Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
  • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S128/00—Surgery
  • Y10S128/92—Computer assisted medical diagnostics
  • Y10S128/923—Computer assisted medical diagnostics by comparison of patient data to other data
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S707/00—Data processing: database and file management or data structures
  • Y10S707/99931—Database or file accessing
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S707/00—Data processing: database and file management or data structures
  • Y10S707/99931—Database or file accessing
  • Y10S707/99933—Query processing, i.e. searching
  • Y10S707/99936—Pattern matching access
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S707/00—Data processing: database and file management or data structures
  • Y10S707/99931—Database or file accessing
  • Y10S707/99937—Sorting
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S707/00—Data processing: database and file management or data structures
  • Y10S707/99941—Database schema or data structure
  • Y10S707/99943—Generating database or data structure, e.g. via user interface
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S707/00—Data processing: database and file management or data structures
  • Y10S707/99941—Database schema or data structure
  • Y10S707/99944—Object-oriented database structure
  • Y10S707/99945—Object-oriented database structure processing

Definitions

• the present invention relates to methods for profiling, engineering,
• invention relates to the development and use of a novel tissue information database for
• Tissue engineering is an emerging segment within the biotechnology industry.
• tissue engineering In order for the rational tissue engineering approach discussed above to be successful, structural information at the tissue level, as well as mechanical and cell function information on tissue, will be required and such information must be made accessible to persons in the tissue engineering, drug design and genomics research fields. It is an object of the present invention to develop such tissue information and to provide this information to persons and entities in the tissue engineering/manufacturing, drug design and genomics research fields. It is a further object of the present invention to use this tissue information to evaluate, classify and/or perform quality control on living and manufactured tissue specimens provided by tissue suppliers.
• tissue information that is the subject of the present invention to identify normal elements of such manufactured tissue specimens in cases where, for example, such manufactured tissue specimens do not appear normal in total but contain elements that appear and/or function normally.
• the present invention is directed to the development of a database that includes indices representative of a tissue population, and the use of the database for classification and evaluation of tissue specimens.
• a sample of normal tissue specimens obtained from a subset of a population of subjects with shared characteristics are profiled in order to generate a plurality of structural indices that correspond to statistically significant representations of characteristics of tissue associated with the population.
• the structural indices include cell density, matrix density, blood vessel density and layer thickness.
• the tissue specimens obtained from the subset of the population are profiled by imaging a plurality of sections of each tissue specimen from the subset. Distributions of cell density values, matrix density values and blood vessel density values associated with the plurality of sections are then determined in accordance with the results of the imaging.
• a cell density index representative of tissue associated with the population is determined in accordance with the distribution of cell density values
• a matrix density index representative of tissue associated with the population is determined in accordance with the distribution of matrix density values
• a blood vessel density index representative of tissue associated with the population is determined in accordance with the distribution of blood vessel density values.
• the cell density index is determined by calculating a statistical average of the distribution of cell density values
• the matrix density index is determined by calculating a statistical average of the distribution of matrix density values
• the blood vessel density index is determined by calculating a statistical average of the distribution of blood vessel density values.
• Each statistical average of a distribution values represents, for example, a mean, median or mode of the distribution of values.
• the structural indices include a further cell density index corresponding to an index of dispersion of the distribution of cell density values, a further matrix density index corresponding to an index of dispersion of the distribution of matrix density values, and a further blood vessel density index corresponding to an index of dispersion of the distribution of blood vessel density values.
• Each index of dispersion of a distribution values represents, for example, a standard deviation, standard error of the mean or range of the distribution of values.
• distributions of relative cell location values, relative matrix location values and relative blood vessel location values associated with the plurality of sections are also determined in accordance with the results of the imaging.
• a relative cell location index representative of tissue associated with the population is determined in accordance with the distribution of relative cell location values
• a relative matrix location index representative of tissue associated with the population is determined in accordance with the distribution of relative matrix location values
• a relative blood vessel location index representative of tissue associated with the population is determined in accordance with the distribution of relative blood vessel location values.
• the relative cell location index is determined by calculating a statistical average of the distribution of relative cell location values
• the relative matrix location index is determined by calculating a statistical average of the distribution of relative matrix location values
• the relative blood vessel location index is determined by calculating a statistical average of the distribution of relative blood vessel location values.
• the structural indices include a further relative cell location index corresponding to an index of dispersion of the distribution of relative cell location values, a further relative matrix location index corresponding to an index of dispersion of the distribution of relative matrix location values, and a further relative blood vessel location index corresponding to an index of dispersion of the distribution of relative blood vessel location values.
• each index of dispersion of a distribution values represents, for example, a standard deviation, standard error of the mean or range of the distribution of values.
• imaging modalities may be used for profiling the tissue specimens and generating the structural indices described above.
• light microscopy, fluorescent microscopy, spectral microscopy, hyper-spectral microscopy, electron microscopy, confocal microscopy and optical coherence tomography may be used for profiling the tissue specimens in accordance with the present invention.
• a combination of such imaging modalities can also be used for profiling tissue specimens in accordance with the present invention.
• one or more mechanical indices may be determined from the normal tissue specimens.
• the sample of normal tissue specimens obtained from the subset of the population with shared characteristics is further profiled in order to generate one or more mechanical indices that correspond to statistically significant representations of characteristics of tissue associated with the population.
