US20060246576A1 - Fluidic system and method for processing biological microarrays in personal instrumentation - Google Patents
Fluidic system and method for processing biological microarrays in personal instrumentation Download PDFInfo
- Publication number
- US20060246576A1 US20060246576A1 US11/388,762 US38876206A US2006246576A1 US 20060246576 A1 US20060246576 A1 US 20060246576A1 US 38876206 A US38876206 A US 38876206A US 2006246576 A1 US2006246576 A1 US 2006246576A1
- Authority
- US
- United States
- Prior art keywords
- sensor
- container
- fluidic system
- fluid
- volume
- 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
- 238000000034 method Methods 0.000 title claims abstract description 121
- 238000012545 processing Methods 0.000 title claims abstract description 45
- 238000002493 microarray Methods 0.000 title claims description 36
- 239000012530 fluid Substances 0.000 claims abstract description 89
- 230000008569 process Effects 0.000 claims description 60
- 238000009396 hybridization Methods 0.000 claims description 42
- 150000007523 nucleic acids Chemical class 0.000 description 44
- 102000039446 nucleic acids Human genes 0.000 description 40
- 108020004707 nucleic acids Proteins 0.000 description 40
- 125000003729 nucleotide group Chemical group 0.000 description 34
- 239000002773 nucleotide Substances 0.000 description 28
- 239000000523 sample Substances 0.000 description 20
- 108020004414 DNA Proteins 0.000 description 18
- 102000053602 DNA Human genes 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 102000040430 polynucleotide Human genes 0.000 description 16
- 108091033319 polynucleotide Proteins 0.000 description 16
- 239000002157 polynucleotide Substances 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 15
- 108700028369 Alleles Proteins 0.000 description 14
- 108020004999 messenger RNA Proteins 0.000 description 13
- 238000012986 modification Methods 0.000 description 13
- 230000004048 modification Effects 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- 230000000295 complement effect Effects 0.000 description 12
- 238000010586 diagram Methods 0.000 description 12
- 229920002477 rna polymer Polymers 0.000 description 12
- 108091034117 Oligonucleotide Proteins 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 108091093037 Peptide nucleic acid Proteins 0.000 description 9
- -1 antibodies Proteins 0.000 description 9
- 229920001222 biopolymer Polymers 0.000 description 8
- 239000000178 monomer Substances 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 230000027455 binding Effects 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 239000002777 nucleoside Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 230000003321 amplification Effects 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000003199 nucleic acid amplification method Methods 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 150000008163 sugars Chemical class 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000003491 array Methods 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 102000006240 membrane receptors Human genes 0.000 description 4
- 108020004084 membrane receptors Proteins 0.000 description 4
- 238000010369 molecular cloning Methods 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 4
- 108090001090 Lectins Proteins 0.000 description 3
- 102000004856 Lectins Human genes 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 108091028664 Ribonucleotide Proteins 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 238000005284 basis set Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000004590 computer program Methods 0.000 description 3
- 239000005547 deoxyribonucleotide Substances 0.000 description 3
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 238000003205 genotyping method Methods 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000002523 lectin Substances 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000012508 resin bead Substances 0.000 description 3
- 239000002336 ribonucleotide Substances 0.000 description 3
- 125000002652 ribonucleotide group Chemical group 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 2
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000012864 cross contamination Methods 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000007834 ligase chain reaction Methods 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000003499 nucleic acid array Methods 0.000 description 2
- 239000002853 nucleic acid probe Substances 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 108010011903 peptide receptors Proteins 0.000 description 2
- 102000014187 peptide receptors Human genes 0.000 description 2
- 150000004713 phosphodiesters Chemical group 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 239000002435 venom Substances 0.000 description 2
- 231100000611 venom Toxicity 0.000 description 2
- 210000001048 venom Anatomy 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108091027305 Heteroduplex Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108091027974 Mature messenger RNA Proteins 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 102000001490 Opioid Peptides Human genes 0.000 description 1
- 108010093625 Opioid Peptides Proteins 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007894 restriction fragment length polymorphism technique Methods 0.000 description 1
- 108020004418 ribosomal RNA Proteins 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
Images
Classifications
-
- 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
- G01N35/0099—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor comprising robots or similar manipulators
-
- 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
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/028—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having reaction cells in the form of microtitration plates
-
- 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
-
- 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
- B01L9/523—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for multisample carriers, e.g. used for microtitration plates
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
- G01N1/31—Apparatus therefor
- G01N1/312—Apparatus therefor for samples mounted on planar substrates
-
- 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"
-
- 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
- G01N2035/00346—Heating or cooling arrangements
- G01N2035/00356—Holding samples at elevated temperature (incubation)
-
- 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
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/04—Details of the conveyor system
- G01N2035/0401—Sample carriers, cuvettes or reaction vessels
- G01N2035/0418—Plate elements with several rows of samples
- G01N2035/0425—Stacks, magazines or elevators for plates
-
- 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
- G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
- G01N35/04—Details of the conveyor system
- G01N2035/0496—Other details
- G01N2035/0498—Drawers used as storage or dispensing means for vessels or cuvettes
-
- 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
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N2035/1027—General features of the devices
- G01N2035/1048—General features of the devices using the transfer device for another function
Definitions
- the present invention relates in general to biological microarray techniques. More particularly, the invention provides a fluidic system and method for processing biological microarrays. Merely by way of example, the invention is described as it applies to personal instrumentation, but it should be recognized that the invention has a broader range of applicability.
- a biological microarray often includes nucleic acid probes that are used to extract sequence information from nucleic acid samples.
- the nucleic acid samples are exposed to the nucleic acid probes under certain conditions that would allow hybridization.
- the biological microarray is processed and scanned to determine to which probes the nucleic acid samples have hybridized. Based on such determination, the sequence information is obtained by comparing patterns of hybridization and non-hybridization.
- the sequence information can be used for sequencing nucleic acids, or diagnostic screening for genetic diseases or for the presence of a particular pathogen or a strain of pathogen.
- the processing of the biological microarray prior to scanning is often performed by a fluidic system.
- the fluidic system includes a fluidic station.
- the fluidic station can wash and stain the microarray.
- the fluidic station often needs to be modified in order to improve automation and lower cost.
- the present invention relates in general to biological microarray techniques. More particularly, the invention provides a fluidic system and method for processing biological microarrays. Merely by way of example, the invention is described as it applies to personal instrumentation, but it should be recognized that the invention has a broader range of applicability.
- a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container.
- the first container is capable of holding a first volume of a first fluid
- the second container is capable of holding a second volume of a second fluid.
- the fluidic system includes a support component configured to support at least the first container and the second container. The first container and the second container are substantially stationary with respect to the support component.
- the fluidic system includes a transport component configured to move a first sensor, with respect to the support component, into the first container and in contact with the first volume of the first fluid, and move a second sensor, with respect to the support component, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously.
- a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container.
- the first container is capable of holding a first volume of a first fluid
- the second container is capable of holding a second volume of a second fluid.
- the fluidic system includes a support component including a panel for supporting at least the first container and the second container. The first container and the second container are substantially stationary with respect to the panel.
- the fluidic system includes a transport component including a gripper and at least one motor. The gripper is capable of gripping the first sensor and the second sensor substantially simultaneously and of releasing the first sensor and the second sensor substantially simultaneously.
- the at least one motor is configured to move the gripped first sensor, with respect to the panel, into the first container and in contact with the first volume of the first fluid.
- the at least one motor is further configured to move the gripped second sensor, with respect to the panel, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously.
