US20100298165A1 - Bioarray chip reaction apparatus and its manufacture - Google Patents
Bioarray chip reaction apparatus and its manufacture Download PDFInfo
- Publication number
- US20100298165A1 US20100298165A1 US12/842,977 US84297710A US2010298165A1 US 20100298165 A1 US20100298165 A1 US 20100298165A1 US 84297710 A US84297710 A US 84297710A US 2010298165 A1 US2010298165 A1 US 2010298165A1
- Authority
- US
- United States
- Prior art keywords
- cavity
- fluid
- probe array
- chip
- package
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 CC1(C)C*CC1 Chemical compound CC1(C)C*CC1 0.000 description 1
Images
Classifications
-
- 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
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
-
- 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
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
-
- 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
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
-
- 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
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L9/00—Supporting devices; Holding devices
- B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
- B01L9/527—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for microfluidic devices, e.g. used for lab-on-a-chip
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- 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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
-
- 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
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/30—Micromixers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/40—Mixers using gas or liquid agitation, e.g. with air supply tubes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/45—Magnetic mixers; Mixers with magnetically driven stirrers
-
- 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
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00364—Pipettes
- B01J2219/00371—Pipettes comprising electrodes
-
- 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
- B01J2219/00351—Means for dispensing and evacuation of reagents
- B01J2219/00427—Means for dispensing and evacuation of reagents using masks
- B01J2219/00432—Photolithographic masks
-
- 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
- B01J2219/00277—Apparatus
- B01J2219/00497—Features relating to the solid phase supports
- B01J2219/00527—Sheets
- B01J2219/00529—DNA chips
-
- 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
- B01J2219/00531—Sheets essentially square
-
- 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
- B01J2219/00536—Sheets in the shape of disks
-
- 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
- B01J2219/0054—Means for coding or tagging the apparatus or the reagents
-
- 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
- B01J2219/0054—Means for coding or tagging the apparatus or the reagents
- B01J2219/00547—Bar codes
-
- 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
- B01J2219/00585—Parallel processes
-
- 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
- B01J2219/0059—Sequential processes
-
- 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
- B01J2219/00596—Solid-phase processes
-
- 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
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
-
- 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
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00608—DNA chips
-
- 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
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
-
- 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
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00623—Immobilisation or binding
- B01J2219/00626—Covalent
-
- 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
- B01J2219/00659—Two-dimensional 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
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00659—Two-dimensional arrays
- B01J2219/00662—Two-dimensional arrays within two-dimensional 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
- B01J2219/00689—Automatic using computers
-
- 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
- B01J2219/00695—Synthesis control routines, e.g. using computer programs
-
- 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
- B01J2219/00709—Type of synthesis
- B01J2219/00711—Light-directed synthesis
-
- 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
- B01J2219/00722—Nucleotides
-
- 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
- B01J2219/00725—Peptides
-
- 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
- B01J2219/00731—Saccharides
-
- 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
- B01L2200/02—Adapting objects or devices to another
- B01L2200/025—Align devices or objects to ensure defined positions relative to each other
-
- 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
- B01L2200/02—Adapting objects or devices to another
- B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
- B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
-
- 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
- B01L2200/06—Fluid handling related problems
- B01L2200/0689—Sealing
-
- 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
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
- B01L2300/0636—Integrated biosensor, microarrays
-
- 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
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
-
- 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
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0825—Test strips
-
- 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
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0877—Flow chambers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
-
- 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
- C12Q1/6869—Methods for sequencing
- C12Q1/6874—Methods for sequencing involving nucleic acid arrays, e.g. sequencing by hybridisation
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/10—Libraries containing peptides or polypeptides, or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/12—Libraries containing saccharides or polysaccharides, or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
- G01N2035/00099—Characterised by type of test elements
- G01N2035/00158—Elements containing microarrays, i.e. "biochip"
-
- 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
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/97—Test strip or test slide
-
- 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
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/973—Simultaneous determination of more than one analyte
-
- 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
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/807—Apparatus included in process claim, e.g. physical support structures
- Y10S436/809—Multifield plates or multicontainer arrays
-
- 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
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/11—Automated chemical analysis
- Y10T436/112499—Automated chemical analysis with sample on test slide
Definitions
- the present inventions relate to the fabrication and placement of materials at known locations on a substrate.
- one embodiment of the invention provides a method and associated apparatus for packaging a substrate having diverse sequences at known locations on its surface.
- sequences on a substrate are known.
- the sequences may be formed according to the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.), PCT WO 92/10092, or U.S. application Ser. No. 08/249,188, now U.S. Pat. No. 5,571,639, incorporated herein by reference for all purposes.
- the prepared substrates will have a wide range of applications.
- the substrates may be used for understanding the structure-activity relationship between different materials or determining the sequence of an unknown material.
- the sequence of such unknown material may be determined by, for example, a process known as sequencing by hybridization.
- a sequences of diverse materials are formed at known locations on the surface of a substrate.
- a solution containing one or more targets to be sequenced is applied to the surface of the substrate.
- the targets will bind or hybridize with only complementary sequences on the substrate.
- the locations at which hybridization occurs can be detected with appropriate detection systems by labeling the targets with a fluorescent dye, radioactive isotope, enzyme, or other marker.
- exemplary systems are described in U.S. Pat. No. 5,143,854 (Pirrung et al.) and U.S. patent application Ser. No. 08/143,312, also incorporated herein by reference for all purposes.
- Information regarding target sequences can be extracted from the data obtained by such detection systems.
- a body containing a cavity is provided.
- a substrate having an array of probes is attached to the cavity using, for example, an adhesive.
- the body includes inlets that allow fluids into and through the cavity.
- a seal is provided for each inlet to retain the fluid within the cavity.
- An opening is formed below the cavity to receive a temperature controller for controlling the temperature in the cavity.
- the body is formed by acoustically welding two pieces together.
- the concept of assembling the body from two pieces is advantageous.
- the various features of the package i.e., the channels, sealing means, and orientation means
- the packages are produced at a relatively low cost.
- a method for making the chip package comprises the steps of first forming a plurality of probe arrays on a substrate and separating the substrate into a plurality of chips.
- each chip contains at least one probe array.
- a chip is then mated to a package having a reaction chamber with fluid inlets. When mated, the probe array is in fluid communication with the reaction chamber.
- the present invention provides an apparatus for packaging a substrate.
- the present apparatus includes a substrate having a first surface and a second surface.
- the first surface includes a probe array and the second surface is an outer periphery of the first surface.
- the present apparatus also includes a body having a mounting surface, an upper surface, and a cavity bounded by the mounting surface and the upper surface.
- the second surface is attached to the cavity and the first surface is within the cavity.
- a cover attached to the mounting surface for defining an upper boundary to the cavity is also included.
- the cavity includes a diffuser and a concentrator. The diffuser and the concentrator permit laminar fluid flow through the cavity.
- FIG. 1 a illustrates a wafer fabricated with a plurality of probe arrays.
- FIG. 1 b illustrates a chip
- FIG. 2 a illustrates a scribe and break device.
- FIG. 2 b illustrates the wafer mounted on a pick and place frame.
- FIGS. 2 c - 2 d illustrate the wafer, as displayed by the scribe and break device during alignment.
- FIG. 3 illustrates a chip packaging device
- FIG. 4 illustrates the chip packaging device assembled from two components.
- FIGS. 5 a - 5 b illustrate the top and bottom view of a top casing of the chip packaging device.
- FIG. 5 c illustrates a different cavity orientation
- FIG. 6 illustrates a cross sectional view of the packaging device.
- FIG. 7 illustrates the bottom view of a bottom casing of the chip packaging device.
- FIGS. 8 a - 8 b illustrate an acoustic welding system.
- FIGS. 9 a - 9 c illustrate the acoustic welding process used in assembling the chip packaging device.
- FIG. 10 illustrates an adhesive dispensing system used in attaching the chip to the chip packaging device.
- FIGS. 11 , 12 a, 12 b and 13 illustrate in greater detail the adhesive dispensing system of FIG. 10 .
- FIGS. 14 a - 14 d illustrate the procedure for aligning the system of FIG. 10 .
- FIGS. 15 a - 15 e illustrate images obtained during the alignment process of FIGS. 14 a - 14 d.
- FIGS. 16 a - 16 b illustrate an alternative embodiment of a packaging device.
- FIGS. 17 a - 17 b illustrate another embodiment of a packaging device.
- FIG. 18 illustrates an alternative embodiment for attaching the chip to the packaging device.
- FIG. 19 illustrates another embodiment for attaching the chip to the packaging device.
- FIGS. 20 a - 20 b illustrate yet another embodiment for attaching the chip to the packaging device.
- FIG. 21 illustrates an alternative embodiment for attaching the chip to the packaging device.
- FIG. 22 illustrates another embodiment for attaching the chip to the packaging device.
- FIG. 23 illustrates an alternative embodiment for sealing the cavity on the packaging device.
- FIG. 24 illustrates another alternative embodiment for sealing the cavity on the packaging device.
- FIG. 25 illustrates yet another embodiment for sealing the cavity on the packaging device.
- FIGS. 26 a - 26 b illustrate an alternative embodiment for sealing the cavity on the packaging device.
- FIGS. 27 a - 27 b illustrate an alternative embodiment for mounting the chip.
- FIG. 28 illustrates an agitation system
- FIG. 29 illustrates an alternative embodiment of the agitation system.
- FIG. 30 illustrates another embodiment of the agitation system.
- FIG. 31 illustrates an alternative embodiment of a chip packaging device.
- FIG. 32 illustrates side-views of the chip packaging device of FIG. 31 .
- FIGS. 33-35 illustrate in greater detail the chip packaging device of FIG. 31 .
- FIG. 36 illustrates a further alternative embodiment of a chip packaging device.
- the present invention provides economical and efficient packaging devices for a substrate having an array of probes fabricated thereon.
- the probe arrays may be fabricated according to the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.), PCT WO 92/10092, or U.S. application Ser. No. 08/249,188 filed May 24, 1994, already incorporated herein by reference for all purposes.
- a plurality of probe arrays are immobilized at known locations on a large substrate or wafer.
- FIG. 1 a illustrates a wafer 100 on which numerous probe arrays 110 are fabricated.
- the wafer 100 may be composed of a wide range of material, either biological, nonbiological, organic, inorganic, or a combination of any of these, existing as particles, strands, precipitates, gels, sheets, tubing, spheres, containers, capillaries, pads, slices, films, plates, slides, etc.
- the wafer may have any convenient shape, such as a disc, square, sphere, circle, etc.
- the wafer is preferably flat but may take on a variety of alternative surface configurations.
- the wafer may contain raised or depressed regions on which a sample is located.
- the wafer and its surface preferably form a rigid support on which the sample can be formed.
- the wafer and its surface are also chosen to provide appropriate light-absorbing characteristics.
- the wafer may be a polymerized Langmuir Blodgett film, functionalized glass, Si, Ge, GaAs, GaP, SiO2, SiN4, modified silicon, or any one of a wide variety of gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, polycarbonate, or combinations thereof.
- gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, polycarbonate, or combinations thereof.
- Other materials with which the wafer can be composed of will be readily apparent to those skilled in the art upon review of this disclosure.
- the wafer is flat glass or single-crystal silicon.
- the surface will usually, though not always, be composed of the same material as the wafer.
- the surface may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed wafer materials.
- Wafer 100 includes a plurality of marks 145 that are located in streets 150 (area adjacent to the probe arrays). Such marks may be used for aligning the masks during the probe fabrication process. In effect, the marks identify the location at which each array 110 is to be fabricated.
- the probe arrays may be formed in any geometric shape. In some embodiments, the shape of the array may be squared to minimize wasted wafer area. After the probe arrays have been fabricated, the wafer is separated into smaller units known as chips. The wafer, for example, may be about 5 ⁇ 5 inches on which 16 probe arrays, each occupying an area of about 12.8 cm 2 , are fabricated.
- FIG. 1 b illustrates a chip that has been separated from the wafer.
- chip 120 contains a probe array 110 and a plurality of alignment marks 145 .
- the marks serve multiple functions, such as: 1) aligning the masks for fabricating the probe arrays, 2) aligning the scriber for separating the wafer into chips, and 3) aligning the chip to the package during the attachment process.
- such chips may be of the type known as Very Large Scale Immobilized Polymer Synthesis (VLSIPSTM) chips.
- VLSIPSTM Very Large Scale Immobilized Polymer Synthesis
- the chip contains an array of genetic probes, such as an array of diverse RNA or DNA probes.
- the probe array will be designed to detect or study a genetic tendency, characteristic, or disease.
- the probe array may be designed to detect or identify genetic diseases such as cystic fibrosis or certain cancers (such as P53 gene relevant to some cancers), as disclosed in U.S. patent application Ser. No. 08/143,312, already incorporated by reference.
- FIG. 2 a illustrates a fully programmable computer controlled scribe and break device, which in some embodiments is a DX-III Scriber breaker manufactured by Dynatex InternationalTM.
- the device 200 includes a base 205 with a rotation stage 220 on which a wafer is mounted.
- the rotation stage includes a vacuum chuck for fixing the wafer thereon.
- a stepper motor which is controlled by the system, rotates stage 220 .
- Located above the stage is a head unit 230 that includes a camera 232 and cutter 231 .
- Head unit 230 is mounted on a dual-axis frame.
- the camera generates an image of the wafer on video display 210 .
- the video display 210 includes a cross hair alignment nark 215 .
- the camera which includes a zoom lens and a fiber optic light, allows a user to inspect the wafer on the video display 210 .
- a control panel 240 is located on the base for operating device 200 .
- a user places a wafer 100 on a frame 210 as illustrated in FIG. 2 b .
- the surface of frame 210 is composed of a flexible and sticky material. The tackiness of the frame prevents the chips from being dispersed and damaged during the breaking process.
- Frame 210 may be a pick and place frame or a hoop that is commonly associated with fabrication of semiconductors.
- a user places the frame with the wafer on the rotation stage 220 . In some embodiments, the frame is held on the rotation stage by vacuum pressure. The user then aligns the wafer by examining the image displayed on the video display 210 .
- wafer alignment is achieved in two steps. First, using the control panel 240 , the user rotates stage 220 . The stage is rotated until streets 150 are aligned with the cross hair 215 on the display, as illustrated in FIG. 2 c . Next, the user moves the cutter until it is aligned at the center of one of the streets. This step is performed by aligning horizontal line 216 of the cross hair between alignment marks 145 , as shown in FIG. 2 d.
- the user instructs the device to scribe the wafer.
- various options are available to the user, such as scribe angle; scribe pressure, and scribe depth. These parameters will vary depending on the composition and/or thickness of the wafer. Preferably, the parameters are set to scribe and break the wafer without causing any damage thereto or penetrating through the frame.
- the device repeatedly scribes the wafer until all the streets in one axis have been scribed, which in one embodiment is repeated 5 times (a 4 ⁇ 4 matrix of probe arrays). The user then rotates the stage 90° to scribe the perpendicular streets.
- the device 200 breaks the wafer by striking it beneath the scribe with an impulse bar located under the rotation table 220 .
- the shock from the impulse bar fractures the wafer along the scribe. Since most of the force is dissipated along the scribe, device 200 is able to produce high breaking forces without exerting significant forces on the wafer. Thus, the chips are separated without causing any damage to the wafer. Once separated, the chips are then packaged.
- other more conventional techniques such as the sawing technique disclosed in U.S. Pat. No. 4,016,855, incorporated herein by reference for all purposes, may be employed.
- FIG. 3 illustrates a device for packaging the chips.
- Package 300 contains a cavity 310 on which a chip is mounted.
- the package includes inlets 350 and 360 which communicate with cavity 310 . Fluids are circulated through the cavity via inlets 350 and 360 .
- a septum, plug, or other seal may be employed to seal the fluids in the cavity.
- Alignment holes 330 and 335 may be provided for alignment purposes.
- the package may include a non-flush edge 320 .
- the packages may be inserted into a holder similar to an audio cassette tape. The asymmetrical design of the package will assure correct package orientation when inserted into the holder.
- FIG. 4 illustrates one embodiment of the package.
- the chip package is manufactured by mating two substantially complementary casings 410 and 420 to form finished assembly 300 .
- casings 410 and 420 are made from injection molded plastic. Injection molding enables the casings to be formed inexpensively. Also, assembling the package from two parts simplifies the construction of various features, such as the internal channels for introducing fluids into the cavity. As a result, the packages may be manufactured at a relatively low cost.
- FIGS. 5 a - 5 b show the top casing 410 in greater detail.
- FIG. 5 a shows a top view
- FIG. 5 b shows a bottom view.
- top casing 410 includes an external planar surface 501 having a cavity 310 therein.
- the surface area of casing 410 sufficiently accommodates the cavity.
- the top casing is of sufficient size to accommodate identification labels or bar codes in addition to the cavity.
- the top casing is about 1.5′′ wide, 2′′ long, and 0.2′′ high.
- Cavity 310 is usually, though not always, located substantially at the center of surface 501 .
- the cavity may have any conceivable size, shape, or orientation.
- the cavity is slightly smaller than the surface area of the chip to be placed thereon and has a volume sufficient to perform hybridization.
- the cavity may be about 0.58′′ wide, 0.58′′ long, and 0.2′′ deep.
- Cavity 310 may include inlets 350 and 360 . Selected fluids are introduced into and out of the cavity via the inlets.
- the inlets are located at opposite ends of the cavity. This configuration improves fluid circulation and regulation of bubble formation in the cavity. The bubbles agitate the fluid, increasing the hybridization rate between the targets and complementary probe sequences.
- the inlets are located at the top and bottom end of the cavity when the package is oriented vertically such as at the opposite corners of the cavity. Locating the inlet at the highest and lowest positions in the cavity facilitates the removal of bubbles from the cavity.
- FIG. 5 c illustrates an alternative embodiment in which cavity 310 is oriented such that the edges of the cavity 310 and the casing 410 are non-parallel. This configuration allows inlets 350 and 360 to be situated at the absolute highest and lowest locations in the cavity when the package is vertically oriented. As a result, bubbles or fluid droplets are prevented from being potentially trapped in the cavity.
- a depression 550 surrounds the cavity.
- a ridge 560 may be provided at the edge of the depression so as to form a trough.
- the ridge serves to support the chip above the cavity.
- an adhesive may be deposited in the trough. This configuration promotes efficient use of chip surface area, thus increasing the number of chips yielded from a wafer.
- Top casing 410 includes alignment holes 330 and 335 .
- holes 330 and 335 are different in size to ensure correct orientation of the package when mounted on an alignment table.
- the holes may have different shapes to achieve this objective.
- the holes taper radially inward from surface 501 toward 502 to reduce the friction against alignment pins while still maintaining adequate contact to prevent slippage.
- channels 551 and 561 are optionally formed on internal surface 502 .
- Channels 551 and 561 communicate with inlets 350 and 360 respectively.
- a depression 590 is formed below cavity.
- the shape of depression 590 is symmetrical to the cavity with exception to corners 595 and 596 , which accommodate the inlets.
- the depth of depression 590 may be, for example, about 0.7′′.
- the bottom wall of the cavity is about 0.05′′ thick.
- Depression 590 may receive a temperature controller to monitor and maintain the cavity at the desired temperature. By separating the temperature controller and cavity with a minimum amount of material, the temperature within the cavity may be controlled more efficiently and accurately.
- channels may be formed on surface 502 for circulating air or water to control the temperature within the cavity.
- certain portions 595 of internal surface 502 may be eliminated or cored without interfering with the structural integrity of the package when assembled. Coring the casing reduces the wall thickness, causing less heat to be retained during the injection molding process; potential shrinkage or warpage of the casing is significantly reduced. Also, coring decreases the time required to cool the casing during the manufacturing process. Thus, manufacturing efficiency is improved.
- the top casing and bottom casing are mated together using a technique known as acoustic or ultrasonic welding.
- energy directors 510 are provided. Energy directors are raised ridges or points, preferably v-shaped, that are used in an acoustic welding process. The energy directors are strategically located, for example, to seal the channels without interfering with other features of the package and to provide an adequate bond between the two casings.
- the casings may be mated together by screws, glue, clips, or other mating techniques.
- FIG. 6 shows a cross sectional view of the cavity 310 with chip 120 mounted thereon in detail.
- a depression 550 is formed around cavity 310 .
- the depression includes a ridge 560 which supports chip 120 .
- the ridge and the depression create a trough around cavity 310 .
- the trough is sufficiently large to receive an adhesive 630 for attaching the chip to the package.
- the trough is about 0.08′′ wide and 0.06′′ deep.
- the edge of the chip protrudes slightly beyond ridge 550 , but without contacting side 625 of the depression. This configuration permits the adhesive to be dispensed onto the trough and provides adequate surface area for the adhesive to attach chip 120 to the package.
- the back surface 130 of chip 120 is at least flush or below the plane formed by surface 501 of casing 410 .
- chip 120 is shielded by surface 501 from potential damage. This configuration also allows the packages to be easily stored with minimal storage area since the surfaces are substantially flat.
- the bottom of the cavity includes a light absorptive material, such as a glass filter or carbon dye, to prevent impinging light from being scattered or reflected during imaging by detection systems.
- a light absorptive material such as a glass filter or carbon dye
- FIG. 7 shows the internal surface of bottom casing 420 in greater detail.
- the bottom casing 420 is substantially planar and contains an opening 760 therein.
- the casing 420 is slightly wider or slightly longer than the top casing.
- casing 420 is about 1.6′′ wide, 2.0′′ long, and 0.1′′ deep, which creates a non-flush edge on the finish assembly. As previously mentioned, this design ensures that the package is correctly oriented when mounted onto the detection systems.
- opening 760 is spatially located at about the depression below the cavity.
- the opening also has substantially the same geometric configuration as the depression to allow the temperature controller to contact as much of the bottom of the cavity as possible.
- Internal surface 701 of casing 420 includes depressions 730 and 740 .
- a port 731 is located in depression 730 and a port 741 is located in depression 740 .
- Ports 731 and 741 communicate with channels on the top casing ( 350 and 360 in FIG. 5 b ) when the package is assembled.
- a seal 790 which may be a septum composed of rubber, teflon/rubber laminate, or other sealing material is provided for each depression.
- the septum may be of the type commonly used to seal and reseal vessels when a needle is inserted into the septum for addition/removal of fluids.
- the septums when seated in the depressions, extend slightly above surface, which in some embodiments is about 0.01′′.
- casing 420 includes the complementary half alignment holes 330 and 335 , each tapering radially inward from the external surface. Further, certain areas 765 on internal surface 701 may be cored, as similar to the internal surface of the top casing.
- FIG. 31 is a simplified illustration of an alternative embodiment of a chip packaging device 3100 according to the present, invention.
- the chip packaging device includes a plurality of casings 3200 , 3300 , and 3400 .
- the casings may be defined as a top casing 3200 , a middle casing 3300 , and a bottom casing 3400 .
- the casings are made of known plastic materials such as ABS plastic, polyvinylchloride, polyethylene, products sold under the trademarks TEFLONTM and KALREZTM and the like, among others.
- the casings can be made by way of injection molding and the like. Assembling the chip packaging device from three casings simplifies construction for the fabrication of internal channels and the like, and can also be made at a relatively low cost.
- Support structures exist at selected locations of the chip packing device.
- the support structures can be used to mount or position the chip packaging device to an apparatus, e.g., scanner or the like.
- the top casing 3200 includes support structures 3201 and 3203 on each side of a center opening 3209 .
- the middle casing 3300 includes similar support structures 3313 and 3315 which are complementary to the support structures 3201 and 3203 , respectively, in the top casing.
- the bottom casing also includes similar support structures 3403 and 3401 , respectively, which are complementary to the support structures in the top casing and the middle casing.
- each of the support structures on each side of the center opening align with each other.
- Each support structure is, for example, an aperture through the casing.
- the aperture includes an outer periphery defined by a geometrical shape which may be round, rectangular, trapezoidal, hexagonal, or the like.
- the present chip packaging device assembles with use of complementary alignment pins and bores on the casings.
- the top casing aligns with and inserts into alignment bores 3301 , 3303 in the middle casing 3300 .
- the middle casing can have alignment pins or the like and the top casing has the alignment bores or the like.
- the bottom casing includes alignment pins 3407 and 3409 which align to and insert into alignment bores (not shown) in bottom portions of the middle casing.
- the use of alignment bores and pins provide for ease in assembly of the chip carrier. Upon assembly, the alignment bores and pins on the casings prevent the casings from moving laterally relative to each other.
- a center opening 3209 in the top casing overlies a center portion 3317 of the middle casing 3300 .
- the center portion 3317 of the middle casing includes an inner annular region (or cavity edges) with a bottom portion which is preferably a flat bottom portion.
- the flat bottom portion of the middle, casing and portions of the bottom casing including edges define a cavity 3405 .
- a chip is placed overlying an underlying portion of the cavity 3407 .
- a temperature control mechanism such as a heater, a cooler, or a combination thereof is disposed into the center opening against the bottom portion of the middle casing.
- the temperature control mechanism can be any suitable thermally controlled element such as a resistive element, a temperature controlled block or mass, thermoelectric modules, or the like.
- the temperature control mechanism transfers heat via conduction to the bottom center portion, which transfers heat to, for example, fluid in the cavity or the chip.
- the temperature control mechanism sinks heat away from, for example, fluid in the cavity or the chip through the bottom center portion.
- the temperature control mechanism maintains a selected temperature in the cavity.
- the temperature control mechanism also includes a temperature detection device such as a thermocouple which provides signals corresponding to temperature readings. A controller receives the signals corresponding to the temperature readings, and adjusts power output to the temperature control mechanism to maintain the selected temperature.
- the top casing 3200 also includes channels 3205 and 3207 for fluid transfer.
- the channels 3205 and 3207 communicate with annular regions 3309 and 3311 , respectively, on the middle casing 3300 for fluid transfer.
- a septum, a plug, an o-ring, a gasket, or the like via annular regions 3309 and 3311 seals fluids within the top casing channels 3205 and 3207 and the middle casing.
- the bottom casing includes channels 3411 and 3413 in communication with channels 3307 and 3305 , respectively.
- a septum, a plug, an o-ring, a gasket, or the like seals the fluids within the bottom casing channels 3411 and 3413 and the middle casing channels 3305 and 3307 .
- the chip packaging device provides an even distribution of fluid (or fluid flow) through the cavity over a top surface (or inner or active surface) of the chip. For example, a selected fluid enters channel 3207 , flows through channel 3307 , changes direction and flows through channel 3411 , and evenly distributes into the cavity 3405 over the top surface of the chip. As previously noted, the cavity is defined by the flat bottom portion and cavity edges. A selected fluid exits the cavity by way of channel 3413 , channel 3305 , and channel 3205 .
- the fluid flow over the top surface of the chip is preferably laminar, but may also be turbulent, a combination thereof or the like. By way of the present chip packaging device, a substantial portion of turbulent flow remains at an upper portion of the channel 3411 , and does not enter the cavity.
- a selected fluid enters the cavity by way of channel 3205 , channel 3305 , and channel 3413 .
- the selected fluid exits the cavity through channel 3411 , channel 3307 , and channel 3207 .
- the fluid flows against the direction of gravity through the cavity.
- other fluid flow routes may also be employed depending upon the particular application.
- FIG. 32 illustrates an assembled chip packaging device 3100 according to the present invention. As shown are a top-view 3200 , a side-view 3500 , a bottom-view 3400 , and a front-view 3600 of the assembled chip packaging device 3100 .
- the assembled chip packaging device 3100 includes the bottom casing 3400 , the middle casing 3300 , and the top casing 3200 .
- the top-view 3200 of the top casing includes alignment structures 3205 , 3215 surrounding opening 3209 .
- the opening 3209 includes a bevelled annular region 3211 surrounding the periphery of the channel 3209 .
- the alignment bores 3203 and 3201 also include bevelled annular regions 3213 and 3215 , respectively.