• One of the mechanical indices may correspond to a modulus of elasticity associated with the normal tissue specimens.
• the mechanical index corresponding to the modulus of elasticity is preferably determined by obtaining a distribution of elasticity values associated with the plurality of sections discussed above, and then determining an elasticity index representative of tissue associated with the population in accordance with the distribution of elasticity values.
• the elasticity index preferably represents the statistical average (e.g., mean, median or mode) of the distribution of elasticity values.
• a further elasticity index representative of the index of dispersion of the distribution of elasticity values is determined. This further elasticity index preferably represents the standard deviation, standard error of the mean or range of the distribution of elasticity values.
• a further mechanical index corresponding to the mechanical strength (e.g., breaking or tensile strength) associated with the normal tissue specimens may also be determined.
• the mechanical index corresponding to the breaking strength is preferably determined by obtaining a distribution of breaking strength values associated with the plurality of sections discussed above, and then determining a breaking strength index representative of tissue associated with the population in accordance with the distribution of breaking strength values.
• the breaking strength index preferably represents the statistical average (e.g., mean, median or mode) of the distribution of breaking strength values.
• a further breaking strength index representative of the index of dispersion of the distribution of breaking strength values is determined. This further breaking strength index preferably represents the standard deviation, standard error of the mean or range of the distribution of breaking strength values.
• one or more cell function indices may be determined from the normal tissue specimens.
• a plurality of cell function assays are performed on the sample of normal tissue specimens from the subset of the population of subjects with shared characteristics. The results of the cell function assays are used to generate a plurality of cell function indices that correspond to statistically significant representations of characteristics of tissue associated with the population.
• the cell function indices are optionally used to form a cell function map that is stored in a tissue information database. In an alternate embodiment, only the cell function indices and/or the cell function map (and not the structural or mechanical indices) are determined.
• the cell function indices used in connection with this aspect of the invention correspond, for example, to (i) location, type and amount of DNA in the normal tissue specimens from the subset, (ii) location, type and amount of mRNA in the normal tissue specimens from the subset, (iii) location, type and amount of cellular proteins in the normal tissue specimens from the subset, (iv) location, type and amount of cellular lipids in the normal tissue specimens from the subset, and/or (v) location, type and amount of cellular ion distributions in the normal tissue specimens from the subset.
• the correlation between various one of the indices described above may also be determined.
• a correlation between two structural indices, a correlation between two mechanical indices, a correlation between two cell function indices, a correlation between a structural index and a mechanical index, a correlation between a structural index and a cell function index, and/or a correlation between a mechanical index and a cell function index may also be determined.
• the normal tissue specimens profiled to generate the structural, mechanical and/or cell function indices described above correspond, for example, to a set of either normal intestine tissue specimens, normal cartilage tissue specimens, normal eye tissue specimens, normal bone tissue specimens, normal fat tissue specimens, normal muscle tissue specimens, normal kidney tissue specimens, normal brain tissue specimens, normal heart tissue specimens, normal liver tissue specimens, normal skin tissue specimens, normal pleura tissue specimens, normal peritoneum tissue specimens, normal pericardium tissue specimens, normal dura-mater tissue specimens, normal oral-nasal mucus membrane tissue specimens, normal pancreas tissue specimens, normal spleen tissue specimens, normal gall bladder tissue specimens, normal blood vessel tissue specimens, normal bladder tissue specimens, normal uterus tissue specimens, normal ovarian tissue specimens, normal urethra tissue specimens, normal penile tissue specimens, normal vaginal tissue specimens, normal esophagus tissue specimens, normal anus tissue specimens, normal adrenal gland
• the tissue specimens profiled correspond to plant or animal tissue types, composite tissue types, virtual tissue types or food tissue types.
• the present invention is directed to a computer implemented method for providing information representative of a plurality of tissue types to a subscriber.
• Tissue information representative of a plurality of tissue types e.g., the structural, mechanical and/or cell function indices described above for a plurality of tissue types and the correlation results described above for a plurality of tissue types
• the database includes, for example, a plurality of structural indices generated from a sample of normal tissue specimens obtained from a subset of a population of subjects with shared characteristics.
• the structural indices correspond to statistically significant representations of characteristics of tissue associated with the population.
• the plurality of structural indices include cell density, matrix density, blood vessel density and layer thickness.
• the database alternatively includes a plurality of the cell function and/or mechanical indices described above either alone, or in combination with the aforementioned structural indices.
• Subscribers or users interested in engineering, classifying, manufacturing or analyzing tissue are provided access to the database in exchange for a subscription fee.
• the subscribers may optionally measure parameters associated with subscriber-supplied tissue samples.
• the subscriber-supplied tissue samples are then classified by comparing measured parameters associated with the subscriber-supplied tissue samples with the tissue information stored in the database (e.g., the structural, mechanical and/or cell function indices described above and/or the correlation results described above.)
• the database optionally stores indices representative of one or more abnormal tissue types, and the subscriber-supplied tissue samples are classified as either normal or abnormal by comparing measured parameters associated with the subscriber-supplied tissue samples to the tissue information stored in the database.