- a method for processing biological sensors includes performing a hybridization process on at least a first sensor and a second sensor, and after the hybridization process, transferring the first sensor and the second sensor into a fluidic system.
- the fluidic system includes at least a first container and a second container, the first container holds a first volume of a first fluid, and the second container holds a second volume of a second fluid.
- the method includes moving the first sensor into the first container and in contact with the first volume of the first fluid, and moving the second sensor into the second container and in contact with the second volume of the second fluid. The moving the first sensor and the moving the second sensor are performed substantially simultaneously.
- Certain embodiments of the present invention provide an automated fluidic system. Some embodiments of the present invention provide a low-cost fluidic system. Certain embodiments of the present invention can improve throughput of the fluidic system. For example, a plurality of biological sensors, such as microarrays, is processed in parallel. Some embodiments of the present invention can reduce cross-contamination between different processes performed on one or more biological sensors. For example, at a given process, different sensors are washed, stained, and/or held in different wells. In another example, a given sensor is washed, stained, and/or held in different wells for different processes respectively. In yet another example, each well is used for at most a single process for at most a single sensor, such as a microarray.
- FIGS. 1-4 show a simplified fluidic system for processing biological sensors according to an embodiment of the present invention
- FIGS. 5 (A) and (B) show a simplified well strip in fluidic system for processing biological sensors according to an embodiment of the present invention
- FIG. 6 is a simplified diagram showing temperature as function of time for well strip in fluidic system for processing biological sensors according to an embodiment of the present invention
- FIGS. 7 (A) and (B) show a simplified gripper in fluidic system for processing biological sensors according to an embodiment of the present invention
- FIG. 8 shows a simplified fluidic system for processing biological sensors according to another embodiment of the present invention.
- FIG. 9 shows a simplified fluidic method for processing biological sensors that is performed by fluidic system 100 or 800 according to an embodiment of the present invention
- FIGS. 10 (A)-(V) are simplified diagrams showing movement of one or more sensors made by fluidic system 100 or 800 according to an embodiment of the present invention
- FIGS. 11 (A) and (B) are simplified microarrays on pegs that can be processed by fluidic system 100 or 800 according to an embodiment of the present invention
- the present invention relates in general to biological microarray techniques. More particularly, the invention provides a fluidic system and method for processing biological microarrays. Merely by way of example, the invention is described as it applies to personal instrumentation, but it should be recognized that the invention has a broader range of applicability.
- an agent includes a plurality of agents, including mixtures thereof.
- An individual is not limited to a human being but may also be other organisms including but not limited to mammals, plants, bacteria, or cells derived from any of the above.
- the practice of the present invention may employ, unless otherwise indicated, conventional techniques and descriptions of organic chemistry, polymer technology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, which are within the skill of the art.
- Such conventional techniques include polymer array synthesis, hybridization, ligation, and detection of hybridization using a label. Specific illustrations of suitable techniques can be had by reference to the example herein below. However, other equivalent conventional procedures can, of course, also be used.
- Such conventional techniques and descriptions can be found in standard laboratory manuals such as Genome Analysis: A Laboratory Manual Series ( Vols.
- the present invention can employ solid substrates, including arrays in some preferred embodiments.
- Methods and techniques applicable to polymer (including protein) array synthesis have been described in U.S. Ser. No. 09/536,841, WO 00/58516, U.S. Pat. Nos.
- Patents that describe synthesis techniques in specific embodiments include U.S. Patent Nos. 5,412,087, 6,147,205, 6,262,216, 6,310,189, 5,889,165, and 5,959,098.
- Nucleic acid arrays that are useful in the present invention include those that are commercially available from Affymetrix (Santa Clara, Calif.) under the brand name GeneChip®. Example arrays are shown on the website at affymetrix.com.
- the present invention also contemplates many uses for polymers attached to solid substrates. These uses include gene expression monitoring, profiling, library screening, genotyping and diagnostics. Gene expression monitoring and profiling methods can be shown in U.S. Pat. Nos. 5,800,992, 6,013,449, 6,020,135, 6,033,860, 6,040,138, 6,177,248 and 6,309,822. Genotyping and uses therefore are shown in U.S. Ser. Nos. 15 10/442,021, 10/013,598 (U.S. Patent Application Publication 20030036069), and U.S. Pat. Nos. 5,856,092, 6,300,063, 5,858,659, 6,284,460, 6,361,947, 6,368,799 and 6,333,179. Other uses are embodied in U.S. Pat. Nos. 5,871,928, 5,902,723, 6,045,996, 5,541,061, and 6,197,506.
- the present invention also contemplates sample preparation methods in certain preferred embodiments.
- the genomic sample Prior to or concurrent with genotyping, the genomic sample may be amplified by a variety of mechanisms, some of which may employ PCR. See, e.g., PCR Technology: Principles and Applications for DNA Amplification (Ed. H.A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattila et al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methods and Applications 1, 17 (1991); PCR (Eds.
- LCR ligase chain reaction
- LCR ligase chain reaction
- Landegren et al. Science 241, 1077 (1988) and Barringer et al. Gene 89:117 (1990)
- transcription amplification Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989) and WO88/10315
- self-sustained sequence replication Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990) and WO90/06995
- selective amplification of target polynucleotide sequences U.S. Pat. No.
- CP-PCR consensus sequence primed polymerase chain reaction
- AP-PCR arbitrarily primed polymerase chain reaction
- NABSA nucleic acid based sequence amplification
- Other amplification methods that may be used are described in U.S. Pat. Nos. 5,242,794, 5,494,810, 4,988,617 and in U.S. Ser. No. 09/854,317, each of which is incorporated herein by reference.
- Hybridization assay procedures and 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 (2 nd Ed. Cold Spring Harbor, N.Y., 1989); Berger and Kimmel Methods in Enzymology, Vol. 152, Guide to Molecular Cloning Techniques (Academic Press, Inc., San Diego, Calif., 1987); Young and Davism, P.N.A.S. 80: 1194 (1983). Methods and apparatus for carrying out repeated and controlled hybridization reactions have been described in U.S. Pat. Nos. 5,871,928, 5,874,219, 6,045,996 and 6,386,749, 6,391,623 each of which are incorporated herein by reference.
- the present invention also contemplates signal detection of hybridization between ligands in certain preferred embodiments. See U.S. Pat. Nos. 5,143,854, 5,578,832; 5,631,734; 5,834,758; 5,936,324; 5,981,956; 6,025,601; 6,141,096; 6,185,030; 6,201,639; 6,218,803; and 6,225,625, in U.S. Ser. No. 10/389,194 and in PCT Application PCT/US99/06097 (published as WO99/47964), each of which also is hereby incorporated by reference in its entirety for all purposes.
- Computer software products of the invention typically include computer readable medium having computer-executable instructions for performing the logic steps of the method of the invention.
- Suitable computer readable medium include floppy disk, CD-ROM/DVD/DVD-ROM, hard-disk drive, flash memory, ROM/RAM, magnetic tapes and etc.
- the computer executable instructions may be written in a suitable computer language or combination of several languages. Basic computational biology methods are described in, e.g.
- the present invention may also make use of various computer program products and software for a variety of purposes, such as probe design, management of data, analysis, and instrument operation. See, U.S. Pat. Nos. 5,593,839, 5,795,716, 5,733,729, 5,974,164, 6,066,454, 6,090,555, 6,185,561, 6,188,783, 6,223,127, 6,229,911 and 6,308,170.