- a bevelled annular region 3217 , 3221 also surrounds each fluid channel 3205 , 3207 to assist with fluid flow therethrough.
- the bottom-view 3400 of the bottom casing includes alignment structures 3401 , 3403 surrounding the cavity 3405 .
- the cavity includes a flat bottom peripheral portion 3415 , a bevelled portion 3417 extending from the flat bottom peripheral portion, and a flat upper portion 3419 surrounding the bevelled portion.
- the chip includes an outer periphery which rests against the flat bottom peripheral portion 3415 .
- the bevelled portion aligns the chip onto the flat bottom peripheral portion 3415 .
- the top casing extends outside 3421 the middle and bottom casings.
- the cavity 3405 is preferably located at a center of the bottom casing, but may also be at other locations.
- the cavity may be round, square, rectangular, or any other shape, and orientation.
- the cavity is preferably smaller than the surface area of the chip to be placed thereon, and has a volume sufficient to perform hybridization and the like.
- the cavity includes dimensions such as a length of about 0.6 inch, a width of about 0.6 inch and a depth of about 0.07 inch.
- the bottom casing with selected cavity dimensions may be removed from the middle and top casings, and replaced with another bottom casing with different cavity dimensions. This allows a user to attach a chip having a different size or shape by changing the bottom casing, thereby providing ease in using different chip sizes, shapes, and the like.
- the size, shape, and orientation of the cavity will depend upon the particular application.
- FIGS. 33-35 illustrate in greater detail the chip packaging device of FIG. 31 .
- FIG. 33 illustrates simplified top-view 3260 and bottom-view 3250 diagrams of the top casing 3200 .
- the reference numerals refer to the same elements as the top casing of FIG. 31 .
- FIG. 34 illustrates a simplified top-view 3350 and bottom-view 3360 diagrams of the middle casing 3300 .
- the reference numerals refer to the same elements as the middle casing of FIG. 31 .
- the bottom-view of the casing includes a substantially smooth and planar bottom surface 3361 . A portion of the bottom surface defines an upper portion of the cavity.
- the bottom surface can also be textured, ridged, or the like to create turbulence or a selected fluid flow through the cavity.
- the bottom surface is preferably a hydrophobic surface which enhances laminar flow through the cavity.
- the type of bottom surface depends upon the particular application.
- FIG. 35 illustrates simplified top-view 3460 and bottom-view 3450 diagrams of the bottom casing 3400 .
- the reference numerals refer to the same elements as the bottom casing of FIG. 31 .
- fluid from channel 3305 changes direction at an upper portion 3431 of the channel and flows to a lower portion 3433 of the channel. Fluid evenly distributes from the lower portion 3433 via a fluid distribution point 3435 . The distributed fluid evenly passes over a slanted edge (or bevelled edge) 3437 which drops fluid evenly to a top surface of the chip in the cavity.
- slanted edge 3427 which slopes up to a fluid concentration point 3425 , fluid leaves the cavity and enters the channel 3411 .
- each channel includes a length L and a width W.
- the distribution point and the concentration point are positioned at a distance away from the cavity to substantially prevent turbulence from forming in the cavity, and in particular over the top surface of the chip.
- the channels are each angled at an angle ⁇ ranging from about 2 degrees to about 90 degrees, but is preferably about 5 degrees to about 45 degrees. The angle enhances an even distribution of laminar flow into the cavity.
- the exact angle, channel shape, and dimensions depend upon the particular application.
- FIG. 36 illustrates a simplified cross-sectional view of an alternative embodiment 3600 of the chip packaging device.
- the chip packaging device includes the three casings 3200 , 3300 , and 3400 of the previous embodiment, and also includes hollow pins, needles, or the like 3601 and 3603 .
- Each of the pins transfers a selected fluid to and from the cavity 3405 .
- each pin 3601 includes an external opening 3609 , a tubular region 3611 , an inner opening 3607 , a pointed tip 3605 , and other elements.
- the pin is made from a suitable material such as a glass, a stainless steel or any other high quality material to transfer fluids to and from the cavity 3405 .
- each pin is inserted into its channel region 3205 or 3207 .
- a point on the pin tip pierces through, for example, a septum at an annular region 3309 or 3311 .
- a selected fluid travels through pin 3603 (through channel 3205 and at least a portion of 3305 ), enters the upper region of channel 3413 , and into the cavity 3405 .
- the selected fluid travels from the cavity, through pin 3601 , and to the external apparatus.
- the selected fluid enters the cavity via pin 3601 and exits the cavity via pin 3603 .
- the selected fluid may also enter the cavity via pin and exit the cavity through the channels without use of a pin.
- the selected fluid may further enter the cavity through the channels without use of a pin and exit through a pin.
- the particular pin used and fluid flow will depend upon the application.
- the even distribution of fluid flow through the cavity prevents “hot spots” from occurring in the cavity.
- the even distribution of fluid through the cavity by way of the previous embodiment substantially prevents fluid from becoming substantially turbulent at certain locations. This prevents “hot spots” caused by such turbulent fluid.
- the hot spots are often caused by higher chemical activity or exothermic reactions and the like by way of turbulence in such certain locations.
- the top and bottom casing are attached by a technique known as ultrasonic or acoustic welding.
- FIG. 8 a is a schematic diagram of acoustic welding system used for assembling the package.
- the welding system 800 is a HS Dialog ultrasonic welder manufactured by Herrmann Ultrasonics Inc.
- System 800 includes a platform 850 mounted on base 810 .
- Platform 850 accommodates the top and bottom casings during the assembling process.
- An acoustic horn 860 is mounted on a frame above platform 850 .
- the horn translates vertically (toward and away from platform 850 ) on the frame by air pressure.
- the horn is connected to a frequency generator 870 , which in some embodiments is a 20 KHz generator manufactured by Herrmann Ultrasonics Inc.
- System 800 is controlled by a controller 880 , which, for example, may be a Dialog 2012 manufactured by Herrmann Ultrasonics Inc.
- Controller 880 may be configured to accept commands from a digital computer system 890 .
- Computer 890 may be any appropriately programmed digital computer of the type that is well known to those skilled in the art such as a Gateway 486DX operating at 33 MHz.
- FIG. 8 b illustrates platform 850 in greater detail.
- the platform 850 is substantially planar and includes alignment pins 851 and 852 .
- Alignment pins 851 and 852 are used to align both the top and bottom casings during the welding process.
- a pad 890 which may be composed of silicone rubber or other energy absorbing material, is located on platform 850 to prevent damage to the package during assembly.
- FIG. 9 a illustrates the acoustic welding system in operation.
- bottom casing 420 having a septum 790 seated in each depression, is mounted onto platform table 850 and held in place by alignment pins.
- Top casing 410 is then aligned above the bottom casing with alignment pins. The system then commences the welding process by lowering horn 860 until it contacts the top surface of casing 410 .
- FIG. 9 b illustrates the casing and horn in detail.
- the horn 860 presses against top casing 410 , thereby forcing energy directors 510 to interface with bottom casing 420 .
- the system then activates the frequency generator, causing the welding horn to vibrate.
- FIG. 9 c illustrates in detail the energy directors during the welding process.
- welding horn 860 forces energy directors 510 against bottom casing 420 .
- the system vibrates the welding horn, which in some embodiments is at 20 KHz.
- the energy generated by the horn melts the energy directors.
- the horn translates downward against the package.
- the pressure exerted by the horn causes the energy directors to fuse with the bottom casing.
- the welding process is completed when the horn reaches its weld depth, for example, of about 0.01′′.
- the various welding parameters may be varied, according to the composition of the materials used, to achieve optimum results.
- an ultraviolet cured adhesive attaches the chip to the package.
- FIG. 10 schematically illustrates an adhesive dispensing system used in attaching the chip.
- the dispensing system 1000 includes an attachment table 1040 to accommodate the package during the attachment process.
- a chip alignment table 1050 for aligning the chip is located adjacent to attachment table 1040 .
- a head unit 1030 for dispensing the adhesive is located above tables 1040 and 1050 .
- the head unit 1030 also includes a camera that generates an output to video display 1070 .
- Video display 1070 in some embodiments, includes a cross hair alignment mark 1071 .
- the head unit is mounted on a dual-axis (x-y) frame for positioning during alignment and attachment of the chip.
- the operation of the dispensing system is controlled by a computer 1060 , which in some embodiments may be Gateway 486DX operating at 33 MHz.
- FIG. 11 illustrates the attachment table in greater detail.
- the attachment table 1040 has a substantially flat platform 1110 supported by a plurality of legs 1105 .
- Alignment pins 1115 and 1116 which secure the package during the attachment process, are located on the surface of platform 1110 .
- Needle 1120 includes a channel 1121 and is connected to a vacuum pump. In operation, the needle is inserted into one of the ports of the package in order to generate a vacuum in the cavity. The vacuum pressure secures the chip to the package during the attachment process.
- FIG. 12 a shows table 1050 in greater detail.
- Table 1050 includes a substantially flat platform 1210 having a depression 1240 for holding a chip.
- a port 1241 is provided in depression 1240 .
- Port 1241 is connected to a vacuum pump which creates a vacuum in the depression for immobilizing the chip therein.
- Platform 1210 is mounted on a combination linear rotary stage 1246 , which in some embodiments may be a model 26LR manufactured by DARDAL, and a single axis translation stage 1245 , which may be a model CR2226HSE2 manufactured by DARDAL.
- FIG. 12 b illustrates depression 1240 in greater detail.
- a ledge 1241 surrounds the depression 1240 .
- Ledge 1241 supports the chip when it is placed above depression 1240 . Since the chips are placed over the depression with the probes facing the table, this design protects the probes from being potentially damaged during alignment.
- FIG. 13 illustrates the head unit 1030 in greater detail.
- the head unit 1030 includes a camera assembly 1320 that generates an output to a video display.
- a light 1360 is provided to enable the camera to focus and image an object of interest.
- the head unit also includes an ultraviolet light 1350 for curing the adhesive, a vacuum pickup 1330 for moving chip during the attachment process, and an adhesive dispenser 1340 .
- a chip package is placed onto table 1040 .
- the alignment pins on the table immobilize the package.
- the user begins the chip attachment process by calibrating the head unit. This may be done by moving the camera above the package and aligning it with a mark on the package, as shown in FIG. 14 a .
- one of the alignment pins may be used as an alignment mark.
- FIG. 14 b illustrates a typical image 1440 generated by the camera during this step. As shown, the bead unit is not aligned with pin 1480 .
- the user translates it in both the x and y direction until pin 1480 is located at the intersection 1477 of the cross hair on the video display, as illustrated in FIG. 14 c.
- FIG. 14 c is a flow chart indicating the steps for aligning the chip.
- the system positions the camera (bead unit) above one of the chip's alignment marks.
- the camera images the alignment mark on the video display.
- the mark is normally misaligned (i.e., the mark is not located at the intersection of the cross hair alignment mark).
- the user adjusts the chip alignment table in both the x and y direction until the mark is substantially located at the intersection of the cross hair. Since no rotational adjustments were made, the mark may be misaligned angularly.
- the user instructs the system to move the camera above a second alignment mark, which usually is at an opposite corner of the chip. Again, an image of the alignment mark is displayed. At this stage, the alignment mark is probably misaligned in the x, y, and angular directions.
- the user adjusts the rotational stage, x-stage, and y-stage, if necessary, to align the mark with the cross hair on the video display. In instances where the rotational stage has been rotated, the first alignment mark will become slightly misaligned. To compensate for this shift, the user repeats the alignment process beginning at step 1450 until both marks are aligned.
- image processing techniques may be applied for automated head unit and chip alignment.
- FIG. 15 a is an example of an image displayed by the video screen during step 1410 .
- the first alignment mark lower left corner of the chip
- FIG. 15 b exemplifies an image of the first alignment mark after adjustments were made by the user.
- FIG. 15 c illustrates a typical image displayed by video screen during step 1430 .
- the second alignment mark upper right corner of the chip
- FIG. 15 d illustrates an image of the second mark following initial adjustments by the user at step 1440 .
- FIG. 15 e illustrates the orientation of the second alignment mark after the chip has been aligned.
- the vacuum holding the chip on the attachment table is released. Thereafter, the pickup on the bead unit removes the chip from the table and aligns it on the cavity of the package. In some embodiments, the chip is mated to the pickup by a vacuum.
- the user may check to ensure that the chip is correctly aligned on the cavity by examining the chip's alignment marks with the camera. If the chip is out of position, the chip is removed and realigned on the alignment table. If the chip is correctly positioned, the system deposits an adhesive by moving the dispenser along the trough surrounding the cavity. In some embodiments, the vacuum is released before depositing the adhesive in the trough. This step is merely precautionary and implemented to ensure that the vacuum does not cause any adhesive to seep into the cavity. Once the adhesive is deposited, the system reexamines the chip to determine if the adhesive had moved the chip out of position. If the chip is still aligned, the head unit locates the ultraviolet light above the adhesive and cures it for a time sufficient to harden the adhesive, which in one embodiment is about 10 seconds. Otherwise, the chip is realigned.
- the chip package Upon completion, the chip package will have a variety of uses. For example, the chip package will be useful in sequencing genetic material by hybridization. In sequencing by hybridization, the chip package is mounted on a hybridization station where it is connected to a fluid delivery system. Such system is connected to the package by inserting needles into the ports and puncturing the septums therein. In this manner, various fluids are introduced into the cavity for contacting the probes during the hybridization process.
- hybridization is performed by first exposing the sample with a prehybridization solution. Next, the sample is incubated under binding conditions with a solution containing targets for a suitable binding period. Binding conditions will vary depending on the application and are selected in accordance with the general binding methods known including those referred to in: Maniatis et al., Molecular Cloning: A Laboratory Manual (1989), 2nd Ed., Cold Spring Harbor, N.Y. and Berger and Kimmel, Methods in Enzymology, Volume 152 , Guide to Molecular Cloning Techniques (1987), Academic Press, Inc., San Diego, Calif.; Young and Davis (1983) Proc. Natl. Acad. Sci .
- the solution may contain about 1 molar of salt and about 1 to 50 nanomolar of targets.
- the fluid delivery system includes an agitator to improve mixing in the cavity, which shortens the incubation period.
- a buffer which may be 6 ⁇ SSPE buffer, to remove the unbound targets.
- the cavity is filled with the buffer after washing the sample.
- the package may be aligned on a detection or imaging system, such as those disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.) or U.S. patent application Ser. No. 08/495,889 (Attorney Docket Number 11509-117), already incorporated herein by reference for all purposes.
- detection systems may take advantage of the package's asymmetry (i.e., non-flush edge) by employing a holder to match the shape of the package specifically.
- the imaging systems are capable of qualitatively analyzing the reaction between the probes and targets. Based on this analysis, sequence information of the targets is extracted.
- FIGS. 16 a - 16 b illustrate an alternative embodiment of the package.
- FIG. 16 a shows a top view
- FIG. 16 b shows a bottom view.
- a cavity 1620 is located on a top surface 1610 of the package body 1600 .
- the body includes alignment holes 1621 and 1622 that are used, for example, in mating the chip to the package.
- a plurality of ridges 1690 is located at end 1660 of the body. The friction created by ridges 1690 allows the package to be handled easily without slippage.
- the body also includes two substantially parallel edges 1630 and 1640 . As shown, edge 1640 is narrowed at end 1665 to create an uneven edge 1645 .
- the asymmetrical design of the body facilitates correct orientation when mounted onto detection systems. For example, detection systems may contain a holder, similar to that of an audio cassette tape, in which end 1665 is inserted.
- ports 1670 and 1671 communicate with cavity 1620 .
- a seal is provided for each port to retain fluids in the cavity.
- the bottom surface may optionally include a plurality of ridges 1690 at end 1660 .
- FIGS. 17 a - 17 b illustrate an alternative embodiment of the package.
- FIG. 17 a shows a top view
- FIG. 17 b shows a bottom view.
- a cavity 1720 is located on a top surface 1710 of the package body 1700 .
- the body may be formed in the shape of a disk with two substantially parallel edges 1730 and 1740 .
- Alignment holes 1721 and 1722 which may be different in size or shape, are located on the body.
- the package is inserted like an audio cassette tape into detection systems in a direction parallel to edges 1730 and 1740 . Edges 1730 and 1740 and alignment holes prevent the package from being inserted incorrectly into the detection systems.
- ports 1730 and 1740 are located on the bottom surface 1715 of the package. Ports 1730 and 1740 communicate with cavity 1720 and each include a seal 1780 for sealing fluids in the cavity.
- FIG. 18 illustrates an alternative embodiment for attaching the chip to the package.
- two concentric ledges 1810 and 1820 surround the perimeter of cavity 310 .
- Ledge 1820 supports the chip 120 when mounted above cavity 310 .
- Ledge 1810 which extends beyond chip 120 , receives an adhesive 1860 such as ultraviolet cured silicone, cement, or other adhesive for attaching the chip thereto.
- FIG. 19 illustrates another embodiment for attaching the chip to the package.
- a ledge 1910 is formed around cavity 310 .
- the ledge is sufficiently large to accommodate an adhesive 1920 such as an adhesive film, adhesive layer, tape, or any other adhesive layer.
- Chip 120 attaches to the package when it contacts the adhesive film.
- FIG. 20 a illustrates yet another embodiment for attaching a chip to the package.
- a clamp 2010 such as a frame having a plurality of fingers 2015 , attaches the chip to the package.
- FIG. 20 b illustrates a cross sectional view.
- a ridge 2020 on surface 501 surrounds cavity 310 .
- the ridge includes a ledge 2025 upon which chip 120 rests.
- a gasket or a seal 2070 is located between the ledge and chip to ensure a tight seal around cavity 310 .
- Clamp 2010 is attached to side 2040 of ridge 2020 and surface 501 .
- clamp 2010 is acoustically welded to the body.
- clamp 2010 includes energy directors 2050 located at its bottom.
- screws, clips, adhesives, or other attachment techniques may be used to mate clamp 2010 to the package.
- fingers 2015 secure chip 120 to the package.
- FIG. 21 illustrates an alternative embodiment for attaching the chip to the package.
- a ridge 2110 having a notch 2115 at or near the top of ridge 2110 , encompasses the cavity 310 .
- Chip 120 is wedged and held into position by notch 2115 .
- a process known as heat staking is used to mount the chip. Heat staking includes applying heat and force at side 2111 of ridge, thus forcing ridge tightly against or around chip 120 .
- FIG. 22 shows another embodiment of attaching a chip onto a package.
- a channel 2250 surrounds cavity 310 .
- a notch 2240 for receiving the chip 120 is formed along or near the top of the cavity 310 .
- a gasket or seal 2270 is placed at the bottom of the notch to ensure a tight seal when the chip is attached.
- a V-shaped, wedge 2260 is inserted into channel 2250 . The wedge forces the body to press against chip's edges and seal 2260 , thus mating the chip to the package. This process is known as compression sealing.
- FIG. 23 shows an alternative embodiment of package that employs check valves to seal the inlets.
- depressions 2305 and 2315 communicate with cavity 310 through inlets 350 and 360 .
- Check valves 2310 and 2320 which in some embodiments may be duck-billed check valves, are seated in depressions 2305 and 2315 .
- a needle is inserted into the check valve. When the needle is removed, the check valve reseals itself to prevent leakage of the fluid.
- FIG. 24 illustrates another package that uses reusable tape for sealing the cavity 310 .
- a tape 2400 is located above inlets 350 and 360 .
- end 2430 of tape is permanently fixed to surface 2480 while end 2410 remains unattached.
- the mid section 2420 of the tape is comprised of non-permanent adhesive. This design allows inlets to be conveniently sealed or unsealed without completely separating the tape from the package.
- FIG. 25 illustrates yet another embodiment of the package that uses plugs to retain fluids within the cavity.
- depressions 2520 and 2530 communicate with cavity 310 via inlets 350 and 360 .
- a plug 2510 which in some embodiment may be composed of rubber or other sealing material, is mated to each of the depressions. Plugs 2510 are easily inserted or removed for sealing and unsealing the cavity during the hybridization process.
- FIG. 26 a illustrates a package utilizing sliding seals for retaining fluids within the cavity.
- the seals are positioned in slots 2610 that are located above the inlets.
- the slots act as runners for guiding the seals to and from the inlets.
- FIG. 26 b illustrates the seal in greater detail.
- Seal 2640 which may be composed of rubber, teflon rubber, or other sealing material, is mated to each slot 2610 .
- the seal includes a handle 2650 which extends through the slot.
- the bottom of the seal includes an annular protrusion 2645 to ensure mating with inlet 350 .
- the inlet is sealed or unsealed by positioning the seal appropriately along the slot.
- spring loaded balls, rotary ball valves, plug valves, or other fluid retention techniques may be employed.
- FIGS. 27 a - 27 b illustrate an alternative embodiment of the package.
- FIG. 27 a illustrates a top view
- FIG. 27 b shows a cross sectional view.
- package 2700 includes a cavity 2710 on a surface 2705 .
- a chip 2790 having an army of probes 2795 on surface 2791 is mated to the bottom of cavity 2710 with an adhesive 2741 .
- the adhesive for example, may be silicone, adhesive tape, or other adhesive. Alternatively, clips or other mounting techniques may be employed.
- the bottom of the cavity may include a depression in which a chip is seated.
- This configuration provides several advantages such as: 1) permitting the use of any type of substrate (i.e., non-transparent or non-translucent), 2) yielding more chips per wafer since the chip does not require an edge for mounting, and 3) allowing chips of various sizes or multiple chips to be mated to the package.
- a cover 2770 is mated to the package for sealing the cavity.
- cover 2770 is composed of a transparent or translucent material such as glass, acrylic, or other material that is penetrable by light.
- Cover 2270 may be mated to surface 2705 with an adhesive 2772 , which in some embodiments may be silicone, adhesive film, or other adhesive.
- a depression may be formed around the cavity such that surface 2271 of the cover is at least flush with surface 2705 .
- the cover may be mated to surface 2705 according to any of the chip attachment techniques described herein.
- Inlets 2750 and 2751 are provided and communicate with cavity 2710 . Selected fluids are circulated through the cavity via inlets 2750 and 2751 . To seal the fluids in the cavity, a septum, plug, or other seal may be employed. In alternative embodiments, any of the fluid retention techniques described herein may be utilized.
- the body is configured with a plurality of cavities.
- the cavities may be in a 96-well micro-titre format.
- a chip is mounted individually to each cavity according to the methods described above.
- the probe arrays may be formed on the wafer in a format matching that of the cavities. Accordingly, separating the wafer is not necessary before attaching the probe arrays to the package. This format provides significant increased throughput by enabling parallel testing of a plurality of samples.
- FIG. 28 illustrates an agitation system in detail.
- the agitation system 2800 includes two liquid containers 2810 and 2820 , which in the some embodiments are about 10 milliliters each.
- Container 2810 communicates with port 350 via tube 2850 and container 2820 communicates with port 360 via tube 2860 .
- An inlet port 2812 and a vent port 2811 are located at or near the top of container 2810 .
- Container 2820 also includes an inlet port 2822 and a vent 2821 at or near its top.
- Port 2812 of container 2810 and port 2822 of container 2820 are both connected to a valve assembly 2828 via valves 2840 and 2841 .
- An agitator 2801 which may be a nitrogen gas (N 2 ) or other gas, is connected to valve assembly 2828 by fitting 2851 .
- Valves 2840 and 2841 regulate the flow of N 2 into their respective containers.
- additional containers may be provided, similar to container 2810 , for introducing a buffer and/or other fluid into the cavity.
- a fluid is placed into container 2810 .
- the fluid for example, may contain targets that are to be hybridized with probes on the chip.
- Container 2810 is sealed by closing port 2811 while container 2820 is vented by opening port 2821 .
- N 2 is injected into container 2810 , forcing the fluid through tube 2850 , cavity 310 , and finally into container 2820 .
- the bubbles formed by the N 2 agitate the fluid as it circulates through the system.
- the system reverses the flow of the fluid by closing valve 2840 and port 2821 and opening valve 2841 and port 2811 . This cycle is repeated until the reaction between the probes and targets is completed.
- foaming may occur when N 2 interacts with the fluid. Foaming potentially inhibits the flow of the fluid through the system.
- a detergent such as CTAB may be added to the fluid. In one embodiment, the amount of CTAB added is about 1 millimolar. Additionally, the CTAB affects the probes and targets positively by increasing the rate at which they bind, thus decreasing the reaction time required.
- the system described in FIG. 28 may be operated in an alternative manner. According to this technique, back pressure formed in the second container is used to reverse the flow of the solution.
- the fluid is placed in container 2810 and both ports 2811 and 2821 are closed.
- N 2 is injected into container 2810
- the fluid is forced through tube 2850 , cavity 310 , and finally into container 2820 .
- the vent port in container 2820 is closed, the pressure therein begins to build as the volume of fluid and N 2 increases.
- the flow of N 2 into container 2810 is terminated by closing valve 2840 .
- the circulatory system is vented by opening port 2811 of container 2810 .
- the pressure in container 2820 forces the solution back through the system toward container 2810 .
- the system is injected with N 2 for about 3 seconds and vented for about 3 seconds. This cycle is repeated until hybridization between the probes and targets is completed.
- FIG. 29 illustrates an alternative embodiment of the agitation system.
- System 2900 includes a vortexer 2910 on which the chip package 300 is mounted.
- a container 2930 for holding the fluid communicates with inlet 350 via tube 2950 .
- a valve 2935 may be provided to control the flow of solution into the cavity.
- circulator 2901 which may be a N 2 source or other gas source, is connected to container 2930 .
- a pump or other fluid transfer device may be employed.
- the flow of N 2 into container 2930 is regulated by a valve 2936 .
- Circulator 2901 is also connected to inlet tube 2950 via a valve 2902 .
- a waste container 2920 communicates with port 360 via outlet tube 2955 .
- a liquid sensor 2940 may be provided for sensing the presence of liquid in outlet tube 2955 .
- Access to the waste container may be controlled by a valve 2921 .
- additional containers (not shown), similar to container 2930 , may be employed for introducing a buffer or other fluid into the cavity.
- valves 2936 , 2935 , and 2921 are opened. This allows N 2 to enter container 2930 which forces the fluid to flow through tube 2950 and into the cavity.
- valves 2935 , 2936 , and 2921 are closed to seal the fluid in the cavity.
- the vortexer is activated to vibrate the chip package, similar to a paint mixer. In some embodiments, the vortexer may vibrate the package at about 3000 cycles per minute. The motion mixes the targets in the fluid, shortening the incubation period. In some embodiments, the vortexer rotates the chip package until hybridization is completed.
- valve 2902 and 2955 are opened to allow N 2 into the cavity. The N 2 empties the fluid into waste container 2920 . Subsequently, the cavity may be filled with a buffer or other fluid.
- FIG. 30 illustrates an alternative embodiment in which the agitation system is partially integrated into the chip package.
- chip package 300 includes a cavity 310 on which the chip is mounted. Cavity 310 is provided with inlets 360 and 350 .
- the package also includes chambers 3010 and 3020 .
- a port 3021 is provided in chamber 3010 and is connected to inlet 360 by a channel 3025 .
- Chamber 3010 is equipped with ports 3011 and 3012 .
- Port 3012 communicates with inlet 350 through a channel 3015 .
- Channel 3015 is provided with a waste port 3016 that communicates with a fluid disposal system 3500 via a tube 3501 .
- a valve 3502 regulates the flow of fluids into the disposal system.
- the disposal system includes a waste container 3510 and fluid recovery container 3520 which are connected to tube 3501 .
- a valve 3530 is provided to direct the flow of fluids into either the waste container or recovery container.
- Port 3011 is coupled to a fluid delivery system 3600 through a tube 3601 . Fluids flowing into chamber 3010 from the fluid delivery system are regulated by a valve 3602 .
- the fluid delivery system includes fluid containers 3610 and 3620 that are interconnected with a tube 3690 .
- Container 3610 which may hold a fluid containing targets, includes ports 3616 and 3615 .
- Port 3616 is connected to tube 3690 .
