Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6813—Hybridisation assays
  • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
  • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
  • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
  • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
  • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
• • 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
  • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00279—Features relating to reactor vessels
  • B01J2219/00306—Reactor vessels in a multiple arrangement
  • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
  • B01J2219/00315—Microtiter plates
  • B01J2219/00317—Microwell devices, i.e. having large numbers of wells
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/00497—Features relating to the solid phase supports
  • B01J2219/00527—Sheets
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00583—Features relative to the processes being carried out
  • B01J2219/00603—Making arrays on substantially continuous surfaces
  • B01J2219/00673—Slice arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00686—Automatic
  • B01J2219/00691—Automatic using robots
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00718—Type of compounds synthesised
  • B01J2219/0072—Organic compounds
  • B01J2219/0074—Biological products
  • B01J2219/00743—Cells
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/12—Specific details about manufacturing devices
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0893—Geometry, shape and general structure having a very large number of wells, microfabricated wells
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/02—Burettes; Pipettes
  • B01L3/0241—Drop counters; Drop formers

Definitions

• the present invention relates to bio-cell chips and methods for preparing the same.
• the amount of specimen could be a restricting factor because it is too small to perform various assays. Therefore, if a cell array only with the minimal number of cells required for the test can be produced, the shortage problem of sample amount can be solved and numerous genes can be detected at the same time with low-cost.
• the present invention provides bio-cell chips in which cells are arrayed, and methods for preparing the same by spot-spraying cells into a small space on the biochip substrate.
• the bio-cell chips according to the present invention are suitable for performing hundreds of assays with a small amount of sample and subjecting hundreds of experimental objects to the same condition while conducting assays.
• the object of the present invention is that thousands of cells can be detected for gene or protein expression at the same time.
• the present invention relates to bio-cell chips and methods for preparing the same.
• the present invention provides bio-cell chips in which cells are arrayed and fixed, replacing DNA in conventional DNA chips. That is to say, the biochips in which plenty of cells are arrayed and fixed in a small space are provided.
• the bio-cell chips according to the present invention may have between 100 and 2000 cells, preferably between 100 and 500 cells arrayed and fixed in a small space, for example,
• a supporting material that is, a chip substrate, on which the bio-cell chips of the present invention can be constructed by arraying and fixing cells may be those employed in conventional biochips. Examples include plastics, silicone and glass slides with low background fluorescence.
• the bio-cell chips of the present invention may be produced according to the established production methods for the conventional biochips such as DNA chips etc.
• One major difference from the conventional production methods using DNA, RNA or protein is that in the case of cell, to array and fix a large number of cells in a small space, cell suspension stored in fixing agents has not to be spread out. Therefore, special measures have to be done.
• the above problem has been solved by the present invention that provides separate rooms for each cell to be fixed apart from each other.
• the method forming the separate rooms is: a) to build septum between samples, b) to produce wells allowing samples to be dispensed into, on the surface of a supporting material, that is, the surface of a chip substrate constituting a chip by cutting it in a uniform shape, or c) to produce grooves on the surface of a supporting material, that is, the surface of a chip substrate constituting a chip by engraving it.
• the difference between a well and a groove lies on that, because the depth of well cannot be increased to a desirable amount, a groove is made by cutting the width of hole to create a prolonged hollow. Thus, it is desirable to produce grooves when a relatively large number of cells per a sample are to be applied.
• the materials for building septum includes, for example, cement such as rubber cement, and sticker. These materials should be completely removed with ease after the fabrication of the bio- cell chip and have no influence on in situ hybridization staining or shape of the cells.
• an alternative method that comprises providing special treatments to modify surface characteristics and then spraying a sample, can be employed.
• special treatments include, for example, treating the surface with a sticky material such as polymers.