• the subscriber-supplied tissue specimens correspond to manufactured tissue specimens
• measured parameters associated with the subscriber-supplied tissue samples correspond to manufactured tissue specimens
• subscriber-supplied tissue samples may be compared to the tissue information stored in the
• Figure 1 is a flow diagram of a method for profiling samples of normal tissue
• each sample profiled is obtained from a subset of a
• Figures 2A, 2B, 2C and 2D are a flow diagram of a method for profiling a
• sample of normal tissue specimens obtained from a subset of a population of subjects with
• Figure 3 is a flow diagram of a method for profiling a sample of normal tissue
• Figures 4A and 4B are a flow diagram of a method for profiling a sample of
• Figures 5 is a diagram of an exemplary data structure for storing structural
• indices associated with a given tissue type (or population of tissue specimens) in a database are indices associated with a given tissue type (or population of tissue specimens) in a database.
• Figure 6 is a diagram of an exemplary data structure for storing mechanical
• indices associated with a given tissue type (or population of tissue specimens) in a database are indices associated with a given tissue type (or population of tissue specimens) in a database.
• Figures 7A, 7B and 7C are a diagram of an exemplary data structure for
• Figure 8 is a diagram of a database for storing structural, mechanical and cell
• Figure 9 is an exemplary cell function map associated with a tissue population
• Figure 10 is a flow diagram showing a method for designing and manufacturing engineered tissue, in accordance with a preferred embodiment of the present invention.
• Figure 11 is a flow diagram showing a method for providing information representative of a plurality of tissue populations to a subscriber and for classifying a user-supplied tissue specimen using such information, in accordance with a preferred embodiment of the present invention.
• a tissue type is selected for analysis.
• the tissue type corresponds to a population of tissue subject having shared characteristics.
• the tissue type corresponds to human lung tissue, intestine tissue, cartilage tissue, etc.
• the tissue type may be further specified as a population of subjects having a common age bracket, race and/or gender.
• the tissue type selected for analysis may correspond to a population of lung tissue subjects associated with Caucasian males between the ages of 18-35.
• the tissue type selected for analysis can correspond to either a normal or an abnormal tissue type.
• the tissue type selected for analysis may correspond to a tissue type associated with a particular plant or animal species, or a food product.
• a sample of specimens is selected from the population selected for analysis in step 50.
• the sample of specimens represents a subset of the selected population and includes a sufficient number of specimens to permit a statistically significant analysis of the population as a whole.
• the sample includes a sufficient number of specimens such that the structural, mechanical and cell function indices generated from the sample correspond to a statistically significant representation of those indices for the population as a whole.
• a plurality of structural indices representative of the selected population are measured from the sample and stored in a database.
• the structural indices are parameters that are representative of the physical structure of the tissue specimens in the sample.
• Exemplary structural indices measured and stored in step 200 include: the average density of each of a plurality of cell types in the specimens in the sample, an index of dispersion (e.g., standard deviation) associated with each measured average cell density, the average density of each of the matrix in the specimens in the sample, an index of dispersion associated with the measured average matrix density, the average layer thickness of each layer in the specimens in the sample, an index of dispersion associated with each measured average layer thickness, the average density of blood vessels in the specimens in the sample, an index of dispersion associated with the measured average blood vessel density, the average relative location of (or distance between) selected types of cells in the specimens in the sample, an index of dispersion associated with each measured average relative location of cell types, the average relative location between blood vessels and selected cell types in the specimens in
• a plurality of mechanical indices representative of the selected population are measured from the sample and stored in the database.
• the mechanical indices are parameters that are representative of the reaction of the tissue specimens in the sample to external forces.
• Exemplary mechanical indices measured and stored in step 300 include: the average elasticity of specimens in the sample, an index of dispersion associated with the measured average elasticity, the average breaking strength of specimens in the sample, and an index of dispersion associated with the measured average breaking strength. It will be understood by those skilled in the art that mechanical indices other than those enumerated above may be measured and stored in step 300, and that the use of such other mechanical indices is within the scope of the present invention.
• a set of exemplary steps that may be used to measure a sample of specimens and generate the mechanical indices enumerated above is shown in detail in Figure 3 and discussed more fully below.
• a plurality of cell function indices representative of the selected population are measured from the sample, stored in a database and optionally used to form a cell function map representative of the selected population.
• the cell function indices are parameters that represent the character and function of cells in the tissue specimens in the sample.
• Exemplary cell function indices measured and stored in step 400 include: the average amount of a first type of DNA in the specimens in the sample and an index of dispersion associated with the measured average amount of the first type of DNA, the average amount of a second type of DNA in the specimens in the sample and an index of dispersion associated with the measured average amount of the second type of DNA, ...
• the average amount of an nth type of DNA in the specimens in the sample and an index of dispersion associated with the measured average amount of the nth type of DNA the average amount of a first type of mRNA in the specimens in the sample and an index of dispersion associated with the measured average amount of the first type of mRNA, the average amount of a second type of mRNA in the specimens in the sample and an index of dispersion associated with the measured average amount of the second type of mRNA, ...
• the average amount of an nth type of mRNA in the specimens in the sample and an index of dispersion associated with the measured average amount of the nth type of mRNA the average amount of a first type of cellular protein in the specimens in the sample and an index of dispersion associated with the measured average amount of the first type of cellular protein, the average amount of a second type of cellular protein in the specimens in the sample and an index of dispersion associated with the measured average amount of the second type of cellular protein, ...