- a valve 3612 controls the flow of the fluid out of container 3610 .
- a circulator 3605 which may be a N 2 source, is connected to port 3615 of container 3610 . Alternatively, any type of gas, pump or other fluid transfer device may be employed. The flow of N 2 into container 3610 is controlled by a valve 3618 .
- a valve 3619 may also be provided to vent container 3610 .
- Container 3620 which may hold a buffer, is provided with ports 3625 and 3626 .
- Circulator 3605 is connected to port 3625 .
- a valve 3621 is provided to control the flow of N 2 into container 3620 .
- Port 3626 is connected to tube 3690 via a valve 3622 .
- Valve 3622 regulates the flow of the buffer out of container 3620 .
- additional containers (not shown), similar to container 3620 , may be configured for introducing other fluids into the cavity.
- a valve 3690 connects circulator 3605 to tube 3690 for controlling the flow of N 2 directly into the package.
- a valve 3652 is provided for venting the fluid delivery system.
- valves 3602 , 3612 and 3618 In the initial operating state, all valves are shut.
- a fluid containing targets is introduced into chamber 3010 by opening valves 3602 , 3612 and 3618 . This injects N 2 into container 3610 which forces the fluid to flow through 3601 and into chamber 3010 .
- valves 3612 and 3618 are closed.
- valve 3642 is opened, allowing N 2 to flow directly into chamber 3010 .
- the N 2 agitates and circulates the fluid into cavity 310 and out to chamber 3020 .
- valve 3642 As the volume of fluid and N 2 in chamber 3020 increase, likewise does the pressure therein.
- valve 3642 When chamber 3020 approaches its capacity, valve 3642 is closed to stop the fluid flow. Thereafter, the system is vented by opening valve 3652 . Venting the system allows the back pressure in chamber 3020 to reverse the flow of fluids back into chamber 3010 .
- valve 3652 When chamber 3010 is filled, valve 3652 is closed and valve 3642 is opened to reverse the fluid
- the system may be drained. This procedure depends on which chamber the fluid is located in. If the fluid is located in chamber 3020 , then valve 3502 is opened, while valve 3530 is positioned to direct the fluid into the appropriate container (recovery or waste). The pressure in chamber 3020 forces the fluid through port 3016 , tube 3501 , and into the disposal system. If the fluid is in chamber 3010 , then valve 3502 and 3642 are opened. As a result, N 2 forces the fluid in chamber 3010 through port 3501 and into the disposal system.
- a buffer or other fluid may be introduced into the cavity.
- the cavity may be filled with a buffer by opening valves 3602 , 3621 , and 3622 . This injects N 2 into container 3620 which forces the buffer therein to flow through the system until it fills cavity 310 .
- ultrasonic radiation, heat, magnetic beads, or other agitation techniques may be employed.
- the present inventions provide commercially feasible devices for packaging a probe chip. It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art upon reviewing the above description. Merely as an example, the package may be molded or machined from a single piece of material instead of two. Also, other asymmetrical designs may be employed to orient the package onto the detection systems.
Abstract
A body 300 having a cavity 310 for mounting a substrate 120 fabricated with probe sequences at known locations according to the methods disclosed in U.S. Pat. No. 5,143,854 and PCT WO 92/10092 or others, is provided. The cavity includes inlets 350 and 360 for introducing selected fluids into the cavity to contact the probes. Accordingly, a commercially feasible device for use in high throughput assay systems is provided.
Description
- This application is a continuation of U.S. patent application Ser. No. 10/992,043, filed on Nov. 17, 2004, which is a continuation of U.S. patent application Ser. No. 10/619,224, filed Jul. 12, 2003, which is a continuation of U.S. patent application Ser. No. 10/229,759, filed Aug. 28, 2002, now U.S. Pat. No. 6,733,977, which is a continuation of U.S. patent application Ser. No. 10/046,623, filed Jan. 14, 2002, now U.S. Pat. No. 6,551,817, which is a continuation of U.S. patent application Ser. No. 09/907,196, filed Jul. 17, 2001, now U.S. Pat. No. 6,399,365, which is a continuation of U.S. patent application Ser. No. 09/302,052, filed Apr. 29, 1999, now U.S. Pat. No. 6,287,850, which is a continuation of U.S. patent application Ser. No. 08/485,452, filed Jun. 7, 1995, now U.S. Pat. No. 5,945,334, which is a continuation-in-part of U.S. patent application Ser. No. 08/255,682, filed Jun. 8, 1994, now abandoned. Each of these applications is incorporated herein in its entirety by reference for all purposes.
- The present inventions relate to the fabrication and placement of materials at known locations on a substrate. In particular, one embodiment of the invention provides a method and associated apparatus for packaging a substrate having diverse sequences at known locations on its surface.
- Techniques for forming sequences on a substrate are known. For example, the sequences may be formed according to the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.), PCT WO 92/10092, or U.S. application Ser. No. 08/249,188, now U.S. Pat. No. 5,571,639, incorporated herein by reference for all purposes. The prepared substrates will have a wide range of applications. For example, the substrates may be used for understanding the structure-activity relationship between different materials or determining the sequence of an unknown material. The sequence of such unknown material may be determined by, for example, a process known as sequencing by hybridization. In one method of sequencing by hybridization, a sequences of diverse materials are formed at known locations on the surface of a substrate. A solution containing one or more targets to be sequenced is applied to the surface of the substrate. The targets will bind or hybridize with only complementary sequences on the substrate.
- The locations at which hybridization occurs can be detected with appropriate detection systems by labeling the targets with a fluorescent dye, radioactive isotope, enzyme, or other marker. Exemplary systems are described in U.S. Pat. No. 5,143,854 (Pirrung et al.) and U.S. patent application Ser. No. 08/143,312, also incorporated herein by reference for all purposes. Information regarding target sequences can be extracted from the data obtained by such detection systems.
- By combining various available technologies, such as photolithography and fabrication techniques, substantial progress has been made in the fabrication and placement of diverse materials on a substrate. For example, thousands of different sequences may be fabricated on a single substrate of about 1.28 cm2 in only a small fraction of the time required by conventional methods. Such improvements make these substrates practical for use in various applications, such as biomedical research, clinical diagnostics, and other industrial markets, as well as the emerging field of genomics, which focuses on determining the relationship between genetic sequences and human physiology.
- As commercialization of such substrates becomes widespread, an economically feasible and high-throughput device and method for packaging the substrates are desired.
- Methods and devices for packaging a substrate having an array of probes fabricated on its surface are disclosed. In some embodiments, a body containing a cavity is provided. A substrate having an array of probes is attached to the cavity using, for example, an adhesive. The body includes inlets that allow fluids into and through the cavity. A seal is provided for each inlet to retain the fluid within the cavity. An opening is formed below the cavity to receive a temperature controller for controlling the temperature in the cavity. By forming a sealed thermostatically controlled chamber in which fluids can easily be introduced, a practical medium for sequencing by hybridization is provided.
- In other embodiments, the body is formed by acoustically welding two pieces together. The concept of assembling the body from two pieces is advantageous. For example, the various features of the package (i.e., the channels, sealing means, and orientation means) are formed without requiring complex machining or designing. Thus, the packages are produced at a relatively low cost.
- In connection with one aspect of the invention, a method for making the chip package is disclosed. In particular, the method comprises the steps of first forming a plurality of probe arrays on a substrate and separating the substrate into a plurality of chips. Typically, each chip contains at least one probe array. A chip is then mated to a package having a reaction chamber with fluid inlets. When mated, the probe array is in fluid communication with the reaction chamber.
- In a specific embodiment, the present invention provides an apparatus for packaging a substrate. The present apparatus includes a substrate having a first surface and a second surface. The first surface includes a probe array and the second surface is an outer periphery of the first surface. The present apparatus also includes a body having a mounting surface, an upper surface, and a cavity bounded by the mounting surface and the upper surface. The second surface is attached to the cavity and the first surface is within the cavity. A cover attached to the mounting surface for defining an upper boundary to the cavity is also included. The cavity includes a diffuser and a concentrator. The diffuser and the concentrator permit laminar fluid flow through the cavity.
- A further understanding of the nature and advantages of the inventions herein may be realized by reference to the remaining portions of the specification and the attached drawings.
-
FIG. 1 a illustrates a wafer fabricated with a plurality of probe arrays. -
FIG. 1 b illustrates a chip. -
FIG. 2 a illustrates a scribe and break device. -
FIG. 2 b illustrates the wafer mounted on a pick and place frame. -
FIGS. 2 c-2 d illustrate the wafer, as displayed by the scribe and break device during alignment. -
FIG. 3 illustrates a chip packaging device. -
FIG. 4 illustrates the chip packaging device assembled from two components. -
FIGS. 5 a-5 b illustrate the top and bottom view of a top casing of the chip packaging device. -
FIG. 5 c illustrates a different cavity orientation. -
FIG. 6 illustrates a cross sectional view of the packaging device. -
FIG. 7 illustrates the bottom view of a bottom casing of the chip packaging device. -
FIGS. 8 a-8 b illustrate an acoustic welding system. -
FIGS. 9 a-9 c illustrate the acoustic welding process used in assembling the chip packaging device. -
FIG. 10 illustrates an adhesive dispensing system used in attaching the chip to the chip packaging device. -
FIGS. 11 , 12 a, 12 b and 13 illustrate in greater detail the adhesive dispensing system ofFIG. 10 . -
FIGS. 14 a-14 d illustrate the procedure for aligning the system ofFIG. 10 . -
FIGS. 15 a-15 e illustrate images obtained during the alignment process ofFIGS. 14 a-14 d. -
FIGS. 16 a-16 b illustrate an alternative embodiment of a packaging device. -
FIGS. 17 a-17 b illustrate another embodiment of a packaging device. -
FIG. 18 illustrates an alternative embodiment for attaching the chip to the packaging device. -
FIG. 19 illustrates another embodiment for attaching the chip to the packaging device. -
FIGS. 20 a-20 b illustrate yet another embodiment for attaching the chip to the packaging device. -
FIG. 21 illustrates an alternative embodiment for attaching the chip to the packaging device. -
FIG. 22 illustrates another embodiment for attaching the chip to the packaging device. -
FIG. 23 illustrates an alternative embodiment for sealing the cavity on the packaging device. -
FIG. 24 illustrates another alternative embodiment for sealing the cavity on the packaging device. -
FIG. 25 illustrates yet another embodiment for sealing the cavity on the packaging device. -
FIGS. 26 a-26 b illustrate an alternative embodiment for sealing the cavity on the packaging device. -
FIGS. 27 a-27 b illustrate an alternative embodiment for mounting the chip. -
FIG. 28 illustrates an agitation system. -
FIG. 29 illustrates an alternative embodiment of the agitation system. -
FIG. 30 illustrates another embodiment of the agitation system. -
FIG. 31 illustrates an alternative embodiment of a chip packaging device. -
FIG. 32 illustrates side-views of the chip packaging device ofFIG. 31 . -
FIGS. 33-35 illustrate in greater detail the chip packaging device ofFIG. 31 . -
FIG. 36 illustrates a further alternative embodiment of a chip packaging device. - I. Definitions
- II. General
- III. Details of One Embodiment of Invention
-
- a. Chip Package
- b. Assembly of Chip Package
- c. Chip Attachment
- IV. Details on Alternative Embodiments
-
- a. Chip Package
- b. Chip Attachment
- c. Fluid Retention
- d. Chip Orientation
- e. Parallel Diagnostics
- V. Details of an Agitation System
- The following terms are intended to have the following general meanings as they are used herein:
-
- 1. Probe: A probe is a surface-immobilized molecule that is recognized by a particular target and is sometimes referred to as a ligand. Examples of probes that can be investigated by this invention include, but are not restricted to, agonists and antagonists for cell membrane receptors, toxins and venoms, viral epitopes, hormones (e.g., opioid peptides, steroids, etc.), hormone receptors, peptides, enzymes, enzyme substrates, cofactors, drugs, lectins, sugars, oligonucleotides or nucleic acids, oligosaccharides, proteins, and monoclonal antibodies.
- 2. Target: A target is a molecule that has an affinity for a given probe and is sometimes referred to as a receptor. Targets may be naturally-occurring or manmade molecules. Also, they can be employed in their unaltered state or as aggregates with other species. Targets may be attached, covalently, or noncovalently, to a binding member, either directly or via a specific binding substance. Examples of targets which can be employed by this invention include, but are not restricted to, antibodies, cell membrane receptors, monoclonal antibodies and antisera reactive with specific antigenic determinants (such as on viruses, cells or other materials), drugs, oligonucleotides or nucleic acids, peptides, cofactors, lectins, sugars, polysaccharides, cells, cellular membranes, and organelles. Targets are sometimes referred to in the art as anti-probes or anti-ligands. As the term “targets” is used herein, no difference in meaning is intended. A “Probe Target Pair” is formed when two macromolecules have combined through molecular recognition to form a complex.
- The present invention provides economical and efficient packaging devices for a substrate having an array of probes fabricated thereon. The probe arrays may be fabricated according to the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.), PCT WO 92/10092, or U.S. application Ser. No. 08/249,188 filed May 24, 1994, already incorporated herein by reference for all purposes. According to one aspect of the techniques described therein, a plurality of probe arrays are immobilized at known locations on a large substrate or wafer.
-
FIG. 1 a illustrates awafer 100 on whichnumerous probe arrays 110 are fabricated. Thewafer 100 may be composed of a wide range of material, either biological, nonbiological, organic, inorganic, or a combination of any of these, existing as particles, strands, precipitates, gels, sheets, tubing, spheres, containers, capillaries, pads, slices, films, plates, slides, etc. The wafer may have any convenient shape, such as a disc, square, sphere, circle, etc. The wafer is preferably flat but may take on a variety of alternative surface configurations. For example, the wafer may contain raised or depressed regions on which a sample is located. The wafer and its surface preferably form a rigid support on which the sample can be formed. The wafer and its surface are also chosen to provide appropriate light-absorbing characteristics. For instance, the wafer may be a polymerized Langmuir Blodgett film, functionalized glass, Si, Ge, GaAs, GaP, SiO2, SiN4, modified silicon, or any one of a wide variety of gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, polycarbonate, or combinations thereof. Other materials with which the wafer can be composed of will be readily apparent to those skilled in the art upon review of this disclosure. In a preferred embodiment, the wafer is flat glass or single-crystal silicon. - Surfaces on the solid wafer will usually, though not always, be composed of the same material as the wafer. Thus, the surface may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed wafer materials.
-
Wafer 100 includes a plurality ofmarks 145 that are located in streets 150 (area adjacent to the probe arrays). Such marks may be used for aligning the masks during the probe fabrication process. In effect, the marks identify the location at which eacharray 110 is to be fabricated. The probe arrays may be formed in any geometric shape. In some embodiments, the shape of the array may be squared to minimize wasted wafer area. After the probe arrays have been fabricated, the wafer is separated into smaller units known as chips. The wafer, for example, may be about 5×5 inches on which 16 probe arrays, each occupying an area of about 12.8 cm2, are fabricated. -
FIG. 1 b illustrates a chip that has been separated from the wafer. As illustrated,chip 120 contains aprobe array 110 and a plurality of alignment marks 145. The marks serve multiple functions, such as: 1) aligning the masks for fabricating the probe arrays, 2) aligning the scriber for separating the wafer into chips, and 3) aligning the chip to the package during the attachment process. In some embodiments, such chips may be of the type known as Very Large Scale Immobilized Polymer Synthesis (VLSIPS™) chips. - According to a specific embodiment, the chip contains an array of genetic probes, such as an array of diverse RNA or DNA probes. In some embodiments, the probe array will be designed to detect or study a genetic tendency, characteristic, or disease. For example, the probe array may be designed to detect or identify genetic diseases such as cystic fibrosis or certain cancers (such as P53 gene relevant to some cancers), as disclosed in U.S. patent application Ser. No. 08/143,312, already incorporated by reference.
- According to one embodiment, the wafer is separated into a plurality of chips using a technique known as scribe and break.
FIG. 2 a illustrates a fully programmable computer controlled scribe and break device, which in some embodiments is a DX-III Scriber breaker manufactured by Dynatex International™. As shown, thedevice 200 includes a base 205 with arotation stage 220 on which a wafer is mounted. The rotation stage includes a vacuum chuck for fixing the wafer thereon. A stepper motor, which is controlled by the system, rotatesstage 220. Located above the stage is ahead unit 230 that includes acamera 232 andcutter 231.Head unit 230 is mounted on a dual-axis frame. The camera generates an image of the wafer onvideo display 210. Thevideo display 210 includes a crosshair alignment nark 215. The camera, which includes a zoom lens and a fiber optic light, allows a user to inspect the wafer on thevideo display 210. A control panel 240 is located on the base for operatingdevice 200. - In operation, a user places a
wafer 100 on aframe 210 as illustrated inFIG. 2 b. The surface offrame 210 is composed of a flexible and sticky material. The tackiness of the frame prevents the chips from being dispersed and damaged during the breaking process.Frame 210 may be a pick and place frame or a hoop that is commonly associated with fabrication of semiconductors. Referring back toFIG. 2 a, a user places the frame with the wafer on therotation stage 220. In some embodiments, the frame is held on the rotation stage by vacuum pressure. The user then aligns the wafer by examining the image displayed on thevideo display 210. - According to one embodiment, wafer alignment is achieved in two steps. First, using the control panel 240, the user rotates
stage 220. The stage is rotated untilstreets 150 are aligned with thecross hair 215 on the display, as illustrated inFIG. 2 c. Next, the user moves the cutter until it is aligned at the center of one of the streets. This step is performed by aligninghorizontal line 216 of the cross hair between alignment marks 145, as shown inFIG. 2 d. - Once the cutter is aligned, the user instructs the device to scribe the wafer. In some embodiments, various options are available to the user, such as scribe angle; scribe pressure, and scribe depth. These parameters will vary depending on the composition and/or thickness of the wafer. Preferably, the parameters are set to scribe and break the wafer without causing any damage thereto or penetrating through the frame. The device repeatedly scribes the wafer until all the streets in one axis have been scribed, which in one embodiment is repeated 5 times (a 4×4 matrix of probe arrays). The user then rotates the stage 90° to scribe the perpendicular streets.
- Once the wafer has been scribed, the user instructs the device to break or separate the wafer into chips. Referring back to
FIG. 2 a, thedevice 200 breaks the wafer by striking it beneath the scribe with an impulse bar located under the rotation table 220. The shock from the impulse bar fractures the wafer along the scribe. Since most of the force is dissipated along the scribe,device 200 is able to produce high breaking forces without exerting significant forces on the wafer. Thus, the chips are separated without causing any damage to the wafer. Once separated, the chips are then packaged. Of course, other more conventional techniques, such as the sawing technique disclosed in U.S. Pat. No. 4,016,855, incorporated herein by reference for all purposes, may be employed. - a. Chip Package
-
FIG. 3 illustrates a device for packaging the chips. Package 300 contains acavity 310 on which a chip is mounted. The package includesinlets cavity 310. Fluids are circulated through the cavity viainlets non-flush edge 320. In some detection systems, the packages may be inserted into a holder similar to an audio cassette tape. The asymmetrical design of the package will assure correct package orientation when inserted into the holder. -
FIG. 4 illustrates one embodiment of the package. As shown inFIG. 4 , the chip package is manufactured by mating two substantiallycomplementary casings finished assembly 300. Preferably,casings -
FIGS. 5 a-5 b show thetop casing 410 in greater detail.FIG. 5 a shows a top view andFIG. 5 b shows a bottom view. Referring toFIG. 5 a,top casing 410 includes an externalplanar surface 501 having acavity 310 therein. In some embodiments, the surface area ofcasing 410 sufficiently accommodates the cavity. Preferably, the top casing is of sufficient size to accommodate identification labels or bar codes in addition to the cavity. In a specific embodiment, the top casing is about 1.5″ wide, 2″ long, and 0.2″ high. -
Cavity 310 is usually, though not always, located substantially at the center ofsurface 501. The cavity may have any conceivable size, shape, or orientation. Preferably, the cavity is slightly smaller than the surface area of the chip to be placed thereon and has a volume sufficient to perform hybridization. In one embodiment, the cavity may be about 0.58″ wide, 0.58″ long, and 0.2″ deep. -
Cavity 310 may includeinlets -
FIG. 5 c illustrates an alternative embodiment in whichcavity 310 is oriented such that the edges of thecavity 310 and thecasing 410 are non-parallel. This configuration allowsinlets - Referring back to
FIG. 5 a, adepression 550 surrounds the cavity. In some embodiments, aridge 560 may be provided at the edge of the depression so as to form a trough. The ridge serves to support the chip above the cavity. To attach the chip to the package, an adhesive may be deposited in the trough. This configuration promotes efficient use of chip surface area, thus increasing the number of chips yielded from a wafer. -
Top casing 410 includes alignment holes 330 and 335. In some embodiments, holes 330 and 335 are different in size to ensure correct orientation of the package when mounted on an alignment table. Alternatively, the holes may have different shapes to achieve this objective. Optionally, the holes taper radially inward fromsurface 501 toward 502 to reduce the friction against alignment pins while still maintaining adequate contact to prevent slippage. - Referring to
FIG. 5 b,channels internal surface 502.Channels inlets depression 590 is formed below cavity. According to some embodiments, the shape ofdepression 590 is symmetrical to the cavity with exception tocorners depression 590 may be, for example, about 0.7″. As a result, the bottom wall of the cavity is about 0.05″ thick.Depression 590 may receive a temperature controller to monitor and maintain the cavity at the desired temperature. By separating the temperature controller and cavity with a minimum amount of material, the temperature within the cavity may be controlled more efficiently and accurately. Alternatively, channels may be formed onsurface 502 for circulating air or water to control the temperature within the cavity. - In some embodiments,
certain portions 595 ofinternal surface 502 may be eliminated or cored without interfering with the structural integrity of the package when assembled. Coring the casing reduces the wall thickness, causing less heat to be retained during the injection molding process; potential shrinkage or warpage of the casing is significantly reduced. Also, coring decreases the time required to cool the casing during the manufacturing process. Thus, manufacturing efficiency is improved. - In one embodiment, the top casing and bottom casing are mated together using a technique known as acoustic or ultrasonic welding. Accordingly, “energy directors” 510 are provided. Energy directors are raised ridges or points, preferably v-shaped, that are used in an acoustic welding process. The energy directors are strategically located, for example, to seal the channels without interfering with other features of the package and to provide an adequate bond between the two casings. Alternatively, the casings may be mated together by screws, glue, clips, or other mating techniques.
-
FIG. 6 shows a cross sectional view of thecavity 310 withchip 120 mounted thereon in detail. As shown, adepression 550 is formed aroundcavity 310. The depression includes aridge 560 which supportschip 120. The ridge and the depression create a trough aroundcavity 310. In some embodiments, the trough is sufficiently large to receive an adhesive 630 for attaching the chip to the package. In one embodiment, the trough is about 0.08″ wide and 0.06″ deep. When mounted, the edge of the chip protrudes slightly beyondridge 550, but without contactingside 625 of the depression. This configuration permits the adhesive to be dispensed onto the trough and provides adequate surface area for the adhesive to attachchip 120 to the package. - According to some embodiments, the
back surface 130 ofchip 120 is at least flush or below the plane formed bysurface 501 ofcasing 410. As a result,chip 120 is shielded bysurface 501 from potential damage. This configuration also allows the packages to be easily stored with minimal storage area since the surfaces are substantially flat. - Optionally, the bottom of the cavity includes a light absorptive material, such as a glass filter or carbon dye, to prevent impinging light from being scattered or reflected during imaging by detection systems. This feature improves the signal-to-noise ratio of such systems by significantly reducing the potential imaging of undesired reflected light.
-
FIG. 7 shows the internal surface ofbottom casing 420 in greater detail. As shown, thebottom casing 420 is substantially planar and contains anopening 760 therein. Preferably, thecasing 420 is slightly wider or slightly longer than the top casing. In one embodiment, casing 420 is about 1.6″ wide, 2.0″ long, and 0.1″ deep, which creates a non-flush edge on the finish assembly. As previously mentioned, this design ensures that the package is correctly oriented when mounted onto the detection systems. - In some embodiments, opening 760 is spatially located at about the depression below the cavity. The opening also has substantially the same geometric configuration as the depression to allow the temperature controller to contact as much of the bottom of the cavity as possible.
-
Internal surface 701 ofcasing 420 includesdepressions port 731 is located indepression 730 and aport 741 is located indepression 740.Ports FIG. 5 b) when the package is assembled. Aseal 790, which may be a septum composed of rubber, teflon/rubber laminate, or other sealing material is provided for each depression. The septum may be of the type commonly used to seal and reseal vessels when a needle is inserted into the septum for addition/removal of fluids. The septums, when seated in the depressions, extend slightly above surface, which in some embodiments is about 0.01″. - This design causes
casings - Also, casing 420 includes the complementary
half alignment holes certain areas 765 oninternal surface 701 may be cored, as similar to the internal surface of the top casing. -
FIG. 31 is a simplified illustration of an alternative embodiment of achip packaging device 3100 according to the present, invention. The chip packaging device includes a plurality ofcasings top casing 3200, amiddle casing 3300, and abottom casing 3400. The casings are made of known plastic materials such as ABS plastic, polyvinylchloride, polyethylene, products sold under the trademarks TEFLON™ and KALREZ™ and the like, among others. Preferably, the casings can be made by way of injection molding and the like. Assembling the chip packaging device from three casings simplifies construction for the fabrication of internal channels and the like, and can also be made at a relatively low cost. - Support structures (or alignment holes) exist at selected locations of the chip packing device. The support structures can be used to mount or position the chip packaging device to an apparatus, e.g., scanner or the like. In an embodiment, the
top casing 3200 includessupport structures center opening 3209. Themiddle casing 3300 includessimilar support structures support structures similar support structures - The present chip packaging device assembles with use of complementary alignment pins and bores on the casings. By way of alignment pins (not shown), the top casing aligns with and inserts into alignment bores 3301, 3303 in the
middle casing 3300. Alternatively, the middle casing can have alignment pins or the like and the top casing has the alignment bores or the like. The bottom casing includesalignment pins - A
center opening 3209 in the top casing overlies acenter portion 3317 of themiddle casing 3300. Thecenter portion 3317 of the middle casing includes an inner annular region (or cavity edges) with a bottom portion which is preferably a flat bottom portion. The flat bottom portion of the middle, casing and portions of the bottom casing including edges define acavity 3405. A chip is placed overlying an underlying portion of thecavity 3407. - Optionally, a temperature control mechanism such as a heater, a cooler, or a combination thereof is disposed into the center opening against the bottom portion of the middle casing. The temperature control mechanism can be any suitable thermally controlled element such as a resistive element, a temperature controlled block or mass, thermoelectric modules, or the like. The temperature control mechanism transfers heat via conduction to the bottom center portion, which transfers heat to, for example, fluid in the cavity or the chip. Alternatively, the temperature control mechanism sinks heat away from, for example, fluid in the cavity or the chip through the bottom center portion. The temperature control mechanism maintains a selected temperature in the cavity. The temperature control mechanism also includes a temperature detection device such as a thermocouple which provides signals corresponding to temperature readings. A controller receives the signals corresponding to the temperature readings, and adjusts power output to the temperature control mechanism to maintain the selected temperature.