- the present invention may have preferred embodiments that include methods for providing genetic information over networks such as the Internet as shown in U.S. Ser. Nos. 10/197,621, 10/063,559 (United States Publication No. 20020183936), Ser. Nos. 10/065,856, 10/065,868, 10/328,818, 10/328,872, 10/423,403, and 60/482,389.
- An “array” is an intentionally created collection of molecules which can be prepared either synthetically or biosynthetically.
- the molecules in the array can be identical or different from each other.
- the array can assume a variety of formats, e.g., libraries of soluble molecules; libraries of compounds tethered to resin beads, silica chips, or other solid supports.
- Nucleic acid library or array is an intentionally created collection of nucleic acids which can be prepared either synthetically or biosynthetically and screened for biological activity in a variety of different formats (e.g., libraries of soluble molecules; and libraries of oligos tethered to resin beads, silica chips, or other solid supports). Additionally, the term “array” is meant to include those libraries of nucleic acids which can be prepared by spotting nucleic acids of essentially any length (e.g., from 1 to about 1000 nucleotide monomers in length) onto a substrate.
- nucleic acid refers to a polymeric form of nucleotides of any length, either ribonucleotides, deoxyribonucleotides or peptide nucleic acids (PNAs), that comprise purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases.
- the backbone of the polynucleotide can comprise sugars and phosphate groups, as may typically be found in RNA or DNA, or modified or substituted sugar or phosphate groups.
- a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs.
- nucleoside, nucleotide, deoxynucleoside and deoxynucleotide generally include analogs such as those described herein. These analogs are those molecules having some structural features in common with a naturally occurring nucleoside or nucleotide such that when incorporated into a nucleic acid or oligonucleoside sequence, they allow hybridization with a naturally occurring nucleic acid sequence in solution. Typically, these analogs are derived from naturally occurring nucleosides and nucleotides by replacing and/or modifying the base, the ribose or the phosphodiester moiety. The changes can be tailor made to stabilize or destabilize hybrid formation or enhance the specificity of hybridization with a complementary nucleic acid sequence as desired.
- Biopolymer or biological polymer is intended to mean repeating units of biological or chemical moieties.
- Representative biopolymers include, but are not limited to, nucleic acids, oligonucleotides, amino acids, proteins, peptides, hormones, oligosaccharides, lipids, glycolipids, lipopolysaccharides, phospholipids, synthetic analogues of the foregoing, including, but not limited to, inverted nucleotides, peptide nucleic acids, Meta-DNA, and combinations of the above.
- Biopolymer synthesis is intended to encompass the synthetic production, both organic and inorganic, of a biopolymer.
- biomonomer which is intended to mean a single unit of biopolymer, or a single unit which is not part of a biopolymer.
- a nucleotide is a biomonomer within an oligonucleotide biopolymer
- an amino acid is a biomonomer within a protein or peptide biopolymer
- avidin, biotin, antibodies, antibody fragments, etc. are also biomonomers.
- initiation Biomonomer or “initiator biomonomer” is meant to indicate the first biomonomer which is covalently attached via reactive nucleophiles to the surface of the polymer, or the first biomonomer which is attached to a linker or spacer arm attached to the polymer, the linker or spacer arm being attached to the polymer via reactive nucleophiles.
- Complementary refers to the hybridization or base pairing between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer binding site on a single stranded nucleic acid to be sequenced or amplified.
- Complementary nucleotides are, generally, A and T (or A and U), or C and G.
- Two single stranded RNA or DNA molecules are said to be complementary when the nucleotides of one strand, optimally aligned and compared and with appropriate nucleotide insertions or deletions, pair with at least about 80% of the nucleotides of the other strand, usually at least about 90% to 95%, and more preferably from about 98 to 100%.
- complementarity exists when an RNA or DNA strand will hybridize under selective hybridization conditions to its complement.
- selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% complementary. See, M. Kanehisa Nucleic Acids Res. 12:203 (1984), incorporated herein by reference.
- a combinatorial synthesis strategy is an ordered strategy for parallel synthesis of diverse polymer sequences by sequential addition of reagents which may be represented by a reactant matrix and a switch matrix, the product of which is a product matrix.
- a reactant matrix is a 1 column by m row matrix of the building blocks to be added.
- the switch matrix is all or a subset of the binary numbers, preferably ordered, between 1 and m arranged in columns.
- a “binary strategy” is one in which at least two successive steps illuminate a portion, often half, of a region of interest on the substrate. In a binary synthesis strategy, all possible compounds which can be formed from an ordered set of reactants are formed.
- binary synthesis refers to a synthesis strategy which also factors a previous addition step. For example, a strategy in which a switch matrix for a masking strategy halves regions that were previously illuminated, illuminating about half of the previously illuminated region and protecting the remaining half (while also protecting about half of previously protected regions and illuminating about half of previously protected regions). It will be recognized that binary rounds may be interspersed with non-binary rounds and that only a portion of a substrate may be subjected to a binary scheme.
- a combinatorial “masking” strategy is a synthesis which uses light or other spatially selective deprotecting or activating agents to remove protecting groups from materials for addition of other materials such as amino acids.
- Effective amount refers to an amount sufficient to induce a desired result.
- Genome is all the genetic material in the chromosomes of an organism.
- DNA derived from the genetic material in the chromosomes of a particular organism is genomic DNA.
- a genomic library is a collection of clones made from a set of randomly generated overlapping DNA fragments representing the entire genome of an organism.
- Hybridization conditions will typically include salt concentrations of less than about 1M, more usually less than about 500 mM and preferably less than about 200 mM.
- Hybridization temperatures can be as low as 5.degree. C., but are typically greater than 22.degree. C., more typically greater than about 30.degree. C., and preferably in excess of about 37.degree. C. Longer fragments may require higher hybridization temperatures for specific hybridization.
- the combination of parameters is more important than the absolute measure of any one alone.
- Hybridizations e.g., allele-specific probe hybridizations, are generally performed under stringent conditions. For example, conditions where the salt concentration is no more than about 1 Molar (M) and a temperature of at least 25 degrees Celsius (° C.), e.g., 750 mM NaCl, 50 mM NaPhosphate, 5 mM EDTA, pH 7.4 (5 ⁇ SSPE) and a temperature of from about 25 to about 30° C.
- M Molar
- SSPE pH 7.4
- Hybridizations are usually performed under stringent conditions, for example, at a salt concentration of no more than 1 M and a temperature of at least 25° C.
- conditions of 5 ⁇ SSPE 750 mM NaCl, 50 mM NaPhosphate, 5 mM EDTA, pH 7.4 and a temperature of 25-30° C. are suitable for allele-specific probe hybridizations.
- stringent conditions see, for example, Sambrook, Fritsche and Maniatis. “ Molecular Cloning A laboratory Manual” 2nd Ed. Cold Spring Harbor Press (1989) which is hereby incorporated by reference in its entirety for all purposes above.
- hybridization refers to the process in which two single-stranded polynucleotides bind non-covalently to form a stable double-stranded polynucleotide; triple-stranded hybridization is also theoretically possible. The resulting (usually) double-stranded polynucleotide is a “hybrid.” The proportion of the population of polynucleotides that forms stable hybrids is referred to herein as the “degree of hybridization.”
- Hybridization probes are oligonucleotides capable of binding in a base-specific manner to a complementary strand of nucleic acid. Such probes include peptide nucleic acids, as described in Nielsen et al., Science 254, 1497-1500 (1991), and other nucleic acid analogs and nucleic acid mimetics.