• the average amount of an nth type of cellular protein in the specimens in the sample and an index of dispersion associated with the measured average amount of the nth type of cellular protein the average amount of a first type of cellular lipid in the specimens in the sample and an index of dispersion associated with the measured average amount of the first type of cellular lipid, the average amount of a second type of cellular lipid in the specimens in the sample and an index of dispersion associated with the measured average amount of the second type of cellular lipid, ... , the average amount of an nth type of cellular lipid in the specimens in the sample and an index of dispersion associated with the measured average amount of the nth
• step 500 correlation operations are performed on the various components
• pairs of structural indices are correlated with each other, selected pairs of mechanical indices
• selected structural indices may be correlated with selected mechanical or cell function
• selected mechanical indices may be correlated with selected cell function indices.
• correlations between the following pairs of indices are performed in step
• step 500 may be measured and stored in step 500, and that the use of such other
• step 600 the process described above may be repeated for
• the present invention may be used to generate a data base such as that shown in Figure 8,
• tissue population collectively represent a "blueprint" of the tissue in the population and may
• given tissue population using the present invention preferably consists of Cartesian
• the coordinates are preferably in two-dimensions or three- dimensions.
• a fourth dimension (corresponding to time) may be included in the tissue design to account for changes to a particular tissue population as it ages over time.
• the time dimension in the tissue design might reflect the differences among the lung tissue of Caucasian males falling in different age brackets (e.g., 18-25 years old, 26-35 years old, etc.).
• each specimen from the sample selected in step 100 is imaged using, for example, light microscopy, fluorescent microscopy, spectral microscopy, hyper-spectral microscopy, electron microscopy, confocal microscopy and/or optical coherence tomography.
• the specimens from the samples may be imaged using a combination of the above imaging modalities.
• a plurality of sections in each tissue specimen in the sample is imaged using one or more of the above imaging modalities in step 202.
• step 204 the imaging information from step 202 is analyzed in order to generate a distribution of density values associated with a particular cell type (i.e., cell type 1) in the specimens in the sample.
• a particular cell type i.e., cell type 1
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the density of the particular cell type (i.e., cell type 1) in the section.
• a distribution of density values for the particular cell type may then be obtained.
• an average cell density index representative of an average density of the particular cell type (i.e., cell type 1) in the population is calculated by taking the statistical average of the distribution of values generated in step 204.
• the statistical average corresponds, for example, to a mean, median or mode of the distribution of values generated in step 204.
• an index of dispersion about the average density of the particular cell type (i.e., cell type 1) in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 204.
• the imaging information from step 202 may be further analyzed in order to generate a further distribution of density values associated with a different cell type (i.e., cell type 2) in the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the density of the particular cell type (i.e., cell type 2) in the section.
• a distribution of density values for the particular cell type i.e., cell type 2 is then obtained.
• an average cell density index representative of an average density of the particular cell type (i.e., cell type 2) in the population is calculated by taking the statistical average of the distribution of values generated in step 210.
• the statistical average corresponds, for example, to a mean, median or mode of the distribution of values generated in step 210.
• an index of dispersion about the average density of the particular cell type (i.e., cell type 2) in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 210.
• 214 may be repeated further times for each other cell type of interest in order to generate an average cell density index and a corresponding index of dispersion for each cell type of interest in the population.
• step 222 the imaging information from step 202 is analyzed in order to generate a distribution of density values associated with the matrix associated with the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the density of the matrix in the section.
• This matrix density in a given specimen may correspond, for example, to the density of one or more proteins in the extra-cellular matrix of the specimen.
• the statistical average corresponds, for example, to a mean, median or mode of the distribution of values generated in step 222.
• an index of dispersion about the average density of the particular matrix associated with the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 222.
• step 228, the imaging information from step 202 is analyzed in order to generate a distribution of layer thickness values associated with the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the thickness a particular tissue layer in the section.
• a distribution of layer thickness values for the particular layer is obtained.
• an average layer thickness index representative of an average thickness of the particular tissue layer associated with the population is calculated by taking the statistical average of the distribution of values generated in step 228.
• the statistical average corresponds, for example, to a mean, median or mode of the distribution of values generated in step 228.
• an index of dispersion about the average layer thickness of the particular layer associated with the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 228.
• steps 228-232 are preferably repeated for each tissue layer of interest, and an average layer thickness index and an index of dispersion about such average are generated for each such layer.
• the other structural, mechanical and cell function indices described herein may be determined separately for each tissue layer in the population.
• step 240 the imaging information from step 202 is analyzed in order to generate a distribution of density values associated with blood vessels in the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the density of blood vessels in the section.
• the blood vessels can be categorized by diameter, and the density of blood vessels in a given specimen can correspond to the density of blood vessels having one diameter. Alternatively, the density of blood vessels in a given specimen will correspond to the density of all blood vessels (regardless of their diameter) in the specimen.
• an average blood vessel density index representative of an average density of blood vessels (i.e., blood vessels per unit area/unit volume) in the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 240.
• an index of dispersion about the average blood vessel density is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 240.
• the imaging information from step 202 is further analyzed in order to generate a distribution of relative cell location values representative of the relative proximity of two particular cell types (i.e., cell types 1 and 2) in the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the average proximity of the two particular cell types (i.e., cell types 1 and 2) in the section.