- The
top casing 3200 also includeschannels channels annular regions middle casing 3300 for fluid transfer. A septum, a plug, an o-ring, a gasket, or the like viaannular regions top casing channels channels channels bottom casing channels middle casing channels - The chip packaging device provides an even distribution of fluid (or fluid flow) through the cavity over a top surface (or inner or active surface) of the chip. For example, a selected fluid enters
channel 3207, flows throughchannel 3307, changes direction and flows throughchannel 3411, and evenly distributes into thecavity 3405 over the top surface of the chip. As previously noted, the cavity is defined by the flat bottom portion and cavity edges. A selected fluid exits the cavity by way ofchannel 3413,channel 3305, andchannel 3205. The fluid flow over the top surface of the chip is preferably laminar, but may also be turbulent, a combination thereof or the like. By way of the present chip packaging device, a substantial portion of turbulent flow remains at an upper portion of thechannel 3411, and does not enter the cavity. - Preferably, a selected fluid enters the cavity by way of
channel 3205,channel 3305, andchannel 3413. The selected fluid exits the cavity throughchannel 3411,channel 3307, andchannel 3207. In a preferred embodiment, the fluid flows against the direction of gravity through the cavity. Of course, other fluid flow routes may also be employed depending upon the particular application. -
FIG. 32 illustrates an assembledchip packaging device 3100 according to the present invention. As shown are a top-view 3200, a side-view 3500, a bottom-view 3400, and a front-view 3600 of the assembledchip packaging device 3100. The assembledchip packaging device 3100 includes thebottom casing 3400, themiddle casing 3300, and thetop casing 3200. - The top-
view 3200 of the top casing includesalignment structures opening 3209. Theopening 3209 includes a bevelledannular region 3211 surrounding the periphery of thechannel 3209. The alignment bores 3203 and 3201 also include bevelledannular regions annular region fluid channel - The bottom-
view 3400 of the bottom casing includesalignment structures cavity 3405. The cavity includes a flat bottomperipheral portion 3415, abevelled portion 3417 extending from the flat bottom peripheral portion, and a flatupper portion 3419 surrounding the bevelled portion. The chip includes an outer periphery which rests against the flat bottomperipheral portion 3415. The bevelled portion aligns the chip onto the flat bottomperipheral portion 3415. Similar to the previous embodiments, the top casing extends outside 3421 the middle and bottom casings. - The
cavity 3405 is preferably located at a center of the bottom casing, but may also be at other locations. The cavity may be round, square, rectangular, or any other shape, and orientation. The cavity is preferably smaller than the surface area of the chip to be placed thereon, and has a volume sufficient to perform hybridization and the like. In one embodiment, the cavity includes dimensions such as a length of about 0.6 inch, a width of about 0.6 inch and a depth of about 0.07 inch. - In a preferred embodiment, the bottom casing with selected cavity dimensions may be removed from the middle and top casings, and replaced with another bottom casing with different cavity dimensions. This allows a user to attach a chip having a different size or shape by changing the bottom casing, thereby providing ease in using different chip sizes, shapes, and the like. Of course, the size, shape, and orientation of the cavity will depend upon the particular application.
-
FIGS. 33-35 illustrate in greater detail the chip packaging device ofFIG. 31 .FIG. 33 illustrates simplified top-view 3260 and bottom-view 3250 diagrams of thetop casing 3200. As shown, the reference numerals refer to the same elements as the top casing ofFIG. 31 .FIG. 34 illustrates a simplified top-view 3350 and bottom-view 3360 diagrams of themiddle casing 3300. As shown, the reference numerals refer to the same elements as the middle casing ofFIG. 31 . In addition, the bottom-view of the casing includes a substantially smooth andplanar bottom surface 3361. A portion of the bottom surface defines an upper portion of the cavity. But the bottom surface can also be textured, ridged, or the like to create turbulence or a selected fluid flow through the cavity. The bottom surface is preferably a hydrophobic surface which enhances laminar flow through the cavity. Of course, the type of bottom surface depends upon the particular application. -
FIG. 35 illustrates simplified top-view 3460 and bottom-view 3450 diagrams of thebottom casing 3400. As shown, the reference numerals refer to the same elements as the bottom casing ofFIG. 31 . In an embodiment, fluid fromchannel 3305 changes direction at anupper portion 3431 of the channel and flows to alower portion 3433 of the channel. Fluid evenly distributes from thelower portion 3433 via afluid distribution point 3435. The distributed fluid evenly passes over a slanted edge (or bevelled edge) 3437 which drops fluid evenly to a top surface of the chip in the cavity. By way of slantededge 3427 which slopes up to afluid concentration point 3425, fluid leaves the cavity and enters thechannel 3411. In particular, fluid leaves the cavity and enters alower portion 3423 of the channel, flows through the channel, and changes directions at anupper portion 3421 of the channel. Each channel includes a length L and a width W. The distribution point and the concentration point are positioned at a distance away from the cavity to substantially prevent turbulence from forming in the cavity, and in particular over the top surface of the chip. The channels are each angled at an angle Θ ranging from about 2 degrees to about 90 degrees, but is preferably about 5 degrees to about 45 degrees. The angle enhances an even distribution of laminar flow into the cavity. Of course, the exact angle, channel shape, and dimensions depend upon the particular application. -
FIG. 36 illustrates a simplified cross-sectional view of analternative embodiment 3600 of the chip packaging device. The chip packaging device includes the threecasings cavity 3405. Preferably, eachpin 3601 includes anexternal opening 3609, atubular region 3611, aninner opening 3607, apointed tip 3605, and other elements. The pin is made from a suitable material such as a glass, a stainless steel or any other high quality material to transfer fluids to and from thecavity 3405. - In a preferred embodiment, each pin is inserted into its
channel region annular region channel 3205 and at least a portion of 3305), enters the upper region ofchannel 3413, and into thecavity 3405. The selected fluid travels from the cavity, throughpin 3601, and to the external apparatus. - Alternatively, the selected fluid enters the cavity via
pin 3601 and exits the cavity viapin 3603. The selected fluid may also enter the cavity via pin and exit the cavity through the channels without use of a pin. The selected fluid may further enter the cavity through the channels without use of a pin and exit through a pin. Of course, the particular pin used and fluid flow will depend upon the application. - It should be noted that the even distribution of fluid flow through the cavity prevents “hot spots” from occurring in the cavity. For example, the even distribution of fluid through the cavity by way of the previous embodiment substantially prevents fluid from becoming substantially turbulent at certain locations. This prevents “hot spots” caused by such turbulent fluid. The hot spots are often caused by higher chemical activity or exothermic reactions and the like by way of turbulence in such certain locations.
- b. Assembly of Chip Package
- According to one embodiment, the top and bottom casing are attached by a technique known as ultrasonic or acoustic welding.
FIG. 8 a is a schematic diagram of acoustic welding system used for assembling the package. In some embodiments, thewelding system 800 is a HS Dialog ultrasonic welder manufactured by Herrmann Ultrasonics Inc.System 800 includes aplatform 850 mounted onbase 810.Platform 850 accommodates the top and bottom casings during the assembling process. - An
acoustic horn 860 is mounted on a frame aboveplatform 850. The horn translates vertically (toward and away from platform 850) on the frame by air pressure. - The horn is connected to a
frequency generator 870, which in some embodiments is a 20 KHz generator manufactured by Herrmann Ultrasonics Inc.System 800 is controlled by acontroller 880, which, for example, may be a Dialog 2012 manufactured by Herrmann Ultrasonics Inc.Controller 880 may be configured to accept commands from adigital computer system 890.Computer 890 may be any appropriately programmed digital computer of the type that is well known to those skilled in the art such as a Gateway 486DX operating at 33 MHz. -
FIG. 8 b illustratesplatform 850 in greater detail. Theplatform 850 is substantially planar and includes alignment pins 851 and 852. Alignment pins 851 and 852 are used to align both the top and bottom casings during the welding process. In some embodiments, apad 890, which may be composed of silicone rubber or other energy absorbing material, is located onplatform 850 to prevent damage to the package during assembly. -
FIG. 9 a illustrates the acoustic welding system in operation. As shown,bottom casing 420, having aseptum 790 seated in each depression, is mounted onto platform table 850 and held in place by alignment pins.Top casing 410 is then aligned above the bottom casing with alignment pins. The system then commences the welding process by loweringhorn 860 until it contacts the top surface ofcasing 410. -
FIG. 9 b illustrates the casing and horn in detail. As shown, thehorn 860 presses againsttop casing 410, thereby forcingenergy directors 510 to interface withbottom casing 420. The system then activates the frequency generator, causing the welding horn to vibrate. -
FIG. 9 c illustrates in detail the energy directors during the welding process. As shown instep 9001, weldinghorn 860forces energy directors 510 againstbottom casing 420. Atstep 9002, the system vibrates the welding horn, which in some embodiments is at 20 KHz. The energy generated by the horn melts the energy directors. Simultaneously, the horn translates downward against the package. Atstep 9003, the pressure exerted by the horn causes the energy directors to fuse with the bottom casing. Atstep 9004, the welding process is completed when the horn reaches its weld depth, for example, of about 0.01″. Of course, the various welding parameters may be varied, according to the composition of the materials used, to achieve optimum results. - c. Chip Attachment
- According to some embodiments, an ultraviolet cured adhesive attaches the chip to the package.
FIG. 10 schematically illustrates an adhesive dispensing system used in attaching the chip. Thedispensing system 1000 includes an attachment table 1040 to accommodate the package during the attachment process. A chip alignment table 1050 for aligning the chip is located adjacent to attachment table 1040. Ahead unit 1030 for dispensing the adhesive is located above tables 1040 and 1050. Thehead unit 1030 also includes a camera that generates an output tovideo display 1070.Video display 1070, in some embodiments, includes a crosshair alignment mark 1071. The head unit is mounted on a dual-axis (x-y) frame for positioning during alignment and attachment of the chip. The operation of the dispensing system is controlled by acomputer 1060, which in some embodiments may be Gateway 486DX operating at 33 MHz. -
FIG. 11 illustrates the attachment table in greater detail. The attachment table 1040 has a substantiallyflat platform 1110 supported by a plurality oflegs 1105. Alignment pins 1115 and 1116, which secure the package during the attachment process, are located on the surface ofplatform 1110. - Optionally, a
needle 1120 is provided.Needle 1120 includes achannel 1121 and is connected to a vacuum pump. In operation, the needle is inserted into one of the ports of the package in order to generate a vacuum in the cavity. The vacuum pressure secures the chip to the package during the attachment process. -
FIG. 12 a shows table 1050 in greater detail. Table 1050 includes a substantiallyflat platform 1210 having adepression 1240 for holding a chip. In some embodiments, aport 1241 is provided indepression 1240.Port 1241 is connected to a vacuum pump which creates a vacuum in the depression for immobilizing the chip therein.Platform 1210 is mounted on a combination linearrotary stage 1246, which in some embodiments may be a model 26LR manufactured by DARDAL, and a singleaxis translation stage 1245, which may be a model CR2226HSE2 manufactured by DARDAL. -
FIG. 12 b illustratesdepression 1240 in greater detail. As shown, aledge 1241 surrounds thedepression 1240.Ledge 1241 supports the chip when it is placed abovedepression 1240. Since the chips are placed over the depression with the probes facing the table, this design protects the probes from being potentially damaged during alignment. -
FIG. 13 illustrates thehead unit 1030 in greater detail. As shown, thehead unit 1030 includes acamera assembly 1320 that generates an output to a video display. A light 1360 is provided to enable the camera to focus and image an object of interest. The head unit also includes anultraviolet light 1350 for curing the adhesive, avacuum pickup 1330 for moving chip during the attachment process, and anadhesive dispenser 1340. - In operation, a chip package is placed onto table 1040. As previously described, the alignment pins on the table immobilize the package. The user begins the chip attachment process by calibrating the head unit. This may be done by moving the camera above the package and aligning it with a mark on the package, as shown in
FIG. 14 a. For convenience, one of the alignment pins may be used as an alignment mark.FIG. 14 b illustrates atypical image 1440 generated by the camera during this step. As shown, the bead unit is not aligned withpin 1480. To align the head unit, the user translates it in both the x and y direction untilpin 1480 is located at theintersection 1477 of the cross hair on the video display, as illustrated inFIG. 14 c. - Next, the chip is inserted into the depression on the chip alignment table.
FIG. 14 c is a flow chart indicating the steps for aligning the chip. Atstep 1410, the system positions the camera (bead unit) above one of the chip's alignment marks. The camera images the alignment mark on the video display. At this point, the mark is normally misaligned (i.e., the mark is not located at the intersection of the cross hair alignment mark). Atstep 1420, the user adjusts the chip alignment table in both the x and y direction until the mark is substantially located at the intersection of the cross hair. Since no rotational adjustments were made, the mark may be misaligned angularly. - At
step 1430, the user instructs the system to move the camera above a second alignment mark, which usually is at an opposite corner of the chip. Again, an image of the alignment mark is displayed. At this stage, the alignment mark is probably misaligned in the x, y, and angular directions. Atstep 1440, the user adjusts the rotational stage, x-stage, and y-stage, if necessary, to align the mark with the cross hair on the video display. In instances where the rotational stage has been rotated, the first alignment mark will become slightly misaligned. To compensate for this shift, the user repeats the alignment process beginning atstep 1450 until both marks are aligned. Of course, image processing techniques may be applied for automated head unit and chip alignment. -
FIG. 15 a is an example of an image displayed by the video screen duringstep 1410. As shown, the first alignment mark (lower left corner of the chip) is not aligned with the cross hair marking.FIG. 15 b exemplifies an image of the first alignment mark after adjustments were made by the user.FIG. 15 c illustrates a typical image displayed by video screen duringstep 1430. As illustrated, the second alignment mark (upper right corner of the chip) is misaligned in the x, y, and angular directions.FIG. 15 d illustrates an image of the second mark following initial adjustments by the user atstep 1440.FIG. 15 e illustrates the orientation of the second alignment mark after the chip has been aligned. - Once the chip is aligned, the vacuum holding the chip on the attachment table is released. Thereafter, the pickup on the bead unit removes the chip from the table and aligns it on the cavity of the package. In some embodiments, the chip is mated to the pickup by a vacuum.
- Optionally, the user may check to ensure that the chip is correctly aligned on the cavity by examining the chip's alignment marks with the camera. If the chip is out of position, the chip is removed and realigned on the alignment table. If the chip is correctly positioned, the system deposits an adhesive by moving the dispenser along the trough surrounding the cavity. In some embodiments, the vacuum is released before depositing the adhesive in the trough. This step is merely precautionary and implemented to ensure that the vacuum does not cause any adhesive to seep into the cavity. Once the adhesive is deposited, the system reexamines the chip to determine if the adhesive had moved the chip out of position. If the chip is still aligned, the head unit locates the ultraviolet light above the adhesive and cures it for a time sufficient to harden the adhesive, which in one embodiment is about 10 seconds. Otherwise, the chip is realigned.
- Upon completion, the chip package will have a variety of uses. For example, the chip package will be useful in sequencing genetic material by hybridization. In sequencing by hybridization, the chip package is mounted on a hybridization station where it is connected to a fluid delivery system. Such system is connected to the package by inserting needles into the ports and puncturing the septums therein. In this manner, various fluids are introduced into the cavity for contacting the probes during the hybridization process.
- Usually, hybridization is performed by first exposing the sample with a prehybridization solution. Next, the sample is incubated under binding conditions with a solution containing targets for a suitable binding period. Binding conditions will vary depending on the application and are selected in accordance with the general binding methods known including those referred to in: Maniatis et al., Molecular Cloning: A Laboratory Manual (1989), 2nd Ed., Cold Spring Harbor, N.Y. and Berger and Kimmel, Methods in Enzymology, Volume 152, Guide to Molecular Cloning Techniques (1987), Academic Press, Inc., San Diego, Calif.; Young and Davis (1983) Proc. Natl. Acad. Sci. (U.S.A.) 80: 1194, which are incorporated herein by reference. In some embodiments, the solution may contain about 1 molar of salt and about 1 to 50 nanomolar of targets. Optionally, the fluid delivery system includes an agitator to improve mixing in the cavity, which shortens the incubation period. Finally, the sample is washed with a buffer, which may be 6× SSPE buffer, to remove the unbound targets. In some embodiments, the cavity is filled with the buffer after washing the sample.
- Thereafter, the package may be aligned on a detection or imaging system, such as those disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.) or U.S. patent application Ser. No. 08/495,889 (Attorney Docket Number 11509-117), already incorporated herein by reference for all purposes. Such detection systems may take advantage of the package's asymmetry (i.e., non-flush edge) by employing a holder to match the shape of the package specifically. Thus, the package is assured of being properly oriented and aligned for scanning. The imaging systems are capable of qualitatively analyzing the reaction between the probes and targets. Based on this analysis, sequence information of the targets is extracted.
- a. Chip Package Orientation
-
FIGS. 16 a-16 b illustrate an alternative embodiment of the package.FIG. 16 a shows a top view andFIG. 16 b shows a bottom view. As shown inFIG. 16 a, acavity 1620 is located on atop surface 1610 of thepackage body 1600. The body includesalignment holes ridges 1690 is located atend 1660 of the body. The friction created byridges 1690 allows the package to be handled easily without slippage. - The body also includes two substantially
parallel edges edge 1640 is narrowed atend 1665 to create anuneven edge 1645. The asymmetrical design of the body facilitates correct orientation when mounted onto detection systems. For example, detection systems may contain a holder, similar to that of an audio cassette tape, in which end 1665 is inserted. - Referring to
FIG. 16 b,ports cavity 1620. A seal is provided for each port to retain fluids in the cavity. Similar to the top surface, the bottom surface may optionally include a plurality ofridges 1690 atend 1660. -
FIGS. 17 a-17 b illustrate an alternative embodiment of the package.FIG. 17 a shows a top view andFIG. 17 b shows a bottom view. Referring toFIG. 17 a, acavity 1720 is located on atop surface 1710 of thepackage body 1700. The body may be formed in the shape of a disk with two substantiallyparallel edges edges Edges - As shown in
FIG. 17 b,ports bottom surface 1715 of the package.Ports cavity 1720 and each include aseal 1780 for sealing fluids in the cavity. - b. Chip Attachment
-
FIG. 18 illustrates an alternative embodiment for attaching the chip to the package. As shown, twoconcentric ledges cavity 310.Ledge 1820 supports thechip 120 when mounted abovecavity 310.Ledge 1810, which extends beyondchip 120, receives an adhesive 1860 such as ultraviolet cured silicone, cement, or other adhesive for attaching the chip thereto. -
FIG. 19 illustrates another embodiment for attaching the chip to the package. According to this embodiment, aledge 1910 is formed aroundcavity 310. Preferably, the ledge is sufficiently large to accommodate an adhesive 1920 such as an adhesive film, adhesive layer, tape, or any other adhesive layer.Chip 120 attaches to the package when it contacts the adhesive film. -
FIG. 20 a illustrates yet another embodiment for attaching a chip to the package. As shown, aclamp 2010, such as a frame having a plurality offingers 2015, attaches the chip to the package.FIG. 20 b illustrates a cross sectional view. Aridge 2020 onsurface 501 surroundscavity 310. The ridge includes aledge 2025 upon whichchip 120 rests. Optionally, a gasket or aseal 2070 is located between the ledge and chip to ensure a tight seal aroundcavity 310.Clamp 2010 is attached toside 2040 ofridge 2020 andsurface 501. In some embodiments,clamp 2010 is acoustically welded to the body. Accordingly,clamp 2010 includesenergy directors 2050 located at its bottom. Alternatively, screws, clips, adhesives, or other attachment techniques may be used to mateclamp 2010 to the package. When mated,fingers 2015secure chip 120 to the package. -
FIG. 21 illustrates an alternative embodiment for attaching the chip to the package. Aridge 2110, having anotch 2115 at or near the top ofridge 2110, encompasses thecavity 310.Chip 120 is wedged and held into position bynotch 2115. Thereafter, a process known as heat staking is used to mount the chip. Heat staking includes applying heat and force atside 2111 of ridge, thus forcing ridge tightly against or aroundchip 120. -
FIG. 22 shows another embodiment of attaching a chip onto a package. As shown, achannel 2250 surroundscavity 310. Anotch 2240 for receiving thechip 120 is formed along or near the top of thecavity 310. In some embodiments, a gasket orseal 2270 is placed at the bottom of the notch to ensure a tight seal when the chip is attached. Once the chip is located at the notch, a V-shaped,wedge 2260 is inserted intochannel 2250. The wedge forces the body to press against chip's edges andseal 2260, thus mating the chip to the package. This process is known as compression sealing. - Other techniques such as insert molding, wave soldering, surface diffusion, laser welding, shrink wrap, o-ring seal, surface etching, or heat staking from the top may also be employed.
- c. Fluid Retention
-
FIG. 23 shows an alternative embodiment of package that employs check valves to seal the inlets. As shown,depressions cavity 310 throughinlets valves depressions -
FIG. 24 illustrates another package that uses reusable tape for sealing thecavity 310. As shown, atape 2400 is located aboveinlets end 2430 of tape is permanently fixed tosurface 2480 whileend 2410 remains unattached. Themid section 2420 of the tape is comprised of non-permanent adhesive. This design allows inlets to be conveniently sealed or unsealed without completely separating the tape from the package. -
FIG. 25 illustrates yet another embodiment of the package that uses plugs to retain fluids within the cavity. As shown,depressions cavity 310 viainlets plug 2510, which in some embodiment may be composed of rubber or other sealing material, is mated to each of the depressions.Plugs 2510 are easily inserted or removed for sealing and unsealing the cavity during the hybridization process. -
FIG. 26 a illustrates a package utilizing sliding seals for retaining fluids within the cavity. The seals are positioned inslots 2610 that are located above the inlets. The slots act as runners for guiding the seals to and from the inlets.FIG. 26 b illustrates the seal in greater detail.Seal 2640, which may be composed of rubber, teflon rubber, or other sealing material, is mated to eachslot 2610. The seal includes ahandle 2650 which extends through the slot. Optionally, the bottom of the seal includes anannular protrusion 2645 to ensure mating withinlet 350. The inlet is sealed or unsealed by positioning the seal appropriately along the slot. Alternatively, spring loaded balls, rotary ball valves, plug valves, or other fluid retention techniques may be employed. - d. Chip Orientation
-
FIGS. 27 a-27 b illustrate an alternative embodiment of the package.FIG. 27 a illustrates a top view andFIG. 27 b shows a cross sectional view. As shown,package 2700 includes acavity 2710 on asurface 2705. Achip 2790 having an army ofprobes 2795 onsurface 2791 is mated to the bottom ofcavity 2710 with an adhesive 2741. The adhesive, for example, may be silicone, adhesive tape, or other adhesive. Alternatively, clips or other mounting techniques may be employed. Optionally, the bottom of the cavity may include a depression in which a chip is seated. - This configuration provides several advantages such as: 1) permitting the use of any type of substrate (i.e., non-transparent or non-translucent), 2) yielding more chips per wafer since the chip does not require an edge for mounting, and 3) allowing chips of various sizes or multiple chips to be mated to the package.
- A
cover 2770 is mated to the package for sealing the cavity. Preferably,cover 2770 is composed of a transparent or translucent material such as glass, acrylic, or other material that is penetrable by light.Cover 2270 may be mated to surface 2705 with an adhesive 2772, which in some embodiments may be silicone, adhesive film, or other adhesive. Optionally, a depression may be formed around the cavity such that surface 2271 of the cover is at least flush withsurface 2705. Alternatively, the cover may be mated to surface 2705 according to any of the chip attachment techniques described herein. -
Inlets cavity 2710. Selected fluids are circulated through the cavity viainlets - e. Parallel Hybridization and Diagnostics
- In an alternative embodiment, the body is configured with a plurality of cavities. The cavities, for example, may be in a 96-well micro-titre format. In some embodiments, a chip is mounted individually to each cavity according to the methods described above. Alternatively, the probe arrays may be formed on the wafer in a format matching that of the cavities. Accordingly, separating the wafer is not necessary before attaching the probe arrays to the package. This format provides significant increased throughput by enabling parallel testing of a plurality of samples.
-
FIG. 28 illustrates an agitation system in detail. As shown, theagitation system 2800 includes twoliquid containers Container 2810 communicates withport 350 viatube 2850 andcontainer 2820 communicates withport 360 viatube 2860. Aninlet port 2812 and a vent port 2811 are located at or near the top ofcontainer 2810.Container 2820 also includes an inlet port 2822 and avent 2821 at or near its top.Port 2812 ofcontainer 2810 and port 2822 ofcontainer 2820 are both connected to avalve assembly 2828 viavalves agitator 2801, which may be a nitrogen gas (N2) or other gas, is connected tovalve assembly 2828 by fitting 2851.Valves container 2810, for introducing a buffer and/or other fluid into the cavity. - In operation, a fluid is placed into
container 2810. The fluid, for example, may contain targets that are to be hybridized with probes on the chip.Container 2810 is sealed by closing port 2811 whilecontainer 2820 is vented by openingport 2821. Next, N2 is injected intocontainer 2810, forcing the fluid throughtube 2850,cavity 310, and finally intocontainer 2820. The bubbles formed by the N2 agitate the fluid as it circulates through the system. When the amount of fluid incontainer 2810 nears empty, the system reverses the flow of the fluid by closingvalve 2840 andport 2821 andopening valve 2841 and port 2811. This cycle is repeated until the reaction between the probes and targets is completed. - In some applications, foaming may occur when N2 interacts with the fluid. Foaming potentially inhibits the flow of the fluid through the system. To alleviate this problem, a detergent such as CTAB may be added to the fluid. In one embodiment, the amount of CTAB added is about 1 millimolar. Additionally, the CTAB affects the probes and targets positively by increasing the rate at which they bind, thus decreasing the reaction time required.