- Hybridizing specifically to refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence or sequences under stringent conditions when that sequence is present in a complex mixture (e.g., total cellular) DNA or RNA.
- a complex mixture e.g., total cellular DNA or RNA.
- Isolated nucleic acid is an object species invention that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
- an isolated nucleic acid comprises at least about 50, 80 or 90% (on a molar basis) of all macromolecular species present.
- the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods).
- a ligand is a molecule that is recognized by a particular receptor.
- the agent bound by or reacting with a receptor is called a “ligand,” a term which is definitionally meaningful only in terms of its counterpart receptor.
- the term “ligand” does not imply any particular molecular size or other structural or compositional feature other than that the substance in question is capable of binding or otherwise interacting with the receptor.
- a ligand may serve either as the natural ligand to which the receptor binds, or as a functional analogue that may act as an agonist or antagonist.
- Linkage disequilibrium or allelic association means the preferential association of a particular allele or genetic marker with a specific allele, or genetic marker at a nearby chromosomal location more frequently than expected by chance for any particular allele frequency in the population.
- locus X has alleles a and b, which occur equally frequently
- linked locus Y has alleles c and d, which occur equally frequently
- linkage disequilibrium may result from natural selection of certain combination of alleles or because an allele has been introduced into a population too recently to have reached equilibrium with linked alleles.
- Mixed population or complex population refers to any sample containing both desired and undesired nucleic acids.
- a complex population of nucleic acids may be total genomic DNA, total genomic RNA or a combination thereof.
- a complex population of nucleic acids may have been enriched for a given population but include other undesirable populations.
- a complex population of nucleic acids may be a sample which has been enriched for desired messenger RNA (mRNA) sequences but still includes some undesired ribosomal RNA sequences (rRNA).
- mRNA messenger RNA
- rRNA undesired ribosomal RNA sequences
- Monomer refers to any member of the set of molecules that can be joined together to form an oligomer or polymer.
- the set of monomers useful in the present invention includes, but is not restricted to, for the example of (poly)peptide synthesis, the set of L-amino acids, D-amino acids, or synthetic amino acids.
- “monomer” refers to any member of a basis set for synthesis of an oligomer. For example, dimers of L-amino acids form a basis set of 400 “monomers” for synthesis of polypeptides. Different basis sets of monomers may be used at successive steps in the synthesis of a polymer.
- mRNA or mRNA transcripts include, but not limited to pre-mRNA transcript(s), transcript processing intermediates, mature mRNA(s) ready for translation and transcripts of the gene or genes, or nucleic acids derived from the mRNA transcript(s). Transcript processing may include splicing, editing and degradation.
- a nucleic acid derived from an mRNA transcript refers to a nucleic acid for whose synthesis the mRNA transcript or a subsequence thereof has ultimately served as a template.
- a cDNA reverse transcribed from an mRNA, an RNA transcribed from that cDNA, a DNA amplified from the cDNA, an RNA transcribed from the amplified DNA, etc. are all derived from the mRNA transcript and detection of such derived products is indicative of the presence and/or abundance of the original transcript in a sample.
- mRNA derived samples include, but are not limited to, mRNA transcripts of the gene or genes, cDNA reverse transcribed from the mRNA, cRNA transcribed from the cDNA, DNA amplified from the genes, RNA transcribed from amplified DNA, and the like.
- Nucleic acid library or array is an intentionally created collection of nucleic acids which can be prepared either synthetically or biosynthetically and screened for biological activity in a variety of different formats (e.g., libraries of soluble molecules; and libraries of oligos tethered to resin beads, silica chips, or other solid supports). Additionally, the term “array” is meant to include those libraries of nucleic acids which can be prepared by spotting nucleic acids of essentially any length (e.g., from 1 to about 1000 nucleotide monomers in length) onto a substrate.
- nucleic acid refers to a polymeric form of nucleotides of any length, either ribonucleotides, deoxyribonucleotides or peptide nucleic acids (PNAs), that comprise purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases.
- the backbone of the polynucleotide can comprise sugars and phosphate groups, as may typically be found in RNA or DNA, or modified or substituted sugar or phosphate groups.
- a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs.
- nucleoside, nucleotide, deoxynucleoside and deoxynucleotide generally include analogs such as those described herein. These analogs are those molecules having some structural features in common with a naturally occurring nucleoside or nucleotide such that when incorporated into a nucleic acid or oligonucleoside sequence, they allow hybridization with a naturally occurring nucleic acid sequence in solution. Typically, these analogs are derived from naturally occurring nucleosides and nucleotides by replacing and/or modifying the base, the ribose or the phosphodiester moiety. The changes can be tailor made to stabilize or destabilize hybrid formation or enhance the specificity of hybridization with a complementary nucleic acid sequence as desired.
- Nucleic acids according to the present invention may include any polymer or oligomer of pyrimidine and purine bases, preferably cytosine, thymine, and uracil, and adenine and guanine, respectively. See Albert L. Lehninger, PRINCIPLES OF BIOCHEMISTRY, at 793-800 (Worth Pub. 1982). Indeed, the present invention contemplates any deoxyribonucleotide, ribonucleotide or peptide nucleic acid component, and any chemical variants thereof, such as methylated, hydroxymethylated or glucosylated forms of these bases, and the like.
- the polymers or oligomers may be heterogeneous or homogeneous in composition, and may be isolated from naturally-occurring sources or may be artificially or synthetically produced.
- the nucleic acids may be DNA or RNA, or a mixture thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states.
- oligonucleotide or “polynucleotide” is a nucleic acid ranging from at least 2, preferable at least 8, and more preferably at least 20 nucleotides in length or a compound that specifically hybridizes to a polynucleotide.
- Polynucleotides of the present invention include sequences of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) which may be isolated from natural sources, recombinantly produced or artificially synthesized and mimetics thereof.
- a further example of a polynucleotide of the present invention may be peptide nucleic acid (PNA).
- the invention also encompasses situations in which there is a nontraditional base pairing such as Hoogsteen base pairing which has been identified in certain tRNA molecules and postulated to exist in a triple helix.
- Nontraditional base pairing such as Hoogsteen base pairing which has been identified in certain tRNA molecules and postulated to exist in a triple helix.
- Polynucleotide and oligonucleotide are used interchangeably in this application.
- Probe is a surface-immobilized molecule that can be recognized by a particular target. See U.S. Pat. No. 6,582,908 for an example of arrays having all possible combinations of probes with 10, 12, and more bases.
- 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, nucleic acids, oligosaccharides, proteins, and monoclonal antibodies.
- hormones e.g., opioid peptides, steroids, etc.
- hormone receptors e.g., enzymes, enzyme substrates, cofactors, drugs, lectins, sugars, oligonucleotides, nucleic acids, oligosaccharides,
- Primer is a single-stranded oligonucleotide capable of acting as a point of initiation for template-directed DNA synthesis under suitable conditions e.g., buffer and temperature, in the presence of four different nucleoside triphosphates and an agent for polymerization, such as, for example, DNA or RNA polymerase or reverse transcriptase.
- the length of the primer in any given case, depends on, for example, the intended use of the primer, and generally ranges from 15 to 30 nucleotides. Short primer molecules generally require cooler temperatures to form sufficiently stable hybrid complexes with the template.
- a primer need not reflect the exact sequence of the template but must be sufficiently complementary to hybridize with such template.
- the primer site is the area of the template to which a primer hybridizes.