• This process can be performed by using image analysis to determine the centers and boundaries of the cell types of interest, and then calculating the distances between the relevant cells in each image. For example, in cases where cells of type 1 are intermixed with cells of type 2, each occurrence of cell type 1 in a section can be identified and the distance to the closest cell of type 2 can then be measured.
• the centroids of the respective spaces occupied by the cells of type 1 and the cells of type 2 can be determined, and the distance between the centroids can then be measured.
• an average relative cell location index representative of an average proximity between the particular cell types of interest (i.e., cell types 1 and 2) in the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 246.
• an index of dispersion about the average proximity between the particular cell types of interest (i.e., cell types 1 and 2) in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 246.
• the imaging information from step 202 is further analyzed in order to generate a distribution of relative cell location values representative of the relative proximity of a further pair of particular cell types (i.e., cell types 1 and 3) in the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed (as discussed in connection with step 246) in order to determine the average proximity of the a different pair of particular cell types (i.e., cell types 1 and 3) in the section.
• a distribution of relative cell location values for the particular cell types of interest may then be obtained.
• an average relative cell location index representative of an average proximity between the particular cell types of interest (i.e., cell types 1 and 3) in the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 252.
• an index of dispersion about the average proximity between the particular cell types of interest (i.e., cell types 1 and 3) in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 252.
• steps 258, 260, 262, steps 246, 248, 250 and 252, 254, 256 may be repeated further times for each other pair of cell types of interest (i.e., cell types a and b) in order to generate an average relative cell location index and a corresponding index of dispersion for each pair of cell types of interest in the population.
• the imaging information from step 202 is further analyzed in order to generate a distribution of relative blood vessel location values representative of the relative proximity of blood vessel to a particular type of cell (i.e., cell types 1) in the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the average proximity of blood vessels to the particular cell type (i.e., cell types 1) in the section.
• This process can be performed by using image analysis to determine the centers and boundaries of the cell types of interest, and then calculating the distances between the relevant cells in each image and the closest blood vessels.
• a distribution of relative blood vessel location values for the particular cell type of interest may then be obtained.
• an average relative blood vessel location index representative of an average proximity between blood vessels and the particular cell type of interest (i.e., cell type 1) in the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 264.
• an index of dispersion about the average proximity between blood vessels and the particular cell type of interest (i.e., cell type 1) in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 264.
• the imaging information from step 202 is further analyzed in order to generate a distribution of relative blood vessel location values representative of the relative proximity between blood vessel of a further particular cell type of interest (i.e., cell type 2) in the specimens in the sample.
• the imaging information corresponding to each imaged section of each specimen is analyzed in order to determine the average proximity of blood vessels to the further particular cell type (i.e., cell type 2) in the section.
• This process can be performed by using image analysis to determine the centers and boundaries of the cell types of interest, and then calculating the distances between the relevant cells in each image and the closest blood vessels.
• an average relative blood vessel location index representative of an average proximity between blood vessels and the cell type of interest (i.e., cell type 2) in the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 270.
• an index of dispersion about the average proximity between blood vessel and the cell type of interest (i.e., cell type 2) in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 270.
• steps 276, 278, 280 steps 264, 266, 268 and 270, 272, 274 may be repeated further times for other cell types of interest (i.e., up to cell type n) in order to generate an average relative blood vessel location index and a corresponding index of dispersion for each cell type of interest in the population.
• step 282 all of the structural indices associated with the population of interest and described above are stored in a tissue data base using, for example, a data structure such as that shown in Figure 5.
• a data structure such as that shown in Figure 5.
• a separate data structure of the form shown in Figure 5 may be generated for each layer of interest.
• FIG. 3 there is shown a flow diagram of method 300 for profiling a sample of normal tissue specimens obtained from a subset of a population of subjects with shared characteristics in order to generate a plurality of mechanical indices that correspond to statistically significant representations of characteristics of tissue associated with the population.
• mechanical tests such as, for example, tensile strength and mechanical elasticity tests, are applied to each specimen from the sample selected in step 100.
• the mechanical tests may be applied to a plurality of sections in each tissue specimen in the sample.
• step 302 the information from the mechanical tests is analyzed in order to generate a distribution of elasticity values associated with the specimens in the sample.
• the mechanical information corresponding to each analyzed section of each specimen is analyzed in order to determine the elasticity of the particular section.
• a distribution of elasticity values for the population may then be obtained.
• an average elasticity index representative of an average elasticity of the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 302.
• an index of dispersion about the average elasticity of the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 302.
• step 308 the information from the mechanical tests is analyzed in order to generate a distribution of breaking strength values associated with the specimens in the sample.
• the mechanical information corresponding to each analyzed section of each specimen is analyzed in order to determine the breaking strength of the particular section.
• a distribution of breaking strength values for the population may then be obtained.
• an average breaking strength index representative of an average breaking strength of the population is calculated by taking the statistical average (e.g., mean, median or mode) of the distribution of values generated in step 308.
• an index of dispersion about the average breaking strength of the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of values generated in step 308.
• step 314 all of the mechanical indices associated with the population of interest and described above are stored in a tissue data base using, for example, a data structure such as that shown in Figure 6.