- The system described in
FIG. 28 may be operated in an alternative manner. According to this technique, back pressure formed in the second container is used to reverse the flow of the solution. In operation, the fluid is placed incontainer 2810 and bothports 2811 and 2821 are closed. As N2 is injected intocontainer 2810, the fluid is forced throughtube 2850,cavity 310, and finally intocontainer 2820. Because the vent port incontainer 2820 is closed, the pressure therein begins to build as the volume of fluid and N2 increases. When the amount of fluid incontainer 2810 nears empty, the flow of N2 intocontainer 2810 is terminated by closingvalve 2840. Next, the circulatory system is vented by opening port 2811 ofcontainer 2810. As a result, the pressure incontainer 2820 forces the solution back through the system towardcontainer 2810. In one embodiment, the system is injected with N2 for about 3 seconds and vented for about 3 seconds. This cycle is repeated until hybridization between the probes and targets is completed. -
FIG. 29 illustrates an alternative embodiment of the agitation system.System 2900 includes avortexer 2910 on which thechip package 300 is mounted. Acontainer 2930 for holding the fluid communicates withinlet 350 viatube 2950. Avalve 2935 may be provided to control the flow of solution into the cavity. In some embodiments,circulator 2901, which may be a N2 source or other gas source, is connected tocontainer 2930. Alternatively, a pump or other fluid transfer device may be employed. The flow of N2 intocontainer 2930 is regulated by avalve 2936.Circulator 2901 is also connected toinlet tube 2950 via avalve 2902. - A
waste container 2920 communicates withport 360 viaoutlet tube 2955. In one embodiment, aliquid sensor 2940 may be provided for sensing the presence of liquid inoutlet tube 2955. Access to the waste container may be controlled by avalve 2921. Optionally, additional containers (not shown), similar tocontainer 2930, may be employed for introducing a buffer or other fluid into the cavity. - The system is initialized by closing all valves and filling
container 2930 with, for example, a fluid containing targets. Next,valves container 2930 which forces the fluid to flow throughtube 2950 and into the cavity. When the cavity is filled,valves valve waste container 2920. Subsequently, the cavity may be filled with a buffer or other fluid. -
FIG. 30 illustrates an alternative embodiment in which the agitation system is partially integrated into the chip package. As shown,chip package 300 includes acavity 310 on which the chip is mounted.Cavity 310 is provided withinlets chambers port 3021 is provided inchamber 3010 and is connected toinlet 360 by achannel 3025. -
Chamber 3010 is equipped withports 3011 and 3012.Port 3012 communicates withinlet 350 through achannel 3015.Channel 3015 is provided with awaste port 3016 that communicates with afluid disposal system 3500 via atube 3501. Avalve 3502 regulates the flow of fluids into the disposal system. In some embodiments, the disposal system includes awaste container 3510 andfluid recovery container 3520 which are connected totube 3501. Avalve 3530 is provided to direct the flow of fluids into either the waste container or recovery container. - Port 3011 is coupled to a
fluid delivery system 3600 through atube 3601. Fluids flowing intochamber 3010 from the fluid delivery system are regulated by avalve 3602. The fluid delivery system includesfluid containers tube 3690.Container 3610, which may hold a fluid containing targets, includesports Port 3616 is connected totube 3690. Avalve 3612 controls the flow of the fluid out ofcontainer 3610. Acirculator 3605, which may be a N2 source, is connected toport 3615 ofcontainer 3610. Alternatively, any type of gas, pump or other fluid transfer device may be employed. The flow of N2 intocontainer 3610 is controlled by avalve 3618. Avalve 3619 may also be provided to ventcontainer 3610. -
Container 3620, which may hold a buffer, is provided withports Circulator 3605 is connected toport 3625. Avalve 3621 is provided to control the flow of N2 intocontainer 3620.Port 3626 is connected totube 3690 via avalve 3622.Valve 3622 regulates the flow of the buffer out ofcontainer 3620. Optionally, additional containers (not shown), similar tocontainer 3620, may be configured for introducing other fluids into the cavity. Avalve 3690 connects circulator 3605 totube 3690 for controlling the flow of N2 directly into the package. Avalve 3652 is provided for venting the fluid delivery system. - In the initial operating state, all valves are shut. To start the hybridization process, a fluid containing targets is introduced into
chamber 3010 by openingvalves container 3610 which forces the fluid to flow through 3601 and intochamber 3010. Whenchamber 3010 is filled,valves valve 3642 is opened, allowing N2 to flow directly intochamber 3010. The N2 agitates and circulates the fluid intocavity 310 and out tochamber 3020. As the volume of fluid and N2 inchamber 3020 increase, likewise does the pressure therein. Whenchamber 3020 approaches its capacity,valve 3642 is closed to stop the fluid flow. Thereafter, the system is vented by openingvalve 3652. Venting the system allows the back pressure inchamber 3020 to reverse the flow of fluids back intochamber 3010. Whenchamber 3010 is filled,valve 3652 is closed andvalve 3642 is opened to reverse the fluid flow. This cycle is repeated until hybridization is completed. - When hybridization is completed, the system may be drained. This procedure depends on which chamber the fluid is located in. If the fluid is located in
chamber 3020, thenvalve 3502 is opened, whilevalve 3530 is positioned to direct the fluid into the appropriate container (recovery or waste). The pressure inchamber 3020 forces the fluid throughport 3016,tube 3501, and into the disposal system. If the fluid is inchamber 3010, thenvalve chamber 3010 throughport 3501 and into the disposal system. - Once the system is emptied, all valves are closed. A buffer or other fluid may be introduced into the cavity. For example, the cavity may be filled with a buffer by opening
valves container 3620 which forces the buffer therein to flow through the system until it fillscavity 310. In the alternative, ultrasonic radiation, heat, magnetic beads, or other agitation techniques may be employed. - The present inventions provide commercially feasible devices for packaging a probe chip. It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art upon reviewing the above description. Merely as an example, the package may be molded or machined from a single piece of material instead of two. Also, other asymmetrical designs may be employed to orient the package onto the detection systems.
- The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims along with their full scope of equivalents.
Claims (35)
1. An apparatus for detecting an analyte in a test sample comprising:
at least one probe array, wherein the at least one probe array comprises:
a plurality of particles having biological polymers immobilized on the plurality of particles thereon;
a slide, wherein the plurality of particles are attached to a surface of the slide; and
a barcode for identifying the at least one probe array on the slide.
2. The apparatus according to claim 1 , wherein the different particles in the plurality of particles have different biological polymers immobilized thereon.
3. The apparatus according to claim 1 , wherein the plurality of particles are spheres.
4. The apparatus according to claim 1 , wherein the slide is silica.
5. The apparatus according to claim 1 , wherein the slide is glass.
6. The apparatus according to claim 1 , wherein the biological polymers are immobilized on the slide at a density exceeding 400 different biological polymers per cm2.
7. The apparatus according to claim 6 , wherein the biological polymers are immobilized on the slide at a density exceeding 100 different biological polymers per cm2.
8. The apparatus according to claim 1 , wherein the plurality of particles forms an ordered arrangement on the surface of the slide.
9. The apparatus according to claim 8 , wherein the ordered arrangement on the surface is circular.
10. The apparatus according to claim 8 , wherein the ordered arrangement on the surface is rectangular.
11. The apparatus according to claim 1 , wherein the at least one probe array is less than 9 probe arrays.
12. The apparatus according to claim 11 , wherein the at least one probe array is 1 probe array.
13. A package for supporting a probe array, comprising:
a plurality of particles having biological polymers immobilized on the plurality of particles thereon;
a slide, wherein the plurality of particles are attached to a surface of the slide; and
a top piece and a bottom piece, wherein the top bottom pieces house the first wafer, creating at least one cavity such that at least one probe array is in fluid communication with the reaction chamber.
14. The package according to claim 13 , further comprising a bar code associated with the at least one probe array.
15. The package according to claim 14 , further comprising at least one aligning pin and holes to assist in assembling the top piece and the bottom piece together.
16. The package according to claim 13 , further comprising screws to assemble the top piece, bottom piece and the at least one probe array together.
17. The package according to claim 13 , further comprising clamps to assemble the top piece, bottom piece and the at least one probe array together.
18. The package according to claim 13 , further comprising at least one inlet port to introduce a fluid into the cavity.
19. The package according to claim 18 , further comprising a septum to seal the at least one inlet ports.
20. The package according to claim 18 , further comprising at least one channel for fluid transfer between the at least one inlet port and the cavity.
21. The package according to claim 14 , further comprising at least one gasket to form a liquid tight seal around the cavity between the top piece and the at least one probe array.
22. The package according to claim 23 , wherein the gaskets are O-rings.
23. The package according to claim 14 , wherein the bottom piece comprises a depression to position the at least one probe array.
24. A method of using a probe array, comprising:
providing at least one probe array, wherein the at least one probe array comprises:
a plurality of particles having biological polymers immobilized on the plurality of particles thereon and a slide, wherein the plurality of particles are attached to a surface of the slide;
providing a housing, wherein the housing comprises a cavity to accommodate a fluid to be in contact with the slide;
placing the slide into the housing;
sealably mounting the slide within the housing comprising a mounting surface and a fluid cavity, wherein the fluid cavity comprises at least one inlet port constructed to permit fluid flow into the cavity through the at least one inlet port, wherein the sealably mounting act provides the at least one probe array located inside the cavity;
introducing the fluid inside the cavity to hybridize the at least one probe array on the slide;
performing hybridization, wherein at least some of the polymers hybridizes to a target;
aligning the at least one probe array, wherein the at least one probe array comprises at least one alignment feature; and
detecting a signal from the at least one probe array using a scanner.
25. The method according to claim 24 , further comprising reading a bar code associated with the probe array, wherein the slide comprises a bar code.
26. The method according to claim 24 , wherein the inlet port comprises of a septum sealed port which uses one or more needles to permit fluid flow into the cavity.
27. The method according to claim 24 , further comprising a fluid mixing step, wherein the cavity is at least partially filled with the fluid during mixing.
28. The method according to claim 27 wherein the fluid mixing occurs using the motion of gas relative to fluid in the cavity.
29. The method according to claim 27 wherein said fluid mixing uses agitation.
30. The method according to claim 27 wherein said agitation uses vortexing.
31. An apparatus for mixing a fluid, the apparatus comprising:
a pump, wherein a first housing comprises the pump;
a probe array;
a substrate, wherein the substrate and the probe array create at least one cavity for a fluid;
at least one bubble disposed within said chamber, wherein the at least one bubble is moved by using the pump to move the bubble relative to the fluid to effect mixing the fluid.
32. The apparatus as in claim 31 wherein the at least one bubble is formed using a nitrogen gas.
33. The apparatus as in claim 31 , wherein, the pump transfers the fluid from a first container through the cavity and into a second container.
34. The apparatus as in claim 31 , wherein, the means for moving the fluid is through agitation.
35. A fluidic station comprising:
a base that is adapted to provide a framework for the fluidics station;
a mounting system coupled to the base, wherein the mounting system is movable between a loading position and a closed position, the mounting system comprising:
a bottom piece adapted to receive a wafer, wherein a wafer comprises at least one probe array, wherein the bottom piece is adapted to receive a top piece positioned above the wafer forming at least one cavity for fluid to be in contact with the wafer and forming a package comprising at least an inlet port and an outlet port for fluid transfer and connecting with at least one cavity;
at least one needle coupled to the base frame, wherein the needle includes a distal end and side ports above the distal ends; and
at least one fluid source in communication with the at least one needle, wherein the wafer is insertable into the mounting system when in the loading position, and wherein the at least one needle is adapted to transfer liquid into the package through the liquid channels when in the closed position.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/842,977 US20100298165A1 (en) | 1994-06-08 | 2010-07-23 | Bioarray chip reaction apparatus and its manufacture |
Applications Claiming Priority (21)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25568294A | 1994-06-08 | 1994-06-08 | |
US08/485,452 US5945334A (en) | 1994-06-08 | 1995-06-07 | Apparatus for packaging a chip |
US09/302,052 US6287850B1 (en) | 1995-06-07 | 1999-04-29 | Bioarray chip reaction apparatus and its manufacture |
US09/907,196 US6399365B2 (en) | 1994-06-08 | 2001-07-17 | Bioarray chip reaction apparatus and its manufacture |
US10/046,623 US6551817B2 (en) | 1994-06-08 | 2002-01-14 | Method and apparatus for hybridization |
US10/229,759 US6733977B2 (en) | 1994-06-08 | 2002-08-28 | Hybridization device and method |
US10/619,224 US20040106130A1 (en) | 1994-06-08 | 2003-07-12 | Bioarray chip reaction apparatus and its manufacture |
US10/789,678 US20040166525A1 (en) | 1994-06-08 | 2004-02-27 | Bioarray chip reaction apparatus and its manufacture |
US10/795,603 US20040171054A1 (en) | 1994-06-08 | 2004-03-08 | Bioarray chip reaction apparatus and its manufacture |
US10/877,666 US20050003421A1 (en) | 1994-06-08 | 2004-06-25 | Bioarray chip reaction apparatus and its manufacture |
US10/976,077 US20050158819A1 (en) | 1994-06-08 | 2004-10-27 | Bioarray chip reaction apparatus and its manufacture |
US10/980,454 US20050084895A1 (en) | 1994-06-08 | 2004-11-02 | Bioarray chip reaction apparatus and its manufacture |
US10/992,043 US20050106615A1 (en) | 1994-06-08 | 2004-11-17 | Bioarray chip reaction apparatus and its manufacture |
US10/996,291 US20050089953A1 (en) | 1994-06-08 | 2004-11-22 | Bioarray chip reaction apparatus and its manufacture |
US10/995,882 US20050208646A1 (en) | 1994-06-08 | 2004-11-22 | Bioarray chip reaction apparatus and its manufacture |
US10/996,201 US20050106617A1 (en) | 1994-06-08 | 2004-11-22 | Bioarray chip reaction apparatus and its manufacture |
US11/015,197 US20050106618A1 (en) | 1994-06-08 | 2004-12-16 | Bioarray chip reaction apparatus and its manufacture |
US11/259,418 US20060040380A1 (en) | 1994-06-08 | 2005-10-26 | Bioarray chip reaction apparatus and its manufacture |
US11/378,954 US20060234267A1 (en) | 1994-06-08 | 2006-03-20 | Bioarray chip reaction apparatus and its manufacture |
US12/265,048 US20090143249A1 (en) | 1994-06-08 | 2008-11-05 | Bioarray chip reaction apparatus and its manufacture |
US12/842,977 US20100298165A1 (en) | 1994-06-08 | 2010-07-23 | Bioarray chip reaction apparatus and its manufacture |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/265,048 Continuation US20090143249A1 (en) | 1994-06-08 | 2008-11-05 | Bioarray chip reaction apparatus and its manufacture |
Publications (1)
Publication Number | Publication Date |
---|---|
US20100298165A1 true US20100298165A1 (en) | 2010-11-25 |
Family
ID=22969439
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/485,452 Expired - Lifetime US5945334A (en) | 1994-06-08 | 1995-06-07 | Apparatus for packaging a chip |
US08/528,173 Expired - Lifetime US6140044A (en) | 1994-06-08 | 1995-09-14 | Method and apparatus for packaging a probe array |
US12/265,048 Abandoned US20090143249A1 (en) | 1994-06-08 | 2008-11-05 | Bioarray chip reaction apparatus and its manufacture |
US12/842,977 Abandoned US20100298165A1 (en) | 1994-06-08 | 2010-07-23 | Bioarray chip reaction apparatus and its manufacture |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/485,452 Expired - Lifetime US5945334A (en) | 1994-06-08 | 1995-06-07 | Apparatus for packaging a chip |
US08/528,173 Expired - Lifetime US6140044A (en) | 1994-06-08 | 1995-09-14 | Method and apparatus for packaging a probe array |
US12/265,048 Abandoned US20090143249A1 (en) | 1994-06-08 | 2008-11-05 | Bioarray chip reaction apparatus and its manufacture |
Country Status (6)
Country | Link |
---|---|
US (4) | US5945334A (en) |
EP (3) | EP0695941B1 (en) |
JP (4) | JPH10505410A (en) |
AU (1) | AU2943695A (en) |
DE (2) | DE69527585T2 (en) |
WO (1) | WO1995033846A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8309045B2 (en) | 2011-02-11 | 2012-11-13 | General Electric Company | System and method for controlling emissions in a combustion system |
WO2017087662A1 (en) * | 2015-11-17 | 2017-05-26 | Pacific Biosciences Of California, Inc. | Packaging methods for fabrication of analytical device packages and analytical device packages made thereof |
Families Citing this family (400)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6905882B2 (en) | 1992-05-21 | 2005-06-14 | Biosite, Inc. | Diagnostic devices and apparatus for the controlled movement of reagents without membranes |
US6767510B1 (en) | 1992-05-21 | 2004-07-27 | Biosite, Inc. | Diagnostic devices and apparatus for the controlled movement of reagents without membranes |
US7524456B1 (en) | 1992-05-21 | 2009-04-28 | Biosite Incorporated | Diagnostic devices for the controlled movement of reagents without membranes |
US6156270A (en) | 1992-05-21 | 2000-12-05 | Biosite Diagnostics, Inc. | Diagnostic devices and apparatus for the controlled movement of reagents without membranes |
US20060229824A1 (en) | 1993-10-26 | 2006-10-12 | Affymetrix, Inc. | Arrays of nucleic acid probes for analyzing biotransformation genes |
US6090555A (en) * | 1997-12-11 | 2000-07-18 | Affymetrix, Inc. | Scanned image alignment systems and methods |
US6741344B1 (en) * | 1994-02-10 | 2004-05-25 | Affymetrix, Inc. | Method and apparatus for detection of fluorescently labeled materials |
US5631734A (en) | 1994-02-10 | 1997-05-20 | Affymetrix, Inc. | Method and apparatus for detection of fluorescently labeled materials |
DE69527585T2 (en) * | 1994-06-08 | 2003-04-03 | Affymetrix Inc | Method and device for packaging chips |
US6287850B1 (en) * | 1995-06-07 | 2001-09-11 | Affymetrix, Inc. | Bioarray chip reaction apparatus and its manufacture |
US5959098A (en) * | 1996-04-17 | 1999-09-28 | Affymetrix, Inc. | Substrate preparation process |
US6239273B1 (en) | 1995-02-27 | 2001-05-29 | Affymetrix, Inc. | Printing molecular library arrays |
US6720149B1 (en) * | 1995-06-07 | 2004-04-13 | Affymetrix, Inc. | Methods for concurrently processing multiple biological chip assays |
US6953663B1 (en) | 1995-11-29 | 2005-10-11 | Affymetrix, Inc. | Polymorphism detection |
US6300063B1 (en) | 1995-11-29 | 2001-10-09 | Affymetrix, Inc. | Polymorphism detection |
US6660233B1 (en) * | 1996-01-16 | 2003-12-09 | Beckman Coulter, Inc. | Analytical biochemistry system with robotically carried bioarray |
US6114122A (en) * | 1996-03-26 | 2000-09-05 | Affymetrix, Inc. | Fluidics station with a mounting system and method of using |
US5885470A (en) | 1997-04-14 | 1999-03-23 | Caliper Technologies Corporation | Controlled fluid transport in microfabricated polymeric substrates |
US5942443A (en) * | 1996-06-28 | 1999-08-24 | Caliper Technologies Corporation | High throughput screening assay systems in microscale fluidic devices |
US6706875B1 (en) * | 1996-04-17 | 2004-03-16 | Affyemtrix, Inc. | Substrate preparation process |
FR2748156B1 (en) * | 1996-04-26 | 1998-08-07 | Suisse Electronique Microtech | DEVICE COMPRISING TWO SUBSTRATES FOR FORMING A MICROSYSTEM OR A PART OF A MICROSYSTEM AND METHOD FOR ASSEMBLING TWO MICRO-FACTORY SUBSTRATES |
JP2000512744A (en) | 1996-05-16 | 2000-09-26 | アフィメトリックス,インコーポレイテッド | System and method for detecting label material |
EP0907412B1 (en) | 1996-06-28 | 2008-08-27 | Caliper Life Sciences, Inc. | High-throughput screening assay systems in microscale fluidic devices |
US6221654B1 (en) | 1996-09-25 | 2001-04-24 | California Institute Of Technology | Method and apparatus for analysis and sorting of polynucleotides based on size |
US6875620B1 (en) * | 1996-10-31 | 2005-04-05 | Agilent Technologies, Inc. | Tiling process for constructing a chemical array |
EP0946287B1 (en) * | 1996-11-18 | 2004-08-18 | Novartis AG | Device for polymers synthesis |
WO1998029736A1 (en) * | 1996-12-31 | 1998-07-09 | Genometrix Incorporated | Multiplexed molecular analysis apparatus and method |
US6425972B1 (en) * | 1997-06-18 | 2002-07-30 | Calipher Technologies Corp. | Methods of manufacturing microfabricated substrates |
DE19734706A1 (en) * | 1997-08-11 | 1999-02-18 | Fraunhofer Ges Forschung | Piezoelectric resonator, method for producing the resonator and its use as a sensor element for detecting the concentration of a substance contained in a fluid and / or the determination of physical properties of the fluid |
US6440725B1 (en) * | 1997-12-24 | 2002-08-27 | Cepheid | Integrated fluid manipulation cartridge |
US6540895B1 (en) | 1997-09-23 | 2003-04-01 | California Institute Of Technology | Microfabricated cell sorter for chemical and biological materials |
US20030039967A1 (en) * | 1997-12-19 | 2003-02-27 | Kris Richard M. | High throughput assay system using mass spectrometry |
US20030096232A1 (en) * | 1997-12-19 | 2003-05-22 | Kris Richard M. | High throughput assay system |
US20100105572A1 (en) * | 1997-12-19 | 2010-04-29 | Kris Richard M | High throughput assay system |
US6050719A (en) * | 1998-01-30 | 2000-04-18 | Affymetrix, Inc. | Rotational mixing method using a cartridge having a narrow interior |
WO1999040434A1 (en) | 1998-02-04 | 1999-08-12 | Invitrogen Corporation | Microarrays and uses therefor |
AU2586799A (en) | 1998-02-06 | 1999-08-23 | Affymetrix, Inc. | Method of quality control in manufacturing processes |
US6150147A (en) * | 1998-02-06 | 2000-11-21 | Affymetrix, Inc. | Biological array fabrication methods with reduction of static charge |
US7095032B2 (en) * | 1998-03-20 | 2006-08-22 | Montagu Jean I | Focusing of microscopes and reading of microarrays |
US6472671B1 (en) * | 2000-02-09 | 2002-10-29 | Jean I. Montagu | Quantified fluorescence microscopy |
AU3771599A (en) * | 1998-05-18 | 1999-12-06 | University Of Washington | Liquid analysis cartridge |
US6830729B1 (en) | 1998-05-18 | 2004-12-14 | University Of Washington | Sample analysis instrument |
US6761816B1 (en) * | 1998-06-23 | 2004-07-13 | Clinical Micro Systems, Inc. | Printed circuit boards with monolayers and capture ligands |
US6908770B1 (en) * | 1998-07-16 | 2005-06-21 | Board Of Regents, The University Of Texas System | Fluid based analysis of multiple analytes by a sensor array |
US6132685A (en) * | 1998-08-10 | 2000-10-17 | Caliper Technologies Corporation | High throughput microfluidic systems and methods |
US6759014B2 (en) * | 2001-01-26 | 2004-07-06 | Symyx Technologies, Inc. | Apparatus and methods for parallel processing of multiple reaction mixtures |
US6913934B2 (en) * | 1998-08-13 | 2005-07-05 | Symyx Technologies, Inc. | Apparatus and methods for parallel processing of multiple reaction mixtures |
US6186659B1 (en) * | 1998-08-21 | 2001-02-13 | Agilent Technologies Inc. | Apparatus and method for mixing a film of fluid |
JP4028964B2 (en) * | 1998-09-09 | 2008-01-09 | 日立ソフトウエアエンジニアリング株式会社 | Biochip and method of using biochip |
FR2784751B1 (en) * | 1998-10-20 | 2001-02-02 | Mesatronic | HOUSING HOUSING OF AN ELECTRONIC CHIP WITH BIOLOGICAL PROBES |
DE19853640C2 (en) * | 1998-11-20 | 2002-01-31 | Molecular Machines & Ind Gmbh | Multi-vessel arrangement with improved sensitivity for optical analysis, processes for its production and its use in optical analysis processes |
US6130745A (en) * | 1999-01-07 | 2000-10-10 | Biometric Imaging, Inc. | Optical autofocus for use with microtiter plates |
US7312087B2 (en) * | 2000-01-11 | 2007-12-25 | Clinical Micro Sensors, Inc. | Devices and methods for biochip multiplexing |
US20040053290A1 (en) * | 2000-01-11 | 2004-03-18 | Terbrueggen Robert Henry | Devices and methods for biochip multiplexing |
US20020177135A1 (en) * | 1999-07-27 | 2002-11-28 | Doung Hau H. | Devices and methods for biochip multiplexing |
US6518056B2 (en) * | 1999-04-27 | 2003-02-11 | Agilent Technologies Inc. | Apparatus, systems and method for assaying biological materials using an annular format |