- the primer pair is a set of primers including a 5′ upstream primer that hybridizes with the 5′ end of the sequence to be amplified and a 3′ downstream primer that hybridizes with the complement of the 3′ end of the sequence to be
- Polymorphism refers to the occurrence of two or more genetically determined alternative sequences or alleles in a population.
- a polymorphic marker or site is the locus at which divergence occurs. Preferred markers have at least two alleles, each occurring at frequency of greater than 1%, and more preferably greater than 10% or 20% of a selected population.
- a polymorphism may comprise one or more base changes, an insertion, a repeat, or a deletion.
- a polymorphic locus may be as small as one base pair.
- Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu.
- the first identified allelic form is arbitrarily designated as the reference form and other allelic forms are designated as alternative or variant alleles.
- the allelic form occurring most frequently in a selected population is sometimes referred to as the wildtype form. Diploid organisms may be homozygous or heterozygous for allelic forms.
- a diallelic polymorphism has two forms.
- a triallelic polymorphism has three forms. Single nucleotide polymorphisms (SNPs) are included in polymorphisms.
- Receptor A molecule that has an affinity for a given ligand. Receptors may be naturally-occurring or manmade molecules. Also, they can be employed in their unaltered state or as aggregates with other species. Receptors may be attached, covalently or noncovalently, to a binding member, either directly or via a specific binding substance. Examples of receptors 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, polynucleotides, nucleic acids, peptides, cofactors, lectins, sugars, polysaccharides, cells, cellular membranes, and organelles.
- Receptors are sometimes referred to in the art as anti-ligands. As the term receptors is used herein, no difference in meaning is intended.
- a “Ligand Receptor Pair” is formed when two macromolecules have combined through molecular recognition to form a complex.
- Other examples of receptors which can be investigated by this invention include but are not restricted to those molecules shown in U.S. Pat. No. 5,143,854, which is hereby incorporated by reference in its entirety.
- Solid support “support”, and “substrate” are used interchangeably and refer to a material or group of materials having a rigid or semi-rigid surface or surfaces.
- at least one surface of the solid support will be substantially flat, although in some embodiments it may be desirable to physically separate synthesis regions for different compounds with, for example, wells, raised regions, pins, etched trenches, or the like.
- the solid support(s) will take the form of beads, resins, gels, microspheres, or other geometric configurations. See U.S. Pat. No. 5,744,305 for exemplary substrates.
- Target A molecule that has an affinity for a given probe.
- Targets may be naturally occurring or man-made 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.
- 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, nucleic acids, peptides, cofactors, lectins, sugars, polysaccharides, cells, cellular membranes, and organelles. Targets are sometimes referred to in the art as anti-probes. 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.
- FIGS. 1-4 show a simplified fluidic system for processing biological sensors according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications.
- the system 100 includes a fluidic component 110 , a support component 120 , and an electrical and mechanical component 130 . Although the above has been shown using a selected group of components for the system 100 , there can be many alternatives, modifications, and variations. For example, some of the components may be expanded and/or combined. Other components may be inserted to those noted above. Depending upon the embodiment, the arrangement of components may be interchanged with others replaced. Further details of these components are found throughout the present specification and more particularly below.
- the fluidic component 110 includes at least some containers. Each of these containers includes one or more fluids for processing at least one biological sensor.
- each container is a well.
- the wells are grouped into one or more plate and/or one or more strip. As shown in FIGS. 1-4 , the wells are grouped into at least a well plate 112 and a well strip 114 .
- the well plate 112 includes 96 wells
- the well strip 114 includes 4 wells.
- each well contains one or more fluids, and different wells contain the same or different fluids. In yet another embodiment, different wells have the same or different depths.
- FIGS. 5 (A) and (B) show a simplified well strip 114 in fluidic system 100 for processing biological sensors according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications.
- the well strip 114 includes a plurality of tubes 510 , a heater 512 , and a thermometer 514 such as a thermocouple.
- a thermometer 514 such as a thermocouple.
- the plurality of tubes 510 provides a plurality of wells for the one or more sensors.
- each of the plurality of tubes 510 includes at least one fluid.
- the fluid is heated by the heater 512 , and the temperature of the fluid is monitored, directly or indirectly, by the thermocouple 514 .
- the thermocouple 514 sends a signal to a temperature controller.
- the temperature controller is also a component of the fluidic system 100 .
- the temperature controller processes the received signal in light of a target temperature and adjusts the power of the heater 512 in order to achieve the targeted temperature for the fluid.
- the targeted temperature is provided to the fluidic system 100 by the user through a temperature interface 140 according to an embodiment of the present invention.
- the temperature interface 140 is a component of the fluidic system 100 .
- FIG. 6 is a simplified diagram showing temperature as function of time for well strip 114 in fluidic system 100 for processing biological sensors according to an embodiment of the present invention.
- This diagram is merely an example, which should not unduly limit the scope of the claims.
- a curve 610 represents the temperature measured by the thermometer 514 as a function of time.
- Curves 620 represent temperatures for fluids in the plurality of tubes 510 , such as wells, as functions of time. The temperatures for fluids have been measured by other thermometers, such as thermocouples, in the plurality of tubes.
- Curves 620 show that at a given time the fluid temperatures in different tubes are close to each other, and the fluid temperatures stabilize at about 50° C. after a period of time.
- the fluidic component 110 also includes holder strips 116 and 118 .
- the holder strip 116 is used to transport the one or more sensors to the fluidic system 100 after a hybridization process is performed.
- the holder strip 116 is a hybridization tray.
- the holder strip 118 is used to transport the one or more sensors out of the fluidic system 100 .
- the holder strip 118 includes at least a cuvette holder.
- the support component 120 includes at least a panel 122 .
- the panel 122 is placed horizontally.
- the fluidic component 110 is placed on the panel 122 .
- the fluidic component 110 is fixed at a predetermined position, directly or indirectly, on the panel 122 .
- the one or more wells of the fluidic component are substantially perpendicular to the panel 122 .
- the well plate 112 includes a plurality of wells arranged into a plurality of rows and a plurality of columns.
- the number of rows is equal to or larger than the number of columns.
- each of the plurality of rows extends from a first side of the well plate to a second side of the well plate.
- the well strip 114 and two holder strips 116 and 118 all are placed next to the first side of the well plate 112 .
- the plurality of rows is perpendicular to the plurality of columns.
- the well strip 114 includes a row of wells.
- the holder strips 116 and 118 each include a row of wells capable of holding the one or more sensors.
- the plurality of rows is parallel to the rows of wells for the well strip 114 and the holder strips 116 and 118 .
- the plurality of columns is parallel to the rows of wells for the well strip 114 and the holder strips 116 and 118 .
- the well plate 112 , the well strip 114 , the holder strip 116 , and/or the holder strip 118 include a plurality of wells. At least one of the plurality of wells contains one or more fluids.
- the volume of the one or more fluids in each well is equal to or smaller than 3 ml or 5 ml.
- the volume of the one or more fluids for low stringency wash or stain is about 1.9 ml, and for high stringency wash is about 3.7 ml.
- different wells have the same or different depths.
- the electrical and mechanical component 130 can move each of the one or more sensors from one position to another position.
- the one or more sensors are not parts of the electrical and mechanical component 130 .
- the electrical and mechanical component 130 is used as a transport component.
- the movement of the sensors can be made in one, two, or three dimensions.
- the movement of the sensors is made at various speed.
- the electrical and mechanical component 130 moves each of the one or more sensors from one well to another well of the fluidic component 110 .