• a data structure such as that shown in Figure 6.
• a separate data structure of the form shown in Figure 6 may be generated for each layer of interest.
• a cell function assay is applied to each specimen from the sample selected in step 100.
• the cell function assay(s) that may be used for a given tissue population include, for example, DNA content, mRNA content, protein content, ion content, lipid content, and their respective individual elements such specific genes, specific mRNA, specific proteins, specific ions, and specific lipid content assays.
• one or more assays are applied to a plurality of sections in each tissue specimen in the sample.
• step 404 the cell function information from step 402 is analyzed in order to identify types of DNA that are present in the specimens in the sample.
• the types of DNA identified for analysis preferably correspond to the types of DNA that distinguish the tissue population of interest from other tissue populations.
• step 406 four cell function indices are determined for each type of DNA that was identified in step 404.
• the following indices are determined in step 404: (i) the average amount of the particular type of DNA in the specimens in the sample, (ii) an index of dispersion associated with the measured average amount of the particular type of DNA, (iii) the average relative location of the particular type of DNA in the specimens in the sample, and (iv) an index of dispersion associated with the measured average relative location of the particular type of DNA.
• the average amount of the particular type of DNA in the specimens in the sample and the index of dispersion associated with the measured average amount of the particular type of DNA are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average amount of the particular type of DNA in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of DNA amount values for the particular type of DNA may then be obtained. An average amount index representative of an average amount of the particular type of DNA in the population is then calculated by taking the statistical average of this distribution. Similarly, an index of dispersion about the average amount of the particular type of DNA in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of DNA amount values obtained for the particular type of DNA from the sample.
• the average relative location of the particular type of DNA in the specimens in the sample and the index of dispersion associated with the measured average relative location of the particular type of DNA are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average relative location of the particular type of DNA in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of DNA relative location values for the particular type of DNA may then be obtained. An average relative location index representative of an average relative location of the particular type of DNA in the population is then calculated by taking the statistical average of this distribution. Similarly, an index of dispersion about the average relative location of the particular type of DNA in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of DNA relative location values obtained for the particular type of DNA from the sample.
• step 408 the cell function information from step 402 is analyzed in order to identify types of mRNA that are present in the specimens in the sample.
• the types of mRNA identified for analysis preferably correspond to the types of mRNA that distinguish the tissue population of interest from other tissue populations.
• step 410 four cell function indices are determined for each type of mRNA that was identified in step 408.
• the following indices are determined in step 410: (i) the average amount of the particular type of mRNA in the specimens in the sample, (ii) an index of dispersion associated with the measured average amount of the particular type of mRNA, (iii) the average relative location of the particular type of mRNA in the specimens in the sample, and (iv) an index of dispersion associated with the measured average relative location of the particular type of mRNA.
• the average amount of the particular type of mRNA in the specimens in the sample and the index of dispersion associated with the measured average amount of the particular type of mRNA are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average amount of the particular type of mRNA in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of mRNA amount values for the particular type of mRNA may then be obtained. An average amount index representative of an average amount of the particular type of mRNA in the population is then calculated by taking the statistical average of this distribution.
• an index of dispersion about the average amount of the particular type of mRNA in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of mRNA amount values obtained for the particular type of mRNA from the sample.
• the average relative location of the particular type of mRNA in the specimens in the sample and the index of dispersion associated with the measured average relative location of the particular type of mRNA are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average relative location of the particular type of mRNA in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of mRNA relative location values for the particular type of mRNA may then be obtained. An average relative location index representative of an average relative location of the particular type of mRNA in the population is then calculated by taking the statistical average of this distribution.
• an index of dispersion about the average relative location of the particular type of mRNA in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of mRNA relative location values obtained for the particular type of mRNA from the sample.
• step 412 the cell function information from step 402 is analyzed in order to identify types of cellular proteins that are present in the specimens in the sample.
• the types of cellular proteins identified for analysis preferably correspond to the types of cellular proteins that distinguish the tissue population of interest from other tissue populations.
• step 414 four cell function indices are determined for each type of cellular protein that was identified in step 412.
• the following indices are determined in step 414: (i) the average amount of the particular type of cellular protein in the specimens in the sample, (ii) an index of dispersion associated with the measured average amount of the particular type of cellular protein, (iii) the average relative location of the particular type of cellular protein in the specimens in the sample, and (iv) an index of dispersion associated with the measured average relative location of the particular type of cellular protein.
• the average amount of the particular type of cellular protein in the specimens in the sample and the index of dispersion associated with the measured average amount of the particular type of cellular protein are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average amount of the particular type of cellular protein in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of cellular protein amount values for the particular type of cellular protein may then be obtained. An average amount index representative of an average amount of the particular type of cellular protein in the population is then calculated by taking the statistical average of this distribution.
• an index of dispersion about the average amount of the particular type of cellular protein in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of cellular protein amount values obtained for the particular type of cellular protein from the sample.
• the average relative location of the particular type of cellular protein in the specimens in the sample and the index of dispersion associated with the measured average relative location of the particular type of cellular protein are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average relative location of the particular type of cellular protein in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of cellular protein relative location values for the particular type of cellular protein may then be obtained. An average relative location index representative of an average relative location of the particular type of cellular protein in the population is then calculated by taking the statistical average of this distribution.