US7276336B1 (en) | 1999-07-22 | 2007-10-02 | Agilent Technologies, Inc. | Methods of fabricating an addressable array of biopolymer probes |
US20040203047A1 (en) * | 1999-04-30 | 2004-10-14 | Caren Michael P. | Polynucleotide array fabrication |
US6225109B1 (en) * | 1999-05-27 | 2001-05-01 | Orchid Biosciences, Inc. | Genetic analysis device |
US6811668B1 (en) | 1999-06-22 | 2004-11-02 | Caliper Life Sciences, Inc. | Apparatus for the operation of a microfluidic device |
FR2795476B1 (en) * | 1999-06-22 | 2001-07-27 | Biomerieux Sa | VALVE FOR DIRECTING A FLUID IN AN ANALYSIS CARD |
EP1360992A3 (en) * | 1999-06-22 | 2004-05-19 | Caliper Life Sciences, Inc. | Apparatus for the operation of a microfluidic device |
US6258593B1 (en) | 1999-06-30 | 2001-07-10 | Agilent Technologies Inc. | Apparatus for conducting chemical or biochemical reactions on a solid surface within an enclosed chamber |
IL147227A0 (en) * | 1999-07-02 | 2002-08-14 | Clondiag Chip Tech Gmbh | Microchip matrix device for duplicating and characterizing nucleic acids |
JP3471664B2 (en) * | 1999-07-08 | 2003-12-02 | Nec液晶テクノロジー株式会社 | Cutting device for bonded substrates for liquid crystal cells |
FR2796571B1 (en) * | 1999-07-19 | 2001-09-14 | Bio Merieux | ANALYSIS DEVICE WITH A BIOPUCE |
US6653151B2 (en) | 1999-07-30 | 2003-11-25 | Large Scale Proteomics Corporation | Dry deposition of materials for microarrays using matrix displacement |
US6864050B2 (en) | 1999-07-30 | 2005-03-08 | Affymetrix, Inc. | Single-phase amplification of nucleic acids |
US6713309B1 (en) | 1999-07-30 | 2004-03-30 | Large Scale Proteomics Corporation | Microarrays and their manufacture |
US7179638B2 (en) | 1999-07-30 | 2007-02-20 | Large Scale Biology Corporation | Microarrays and their manufacture by slicing |
US6495104B1 (en) | 1999-08-19 | 2002-12-17 | Caliper Technologies Corp. | Indicator components for microfluidic systems |
US6867851B2 (en) * | 1999-11-04 | 2005-03-15 | Regents Of The University Of Minnesota | Scanning of biological samples |
US6784982B1 (en) * | 1999-11-04 | 2004-08-31 | Regents Of The University Of Minnesota | Direct mapping of DNA chips to detector arrays |
US6569674B1 (en) | 1999-12-15 | 2003-05-27 | Amersham Biosciences Ab | Method and apparatus for performing biological reactions on a substrate surface |
US6642046B1 (en) * | 1999-12-09 | 2003-11-04 | Motorola, Inc. | Method and apparatus for performing biological reactions on a substrate surface |
US6589778B1 (en) | 1999-12-15 | 2003-07-08 | Amersham Biosciences Ab | Method and apparatus for performing biological reactions on a substrate surface |
US6420114B1 (en) * | 1999-12-06 | 2002-07-16 | Incyte Genomics, Inc. | Microarray hybridization chamber |
CA2394275A1 (en) * | 1999-12-15 | 2001-06-21 | Motorola, Inc. | Apparatus for performing biological reactions |
US20030091477A1 (en) * | 1999-12-22 | 2003-05-15 | Paul Eric A. | Flow-thru chip cartridge, chip holder, system & method thereof |
FR2803225B1 (en) * | 1999-12-29 | 2002-06-14 | Biomerieux Sa | ANALYZING APPARATUS WITH VARIABLE GEOMETRY REACTIONAL COMPARTMENT, LIQUID MIXING AND GUIDING METHOD |
DE10002920A1 (en) * | 2000-01-19 | 2001-07-26 | Epigenomics Ag | Device for contacting biological material immobilized on surface with solution of second biological material, especially hybridization of DNA samples, comprises a cavity receiving solution with cover which has seal around its edges |
US6587579B1 (en) | 2000-01-26 | 2003-07-01 | Agilent Technologies Inc. | Feature quality in array fabrication |
US6458526B1 (en) | 2000-01-28 | 2002-10-01 | Agilent Technologies, Inc. | Method and apparatus to inhibit bubble formation in a fluid |
EP2230314A1 (en) * | 2000-01-31 | 2010-09-22 | The Board of Regents,The University of Texas System | Method of sensing an analyte |
FR2806009B1 (en) | 2000-03-07 | 2002-05-31 | Bio Merieux | METHOD FOR IMPLEMENTING AN ANALYSIS CARD |
AU2001259512B2 (en) | 2000-05-04 | 2007-03-01 | Yale University | High density protein arrays for screening of protein activity |
SG91870A1 (en) * | 2000-05-26 | 2002-10-15 | Casem Asia Pte Ltd | Method and device for bleed out control in solder bonding |
DE10026647A1 (en) * | 2000-05-29 | 2001-12-06 | Merck Patent Gmbh | Positioning device |
DE10027524A1 (en) * | 2000-06-02 | 2001-12-13 | Max Planck Gesellschaft | Device and method for processing substrate-bound samples |
JP4644914B2 (en) * | 2000-06-02 | 2011-03-09 | 株式会社村田製作所 | Solid phase substrate for probe array and probe array |
US7351376B1 (en) | 2000-06-05 | 2008-04-01 | California Institute Of Technology | Integrated active flux microfluidic devices and methods |
EP1161989B8 (en) * | 2000-06-08 | 2007-11-07 | F.Hoffmann-La Roche Ag | Device for packaging a chip shaped carrier and process for assembling a plurality of such carriers |
EP1161984A1 (en) * | 2000-06-08 | 2001-12-12 | F. Hoffmann-La Roche Ag | Device for packaging a chip shaped carrier and process for assembling a plurality of such carriers |
WO2002001194A1 (en) * | 2000-06-25 | 2002-01-03 | Affymetrix, Inc. | Optically active substrates |
EP1307283A2 (en) * | 2000-06-28 | 2003-05-07 | Illumina, Inc. | Composite arrays utilizing microspheres with a hybridization chamber |
CN1137999C (en) * | 2000-07-04 | 2004-02-11 | 清华大学 | Integrated microarray device |
US6511277B1 (en) * | 2000-07-10 | 2003-01-28 | Affymetrix, Inc. | Cartridge loader and methods |
US7518724B2 (en) * | 2000-07-11 | 2009-04-14 | Maven Technologies | Image acquisition, processing, and display |
US7126688B2 (en) * | 2000-07-11 | 2006-10-24 | Maven Technologies, Llc | Microarray scanning |
US7023547B2 (en) | 2000-07-11 | 2006-04-04 | Maven Technologies, Llc | Apparatus including a biochip for imaging of biological samples and method |
US6833920B2 (en) | 2000-07-11 | 2004-12-21 | Maven Technologies Llc | Apparatus and method for imaging |
US6594011B1 (en) | 2000-07-11 | 2003-07-15 | Maven Technologies, Llc | Imaging apparatus and method |
US7193711B2 (en) * | 2000-07-11 | 2007-03-20 | Maven Technologies, Llc | Imaging method and apparatus |
DE10037687A1 (en) * | 2000-08-01 | 2002-02-14 | Trace Biotech Ag | Processes for the production of oligonucleotide arrays and for carrying out hybridization assays, and systems for carrying out these processes |
US6422249B1 (en) | 2000-08-10 | 2002-07-23 | Affymetrix Inc. | Cartridge washing system and methods |
US20040185464A1 (en) * | 2000-09-15 | 2004-09-23 | Kris Richard M. | High throughput assay system |
GB0022978D0 (en) | 2000-09-19 | 2000-11-01 | Oxford Glycosciences Uk Ltd | Detection of peptides |
US20060141507A1 (en) * | 2000-09-27 | 2006-06-29 | Kronick Mel N | Manufacture and use of non-standard size microarray slides |
US6864097B1 (en) * | 2000-09-27 | 2005-03-08 | Agilent Technologies, Inc. | Arrays and their reading |
EP1203945B1 (en) * | 2000-10-26 | 2006-12-20 | Agilent Technologies, Inc. (a Delaware corporation) | Microarray |
JP3921047B2 (en) * | 2000-12-11 | 2007-05-30 | 日立ソフトウエアエンジニアリング株式会社 | Hybridization reaction apparatus and hybridization method |
US20020168652A1 (en) * | 2000-12-22 | 2002-11-14 | Werner Martina Elisabeth | Surface assembly for immobilizing DNA capture probes and bead-based assay including optical bio-discs and methods relating thereto |
DE60015590T2 (en) | 2000-12-28 | 2005-11-10 | Roche Diagnostics Gmbh | A method of treating nucleic acid samples by vibration of a portion of a cartridge wall, system and cartridge for performing the same |
ES2269093T3 (en) * | 2000-12-28 | 2007-04-01 | F. Hoffmann-La Roche Ag | METHOD, SYSTEM AND CARTRIDGE FOR THE PROCEDURE OF A SAMPLE OF NUCLEIC ACID THROUGH THE OSCILATION OF THE CARTRIDGE. |
DE20100345U1 (en) | 2001-01-09 | 2002-05-23 | Evotec Biosystems Ag | sample carrier |
US20030170148A1 (en) * | 2001-01-31 | 2003-09-11 | Mcentee John F. | Reaction chamber roll pump |
US6879915B2 (en) | 2001-01-31 | 2005-04-12 | Agilent Technologies, Inc. | Chemical array fabrication and use |
US7112305B2 (en) * | 2001-01-31 | 2006-09-26 | Agilent Technologies, Inc. | Automation-optimized microarray package |
US6746649B2 (en) * | 2001-01-31 | 2004-06-08 | Agilent Technologies, Inc. | Reaction chamber roll pump |
AU2002255515A1 (en) * | 2001-02-05 | 2002-08-19 | Board Of Regents, The University Of Texas System | The use of mesoscale self-assembly and recognition to effect delivery of sensing reagent for arrayed sensors |
KR100916074B1 (en) * | 2001-03-09 | 2009-09-08 | 바이오마이크로 시스템즈, 인크. | Method and system for microfluidic interfacing to arrays |
EP1384022A4 (en) | 2001-04-06 | 2004-08-04 | California Inst Of Techn | Nucleic acid amplification utilizing microfluidic devices |
US6943036B2 (en) * | 2001-04-30 | 2005-09-13 | Agilent Technologies, Inc. | Error detection in chemical array fabrication |
DE10122457A1 (en) * | 2001-05-09 | 2002-11-21 | Bosch Gmbh Robert | Container for an analysis chip |
US20050009101A1 (en) * | 2001-05-17 | 2005-01-13 | Motorola, Inc. | Microfluidic devices comprising biochannels |
DE50212817D1 (en) | 2001-05-25 | 2008-11-06 | Tecan Trading Ag | Device and process unit for providing a hybridization space |
US20030008310A1 (en) * | 2001-05-29 | 2003-01-09 | Williams Jeffrey S. | Method and apparatus for facilitating the creation and analysis of microarrays |
US7294478B1 (en) | 2001-06-06 | 2007-11-13 | Rosetta Inpharmatics Llc | Microarray reaction cartridge |
US6485918B1 (en) | 2001-07-02 | 2002-11-26 | Packard Bioscience Corporation | Method and apparatus for incubation of a liquid reagent and target spots on a microarray substrate |
US7297553B2 (en) | 2002-05-28 | 2007-11-20 | Nanosphere, Inc. | Method for attachment of silylated molecules to glass surfaces |
US7687437B2 (en) | 2001-07-13 | 2010-03-30 | Nanosphere, Inc. | Method for immobilizing molecules onto surfaces |
WO2003093168A2 (en) * | 2001-07-26 | 2003-11-13 | Motorola, Inc. | System and methods for mixing within a microfluidic device |
EP1281966A3 (en) * | 2001-07-30 | 2003-06-18 | Fuji Photo Film Co., Ltd. | Method and apparatus for conducting a receptor-ligand reaction |
EP1281439A1 (en) * | 2001-07-30 | 2003-02-05 | F. Hoffmann-La Roche Ag | Device for receiving a chip shaped carrier and process for assembling a plurality of such devices |
JP2003057236A (en) * | 2001-08-10 | 2003-02-26 | Inst Of Physical & Chemical Res | Method for manufacturing biomolecule microarray and spot apparatus |
EP1425090A2 (en) * | 2001-09-07 | 2004-06-09 | Corning Incorporated | MICROCOLUMN−PLATFORM BASED ARRAY FOR HIGH−THROUGHPUT ANALYSIS |
WO2003027221A1 (en) * | 2001-09-23 | 2003-04-03 | Irm Llc | Closed cell washer |
US6767733B1 (en) | 2001-10-10 | 2004-07-27 | Pritest, Inc. | Portable biosensor apparatus with controlled flow |
US20030113724A1 (en) * | 2001-10-12 | 2003-06-19 | Schembri Carol T. | Packaged microarray apparatus and a method of bonding a microarray into a package |
WO2003034064A2 (en) * | 2001-10-12 | 2003-04-24 | Duke University | Image analysis of high-density synthetic dna microarrays |
WO2003033128A2 (en) * | 2001-10-12 | 2003-04-24 | Duke University | Methods for image analysis of high-density synthetic dna microarrays |
US7691333B2 (en) | 2001-11-30 | 2010-04-06 | Fluidigm Corporation | Microfluidic device and methods of using same |
JP4355210B2 (en) | 2001-11-30 | 2009-10-28 | フルイディグム コーポレイション | Microfluidic device and method of using microfluidic device |
US20040038388A1 (en) * | 2001-12-19 | 2004-02-26 | Affymetrix, Inc. | Manufacturing process for array plate assembly |
US20040020993A1 (en) * | 2001-12-28 | 2004-02-05 | Green Larry R. | Method for luminescent identification and calibration |
US7335153B2 (en) | 2001-12-28 | 2008-02-26 | Bio Array Solutions Ltd. | Arrays of microparticles and methods of preparation thereof |
DE10201463B4 (en) | 2002-01-16 | 2005-07-21 | Clondiag Chip Technologies Gmbh | Reaction vessel for performing array method |
JP3818926B2 (en) * | 2002-02-04 | 2006-09-06 | 富士写真フイルム株式会社 | Receptor-ligand association reaction method |
ATE467115T1 (en) | 2002-03-15 | 2010-05-15 | Affymetrix Inc | SYSTEM AND METHOD FOR SCANNING BIOLOGICAL MATERIALS |
US6916621B2 (en) | 2002-03-27 | 2005-07-12 | Spectral Genomics, Inc. | Methods for array-based comparitive binding assays |
AU2003224817B2 (en) | 2002-04-01 | 2008-11-06 | Fluidigm Corporation | Microfluidic particle-analysis systems |
AU2003228711C1 (en) * | 2002-04-26 | 2010-01-07 | Board Of Regents, The University Of Texas System | Method and system for the detection of cardiac risk factors |
US20040060987A1 (en) * | 2002-05-07 | 2004-04-01 | Green Larry R. | Digital image analysis method for enhanced and optimized signals in fluorophore detection |
US20030208936A1 (en) * | 2002-05-09 | 2003-11-13 | Lee Charles Hee | Method for manufacturing embroidery decorated cards and envelopes |
AU2003237283A1 (en) * | 2002-05-28 | 2003-12-12 | Autogenomics, Inc. | Integrated sample processing platform |
US6939673B2 (en) * | 2002-06-14 | 2005-09-06 | Agilent Technologies, Inc. | Manufacture of arrays with reduced error impact |
US20030232427A1 (en) * | 2002-06-18 | 2003-12-18 | Montagu Jean I. | Optically active substrates for examination of biological materials |
US7223592B2 (en) * | 2002-06-21 | 2007-05-29 | Agilent Technologies, Inc. | Devices and methods for performing array based assays |
US20030235518A1 (en) * | 2002-06-21 | 2003-12-25 | Shea Laurence R. | Array assay devices and methods of using the same |
US7220573B2 (en) * | 2002-06-21 | 2007-05-22 | Agilent Technologies, Inc. | Array assay devices and methods of using the same |
US7080766B2 (en) * | 2002-07-01 | 2006-07-25 | Agilent Technologies, Inc. | Manufacture of singulated supports comprising arrays |
US7154598B2 (en) * | 2002-07-12 | 2006-12-26 | Decision Biomarkers, Inc. | Excitation and imaging of fluorescent arrays |
US20040101444A1 (en) * | 2002-07-15 | 2004-05-27 | Xeotron Corporation | Apparatus and method for fluid delivery to a hybridization station |
EP1385006A3 (en) * | 2002-07-24 | 2004-09-01 | F. Hoffmann-La Roche Ag | System and cartridge for processing a biological sample |
US7452712B2 (en) | 2002-07-30 | 2008-11-18 | Applied Biosystems Inc. | Sample block apparatus and method of maintaining a microcard on a sample block |
US7745203B2 (en) | 2002-07-31 | 2010-06-29 | Kabushiki Kaisha Toshiba | Base sequence detection apparatus and base sequence automatic analyzing apparatus |
JP4057967B2 (en) * | 2002-07-31 | 2008-03-05 | 株式会社東芝 | Automatic nucleotide sequence analyzer |
US7384742B2 (en) * | 2002-08-16 | 2008-06-10 | Decision Biomarkers, Inc. | Substrates for isolating reacting and microscopically analyzing materials |
US20060127946A1 (en) * | 2002-08-16 | 2006-06-15 | Montagu Jean I | Reading of fluorescent arrays |
US20040043494A1 (en) * | 2002-08-30 | 2004-03-04 | Amorese Douglas A. | Apparatus for studying arrays |
US20060147924A1 (en) * | 2002-09-11 | 2006-07-06 | Ramsing Neils B | Population of nucleic acids including a subpopulation of lna oligomers |
EP2298448A3 (en) | 2002-09-25 | 2012-05-30 | California Institute of Technology | Microfluidic large scale integration |
WO2004040001A2 (en) | 2002-10-02 | 2004-05-13 | California Institute Of Technology | Microfluidic nucleic acid analysis |
US6913931B2 (en) * | 2002-10-03 | 2005-07-05 | 3M Innovative Properties Company | Devices, methods and systems for low volume microarray processing |
US20040120861A1 (en) * | 2002-10-11 | 2004-06-24 | Affymetrix, Inc. | System and method for high-throughput processing of biological probe arrays |
US20040219565A1 (en) * | 2002-10-21 | 2004-11-04 | Sakari Kauppinen | Oligonucleotides useful for detecting and analyzing nucleic acids of interest |
JP3883951B2 (en) * | 2002-10-24 | 2007-02-21 | 富士フイルムホールディングス株式会社 | Assay method and biochemical analyzer using biochemical analysis unit |
EP1419821A1 (en) * | 2002-11-14 | 2004-05-19 | F. Hoffmann-La Roche Ag | Method, system and reaction vessel for processing a biological sample contained in a liquid |
EP1419820A1 (en) * | 2002-11-14 | 2004-05-19 | F. Hoffmann-La Roche Ag | Method, system and reaction vessel for processing a biological sample contained in a liquid |
US20040101861A1 (en) * | 2002-11-27 | 2004-05-27 | Little Roger G. | Resonant cavity photodiode array for rapid DNA microarray readout |
JP3969651B2 (en) * | 2002-11-28 | 2007-09-05 | 住友ベークライト株式会社 | Plastic substrate for microarray |
US20040259111A1 (en) * | 2002-12-10 | 2004-12-23 | Rosetta Inpharmatics Llc | Automated system and method for preparing an assay ready biological sample |
US20040126766A1 (en) * | 2002-12-26 | 2004-07-01 | Amorese Douglas A. | Breakaway seal for processing a subarray of an array |
US7041481B2 (en) | 2003-03-14 | 2006-05-09 | The Regents Of The University Of California | Chemical amplification based on fluid partitioning |
US7476363B2 (en) | 2003-04-03 | 2009-01-13 | Fluidigm Corporation | Microfluidic devices and methods of using same |
US7604965B2 (en) | 2003-04-03 | 2009-10-20 | Fluidigm Corporation | Thermal reaction device and method for using the same |
US8828663B2 (en) | 2005-03-18 | 2014-09-09 | Fluidigm Corporation | Thermal reaction device and method for using the same |
US20050145496A1 (en) | 2003-04-03 | 2005-07-07 | Federico Goodsaid | Thermal reaction device and method for using the same |
DE10316723A1 (en) * | 2003-04-09 | 2004-11-18 | Siemens Ag | Test slide with sample wells, forming sealed reaction chamber with casing, also includes bonded seal forming resting surface for casing |
US8652774B2 (en) * | 2003-04-16 | 2014-02-18 | Affymetrix, Inc. | Automated method of manufacturing polyer arrays |
DE10318219A1 (en) * | 2003-04-22 | 2004-11-11 | Febit Ag | Plastics housing, to handle and protect a biochip for synthesis and analysis applications, has a recess in the base body to accommodate the biochip with a frame to define its position |
US20050064452A1 (en) * | 2003-04-25 | 2005-03-24 | Schmid Matthew J. | System and method for the detection of analytes |
DE10319712A1 (en) * | 2003-05-02 | 2004-11-25 | Sirs-Lab Gmbh | Apparatus for duplicating reactions of samples, of biological molecules in microbiology, has a reaction vessel clamped over the sample holding zone wholly covered by the lower vessel openings |
US9317922B2 (en) | 2003-05-16 | 2016-04-19 | Board Of Regents The University Of Texas System | Image and part recognition technology |
WO2004104922A2 (en) * | 2003-05-16 | 2004-12-02 | Board Of Regents, The University Of Texas System | Image and part recognition technology |
US20040235147A1 (en) * | 2003-05-21 | 2004-11-25 | Affymetrix, Inc. | System, method, and encased probe array product |
DE10323197B4 (en) * | 2003-05-22 | 2008-10-02 | Clondiag Chip Technologies Gmbh | Device for holding and detecting substance libraries |
US20040241659A1 (en) * | 2003-05-30 | 2004-12-02 | Applera Corporation | Apparatus and method for hybridization and SPR detection |
AU2004245119A1 (en) * | 2003-06-05 | 2004-12-16 | Bioprocessors Corp. | Apparatus and method for manipulating substrates |
AU2004245123A1 (en) * | 2003-06-05 | 2004-12-16 | Bioprocessors Corp. | System and method for process automation |
US20040248323A1 (en) | 2003-06-09 | 2004-12-09 | Protometrix, Inc. | Methods for conducting assays for enzyme activity on protein microarrays |
EP1654066B1 (en) | 2003-07-31 | 2014-11-12 | Handylab, Inc. | Processing particle-containing samples |
DE10336375A1 (en) * | 2003-08-06 | 2004-12-02 | Infineon Technologies Ag | Fixing biochips in small sample tubes, attaches wafer to sheet, parts biochips from each other and removes them individually for adhesive transfer process |
US7317415B2 (en) | 2003-08-08 | 2008-01-08 | Affymetrix, Inc. | System, method, and product for scanning of biological materials employing dual analog integrators |
DE10336849A1 (en) | 2003-08-11 | 2005-03-10 | Thinxxs Gmbh | flow cell |
US9492820B2 (en) | 2003-09-19 | 2016-11-15 | Applied Biosystems, Llc | High density plate filler |
US7998435B2 (en) | 2003-09-19 | 2011-08-16 | Life Technologies Corporation | High density plate filler |
US7695688B2 (en) * | 2003-09-19 | 2010-04-13 | Applied Biosystems, Llc | High density plate filler |
US7407630B2 (en) | 2003-09-19 | 2008-08-05 | Applera Corporation | High density plate filler |
US8277760B2 (en) | 2003-09-19 | 2012-10-02 | Applied Biosystems, Llc | High density plate filler |
US20070212689A1 (en) * | 2003-10-30 | 2007-09-13 | Bianchi Diana W | Prenatal Diagnosis Using Cell-Free Fetal DNA in Amniotic Fluid |
US20070128607A1 (en) * | 2003-11-04 | 2007-06-07 | Martin Dugas | Method for distinguishing aml subtypes with different gene dosages |
EP1682901A2 (en) * | 2003-11-04 | 2006-07-26 | Roche Diagnostics GmbH | Method for distinguishing leukemia subtypes |
EP1533618A1 (en) * | 2003-11-04 | 2005-05-25 | Ludwig-Maximilians-Universität München | Method for distinguishing prognostically definable AML |
US20070207459A1 (en) * | 2003-11-04 | 2007-09-06 | Martin Dugas | Method For Distinguishing Immunologically Defined All Subtype |
EP1530046A1 (en) * | 2003-11-04 | 2005-05-11 | Ludwig-Maximilians-Universität München | Method for distinguishing AML subtypes with aberrant and prognostically intermediate karyotypes |
US20070292970A1 (en) * | 2003-11-04 | 2007-12-20 | Martin Dugas | Method for Distinguishing Aml-Specific Flt3 Length Mutations From Tkd Mutations |
US20070212688A1 (en) * | 2003-11-04 | 2007-09-13 | Martin Dugas | Method For Distinguishing Cbf-Positive Aml Subtypes From Cbf-Negative Aml Subtypes |
US20070212687A1 (en) * | 2003-11-04 | 2007-09-13 | Martin Dugas | Method For Distinguishing Mll-Ptd-Positive Aml From Other Aml Subtypes |
US20070105118A1 (en) * | 2003-11-04 | 2007-05-10 | Martin Dugas | Method for distinguishing aml subtypes with recurring genetic aberrations |
WO2005045435A2 (en) * | 2003-11-04 | 2005-05-19 | Roche Diagnostics Gmbh | METHOD FOR DISTINGUISHING T(11q23)/MLL-POSITIVE LEUKEMIAS FROM T(11q23)MLL NEGATIVE LEUKEMIAS |
DE10352716A1 (en) * | 2003-11-05 | 2005-06-16 | Einsle, Xaver | platform |
KR100695123B1 (en) | 2003-12-03 | 2007-03-14 | 삼성전자주식회사 | Polynucleotide microarray comprising 2 or more groups of probe polynucleotide immobilized on a substrate in accordance with Tm and method for detecting a target polynucleotide |
CA2549190A1 (en) * | 2003-12-11 | 2005-06-30 | Board Of Regents, The University Of Texas System | Method and system for the analysis of saliva using a sensor array |
KR100601936B1 (en) * | 2003-12-17 | 2006-07-14 | 삼성전자주식회사 | A patch for microarray reaction chamber having adhesive means support and two or more adhesion materials |
WO2005067649A2 (en) * | 2004-01-08 | 2005-07-28 | The Ohio State University | Use of databases to create gene expression microarrays |
US20050180894A1 (en) * | 2004-02-13 | 2005-08-18 | Affymetrix, Inc. | System, method, and product for efficient fluid transfer using and addressable adaptor |
US8101431B2 (en) | 2004-02-27 | 2012-01-24 | Board Of Regents, The University Of Texas System | Integration of fluids and reagents into self-contained cartridges containing sensor elements and reagent delivery systems |
US8105849B2 (en) | 2004-02-27 | 2012-01-31 | Board Of Regents, The University Of Texas System | Integration of fluids and reagents into self-contained cartridges containing sensor elements |
US8852862B2 (en) | 2004-05-03 | 2014-10-07 | Handylab, Inc. | Method for processing polynucleotide-containing samples |
JP5149622B2 (en) * | 2004-05-20 | 2013-02-20 | クエスト ダイアグノスティックス インヴェストメンツ インコーポレイテッド | Single label comparative hybridization |
EP1612561A1 (en) * | 2004-07-02 | 2006-01-04 | Roche Diagnostics GmbH | Instrument for efficient treatment of analytical devices |
DE202004011272U1 (en) * | 2004-07-17 | 2004-09-09 | Tecan Trading Ag | Device for providing a hybridization chamber and for influencing air bubbles therein |
KR100668304B1 (en) * | 2004-09-16 | 2007-01-12 | 삼성전자주식회사 | A device for the injection of PCR solution into a PCR channel and a PCR chip unit comprising the device |
CA2582137A1 (en) * | 2004-10-05 | 2007-02-15 | Wyeth | Probe arrays for detecting multiple strains of different species |
KR100601966B1 (en) * | 2004-10-07 | 2006-07-18 | 삼성전자주식회사 | A microchip unit and a method for conducting a biochemical reaction by using the microchip unit |
US7682782B2 (en) | 2004-10-29 | 2010-03-23 | Affymetrix, Inc. | System, method, and product for multiple wavelength detection using single source excitation |
JP2006126204A (en) * | 2004-10-29 | 2006-05-18 | Affymetrix Inc | Automated method for manufacturing polymer array |
WO2006048262A2 (en) * | 2004-11-04 | 2006-05-11 | Roche Diagnostics Gmbh | Classification of acute myeloid leukemia |
DE102004056735A1 (en) | 2004-11-09 | 2006-07-20 | Clondiag Chip Technologies Gmbh | Device for performing and analyzing microarray experiments |
JP4761241B2 (en) * | 2004-11-18 | 2011-08-31 | 独立行政法人理化学研究所 | Biomolecule interaction test apparatus, biomolecule interaction test method, biomolecule melting temperature measurement method, nucleic acid sequence detection method |
JP4610309B2 (en) * | 2004-11-19 | 2011-01-12 | 独立行政法人理化学研究所 | Method for interacting biomolecules and method for moving biomolecules |
WO2006054449A1 (en) * | 2004-11-18 | 2006-05-26 | Riken | Biomolecule interaction test instrument, biomolecule interaction test method, biomolecule dissolution temperature measuring method, nucleic acid sequence detecting method biomolecule interacting method, and biomolecule mobilizing method |
EP1842045A4 (en) * | 2005-01-18 | 2009-04-15 | Solus Biosystems Inc | Multiple sample screening using ir spectroscopy |
DE602006018861D1 (en) * | 2005-01-27 | 2011-01-27 | Quest Diagnostics Invest Inc | FAST COMPARATIVE GENOM HYBRIDIZATION |
US7910356B2 (en) | 2005-02-01 | 2011-03-22 | Purdue Research Foundation | Multiplexed biological analyzer planar array apparatus and methods |
US20070023643A1 (en) | 2005-02-01 | 2007-02-01 | Nolte David D | Differentially encoded biological analyzer planar array apparatus and methods |
