, size and configuration of remote sensing spectral imaging systems (e.g., Landsat, AVIRIS) has limited their use to air and satellite-born applications [See, Maymon and Neeck (1988) Proceedings of SPIE—Recent Advances in Sensors, Radiometry and Data Processing for Remote Sensing, 924, pp. 10-22; Dozier (1988) Proceedings of SPIE—Recent Advances in Sensors, Radiometry and Data Processing for Remote Sensing, 924, pp. 23-30].
There are three basic types of spectral dispersion methods that might be considered for a spectral bio-imaging system: (i) spectral grating or prism, (ii) spectral filters and (iii) interferometric spectroscopy. As will be described below, the latter is best suited to implement the method of the present invention, yet as will be appreciated by one ordinarily skilled in the art, grating, prism and filters based spectral bio-imaging systems may also be found useful in some applications.
In a grating or prism (i.e., monochromator) based systems, also known as slit-type imaging spectrometers, such as for example the DILOR system: [see, Valisa et al. (September 1995) presentation at the SPIE Conference European Medical Optics Week, BiOS Europe 1995, Barcelona, Spain], only one axis of a CCD (charge coupled device) array detector (the spatial axis) provides real imagery data, while a second (spectral) axis is used for sampling the intensity of the light which is dispersed by the grating or prism as function of wavelength. The system also has a slit in a first focal plane, limiting the field of view at any given time to a line of pixels. Therefore, a full image can only be obtained after scanning the grating (or prism) or the incoming beam in a direction parallel to the spectral axis of the CCD in a method known in the literature as line scanning. The inabi
Ben-Yosef Nissim
Buckwald Robert A.
Cabib Dario
Applied Spectral Imaging Ltd.
Chang Jon
G. E. Ehrlich (1995) Ltd.
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