• an index of dispersion about the average relative location of the particular type of cellular protein in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of cellular protein relative location values obtained for the particular type of cellular protein from the sample.
• step 416 the cell function information from step 402 is analyzed in order to identify types of cellular lipids that are present in the specimens in the sample.
• the types of cellular lipids identified for analysis preferably correspond to the types of cellular lipids that distinguish the tissue population of interest from other tissue populations.
• step 418 four cell function indices are determined for each type of cellular lipid that was identified in step 416. More particularly, for each identified type of cellular lipid, the following indices are determined in step 418: (i) the average amount of the particular type of cellular lipid in the specimens in the sample, (ii) an index of dispersion associated with the measured average amount of the particular type of cellular lipid, (iii) the average relative location of the particular type of cellular lipid in the specimens in the sample, and (iv) an index of dispersion associated with the measured average relative location of the particular type of cellular lipid.
• the average amount of the particular type of cellular lipid in the specimens in the sample and the index of dispersion associated with the measured average amount of the particular type of cellular lipid are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average amount of the particular type of cellular lipid in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of cellular lipid amount values for the particular type of cellular lipid may then be obtained. An average amount index representative of an average amount of the particular type of cellular lipid in the population is then calculated by taking the statistical average of this distribution.
• an index of dispersion about the average amount of the particular type of cellular lipid in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of cellular lipid amount values obtained for the particular type of cellular lipid from the sample.
• the average relative location of the particular type of cellular lipid in the specimens in the sample and the index of dispersion associated with the measured average relative location of the particular type of cellular lipid are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average relative location of the particular type of cellular lipid in each such section. By performing such an analysis on each section of each specimen in the sample, a distribution of cellular lipid relative location values for the particular type of cellular lipid may then be obtained. An average relative location index representative of an average relative location of the particular type of cellular lipid in the population is then calculated by taking the statistical average of this distribution.
• an index of dispersion about the average relative location of the particular type of cellular lipid in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the distribution of cellular lipid relative location values obtained for the particular type of cellular lipid from the sample.
• step 420 the cell function information from step 402 is analyzed in order to identify types of cellular ion distributions that are present in the specimens in the sample.
• the types of cellular ion distributions identified for analysis preferably correspond to the types of cellular ion distributions that distinguish the tissue population of interest from other tissue populations.
• step 422 four cell function indices are determined for each type of cellular ion distribution that was identified in step 420.
• the following indices are determined in step 422: (i) the average amount of the particular type of cellular ion distribution in the specimens in the sample, (ii) an index of dispersion associated with the measured average amount of the particular type of cellular ion distribution, (iii) the average relative location of the particular type of cellular ion distribution in the specimens in the sample, and (iv) an index of dispersion associated with the measured average relative location of the particular type of cellular ion distribution.
• the average amount of the particular type of cellular ion distribution in the specimens in the sample and the index of dispersion associated with the measured average amount of the particular type of cellular ion distribution are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average amount of the particular type of cellular ion distribution in each such section. By performing such an analysis on each section of each specimen in the sample, a sample distribution of cellular ion amount values for the particular type of cellular ion distribution may then be obtained. An average amount index representative of an average amount of the particular type of cellular ion distribution in the population is then calculated by taking the statistical average of the sample distribution. Similarly, an index of dispersion about the average amount of the particular type of cellular ion distribution in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the sample distribution.
• the average relative location of the particular type of cellular ion distribution in the specimens in the sample and the index of dispersion associated with the measured average relative location of the particular type of cellular ion distribution are determined by first analyzing the cell function information corresponding to each section of each specimen in the sample in order to determine the average relative location of the particular type of cellular ion distribution in each such section. By performing such an analysis on each section of each specimen in the sample, a sample distribution of relative location values for the particular type of cellular ion distribution may then be obtained. An average relative location index representative of an average relative location of the particular type of cellular ion distribution in the population is then calculated by taking the statistical average of the sample distribution. Similarly, an index of dispersion about the average relative location of the particular type of cellular ion distribution in the population is calculated by, for example, taking the standard deviation, standard error, or standard error of the mean of the sample distribution.
• step 424 the cell function indices associated with the population of interest and described above are optionally used to form a cell function map representative of the population of interest.
• An exemplary cell function map formed using such cell function indices is shown in Figure 9.
• the cell function map is also preferably stored in the data base with the structural, mechanical and cell function indices associated with the population of interest.
• step 426 all of the cell function indices associated with the population of interest and described above are stored in a tissue data base using, for example, a data structure such as that shown in Figures 7A, 7B and 7C. Again, for tissue populations having multiple layers, a separate data structure of the form shown in Figures 7A, 7B and 7C may be generated for each layer of interest.
• the cell function map is also preferably stored in the data base with the cell function indices associated with the population of interest.
• process 1000 described above may be repeated for each tissue population of interest.
• the present invention may be used to generate a data base such as that shown in Figure 8, which includes structural, mechanical and cell function indices for many different tissue populations.
• the data base shown in Figure 8 also optionally includes correlation values (as discussed above) and a cell function map for each population of interest.