US7663092B2 (en) | 2005-02-01 | 2010-02-16 | Purdue Research Foundation | Method and apparatus for phase contrast quadrature interferometric detection of an immunoassay |
KR100624464B1 (en) * | 2005-03-29 | 2006-09-19 | 삼성전자주식회사 | Semiautomatic operating device for microchip unit |
US20060246576A1 (en) * | 2005-04-06 | 2006-11-02 | Affymetrix, Inc. | Fluidic system and method for processing biological microarrays in personal instrumentation |
WO2007053186A2 (en) | 2005-05-31 | 2007-05-10 | Labnow, Inc. | Methods and compositions related to determination and use of white blood cell counts |
WO2006132666A1 (en) * | 2005-06-06 | 2006-12-14 | Decision Biomarkers, Inc. | Assays based on liquid flow over arrays |
WO2006132324A1 (en) * | 2005-06-10 | 2006-12-14 | Olympus Corporation | Reaction container and reaction apparatus employing the same |
US20060292576A1 (en) * | 2005-06-23 | 2006-12-28 | Quest Diagnostics Investments Incorporated | Non-in situ hybridization method for detecting chromosomal abnormalities |
US8288151B2 (en) * | 2005-06-29 | 2012-10-16 | Canon Kabushiki Kaisha | Biochemical reaction cassette |
WO2007050811A2 (en) | 2005-10-27 | 2007-05-03 | The President And Fellows Of Harvard College | Methods and compositions for labeling nucleic acids |
US8075852B2 (en) | 2005-11-02 | 2011-12-13 | Affymetrix, Inc. | System and method for bubble removal |
US20070122848A1 (en) | 2005-11-29 | 2007-05-31 | Canon Kabushiki Kaisha | Biochemical reaction cassette and detection apparatus for biochemical reaction cassette |
US8076074B2 (en) | 2005-11-29 | 2011-12-13 | Quest Diagnostics Investments Incorporated | Balanced translocation in comparative hybridization |
HU227586B1 (en) * | 2005-12-23 | 2011-08-29 | Thales Rt | Method for forming sealed channel of microfluidical reactor and microfluidical reactor containing the same |
US20090305238A1 (en) * | 2006-01-23 | 2009-12-10 | Applera Corporation | Microarray Microcard |
US8055098B2 (en) | 2006-01-27 | 2011-11-08 | Affymetrix, Inc. | System, method, and product for imaging probe arrays with small feature sizes |
US9445025B2 (en) | 2006-01-27 | 2016-09-13 | Affymetrix, Inc. | System, method, and product for imaging probe arrays with small feature sizes |
US7998708B2 (en) | 2006-03-24 | 2011-08-16 | Handylab, Inc. | Microfluidic system for amplifying and detecting polynucleotides in parallel |
US8883490B2 (en) | 2006-03-24 | 2014-11-11 | Handylab, Inc. | Fluorescence detector for microfluidic diagnostic system |
DK2001990T3 (en) | 2006-03-24 | 2016-10-03 | Handylab Inc | Integrated microfluidic sample processing system and method for its use |
US10900066B2 (en) | 2006-03-24 | 2021-01-26 | Handylab, Inc. | Microfluidic system for amplifying and detecting polynucleotides in parallel |
US11806718B2 (en) | 2006-03-24 | 2023-11-07 | Handylab, Inc. | Fluorescence detector for microfluidic diagnostic system |
JP4645739B2 (en) * | 2006-04-03 | 2011-03-09 | 株式会社島津製作所 | Optical measuring device for trace liquid samples |
US7702468B2 (en) | 2006-05-03 | 2010-04-20 | Population Diagnostics, Inc. | Evaluating genetic disorders |
US10522240B2 (en) | 2006-05-03 | 2019-12-31 | Population Bio, Inc. | Evaluating genetic disorders |
AU2007260676A1 (en) | 2006-06-14 | 2007-12-21 | Artemis Health, Inc. | Rare cell analysis using sample splitting and DNA tags |
EP3406736B1 (en) | 2006-06-14 | 2022-09-07 | Verinata Health, Inc. | Methods for the diagnosis of fetal abnormalities |
EP2589668A1 (en) | 2006-06-14 | 2013-05-08 | Verinata Health, Inc | Rare cell analysis using sample splitting and DNA tags |
EP2043785A2 (en) * | 2006-06-29 | 2009-04-08 | GE Healthcare Bio-Sciences AB | Chamber apparatus |
US20080026373A1 (en) * | 2006-07-26 | 2008-01-31 | Rodionova Natalia A | Assays Based On Light Emission From Analyte Complexes Within A Cassette |
EP1900824A1 (en) * | 2006-09-14 | 2008-03-19 | Deutsches Krebsforschungszentrum Stiftung Des Öffentlichen Rechts | Gene expression signature for the prognosis, diagnosis and therapy of prostate cancer and uses thereof |
US7522282B2 (en) | 2006-11-30 | 2009-04-21 | Purdue Research Foundation | Molecular interferometric imaging process and apparatus |
US7807359B2 (en) * | 2006-12-01 | 2010-10-05 | Quest Diagnostics Investments Incorporated | Methods of detecting TPMT mutations |
KR100834745B1 (en) * | 2006-12-20 | 2008-06-09 | 삼성전자주식회사 | Oligomer probe array chip based on analysis-friendly layout, mask being used in fabrication thereof, and hybridization analysis method thereof |
US8930178B2 (en) | 2007-01-04 | 2015-01-06 | Children's Hospital Medical Center | Processing text with domain-specific spreading activation methods |
WO2008089495A2 (en) | 2007-01-19 | 2008-07-24 | Purdue Research Foundation | System with extended range of molecular sensing through integrated multi-modal data acquisition |
AU2008212117B2 (en) | 2007-02-07 | 2014-09-11 | Decode Genetics Ehf. | Genetic variants contributing to risk of prostate cancer |
US7867783B2 (en) | 2007-02-22 | 2011-01-11 | Maven Technologies, Llc | Apparatus and method for performing ligand binding assays on microarrays in multiwell plates |
CA2681722A1 (en) * | 2007-03-26 | 2008-10-02 | Purdue Research Foundation | Method and apparatus for conjugate quadrature interferometric detection of an immunoassay |
JP2008249439A (en) * | 2007-03-30 | 2008-10-16 | Sumitomo Bakelite Co Ltd | Substrate for microarray and usage method therefor |
US7863037B1 (en) | 2007-04-04 | 2011-01-04 | Maven Technologies, Llc | Ligand binding assays on microarrays in closed multiwell plates |
EP2481805A3 (en) | 2007-04-30 | 2012-10-24 | The Ohio State University Research Foundation | Methods for differentiating pancreatic cancer from normal pancreatic function and/or chronic pancreatitis |
US20090041633A1 (en) * | 2007-05-14 | 2009-02-12 | Dultz Shane C | Apparatus and method for performing ligand binding assays on microarrays in multiwell plates |
US7799558B1 (en) | 2007-05-22 | 2010-09-21 | Dultz Shane C | Ligand binding assays on microarrays in closed multiwell plates |
CN101772578A (en) | 2007-05-25 | 2010-07-07 | 解码遗传学私营有限责任公司 | Genetic variants on CHR 5pl2 and 10q26 as markers for use in breast cancer risk assessment, diagnosis, prognosis and treatment |
US9186677B2 (en) | 2007-07-13 | 2015-11-17 | Handylab, Inc. | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
WO2009012185A1 (en) | 2007-07-13 | 2009-01-22 | Handylab, Inc. | Polynucleotide capture materials, and methods of using same |
US8105783B2 (en) | 2007-07-13 | 2012-01-31 | Handylab, Inc. | Microfluidic cartridge |
US8287820B2 (en) | 2007-07-13 | 2012-10-16 | Handylab, Inc. | Automated pipetting apparatus having a combined liquid pump and pipette head system |
US8182763B2 (en) | 2007-07-13 | 2012-05-22 | Handylab, Inc. | Rack for sample tubes and reagent holders |
US7507539B2 (en) * | 2007-07-30 | 2009-03-24 | Quest Diagnostics Investments Incorporated | Substractive single label comparative hybridization |
KR101414232B1 (en) * | 2007-08-02 | 2014-08-06 | 삼성전자 주식회사 | Biochip package and biochip packaging substrate |
HK1129808A2 (en) * | 2007-10-03 | 2009-12-04 | Diagcor Bioscience Inc Ltd | Reversed flow through platform for rapid analysis of target analytes with increased sensitivity and specificity and the device thereof |
WO2009047809A2 (en) * | 2007-10-12 | 2009-04-16 | Decode Genetics Ehf | Sequence variants for inferring human pigmentation patterns |
EP2056114A1 (en) * | 2007-10-29 | 2009-05-06 | Koninklijke Philips Electronics N.V. | Automatic detection of infectious diseases |
US8093063B2 (en) * | 2007-11-29 | 2012-01-10 | Quest Diagnostics Investments Incorporated | Assay for detecting genetic abnormalities in genomic nucleic acids |
US8697360B2 (en) | 2007-11-30 | 2014-04-15 | Decode Genetics Ehf. | Genetic variants on CHR 11Q and 6Q as markers for prostate and colorectal cancer predisposition |
US8304255B1 (en) | 2008-02-11 | 2012-11-06 | Access Medical Systems, Ltd. | Immunoassay cuvettes |
EP2247755B1 (en) * | 2008-02-14 | 2015-01-28 | Decode Genetics EHF | Susceptibility variants for lung cancer |
EP2107125A1 (en) | 2008-03-31 | 2009-10-07 | Eppendorf Array Technologies SA (EAT) | Real-time PCR of targets on a micro-array |
EP2274450A2 (en) | 2008-04-01 | 2011-01-19 | Decode Genetics EHF | Susceptibility variants for peripheral arterial disease and abdominal aortic aneurysm |
JP5040777B2 (en) * | 2008-04-03 | 2012-10-03 | 住友ベークライト株式会社 | Plastic substrate for microarray |
US20110118125A1 (en) * | 2008-05-03 | 2011-05-19 | Tufts Medical Center, Inc. | Neonatal salivary genomics |
US8039817B2 (en) | 2008-05-05 | 2011-10-18 | Illumina, Inc. | Compensator for multiple surface imaging |
US7981664B1 (en) | 2008-05-22 | 2011-07-19 | Maven Technologies, Llc | Apparatus and method for performing ligand binding assays on microarrays in multiwell plates |
US8039270B2 (en) * | 2008-05-22 | 2011-10-18 | Maven Technologies, Llc | Apparatus and method for performing ligand binding assays on microarrays in multiwell plates |
CN102137938B (en) * | 2008-07-04 | 2015-01-21 | 解码遗传学私营有限责任公司 | Copy number variations predictive of risk of schizophrenia |
WO2010004591A2 (en) | 2008-07-07 | 2010-01-14 | Decode Genetics Ehf | Genetic variants for breast cancer risk assessment |
JP4687756B2 (en) | 2008-07-07 | 2011-05-25 | 株式会社村田製作所 | Probe array and manufacturing method thereof |
EP2153892A1 (en) * | 2008-07-23 | 2010-02-17 | ETH Zurich | Microreactor system and method for operating such microreactor system |
CA2733910A1 (en) * | 2008-08-12 | 2010-02-18 | Decode Genetics Ehf. | Genetic variants useful for risk assessment of thyroid cancer |
WO2010018601A2 (en) * | 2008-08-15 | 2010-02-18 | Decode Genetics Ehf | Genetic variants predictive of cancer risk |
KR101523727B1 (en) * | 2008-09-16 | 2015-05-29 | 삼성전자주식회사 | Bio Chip Package Body, Method Of Forming The Bio Chip Package Body And Bio Chip Package Comprising The Bio Chip Package Body |
US11130128B2 (en) | 2008-09-23 | 2021-09-28 | Bio-Rad Laboratories, Inc. | Detection method for a target nucleic acid |
US8709762B2 (en) | 2010-03-02 | 2014-04-29 | Bio-Rad Laboratories, Inc. | System for hot-start amplification via a multiple emulsion |
US9132394B2 (en) | 2008-09-23 | 2015-09-15 | Bio-Rad Laboratories, Inc. | System for detection of spaced droplets |
US9156010B2 (en) | 2008-09-23 | 2015-10-13 | Bio-Rad Laboratories, Inc. | Droplet-based assay system |
US8633015B2 (en) | 2008-09-23 | 2014-01-21 | Bio-Rad Laboratories, Inc. | Flow-based thermocycling system with thermoelectric cooler |
US8951939B2 (en) | 2011-07-12 | 2015-02-10 | Bio-Rad Laboratories, Inc. | Digital assays with multiplexed detection of two or more targets in the same optical channel |
US10512910B2 (en) | 2008-09-23 | 2019-12-24 | Bio-Rad Laboratories, Inc. | Droplet-based analysis method |
US9492797B2 (en) | 2008-09-23 | 2016-11-15 | Bio-Rad Laboratories, Inc. | System for detection of spaced droplets |
US9764322B2 (en) | 2008-09-23 | 2017-09-19 | Bio-Rad Laboratories, Inc. | System for generating droplets with pressure monitoring |
US9417190B2 (en) | 2008-09-23 | 2016-08-16 | Bio-Rad Laboratories, Inc. | Calibrations and controls for droplet-based assays |
WO2011120024A1 (en) | 2010-03-25 | 2011-09-29 | Quantalife, Inc. | Droplet generation for droplet-based assays |
CH699853A1 (en) * | 2008-11-13 | 2010-05-14 | Tecan Trading Ag | Meter and method for determining provided by a laboratory fluid system parameters. |
US8039794B2 (en) * | 2008-12-16 | 2011-10-18 | Quest Diagnostics Investments Incorporated | Mass spectrometry assay for thiopurine-S-methyl transferase activity and products generated thereby |
US8374818B2 (en) * | 2008-12-19 | 2013-02-12 | Affymetrix, Inc. | System, method and apparatus for calibrating inspection tools |
CN102449165B (en) | 2009-04-03 | 2014-07-09 | 解码遗传学私营有限责任公司 | Genetic markers for risk management of atrial fibrillation and stroke |
CN102341162B (en) | 2009-04-14 | 2015-04-01 | 比奥卡尔齐什股份有限公司 | Hifu induced cavitation with reduced power threshold |
CA2752823C (en) | 2009-04-15 | 2016-08-30 | Biocartis Sa | Protection of bioanalytical sample chambers |
ES2822105T3 (en) | 2009-04-15 | 2021-04-29 | Biocartis Nv | Optical detection system to monitor the rtPCR reaction |
WO2010127464A1 (en) | 2009-05-06 | 2010-11-11 | Biocartis Sa | Device for cutting a sample carrier |
AU2010245598A1 (en) * | 2009-05-08 | 2011-11-17 | Decode Genetics Ehf | Genetic variants contributing to risk of prostate cancer |
US9767342B2 (en) | 2009-05-22 | 2017-09-19 | Affymetrix, Inc. | Methods and devices for reading microarrays |
CA2764678C (en) | 2009-06-04 | 2017-12-12 | Lockheed Martin Corporation | Multiple-sample microfluidic chip for dna analysis |
US8796182B2 (en) | 2009-07-10 | 2014-08-05 | Decode Genetics Ehf. | Genetic markers associated with risk of diabetes mellitus |
US8445201B2 (en) * | 2009-07-31 | 2013-05-21 | Affymetrix, Inc. | Hybridization device, methods, and system using mixing beads |
JP6155418B2 (en) | 2009-09-02 | 2017-07-05 | バイオ−ラッド・ラボラトリーズ・インコーポレーテッド | System for mixing fluids by combining multiple emulsions |
CA2774116A1 (en) * | 2009-09-25 | 2011-03-31 | Signature Genomics Laboratories Llc | Multiplex (+/-) stranded arrays and assays for detecting chromosomal abnormalities associated with cancer and other diseases |
US8501122B2 (en) | 2009-12-08 | 2013-08-06 | Affymetrix, Inc. | Manufacturing and processing polymer arrays |
US8355133B2 (en) | 2009-12-30 | 2013-01-15 | Maven Technologies, Llc | Biological testing with sawtooth-shaped prisms |
US8399198B2 (en) | 2010-03-02 | 2013-03-19 | Bio-Rad Laboratories, Inc. | Assays with droplets transformed into capsules |
KR20110106684A (en) * | 2010-03-23 | 2011-09-29 | 삼성전자주식회사 | Microarray package device and method for manufacturing the same |
CA2767113A1 (en) | 2010-03-25 | 2011-09-29 | Bio-Rad Laboratories, Inc. | Detection system for droplet-based assays |
EP2556170A4 (en) | 2010-03-25 | 2014-01-01 | Quantalife Inc | Droplet transport system for detection |
CN102200536B (en) * | 2010-03-25 | 2015-05-27 | 艾博生物医药(杭州)有限公司 | Device for detecting analyzed objects in test liquid samples |
EP2601609B1 (en) | 2010-08-02 | 2017-05-17 | Population Bio, Inc. | Compositions and methods for discovery of causative mutations in genetic disorders |
KR200476469Y1 (en) * | 2010-08-24 | 2015-03-06 | 주식회사 파나진 | Device for attaching biochip on hybridization chamber |
CA2814720C (en) | 2010-10-15 | 2016-12-13 | Lockheed Martin Corporation | Micro fluidic optic design |
EP3574990B1 (en) | 2010-11-01 | 2022-04-06 | Bio-Rad Laboratories, Inc. | System for forming emulsions |
EP2663656B1 (en) | 2011-01-13 | 2016-08-24 | Decode Genetics EHF | Genetic variants as markers for use in urinary bladder cancer risk assessment |
AU2012231098B2 (en) | 2011-03-18 | 2016-09-29 | Bio-Rad Laboratories, Inc. | Multiplexed digital assays with combinatorial use of signals |
CA2833262C (en) | 2011-04-15 | 2020-08-18 | Becton, Dickinson And Company | Scanning real-time microfluidic thermocycler and methods for synchronized thermocycling and scanning optical detection |
CA2834291A1 (en) | 2011-04-25 | 2012-11-01 | Biorad Laboratories, Inc. | Methods and compositions for nucleic acid analysis |
WO2013019751A1 (en) | 2011-07-29 | 2013-02-07 | Bio-Rad Laboratories, Inc., | Library characterization by digital assay |
EP2766483B1 (en) | 2011-10-10 | 2022-03-23 | The Hospital For Sick Children | Methods and compositions for screening and treating developmental disorders |
US9599561B2 (en) | 2011-10-13 | 2017-03-21 | Affymetrix, Inc. | Methods, systems and apparatuses for testing and calibrating fluorescent scanners |
EP2773779B1 (en) | 2011-11-04 | 2020-10-14 | Population Bio, Inc. | Methods and compositions for diagnosing, prognosing, and treating neurological conditions |
CN104040238B (en) | 2011-11-04 | 2017-06-27 | 汉迪拉布公司 | Polynucleotides sample preparation apparatus |
US9212381B2 (en) | 2011-11-10 | 2015-12-15 | President And Fellows Of Harvard College | Methods and compositions for labeling polypeptides |
EP2785874B1 (en) | 2011-11-30 | 2018-09-26 | Children's Hospital Medical Center | Personalized pain management and anesthesia: preemptive risk identification and therapeutic decision support |
EP2812452B1 (en) | 2012-02-09 | 2020-05-27 | Population Bio, Inc. | Methods and compositions for screening and treating developmental disorders |
US9322054B2 (en) | 2012-02-22 | 2016-04-26 | Lockheed Martin Corporation | Microfluidic cartridge |
WO2013155531A2 (en) | 2012-04-13 | 2013-10-17 | Bio-Rad Laboratories, Inc. | Sample holder with a well having a wicking promoter |
US9976180B2 (en) | 2012-09-14 | 2018-05-22 | Population Bio, Inc. | Methods for detecting a genetic variation in subjects with parkinsonism |
EP2900835A4 (en) | 2012-09-27 | 2016-05-11 | Population Diagnotics Inc | Methods and compositions for screening and treating developmental disorders |
WO2014074942A1 (en) | 2012-11-08 | 2014-05-15 | Illumina, Inc. | Risk variants of alzheimer's disease |
JP6202088B2 (en) * | 2013-03-15 | 2017-09-27 | 株式会社ニコン | Biochip fixing device and biochip fixing method |
US20140274749A1 (en) | 2013-03-15 | 2014-09-18 | Affymetrix, Inc. | Systems and Methods for SNP Characterization and Identifying off Target Variants |
JPWO2015016315A1 (en) * | 2013-08-02 | 2017-03-02 | 株式会社ニコン | Plate, plate manufacturing method, biochip observation method, and screening method |
EP3040723A4 (en) * | 2013-08-30 | 2017-07-12 | Nikon Corporation | Biochip support member, method for manufacturing biochip support member, biochip package, screening device, and screening method |
US9352315B2 (en) | 2013-09-27 | 2016-05-31 | Taiwan Semiconductor Manufacturing Company, Ltd. | Method to produce chemical pattern in micro-fluidic structure |
DK3511422T3 (en) | 2013-11-12 | 2023-02-06 | Population Bio Inc | METHODS AND COMPOSITIONS FOR DIAGNOSING, PROGNOSIS AND TREATMENT OF ENDOMETRIOSIS |
WO2015079998A1 (en) * | 2013-11-29 | 2015-06-04 | 三菱レイヨン株式会社 | Biochip holder, method for manufacturing biochip holder, biochip retainer, and biochip-holder kit |
JP6479037B2 (en) * | 2013-12-06 | 2019-03-06 | バクテリオスキャン エルティーディー | Optical measurement cuvette with sample chamber |
CN103640211A (en) * | 2013-12-23 | 2014-03-19 | 中国石油大学(华东) | Flexible material assisted polymer micro-structure ultrasonic bonding encapsulating method |
AU2015218692A1 (en) | 2014-02-24 | 2016-09-15 | Children's Hospital Medical Center | Methods and compositions for personalized pain management |
US10634590B2 (en) * | 2014-03-11 | 2020-04-28 | Emd Millipore Corporation | IHC, tissue slide fluid exchange disposable and system |
JP2015194379A (en) * | 2014-03-31 | 2015-11-05 | 株式会社ニコン | Biochip and detection method of alignment mark in biochip |
US10655188B2 (en) | 2014-06-13 | 2020-05-19 | Q-Linea Ab | Method for determining the identity and antimicrobial susceptibility of a microorganism |
EP3177738B1 (en) | 2014-08-08 | 2019-10-09 | Children's Hospital Medical Center | Diagnostic method for distinguishing forms of esophageal eosinophilia |
WO2016036403A1 (en) | 2014-09-05 | 2016-03-10 | Population Diagnostics Inc. | Methods and compositions for inhibiting and treating neurological conditions |
GB201507026D0 (en) | 2015-04-24 | 2015-06-10 | Linea Ab Q | Medical sample transportation container |
TWI553796B (en) * | 2015-08-18 | 2016-10-11 | 姜崇義 | Packaging method and system of temperature sensing chip |
EP4059570A1 (en) | 2016-01-13 | 2022-09-21 | Children's Hospital Medical Center | Compositions and methods for treating allergic inflammatory conditions |
US9659838B1 (en) * | 2016-03-28 | 2017-05-23 | Lockheed Martin Corporation | Integration of chip level micro-fluidic cooling in chip packages for heat flux removal |
GB2554767A (en) | 2016-04-21 | 2018-04-11 | Q Linea Ab | Detecting and characterising a microorganism |
US11618924B2 (en) | 2017-01-20 | 2023-04-04 | Children's Hospital Medical Center | Methods and compositions relating to OPRM1 DNA methylation for personalized pain management |
US10240205B2 (en) | 2017-02-03 | 2019-03-26 | Population Bio, Inc. | Methods for assessing risk of developing a viral disease using a genetic test |
US11859250B1 (en) | 2018-02-23 | 2024-01-02 | Children's Hospital Medical Center | Methods for treating eosinophilic esophagitis |
JP2018124289A (en) * | 2018-04-10 | 2018-08-09 | 株式会社ニコン | Biochip, and alignment mark detection method in biochip |
CA3108807A1 (en) | 2018-08-08 | 2020-02-13 | Pml Screening, Llc | Methods for assessing the risk of developing progressive multifocal leukoencephalopathy caused by john cunningham virus by genetic testing |
DE102020213471A1 (en) | 2020-10-27 | 2022-04-28 | Robert Bosch Gesellschaft mit beschränkter Haftung | Processing device for processing a sample liquid, method for producing a processing device and method for operating a processing device |
JP2024029793A (en) * | 2022-08-23 | 2024-03-07 | 東洋製罐グループホールディングス株式会社 | Microfluidic device, microfluidic device manufacturing method, and inspection system |
Citations (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3802966A (en) * | 1969-08-22 | 1974-04-09 | Ethyl Corp | Apparatus for delivering a fluid suspension to a forming unit clear reactor power plant |
US3873268A (en) * | 1971-07-06 | 1975-03-25 | Pfizer | Multiple solution testing device |
US4016855A (en) * | 1974-09-04 | 1977-04-12 | Hitachi, Ltd. | Grinding method |
US4190040A (en) * | 1978-07-03 | 1980-02-26 | American Hospital Supply Corporation | Resealable puncture housing for surgical implantation |
US4204929A (en) * | 1978-04-18 | 1980-05-27 | University Patents, Inc. | Isoelectric focusing method |
US4373071A (en) * | 1981-04-30 | 1983-02-08 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4447140A (en) * | 1982-09-29 | 1984-05-08 | Campbell Jeptha E | Microscope slides |
US4500707A (en) * | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US4728502A (en) * | 1984-05-02 | 1988-03-01 | Hamill Brendan J | Apparatus for the chemical synthesis of oligonucleotides |
US4731325A (en) * | 1984-02-17 | 1988-03-15 | Orion-Yhtyma | Arrays of alternating nucleic acid fragments for hybridization arrays |
US4812512A (en) * | 1985-06-27 | 1989-03-14 | Roussel Uclaf | Supports and their use |
US4815274A (en) * | 1984-11-19 | 1989-03-28 | Vincent Patents Limited | Exhaust systems for multi-cylinder internal combustion engines |
US4912035A (en) * | 1987-06-11 | 1990-03-27 | Eastman Kodak Company | Method for minimizing interference by reductants when detecting cells in biological fluids |
US4992383A (en) * | 1988-08-05 | 1991-02-12 | Porton Instruments, Inc. | Method for protein and peptide sequencing using derivatized glass supports |
US5091652A (en) * | 1990-01-12 | 1992-02-25 | The Regents Of The University Of California | Laser excited confocal microscope fluorescence scanner and method |
US5100626A (en) * | 1990-05-24 | 1992-03-31 | Levin Andrew E | Binding assay device with removable cassette and manifold |
US5188963A (en) * | 1989-11-17 | 1993-02-23 | Gene Tec Corporation | Device for processing biological specimens for analysis of nucleic acids |
US5192503A (en) * | 1990-05-23 | 1993-03-09 | Mcgrath Charles M | Probe clip in situ assay apparatus |
US5196305A (en) * | 1989-09-12 | 1993-03-23 | Eastman Kodak Company | Diagnostic and amplification methods using primers having thymine at 3' end to overcome primer-target mismatch at the 3' end |
US5200051A (en) * | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US5204253A (en) * | 1990-05-29 | 1993-04-20 | E. I. Du Pont De Nemours And Company | Method and apparatus for introducing biological substances into living cells |
US5281516A (en) * | 1988-08-02 | 1994-01-25 | Gene Tec Corporation | Temperature control apparatus and method |
US5281540A (en) * | 1988-08-02 | 1994-01-25 | Abbott Laboratories | Test array for performing assays |
US5287272A (en) * | 1988-04-08 | 1994-02-15 | Neuromedical Systems, Inc. | Automated cytological specimen classification system and method |
US5288514A (en) * | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
US5300779A (en) * | 1985-08-05 | 1994-04-05 | Biotrack, Inc. | Capillary flow device |
US5304487A (en) * | 1992-05-01 | 1994-04-19 | Trustees Of The University Of Pennsylvania | Fluid handling in mesoscale analytical devices |
US5310469A (en) * | 1991-12-31 | 1994-05-10 | Abbott Laboratories | Biosensor with a membrane containing biologically active material |
US5314829A (en) * | 1992-12-18 | 1994-05-24 | California Institute Of Technology | Method for imaging informational biological molecules on a semiconductor substrate |
US5382512A (en) * | 1993-08-23 | 1995-01-17 | Chiron Corporation | Assay device with captured particle reagent |
US5382511A (en) * | 1988-08-02 | 1995-01-17 | Gene Tec Corporation | Method for studying nucleic acids within immobilized specimens |
US5384261A (en) * | 1991-11-22 | 1995-01-24 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis using mechanically directed flow paths |
US5384216A (en) * | 1992-05-27 | 1995-01-24 | Toshiba Battery Co., Ltd. | Paste-type electrode for alkali secondary cell |
US5482591A (en) * | 1992-10-30 | 1996-01-09 | Specialty Silicone Products, Inc. | Laminated seals and method of production |
US5485277A (en) * | 1994-07-26 | 1996-01-16 | Physical Optics Corporation | Surface plasmon resonance sensor and methods for the utilization thereof |
US5486452A (en) * | 1981-04-29 | 1996-01-23 | Ciba-Geigy Corporation | Devices and kits for immunological analysis |
US5486335A (en) * | 1992-05-01 | 1996-01-23 | Trustees Of The University Of Pennsylvania | Analysis based on flow restriction |
US5494124A (en) * | 1993-10-08 | 1996-02-27 | Vortexx Group, Inc. | Negative pressure vortex nozzle |
US5498392A (en) * | 1992-05-01 | 1996-03-12 | Trustees Of The University Of Pennsylvania | Mesoscale polynucleotide amplification device and method |