- the electrical and mechanical component 130 can move each of the one or more sensors within a corresponding well of the fluidic component 110 , and/or move each of the one or more sensors into and/or out of a corresponding well of the fluidic component 110 .
- the electrical and mechanical component 130 includes at least a gripper 132 , and motors 134 , 136 , and 138 .
- the motors 134 , 136 , and 138 each can move one or more sensors in two opposite directions of one dimension.
- the motor 134 can move the one or more sensors in two opposite directions that are perpendicular to the panel 122 .
- the motors 136 and 138 can move the one or more sensors in directions that are parallel to the panel 122 .
- the motor 136 can move the one or more sensors in directions that are parallel to the well strip 114 .
- the motor 138 can move the one or more sensors in directions that are perpendicular to the well strip 114 .
- the electrical and mechanical component 130 includes other components.
- the electrical and mechanical component 130 includes at least a high-voltage power supply and a low-voltage power supply.
- the power suppliers are used to provide voltages at predetermined values and/or within predetermined ranges to, for example, the motors 134 , 136 , and 138 .
- the power suppliers receive 115-votage AC power from an external source.
- FIGS. 7 (A) and (B) show a simplified gripper 132 in fluidic system 100 for processing biological sensors according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications.
- the gripper 132 includes an actuator 710 , and two arms 720 and 730 .
- the above has been shown using a selected group of components for the gripper 132 , there can be many alternatives, modifications, and variations. For example, some of the components may be expanded and/or combined. Other components may be inserted to those noted above. Depending upon the embodiment, the arrangement of components may be interchanged with others replaced. Further details of these components are found throughout the present specification and more particularly below.
- the actuator 710 is used to move the arms 720 and 730 .
- the actuator 710 is an electrical actuator.
- the actuator 710 is a pneumatic actuator.
- the pneumatic actuator receives a gas at a first pressure from a gas regulator, and the gas regulator converts the gas at a second pressure to the gas at the first pressure.
- the gas is clean dry air.
- the first pressure is monitored by a pressure meter 150 , which is a component of the fluidic system 100 .
- the arm 720 includes a plurality of fingers, such as fingers 722 , 724 , 726 , and 728 , as shown in FIG. 7 (A).
- the arm 730 also includes a plurality of fingers.
- the gripper 132 is used to grip the one or more sensors.
- the one or more sensors are not parts of the system 100 .
- FIGS. 1-4 are merely examples, which should not unduly limit the scope of the claims.
- the well plate 112 can be replaced by a well strip with a single row or a single column.
- the strips 114 , 116 , and/or 118 can be replaced by a plate with a plurality of rows and a plurality of columns.
- one or more additional plates, and/or one or more additional strips can be included in the fluidic component 110 .
- FIG. 8 shows a simplified fluidic system for processing biological sensors according to another embodiment of the present invention.
- the system 800 includes a fluidic component, a support component, and an electrical and mechanical component.
- the fluidic component, the support component, and the electrical and mechanical component are either the same as or modified from the fluidic component 110 , the support component 120 , and the electrical and mechanical component 130 respectively.
- the fluidic component of the system 800 is either partially or completely enclosed by a cover 810 .
- the fluidic component of the system 800 includes a well plate, a well strip, and two holder strips.
- the well plate includes a plurality of wells arranged into a plurality of rows and a plurality of columns.
- the number of rows is equal to or larger than the number of columns.
- each of the plurality of columns extends from a first side of the well plate to a second side of the well plate.
- the well strip and two holder strips all are placed next to the first side of the well plate.
- the plurality of rows is perpendicular to the plurality of columns.
- the well strip includes a row of wells
- each of the holder strips includes a row of wells that are capable of holding the one or more sensors.
- the plurality of rows is parallel to the rows of wells for the well strip and the holder strips.
- the plurality of columns is parallel to the rows of wells for the well strip and the holder strips.
- a fluidic system for processing biological sensors includes a fluidic component, a support component, and an electrical and mechanical component.
- the fluidic system is the system 100 or 800 .
- the electrical and mechanical component can move each of one or more sensors within a corresponding well of the fluidic component, and/or move each of the one or more sensors into and/or out of a corresponding well of the fluidic component.
- the fluidic component includes a well plate, a well strip, and two holder strips.
- one holder strip is used to transport the one or more sensors to the fluidic system after a hybridization process is performed.
- another holder strip is used to transport the one or more microarrays out of the fluidic system.
- the movement of the one or more sensors into, within, and/or out of the fluidic system 100 or 800 is controlled by instructions received by the electrical and mechanical component from a processing system.
- the processing system is external to the fluidic system.
- the processing system is a component of the fluidic system.
- the processing system includes a computer or a processor.
- the computer or the processor is directed by a code.
- the computer or the processor is directed by instructions included by a computer-readable medium in a computer program product.
- FIG. 9 shows a simplified fluidic method for processing biological sensors that is performed by fluidic system 100 or 800 according to an embodiment of the present invention.
- the method 900 includes a process 910 for low stringency wash, a process 920 for high stringency wash, a process 930 for Streptavidin Phycoerythrin (SAPE) stain, a process 940 for low stringency wash, a process 950 for antibody (AB) stain, a process 960 for low stringency wash, a process 970 for SAPE stain, and a process 980 for low stringency wash.
- SAPE Streptavidin Phycoerythrin
- each of the one or more sensors is washed in a plurality of wells at room temperature.
- the plurality of wells includes two wells.
- the plurality of wells includes four wells.
- the corresponding sensor is mixed with the fluid in the well for a plurality of times.
- the plurality of times includes 23 times within 3 minutes.
- the plurality of times includes 36 times within 2 minutes.
- each of the one or more sensors is washed in at least one well.
- the fluid is at an elevated temperature, and the corresponding sensor is mixed with the fluid for a period of time.
- the elevated temperature is 48° C., and the period of time is 25 minutes.
- the elevated temperature is 41° C., and the period of time is also 25 minutes.
- each of the one or more sensors is stained in at least one well at room temperature.
- the corresponding sensor is mixed with the fluid for a period of time.
- the period of time is 10 minutes.
- each of the one or more sensors is stained in at least one well at room temperature.
- the corresponding sensor is mixed with the fluid for a period of time.
- the period of time is 10 minutes.
- the processes 910 , 920 , 930 , 940 , 950 , 960 , 970 , and 980 are all performed by the fluidic system 100 or 800 according to an embodiment of the present invention.
- the one or more sensors Prior to the process 910 , the one or more sensors are processed for hybridization. For example, the hybridization process is performed at 48° C. for 16 hours.
- the one or more sensors are scanned.
- FIGS. 10 (A)-(V) are simplified diagrams showing movement of one or more sensors made by fluidic system 100 or 800 according to an embodiment of the present invention. This diagram is merely an example, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications.
- each of FIGS. 10 (A)-(V) shows the well plate 112 , the well strip 114 , and the holder strip 116 and 118 .
- the well plate includes 96 wells that are arranged into rows 1 - 12 and columns A-H.
- the row 1 is intended for SAPE stain
- the row 3 is intended for AB stain
- rows 5 - 12 are intended for low stringency wash.
- the well strip 112 is intended for high stringency wash.
- the holder strip 116 is a hybridization tray that is intended to transport the one or more sensors to the fluidic system 100 after a hybridization process is performed.
- the holder strip 118 includes a cuvette holder and is intended to transport the one or more microarrays out of the fluidic system 100 .