• cells can be a) located and fixed in separate rooms or b) arrayed by spotting or spraying the cell suspension, and fixed separately by aid of a sticky material treated on the surface of a chip substrate.
• the above rooms can be formed by septum, wells or grooves engraved on the surface of the chip substrate, and the above septum can be made up with cement or sticker.
• methods of spraying samples of cells include operating an automated robot system that allows at least 500 or an average of 2000 cells to be loaded at the same time.
• the above robot system can be operated two different ways. One is to load different kinds of samples of at least 500 or an average of 2000 on a slide and to apply one kind of an in situ hybridization agent. The other is to react different kinds of in situ hybridization reaction reagents with one kind of samples using the smallest amount automatic system.
• Each sample has its own number and operating a program associated with a reading microscope makes it possible to find and approach target samples automatically. Determinations of results can be carried out on the whole samples throughout a slide automatically using a program inputted with detection data.
• the present invention do not cause slide to slide variation that is a major concern in in situ hybridization technique.
• the conditions subjected to each slide may be not identical, which often makes results assessment difficult.
• Standardization can be achieved by using bio-cell chips applied almost about 100 to 5000 samples on a slide.
• the bio-cell chips according to the present invention provide simultaneous detection of gene expression for thousands of cells.
• the bio-cell chips of the present invention have made it possible to detect gene expression for a great number of samples with an extremely small amount of sample and a small amount of reagent at the same time, which has brought innovations in terms of cost, time and effort in the field of a disease diagnosis and drug effect evaluation for cancer or genetic disease as well as has greatly improved reliability of the results.
• the bio-cell chips will be used for a mass screening in the diagnosis of tumor of which cells can be easily obtainable from a human body with non-invasive methods. For example, in case of lung cancer or bladder cancer, cells collected from sputum or urine can be stained, and then cancer cells with specific genetic alterations or with specific antigens can be detected using an automated analysis system with high accuracy.
• Tumor cell lines array chips in which various tumor cell lines will be laid on one place can be fabricated, and standardization of the assays will also be achieved.
• Bio-cell chips containing tumor cells collected and isolated from a patient's tumor can be fabricated and also provided to basic biological researchers.
• ISH in situ hybridization
• Example 1 100 samples were applied on a slide manually or using a multi-dispenser offering the ability to dispense a small quantity of cell suspension, and then molecular cytogenetic study and detection of genetic changes were conducted. Staining was successfully completed with a small amount of sample and a small amount of reagent.
• the amount of the reagent typically used was lO ⁇ l per one slide. Detections of genetic changes of 100 samples were conducted with the same amount of the reagent required in one sample.
• Experimental example 1 The amount of the reagent typically used was lO ⁇ l per one slide. Detections of genetic changes of 100 samples were conducted with the same amount of the reagent required in one sample.
• Bio-cell chips are also available for cancer diagnosis using cells obtained from a large number of patients.
• cells of sputum are examined. While usually PAP staining is used and the cells are examined one by one, it is often difficult to discriminate between a cancer cell and a dysplastic cell morphologically. If it is possible to detect specific genetic alterations in lung cancer cells of the Korean people, specificity of diagnosis can be increased.
• a bio-cell chip containing each cell isolated from patients' sputum is fabricated and then specific genetic alterations are detected using in situ hybridization technique. It is possible to diagnose lung cancer for a massive group of patients, while also not requiring manual labor.
• Cells obtainable from a human body without any medical procedure include bladder cancer cells naturally excreted with urine.
• a bio-cell chip was fabricated with cells isolated from urine samples and then specific genetic alterations of bladder cancer are detected using in situ hybridization technique. It is possible to accomplish massive diagnosis and follow-up study for bladder cancer without calling on patients to the hospital for study, while also not requiring a special procedure.

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• 2002
  • 2002-02-18 KR KR1020020008394A patent/KR20030068780A/ko not_active Application Discontinuation
• 2003
  • 2003-02-14 WO PCT/KR2003/000322 patent/WO2003068982A1/en active Application Filing
  • 2003-02-14 AU AU2003217497A patent/AU2003217497A1/en not_active Abandoned
  • 2003-02-14 JP JP2003568093A patent/JP2005517411A/ja active Pending

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