US5508200A (en) * | 1992-10-19 | 1996-04-16 | Tiffany; Thomas | Method and apparatus for conducting multiple chemical assays |
US5593839A (en) * | 1994-05-24 | 1997-01-14 | Affymetrix, Inc. | Computer-aided engineering system for design of sequence arrays and lithographic masks |
US5599668A (en) * | 1994-09-22 | 1997-02-04 | Abbott Laboratories | Light scattering optical waveguide method for detecting specific binding events |
US5605653A (en) * | 1995-11-09 | 1997-02-25 | Devos; Jerry | Liquid circulation apparatus |
US5631734A (en) * | 1994-02-10 | 1997-05-20 | Affymetrix, Inc. | Method and apparatus for detection of fluorescently labeled materials |
US5707798A (en) * | 1993-07-13 | 1998-01-13 | Novo Nordisk A/S | Identification of ligands by selective amplification of cells transfected with receptors |
US5714380A (en) * | 1986-10-23 | 1998-02-03 | Amoco Corporation | Closed vessel for isolating target molecules and for performing amplification |
US5741463A (en) * | 1993-04-19 | 1998-04-21 | Sanadi; Ashok Ramesh | Apparatus for preventing cross-contamination of multi-well test plates |
US5757666A (en) * | 1993-04-23 | 1998-05-26 | Boehringer Mannheim Gmbh | System for analyzing compounds contained liquid samples |
US5856174A (en) * | 1995-06-29 | 1999-01-05 | Affymetrix, Inc. | Integrated nucleic acid diagnostic device |
US5858804A (en) * | 1994-11-10 | 1999-01-12 | Sarnoff Corporation | Immunological assay conducted in a microlaboratory array |
US5869643A (en) * | 1993-12-16 | 1999-02-09 | Genset | Process for preparing polynucleotides on a solid support in a tightly packed bed |
US5874219A (en) * | 1995-06-07 | 1999-02-23 | Affymetrix, Inc. | Methods for concurrently processing multiple biological chip assays |
US6054100A (en) * | 1996-11-18 | 2000-04-25 | Robbins Scientific Corporation | Apparatus for multi-well microscale synthesis |
US6177990B1 (en) * | 1997-05-23 | 2001-01-23 | Molecular Dynamics, Inc. | Optical substrate for enhanced detectability of fluorescence |
US6180351B1 (en) * | 1999-07-22 | 2001-01-30 | Agilent Technologies Inc. | Chemical array fabrication with identifier |
US6186659B1 (en) * | 1998-08-21 | 2001-02-13 | Agilent Technologies Inc. | Apparatus and method for mixing a film of fluid |
US6215894B1 (en) * | 1999-02-26 | 2001-04-10 | General Scanning, Incorporated | Automatic imaging and analysis of microarray biochips |
US6232072B1 (en) * | 1999-10-15 | 2001-05-15 | Agilent Technologies, Inc. | Biopolymer array inspection |
US6238862B1 (en) * | 1995-09-18 | 2001-05-29 | Affymetrix, Inc. | Methods for testing oligonucleotide arrays |
US6238910B1 (en) * | 1998-08-10 | 2001-05-29 | Genomic Solutions, Inc. | Thermal and fluid cycling device for nucleic acid hybridization |
US6355431B1 (en) * | 1999-04-20 | 2002-03-12 | Illumina, Inc. | Detection of nucleic acid amplification reactions using bead arrays |
US6355432B1 (en) * | 1989-06-07 | 2002-03-12 | Affymetrix Lnc. | Products for detecting nucleic acids |
US6361744B1 (en) * | 1998-03-06 | 2002-03-26 | Abner Levy | Self-resealing closure for containers |
US6372507B1 (en) * | 1998-02-10 | 2002-04-16 | Lee Angros | Analytic plate with containment border |
US6376619B1 (en) * | 1998-04-13 | 2002-04-23 | 3M Innovative Properties Company | High density, miniaturized arrays and methods of manufacturing same |
US6376256B1 (en) * | 1996-08-21 | 2002-04-23 | Smithkline Beecham Corporation | Rapid process for arraying and synthesizing bead-based combinatorial libraries |
US6391623B1 (en) * | 1996-03-26 | 2002-05-21 | Affymetrix, Inc. | Fluidics station injection needles with distal end and side ports and method of using |
US6396995B1 (en) * | 1999-05-20 | 2002-05-28 | Illumina, Inc. | Method and apparatus for retaining and presenting at least one microsphere array to solutions and/or to optical imaging systems |
US6395483B1 (en) * | 1999-09-02 | 2002-05-28 | 3M Innovative Properties Company | Arrays with mask layers |
US20020064889A1 (en) * | 1999-04-30 | 2002-05-30 | Caren Michael P. | Fabricating biopolymer arrays |
US6514465B2 (en) * | 1999-12-21 | 2003-02-04 | Tecan Trading Ag | Apparatus for receiving an object, arrangement for transporting and for receiving and object and method for their operation |
US20030032204A1 (en) * | 2001-07-19 | 2003-02-13 | Walt David R. | Optical array device and methods of use thereof for screening, analysis and manipulation of particles |
US20030040129A1 (en) * | 2001-08-20 | 2003-02-27 | Shah Haresh P. | Binding assays using magnetically immobilized arrays |
US6545758B1 (en) * | 2000-08-17 | 2003-04-08 | Perry Sandstrom | Microarray detector and synthesizer |
US6544732B1 (en) * | 1999-05-20 | 2003-04-08 | Illumina, Inc. | Encoding and decoding of array sensors utilizing nanocrystals |
US6551817B2 (en) * | 1994-06-08 | 2003-04-22 | Affymetrix, Inc. | Method and apparatus for hybridization |
US6555361B1 (en) * | 1999-03-24 | 2003-04-29 | Corning Incorporated | Hybridization chamber for high density nucleic acid arrays |
US20030087292A1 (en) * | 2001-10-04 | 2003-05-08 | Shiping Chen | Methods and systems for promoting interactions between probes and target molecules in fluid in microarrays |
US20030096239A1 (en) * | 2000-08-25 | 2003-05-22 | Kevin Gunderson | Probes and decoder oligonucleotides |
US6682702B2 (en) * | 2001-08-24 | 2004-01-27 | Agilent Technologies, Inc. | Apparatus and method for simultaneously conducting multiple chemical reactions |
US6713304B2 (en) * | 1998-02-10 | 2004-03-30 | Lee H. Angros | Method of forming a containment border on an analytic plate |
US6720149B1 (en) * | 1995-06-07 | 2004-04-13 | Affymetrix, Inc. | Methods for concurrently processing multiple biological chip assays |
US20040086868A1 (en) * | 2002-10-30 | 2004-05-06 | Parker Russell A. | Enclosed arrays and their reading |
US20050026299A1 (en) * | 2003-07-31 | 2005-02-03 | Arindam Bhattacharjee | Chemical arrays on a common carrier |
US20050037365A1 (en) * | 2003-08-14 | 2005-02-17 | David Anvar | Arrays for multiplexed surface plasmon resonance detection of biological molecules |
US6864580B2 (en) * | 2001-01-25 | 2005-03-08 | Renesas Technology Corp. | Semiconductor device and method of manufacturing the same |
US20050079529A1 (en) * | 1989-06-07 | 2005-04-14 | Affymetrix, Inc. | Very large scale immobilized polymer synthesis |
US20060045812A1 (en) * | 1996-01-16 | 2006-03-02 | Affymetrix, Inc. | Analytical biochemistry system with robotically carried bioarray |
US7018842B2 (en) * | 2002-02-28 | 2006-03-28 | Agilent Technologies, Inc. | Reading dry chemical arrays through the substrate |
US20060078463A1 (en) * | 2002-06-21 | 2006-04-13 | Shea Laurence R | Array assay devices and methods of using the same |
US7510841B2 (en) * | 1998-12-28 | 2009-03-31 | Illumina, Inc. | Methods of making and using composite arrays for the detection of a plurality of target analytes |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1617732C2 (en) * | 1966-03-01 | 1972-12-21 | Promoveo-Sobioda & Cie, Seyssinet (Frankreich) | Device for examining living cells of microorganisms |
BE793185A (en) * | 1971-12-23 | 1973-04-16 | Atomic Energy Commission | APPARATUS FOR QUICKLY ANALYZING AND SORTING PARTICLES SUCH AS BIOLOGICAL CELLS |
US4963498A (en) * | 1985-08-05 | 1990-10-16 | Biotrack | Capillary flow device |
JPH0750094B2 (en) * | 1987-01-28 | 1995-05-31 | 富士写真フイルム株式会社 | Continuous manufacturing method for chemical analysis slides |
US5700637A (en) * | 1988-05-03 | 1997-12-23 | Isis Innovation Limited | Apparatus and method for analyzing polynucleotide sequences and method of generating oligonucleotide arrays |
US5320808A (en) * | 1988-08-02 | 1994-06-14 | Abbott Laboratories | Reaction cartridge and carousel for biological sample analyzer |
US5143854A (en) * | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5346672A (en) * | 1989-11-17 | 1994-09-13 | Gene Tec Corporation | Devices for containing biological specimens for thermal processing |
ES2155822T3 (en) * | 1990-12-06 | 2001-06-01 | Affymetrix Inc | COMPOUNDS AND ITS USE IN A BINARY SYNTHESIS STRATEGY. |
US5474796A (en) * | 1991-09-04 | 1995-12-12 | Protogene Laboratories, Inc. | Method and apparatus for conducting an array of chemical reactions on a support surface |
US5846708A (en) * | 1991-11-19 | 1998-12-08 | Massachusetts Institiute Of Technology | Optical and electrical methods and apparatus for molecule detection |
WO1993009668A1 (en) * | 1991-11-22 | 1993-05-27 | Affymax Technology N.V. | Combinatorial strategies for polymer synthesis |
US5412087A (en) * | 1992-04-24 | 1995-05-02 | Affymax Technologies N.V. | Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces |
US5637469A (en) * | 1992-05-01 | 1997-06-10 | Trustees Of The University Of Pennsylvania | Methods and apparatus for the detection of an analyte utilizing mesoscale flow systems |
FI923220A (en) * | 1992-07-14 | 1994-01-15 | Wallac Oy | APPARATUS AND EQUIPMENT FOER HANTERING AV PROV SAMT PROVUPPSAMLINGSSYSTEM |
DE69527585T2 (en) * | 1994-06-08 | 2003-04-03 | Affymetrix Inc | Method and device for packaging chips |
US6864097B1 (en) * | 2000-09-27 | 2005-03-08 | Agilent Technologies, Inc. | Arrays and their reading |
-
1995
- 1995-05-19 DE DE69527585T patent/DE69527585T2/en not_active Expired - Lifetime
- 1995-05-19 EP EP95303356A patent/EP0695941B1/en not_active Expired - Lifetime
- 1995-06-07 US US08/485,452 patent/US5945334A/en not_active Expired - Lifetime
- 1995-06-08 EP EP05009507A patent/EP1562045A3/en not_active Withdrawn
- 1995-06-08 JP JP8501333A patent/JPH10505410A/en not_active Withdrawn
- 1995-06-08 WO PCT/US1995/007377 patent/WO1995033846A1/en active IP Right Grant
- 1995-06-08 AU AU29436/95A patent/AU2943695A/en not_active Abandoned
- 1995-06-08 EP EP95925244A patent/EP0764214B1/en not_active Revoked
- 1995-06-08 DE DE69534418T patent/DE69534418T2/en not_active Expired - Lifetime
- 1995-06-08 JP JP14219595A patent/JP3790280B2/en not_active Expired - Fee Related
- 1995-09-14 US US08/528,173 patent/US6140044A/en not_active Expired - Lifetime
-
2005
- 2005-08-04 JP JP2005227258A patent/JP3884048B2/en not_active Expired - Fee Related
- 2005-11-21 JP JP2005336411A patent/JP2006153877A/en not_active Withdrawn
-
2008
- 2008-11-05 US US12/265,048 patent/US20090143249A1/en not_active Abandoned
-
2010
- 2010-07-23 US US12/842,977 patent/US20100298165A1/en not_active Abandoned
Patent Citations (100)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3802966A (en) * | 1969-08-22 | 1974-04-09 | Ethyl Corp | Apparatus for delivering a fluid suspension to a forming unit clear reactor power plant |
US3873268A (en) * | 1971-07-06 | 1975-03-25 | Pfizer | Multiple solution testing device |
US4016855A (en) * | 1974-09-04 | 1977-04-12 | Hitachi, Ltd. | Grinding method |
US4204929A (en) * | 1978-04-18 | 1980-05-27 | University Patents, Inc. | Isoelectric focusing method |
US4190040A (en) * | 1978-07-03 | 1980-02-26 | American Hospital Supply Corporation | Resealable puncture housing for surgical implantation |
US4500707A (en) * | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US5486452A (en) * | 1981-04-29 | 1996-01-23 | Ciba-Geigy Corporation | Devices and kits for immunological analysis |
US4373071A (en) * | 1981-04-30 | 1983-02-08 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4447140A (en) * | 1982-09-29 | 1984-05-08 | Campbell Jeptha E | Microscope slides |
US4731325A (en) * | 1984-02-17 | 1988-03-15 | Orion-Yhtyma | Arrays of alternating nucleic acid fragments for hybridization arrays |
US4728502A (en) * | 1984-05-02 | 1988-03-01 | Hamill Brendan J | Apparatus for the chemical synthesis of oligonucleotides |
US4815274A (en) * | 1984-11-19 | 1989-03-28 | Vincent Patents Limited | Exhaust systems for multi-cylinder internal combustion engines |
US4812512A (en) * | 1985-06-27 | 1989-03-14 | Roussel Uclaf | Supports and their use |
US5300779A (en) * | 1985-08-05 | 1994-04-05 | Biotrack, Inc. | Capillary flow device |
US5714380A (en) * | 1986-10-23 | 1998-02-03 | Amoco Corporation | Closed vessel for isolating target molecules and for performing amplification |
US4912035A (en) * | 1987-06-11 | 1990-03-27 | Eastman Kodak Company | Method for minimizing interference by reductants when detecting cells in biological fluids |
US5287272A (en) * | 1988-04-08 | 1994-02-15 | Neuromedical Systems, Inc. | Automated cytological specimen classification system and method |
US5287272B1 (en) * | 1988-04-08 | 1996-08-27 | Neuromedical Systems Inc | Automated cytological specimen classification system and method |
US5382511A (en) * | 1988-08-02 | 1995-01-17 | Gene Tec Corporation | Method for studying nucleic acids within immobilized specimens |
US5281516A (en) * | 1988-08-02 | 1994-01-25 | Gene Tec Corporation | Temperature control apparatus and method |
US5281540A (en) * | 1988-08-02 | 1994-01-25 | Abbott Laboratories | Test array for performing assays |
US4992383A (en) * | 1988-08-05 | 1991-02-12 | Porton Instruments, Inc. | Method for protein and peptide sequencing using derivatized glass supports |
US5200051A (en) * | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US20050079529A1 (en) * | 1989-06-07 | 2005-04-14 | Affymetrix, Inc. | Very large scale immobilized polymer synthesis |
US6355432B1 (en) * | 1989-06-07 | 2002-03-12 | Affymetrix Lnc. | Products for detecting nucleic acids |
US5196305A (en) * | 1989-09-12 | 1993-03-23 | Eastman Kodak Company | Diagnostic and amplification methods using primers having thymine at 3' end to overcome primer-target mismatch at the 3' end |
US5188963A (en) * | 1989-11-17 | 1993-02-23 | Gene Tec Corporation | Device for processing biological specimens for analysis of nucleic acids |
US5091652A (en) * | 1990-01-12 | 1992-02-25 | The Regents Of The University Of California | Laser excited confocal microscope fluorescence scanner and method |
US5192503A (en) * | 1990-05-23 | 1993-03-09 | Mcgrath Charles M | Probe clip in situ assay apparatus |
US5100626A (en) * | 1990-05-24 | 1992-03-31 | Levin Andrew E | Binding assay device with removable cassette and manifold |
US5204253A (en) * | 1990-05-29 | 1993-04-20 | E. I. Du Pont De Nemours And Company | Method and apparatus for introducing biological substances into living cells |
US5384261A (en) * | 1991-11-22 | 1995-01-24 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis using mechanically directed flow paths |
US5310469A (en) * | 1991-12-31 | 1994-05-10 | Abbott Laboratories | Biosensor with a membrane containing biologically active material |
US5304487A (en) * | 1992-05-01 | 1994-04-19 | Trustees Of The University Of Pennsylvania | Fluid handling in mesoscale analytical devices |
US5486335A (en) * | 1992-05-01 | 1996-01-23 | Trustees Of The University Of Pennsylvania | Analysis based on flow restriction |
US5498392A (en) * | 1992-05-01 | 1996-03-12 | Trustees Of The University Of Pennsylvania | Mesoscale polynucleotide amplification device and method |
US5384216A (en) * | 1992-05-27 | 1995-01-24 | Toshiba Battery Co., Ltd. | Paste-type electrode for alkali secondary cell |
US5288514A (en) * | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
US5508200A (en) * | 1992-10-19 | 1996-04-16 | Tiffany; Thomas | Method and apparatus for conducting multiple chemical assays |
US5482591A (en) * | 1992-10-30 | 1996-01-09 | Specialty Silicone Products, Inc. | Laminated seals and method of production |
US5314829A (en) * | 1992-12-18 | 1994-05-24 | California Institute Of Technology | Method for imaging informational biological molecules on a semiconductor substrate |
US5741463A (en) * | 1993-04-19 | 1998-04-21 | Sanadi; Ashok Ramesh | Apparatus for preventing cross-contamination of multi-well test plates |
US5757666A (en) * | 1993-04-23 | 1998-05-26 | Boehringer Mannheim Gmbh | System for analyzing compounds contained liquid samples |
US5707798A (en) * | 1993-07-13 | 1998-01-13 | Novo Nordisk A/S | Identification of ligands by selective amplification of cells transfected with receptors |
US5382512A (en) * | 1993-08-23 | 1995-01-17 | Chiron Corporation | Assay device with captured particle reagent |
US5494124A (en) * | 1993-10-08 | 1996-02-27 | Vortexx Group, Inc. | Negative pressure vortex nozzle |
US5869643A (en) * | 1993-12-16 | 1999-02-09 | Genset | Process for preparing polynucleotides on a solid support in a tightly packed bed |
US5631734A (en) * | 1994-02-10 | 1997-05-20 | Affymetrix, Inc. | Method and apparatus for detection of fluorescently labeled materials |
US5593839A (en) * | 1994-05-24 | 1997-01-14 | Affymetrix, Inc. | Computer-aided engineering system for design of sequence arrays and lithographic masks |
US20050089953A1 (en) * | 1994-06-08 | 2005-04-28 | Affymetrix, Inc. | Bioarray chip reaction apparatus and its manufacture |
US20060040380A1 (en) * | 1994-06-08 | 2006-02-23 | Affymetrix, Inc. | Bioarray chip reaction apparatus and its manufacture |
US20050084895A1 (en) * | 1994-06-08 | 2005-04-21 | Affymetrix, Inc. | Bioarray chip reaction apparatus and its manufacture |
US20050003421A1 (en) * | 1994-06-08 | 2005-01-06 | Affymetrix, Inc. | Bioarray chip reaction apparatus and its manufacture |
US6551817B2 (en) * | 1994-06-08 | 2003-04-22 | Affymetrix, Inc. | Method and apparatus for hybridization |
US5485277A (en) * | 1994-07-26 | 1996-01-16 | Physical Optics Corporation | Surface plasmon resonance sensor and methods for the utilization thereof |
US5599668A (en) * | 1994-09-22 | 1997-02-04 | Abbott Laboratories | Light scattering optical waveguide method for detecting specific binding events |
US5858804A (en) * | 1994-11-10 | 1999-01-12 | Sarnoff Corporation | Immunological assay conducted in a microlaboratory array |
US6720149B1 (en) * | 1995-06-07 | 2004-04-13 | Affymetrix, Inc. | Methods for concurrently processing multiple biological chip assays |
US20050042628A1 (en) * | 1995-06-07 | 2005-02-24 | Affymetrix, Inc. | Methods for concurrently processing multiple biological chip assays |
US20020018991A1 (en) * | 1995-06-07 | 2002-02-14 | Richard P. Rava | Method for concurrently processing multiple biological chip assays |
US5874219A (en) * | 1995-06-07 | 1999-02-23 | Affymetrix, Inc. | Methods for concurrently processing multiple biological chip assays |
US5856174A (en) * | 1995-06-29 | 1999-01-05 | Affymetrix, Inc. | Integrated nucleic acid diagnostic device |
US6238862B1 (en) * | 1995-09-18 | 2001-05-29 | Affymetrix, Inc. | Methods for testing oligonucleotide arrays |
US5605653A (en) * | 1995-11-09 | 1997-02-25 | Devos; Jerry | Liquid circulation apparatus |
US20060045812A1 (en) * | 1996-01-16 | 2006-03-02 | Affymetrix, Inc. | Analytical biochemistry system with robotically carried bioarray |
US6391623B1 (en) * | 1996-03-26 | 2002-05-21 | Affymetrix, Inc. | Fluidics station injection needles with distal end and side ports and method of using |
US6376256B1 (en) * | 1996-08-21 | 2002-04-23 | Smithkline Beecham Corporation | Rapid process for arraying and synthesizing bead-based combinatorial libraries |
US6054100A (en) * | 1996-11-18 | 2000-04-25 | Robbins Scientific Corporation | Apparatus for multi-well microscale synthesis |
US6177990B1 (en) * | 1997-05-23 | 2001-01-23 | Molecular Dynamics, Inc. | Optical substrate for enhanced detectability of fluorescence |
US6372507B1 (en) * | 1998-02-10 | 2002-04-16 | Lee Angros | Analytic plate with containment border |
US6713304B2 (en) * | 1998-02-10 | 2004-03-30 | Lee H. Angros | Method of forming a containment border on an analytic plate |
US6361744B1 (en) * | 1998-03-06 | 2002-03-26 | Abner Levy | Self-resealing closure for containers |
US6376619B1 (en) * | 1998-04-13 | 2002-04-23 | 3M Innovative Properties Company | High density, miniaturized arrays and methods of manufacturing same |
US6238910B1 (en) * | 1998-08-10 | 2001-05-29 | Genomic Solutions, Inc. | Thermal and fluid cycling device for nucleic acid hybridization |
US6186659B1 (en) * | 1998-08-21 | 2001-02-13 | Agilent Technologies Inc. | Apparatus and method for mixing a film of fluid |
US6513968B2 (en) * | 1998-08-21 | 2003-02-04 | Agilent Technologies, Inc. | Apparatus and method for mixing a film of fluid |
US7510841B2 (en) * | 1998-12-28 | 2009-03-31 | Illumina, Inc. | Methods of making and using composite arrays for the detection of a plurality of target analytes |
US6215894B1 (en) * | 1999-02-26 | 2001-04-10 | General Scanning, Incorporated | Automatic imaging and analysis of microarray biochips |
US6555361B1 (en) * | 1999-03-24 | 2003-04-29 | Corning Incorporated | Hybridization chamber for high density nucleic acid arrays |
US6355431B1 (en) * | 1999-04-20 | 2002-03-12 | Illumina, Inc. | Detection of nucleic acid amplification reactions using bead arrays |
US20020064889A1 (en) * | 1999-04-30 | 2002-05-30 | Caren Michael P. | Fabricating biopolymer arrays |
US6544732B1 (en) * | 1999-05-20 | 2003-04-08 | Illumina, Inc. | Encoding and decoding of array sensors utilizing nanocrystals |
US6396995B1 (en) * | 1999-05-20 | 2002-05-28 | Illumina, Inc. | Method and apparatus for retaining and presenting at least one microsphere array to solutions and/or to optical imaging systems |
US6180351B1 (en) * | 1999-07-22 | 2001-01-30 | Agilent Technologies Inc. | Chemical array fabrication with identifier |
US6395483B1 (en) * | 1999-09-02 | 2002-05-28 | 3M Innovative Properties Company | Arrays with mask layers |
US6232072B1 (en) * | 1999-10-15 | 2001-05-15 | Agilent Technologies, Inc. | Biopolymer array inspection |
US6514465B2 (en) * | 1999-12-21 | 2003-02-04 | Tecan Trading Ag | Apparatus for receiving an object, arrangement for transporting and for receiving and object and method for their operation |
US6545758B1 (en) * | 2000-08-17 | 2003-04-08 | Perry Sandstrom | Microarray detector and synthesizer |
US20030096239A1 (en) * | 2000-08-25 | 2003-05-22 | Kevin Gunderson | Probes and decoder oligonucleotides |
US6864580B2 (en) * | 2001-01-25 | 2005-03-08 | Renesas Technology Corp. | Semiconductor device and method of manufacturing the same |
US20030032204A1 (en) * | 2001-07-19 | 2003-02-13 | Walt David R. | Optical array device and methods of use thereof for screening, analysis and manipulation of particles |
US6991939B2 (en) * | 2001-07-19 | 2006-01-31 | Tufts University | Optical array device and methods of use thereof for screening, analysis and manipulation of particles |
US20030040129A1 (en) * | 2001-08-20 | 2003-02-27 | Shah Haresh P. | Binding assays using magnetically immobilized arrays |
US6682702B2 (en) * | 2001-08-24 | 2004-01-27 | Agilent Technologies, Inc. | Apparatus and method for simultaneously conducting multiple chemical reactions |
US20030087292A1 (en) * | 2001-10-04 | 2003-05-08 | Shiping Chen | Methods and systems for promoting interactions between probes and target molecules in fluid in microarrays |
US7018842B2 (en) * | 2002-02-28 | 2006-03-28 | Agilent Technologies, Inc. | Reading dry chemical arrays through the substrate |
US20060078463A1 (en) * | 2002-06-21 | 2006-04-13 | Shea Laurence R | Array assay devices and methods of using the same |
US20040086868A1 (en) * | 2002-10-30 | 2004-05-06 | Parker Russell A. | Enclosed arrays and their reading |
US20050026299A1 (en) * | 2003-07-31 | 2005-02-03 | Arindam Bhattacharjee | Chemical arrays on a common carrier |
US20050037365A1 (en) * | 2003-08-14 | 2005-02-17 | David Anvar | Arrays for multiplexed surface plasmon resonance detection of biological molecules |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8309045B2 (en) | 2011-02-11 | 2012-11-13 | General Electric Company | System and method for controlling emissions in a combustion system |
WO2017087662A1 (en) * | 2015-11-17 | 2017-05-26 | Pacific Biosciences Of California, Inc. | Packaging methods for fabrication of analytical device packages and analytical device packages made thereof |
US9754836B2 (en) | 2015-11-17 | 2017-09-05 | Pacific Biosciences Of California, Inc. | Packaging methods for fabrication of analytical device packages and analytical device packages made thereof |
Also Published As
Publication number | Publication date |
---|---|
US5945334A (en) | 1999-08-31 |
JP3790280B2 (en) | 2006-06-28 |
EP1562045A2 (en) | 2005-08-10 |
US6140044A (en) | 2000-10-31 |
EP0764214B1 (en) | 2005-08-31 |
JP2006153877A (en) | 2006-06-15 |
DE69527585D1 (en) | 2002-09-05 |
EP0695941B1 (en) | 2002-07-31 |
WO1995033846A1 (en) | 1995-12-14 |
JP3884048B2 (en) | 2007-02-21 |
EP0695941A2 (en) | 1996-02-07 |
EP0764214A1 (en) | 1997-03-26 |
AU2943695A (en) | 1996-01-04 |
DE69534418D1 (en) | 2005-10-06 |
JPH08166387A (en) | 1996-06-25 |
EP1562045A3 (en) | 2005-11-02 |
EP0695941A3 (en) | 1996-12-27 |
EP0764214A4 (en) | 1997-05-07 |
DE69534418T2 (en) | 2006-06-22 |
US20090143249A1 (en) | 2009-06-04 |
JPH10505410A (en) | 1998-05-26 |
DE69527585T2 (en) | 2003-04-03 |
JP2005345481A (en) | 2005-12-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6733977B2 (en) | Hybridization device and method | |
US5945334A (en) | Apparatus for packaging a chip | |
US8697452B2 (en) | Thermal cycling assay apparatus and method | |
US9623413B2 (en) | Integrated chip carriers with thermocycler interfaces and methods of using the same | |
US7670992B2 (en) | Method of producing probe arrays for biological materials using fine particles | |
US20040141880A1 (en) | System and cartridge for processing a biological sample | |
WO2000061198A1 (en) | Method of producing probe arrays for biological materials using fine particles | |
TW200931018A (en) | Reaction chip and method of manufacturing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: GENERAL ELECTRIC CAPITAL CORPORATION, AS AGENT, MA Free format text: SECURITY AGREEMENT;ASSIGNOR:AFFYMETRIX, INC.;REEL/FRAME:028465/0541 Effective date: 20120625 |
|
STCB | Information on status: application discontinuation |
Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION |
|
AS | Assignment |
Owner name: AFFYMETRIX, INC., CALIFORNIA Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:GENERAL ELECTRIC CAPITAL CORPORATION, AS AGENT;REEL/FRAME:037109/0132 Effective date: 20151028 |