- the well is marked with a square with hatch pattern.
- the one or more sensors are transported to the fluidic system 100 by the holder strip 116 .
- the one or more sensors are processed with low stringency wash according to the process 910 as shown in FIGS. 10 (B)-(E).
- Each sensor is washed in four wells in rows 12 , 11 , 10 , and 9 respectively.
- the sensor is agitated substantially parallel to the well depth in order to achieve a plurality of times of mixture with the fluid within the well.
- the one or more sensors are moved to the well strip 114 and processed with high stringency wash as shown in FIG. 10 (F).
- FIG. 10 (G) shows the one or more sensors are moved from the well strip 114 to the row 1 of the well plate 112 .
- the one or more sensors are stained with SAPE according to the process 930 .
- another low stringency wash is performed on the one or more sensors as shown in FIGS. 10 (H)-(K).
- Each sensor is washed in four wells in rows 8 , 7 , 6 , and 5 respectively.
- the sensor is agitated substantially parallel to the well depth in order to achieve a plurality of times of mixture with the fluid within the well.
- the one or more sensors are moved to the row 3 of the well plate 112 as shown in FIG. 10 (L).
- the one or more sensors are stained with AB according to the process 950 .
- the one or more sensors are processed with low stringency wash according to the process 960 as shown in FIGS. 10 (M)-(P).
- Each sensor is washed in four wells in rows 12 , 11 , 10 , and 9 respectively, and none of these four wells has been used at the process 910 .
- the sensor is agitated substantially parallel to the well depth in order to achieve a plurality of times of mixture with the fluid within the well.
- FIG. 10 (Q) shows the one or more sensors are moved from the row 9 to the row 1 of the well plate 112 .
- the one or more sensors are stained with SAPE according to the process 970 . None of the wells used in the process 970 has been used in the process 930 .
- another low stringency wash is performed on the one or more sensors as shown in FIGS. 10 (R)-(U). Each sensor is washed in four wells in rows 8 , 7 , 6 , and 5 respectively, and none of these four wells has been used at the process 940 .
- the sensor is agitated substantially parallel to the well depth in order to achieve a plurality of times of mixture with the fluid within the well.
- the one or more sensors are placed into the holder strip 118 as shown in FIG. 10 (V). These sensors can be transported from the fluidic system 100 to a scanner.
- the fluidic system 100 or 800 can be used to process biological sensors according to certain embodiments of the present invention. As an example, the processing is performed according to the method 900 .
- the biological sensors can be various types. See U.S. patent application Ser. Nos. 10/826,577 filed Apr. 16, 2004 and Ser. No. 11/243,621 filed Oct. 4, 2005, each of which is incorporated by reference herein.
- each of the one or more biological sensors is a biological microarray.
- the biological microarray has a sensor length, a sensor width, and a sensor thickness.
- the senor length is equal to or shorter than 10 mm
- the sensor width is equal to or narrower than 10 mm
- the sensor thickness is equal to or thinner than 1000 ⁇ m.
- the sensor length is equal to about 6.3 mm
- the sensor width is equal to about 6.3 mm
- the sensor thickness is equal to about 700 ⁇ m.
- each biological sensor is a biological microarray.
- each biological sensor is attached to a support component.
- the support component is a peg.
- FIGS. 11 (A) and (B) are simplified microarrays on pegs that can be processed by fluidic system 100 or 800 according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications.
- FIG. 11 (A) a biological microarray is attached to one peg, and each biological microarray can be manipulated individually by the fluidic system 100 or 800 .
- FIG. 11 (A) a biological microarray is attached to one peg, and each biological microarray can be manipulated individually by the fluidic system 100 or 800 . As shown in FIG.
- a plurality of biological microarrays is attached to a plurality of pegs respectively, and the plurality of pegs is connected by a base component.
- the plurality of pegs includes four pegs, and the plurality of biological microarrays includes four microarrays.
- the plurality of pegs includes eight pegs, and the plurality of biological microarrays includes eight microarrays.
- the plurality of microarrays is manipulated together by the fluidic system 100 or 800 .
- the fluidic system 100 or 800 can be used to process biological sensors ready for scan according to certain embodiments of the present invention.
- the processing is performed according to the method 900 .
- the scanner for scanning the processed biological sensors can be of various types.
- the scanner is made by Axon.
- a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container.
- the first container is capable of holding a first volume of a first fluid
- the second container is capable of holding a second volume of a second fluid.
- the fluidic system includes a support component configured to support at least the first container and the second container. The first container and the second container are substantially stationary with respect to the support component.
- the fluidic system includes a transport component configured to move a first sensor, with respect to the support component, into the first container and in contact with the first volume of the first fluid, and move a second sensor, with respect to the support component, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously.
- the fluidic system is implemented according the system 100 and/or the system 800 .
- a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container.
- the first container is capable of holding a first volume of a first fluid
- the second container is capable of holding a second volume of a second fluid.
- the fluidic system includes a support component including a panel for supporting at least the first container and the second container. The first container and the second container are substantially stationary with respect to the panel.
- the fluidic system includes a transport component including a gripper and at least one motor. The gripper is capable of gripping the first sensor and the second sensor substantially simultaneously and of releasing the first sensor and the second sensor substantially simultaneously.
- the at least one motor is configured to move the gripped first sensor, with respect to the panel, into the first container and in contact with the first volume of the first fluid.
- the at least one motor is further configured to move the gripped second sensor, with respect to the panel, into the second container and in contact with the second volume of the second fluid.
- the first sensor and the second sensor are moved substantially simultaneously.
- the fluidic system is implemented according the system 100 and/or the system 800 .
- a method for processing biological sensors includes performing a hybridization process on at least a first sensor and a second sensor, and after the hybridization process, transferring the first sensor and the second sensor into a fluidic system.
- the fluidic system includes at least a first container and a second container, the first container holds a first volume of a first fluid, and the second container holds a second volume of a second fluid.
- the method includes moving the first sensor into the first container and in contact with the first volume of the first fluid, and moving the second sensor into the second container and in contact with the second volume of the second fluid. The moving the first sensor and the moving the second sensor are performed substantially simultaneously.
- the fluidic system is implemented according the system 100 and/or the system 800 .
- the fluidic system 100 or the fluidic system 800 is used as a fluidic station.
- the fluidic station as shown in FIG. 1 , has a footprint of 19.5-inch width and 17.5-inch depth. Additionally, the fluidic station has a height of 15 inch.
- certain embodiments of the present invention are used for personal and portable instruments as well as methods for processing biological microarrays.
- the present invention has various advantages. Certain embodiments of the present invention provide an automated fluidic system. Some embodiments of the present invention provide a low-cost fluidic system. Certain embodiments of the present invention can improve throughput of the fluidic system. For example, a plurality of biological sensors, such as microarrays, is processed in parallel. Some embodiments of the present invention can reduce cross-contamination between different processes performed on one or more biological sensors. For example, at a given process, different sensors are washed, stained, and/or held in different wells. In another example, a given sensor is washed, stained, and/or held in different wells for different processes respectively. In yet another example, each well is used for at most a single process for at most a single sensor, such as a microarray.
Landscapes
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Engineering & Computer Science (AREA)
- Robotics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
A fluidic system and method for processing biological sensors. The fluidic system includes a fluidic component including at least a first container and a second container. The first container is capable of holding a first volume of a first fluid, and the second container is capable of holding a second volume of a second fluid. Additionally, the fluidic system includes a support component configured to support at least the first container and the second container. The first container and the second container are substantially stationary with respect to the support component. Moreover, the fluidic system includes a transport component configured to move a first sensor, with respect to the support component, into the first container and in contact with the first volume of the first fluid, and move a second sensor, with respect to the support component, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously.