• process 1000 is used to generate a database that includes structural, mechanical and cell function indices and optionally the correlation values and cell function map information discussed above for each of the following tissue populations: normal intestine tissue, normal cartilage tissue, normal eye tissue, normal bone tissue, normal fat tissue, normal muscle tissue, normal kidney tissue, normal brain tissue, normal heart tissue, normal liver tissue, normal skin tissue, normal pleura tissue, normal peritoneum tissue, normal pericardium tissue, normal dura-mater tissue, normal oral-nasal mucus membrane tissue, normal pancreas tissue, normal spleen tissue, normal gall bladder tissue, normal blood vessel tissue, normal bladder tissue, normal uterus tissue, normal ovarian tissue, normal urethra tissue, normal penile tissue, normal vaginal tissue, normal esophagus tissue, normal anus tissue, normal adrenal gland tissue, normal ligament tissue, normal intervertebral disk tissue, normal bursa tissue, normal meniscus tissue, normal fascia tissue, normal bone marrow tissue, normal tendon tissue, normal pulle
• process 1000 is used to generate a database that includes multiple sets of structural, mechanical and cell function indices and optionally the correlation values and cell function map information discussed above for each of the tissue types set forth in the paragraph above.
• tissue type e.g., normal lung tissue
• multiple tissue populations are defined based on age bracket, race and/or gender.
• a first normal lung tissue population will include lung tissue from Caucasian males between ages x-y;
• a second normal lung tissue population will include lung tissue from Asian males between ages x-y;
• a third normal lung tissue population will include lung tissue from Caucasian females between ages x-y; and so on.
• a separate set of structural, mechanical and cell function indices and optionally the correlation values and cell function map information discussed above is determined using process 1000 for each of the different lung tissue populations and then stored in the tissue information database.
• the different populations associated with a given tissue type may also be defined based on other criteria such as the physical fitness level, behavior, geographic location, nationality or disease(s) associated with the subjects having the given tissue type.
• process 1000 is used to generate a database that includes structural, mechanical and cell function indices and optionally the correlation values and cell function map information discussed above for populations of abnormal tissue types, for population of tissue types associated with specific plant or animal species, for populations of non-living tissue types and for populations of virtual tissue types.
• the present invention may be used to profile "composite" tissue types, i.e., tissue populations that consist of two or more normal tissue types.
• the sample of normal tissue specimens profiled during process 1000 correspond to first and second groups of different normal tissue specimens, wherein the first and second groups each correspond, for example, to a set of either normal intestine tissue specimens, normal cartilage tissue specimens, normal eye tissue specimens, normal bone tissue specimens, normal fat tissue specimens, normal muscle tissue specimens, normal kidney tissue specimens, normal brain tissue specimens, normal heart tissue specimens, normal liver tissue specimens, normal skin tissue specimens, normal pleura tissue specimens, normal peritoneum tissue specimens, normal pericardium tissue specimens, normal dura-mater tissue specimens, normal oral-nasal mucus membrane tissue specimens, normal pancreas tissue specimens, normal spleen tissue specimens, normal gall bladder tissue specimens, normal blood vessel tissue specimens, normal bladder tissue specimens, normal uterus tissue specimens,
• process 1000 is thus used to generate a database that includes structural, mechanical and cell function indices and optionally the correlation values and cell function map information discussed above for composite tissue types. Such information may then be used as a blueprint for design, engineering and manufacture of composite tissue designs.
• process 1000 is used to generate structural, mechanical and cell function indices for each tissue population of interest. It will be understood by those skilled in the art that all such indices need not be generated for every tissue population of interest, and that the present invention can be used for rational design without the use of all of the indices described herein. For example, for a particular tissue population, only selected ones of the structural indices described herein may be generated and used for the design and manufacture of engineered tissue.
• the tissue database described herein (e.g., Figure 8) is used to provide information representative of a plurality of tissue types to subscribers over a computer network, such as the internet. Subscribers to such information would include, for example, persons or businesses in the tissue engineering, drug design, gene discovery and genomics research fields. In this embodiment (shown in Figure 8)
• each subscriber is granted access to all or part of the database (e.g., a subscriber may granted access to information corresponding to only a particular tissue type or a particular tissue population) based on a subscription fee paid by the user.
• the subscribers may also use such information to classify tissue specimens (e.g., human tissue specimens, animal tissue specimens, plant tissue specimens, food tissue specimens, or manufactured tissue specimens) provided by the subscriber.
• the user can measure parameters (e.g., structural, mechanical and/or cell function indices) associated with the subscriber's tissue specimens (using the techniques described above) and then compare this information to the corresponding parameters for normal tissue in the database in order to classify the subscriber's tissue specimens as either normal or abnormal.
• parameters e.g., structural, mechanical and/or cell function indices
• a subscriber can assess the normalcy of subscriber-supplied tissue specimens which are believed to correspond to normal lung tissue specimens by retrieving the structural, mechanical and/or cell function indices corresponding to normal lung tissue stored in the database, and then comparing these stored indices to corresponding parameters measured from the subscriber- supplied samples.
• the subscriber-supplied specimen will be classified as abnormal.
• measured parameters associated with the subscriber-supplied tissue samples may be compared to the tissue information stored in the database in order to identify normal elements of such manufactured tissue specimens in cases where, for example, such manufactured tissue
• tissue specimens using the tissue information in the database is performed by a subscriber to
• the classification process can also be performed by the party responsible for

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