Description
- This application claims priority to U.S. Provisional Application No. 60/669,130, filed Apr. 6, 2005, which is incorporated by reference herein.
- Not applicable.
- Not applicable.
- The present invention relates in general to biological microarray techniques. More particularly, the invention provides a fluidic system and method for processing biological microarrays. Merely by way of example, the invention is described as it applies to personal instrumentation, but it should be recognized that the invention has a broader range of applicability.
- A biological microarray often includes nucleic acid probes that are used to extract sequence information from nucleic acid samples. The nucleic acid samples are exposed to the nucleic acid probes under certain conditions that would allow hybridization. Afterwards, the biological microarray is processed and scanned to determine to which probes the nucleic acid samples have hybridized. Based on such determination, the sequence information is obtained by comparing patterns of hybridization and non-hybridization. As an example, the sequence information can be used for sequencing nucleic acids, or diagnostic screening for genetic diseases or for the presence of a particular pathogen or a strain of pathogen.
- The processing of the biological microarray prior to scanning is often performed by a fluidic system. For example, the fluidic system includes a fluidic station. The fluidic station can wash and stain the microarray. With the advancement of the microarray design, the fluidic station often needs to be modified in order to improve automation and lower cost.
- Hence it is highly desirable to improve fluidic techniques for processing microarrays.
- The present invention relates in general to biological microarray techniques. More particularly, the invention provides a fluidic system and method for processing biological microarrays. Merely by way of example, the invention is described as it applies to personal instrumentation, but it should be recognized that the invention has a broader range of applicability.
- According to one embodiment of the present invention, a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container. The first container is capable of holding a first volume of a first fluid, and the second container is capable of holding a second volume of a second fluid. Additionally, the fluidic system includes a support component configured to support at least the first container and the second container. The first container and the second container are substantially stationary with respect to the support component. Moreover, the fluidic system includes a transport component configured to move a first sensor, with respect to the support component, into the first container and in contact with the first volume of the first fluid, and move a second sensor, with respect to the support component, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously.
- According to another embodiment, a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container. The first container is capable of holding a first volume of a first fluid, and the second container is capable of holding a second volume of a second fluid. Additionally, the fluidic system includes a support component including a panel for supporting at least the first container and the second container. The first container and the second container are substantially stationary with respect to the panel. Moreover, the fluidic system includes a transport component including a gripper and at least one motor. The gripper is capable of gripping the first sensor and the second sensor substantially simultaneously and of releasing the first sensor and the second sensor substantially simultaneously. The at least one motor is configured to move the gripped first sensor, with respect to the panel, into the first container and in contact with the first volume of the first fluid. The at least one motor is further configured to move the gripped second sensor, with respect to the panel, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously.
- According to another embodiment, a method for processing biological sensors includes performing a hybridization process on at least a first sensor and a second sensor, and after the hybridization process, transferring the first sensor and the second sensor into a fluidic system. The fluidic system includes at least a first container and a second container, the first container holds a first volume of a first fluid, and the second container holds a second volume of a second fluid. Additionally, the method includes moving the first sensor into the first container and in contact with the first volume of the first fluid, and moving the second sensor into the second container and in contact with the second volume of the second fluid. The moving the first sensor and the moving the second sensor are performed substantially simultaneously.
- Many benefits are achieved by way of the present invention over conventional techniques. Certain embodiments of the present invention provide an automated fluidic system. Some embodiments of the present invention provide a low-cost fluidic system. Certain embodiments of the present invention can improve throughput of the fluidic system. For example, a plurality of biological sensors, such as microarrays, is processed in parallel. Some embodiments of the present invention can reduce cross-contamination between different processes performed on one or more biological sensors. For example, at a given process, different sensors are washed, stained, and/or held in different wells. In another example, a given sensor is washed, stained, and/or held in different wells for different processes respectively. In yet another example, each well is used for at most a single process for at most a single sensor, such as a microarray.
- Depending upon embodiment, one or more of these benefits may be achieved. These benefits and various additional objects, features and advantages of the present invention can be fully appreciated with reference to the detailed description and accompanying drawings that follow.
-
FIGS. 1-4 show a simplified fluidic system for processing biological sensors according to an embodiment of the present invention; - FIGS. 5(A) and (B) show a simplified well strip in fluidic system for processing biological sensors according to an embodiment of the present invention;
-
FIG. 6 is a simplified diagram showing temperature as function of time for well strip in fluidic system for processing biological sensors according to an embodiment of the present invention; - FIGS. 7(A) and (B) show a simplified gripper in fluidic system for processing biological sensors according to an embodiment of the present invention;
-
FIG. 8 shows a simplified fluidic system for processing biological sensors according to another embodiment of the present invention; -
FIG. 9 shows a simplified fluidic method for processing biological sensors that is performed byfluidic system - FIGS. 10(A)-(V) are simplified diagrams showing movement of one or more sensors made by
fluidic system - FIGS. 11(A) and (B) are simplified microarrays on pegs that can be processed by
fluidic system - The present invention relates in general to biological microarray techniques. More particularly, the invention provides a fluidic system and method for processing biological microarrays. Merely by way of example, the invention is described as it applies to personal instrumentation, but it should be recognized that the invention has a broader range of applicability.
- The present invention cites certain patents, applications and other references. When a patent, application, or other reference is cited or repeated below, it should be understood that it is incorporated by reference in its entirety for all purposes as well as for the proposition that is recited.
- As used in this application, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an agent” includes a plurality of agents, including mixtures thereof.
- An individual is not limited to a human being but may also be other organisms including but not limited to mammals, plants, bacteria, or cells derived from any of the above.
- Throughout this disclosure, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
- The practice of the present invention may employ, unless otherwise indicated, conventional techniques and descriptions of organic chemistry, polymer technology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology, which are within the skill of the art. Such conventional techniques include polymer array synthesis, hybridization, ligation, and detection of hybridization using a label. Specific illustrations of suitable techniques can be had by reference to the example herein below. However, other equivalent conventional procedures can, of course, also be used. Such conventional techniques and descriptions can be found in standard laboratory manuals such as Genome Analysis: A Laboratory Manual Series (Vols. I-IV), Using Antibodies: A Laboratory Manual, Cells: A Laboratory Manual, PCR Primer: A Laboratory Manual, and Molecular Cloning: A Laboratory Manual (all from Cold Spring Harbor Laboratory Press), Stryer, L. (1995) Biochemistry (4th Ed.) Freeman, New York, Gait, “Oligonucleotide Synthesis: A Practical Approach” 1984, IRL Press, London, Nelson and Cox (2000), Lehninger, Principles of
Biochemistry 3rd Ed., W.H. Freeman Pub., New York, N.Y. and Berg et al. (2002) Biochemistry, 5th Ed., W.H. Freeman Pub., New York, N.Y., all of which are herein incorporated in their entirety by reference for all purposes. - The present invention can employ solid substrates, including arrays in some preferred embodiments. Methods and techniques applicable to polymer (including protein) array synthesis have been described in U.S. Ser. No. 09/536,841, WO 00/58516, U.S. Pat. Nos. 5,143,854, 5,242,974, 5,252,743, 5,324,633, 5,384,261, 5,405,783, 5,424,186, 5,451,683, 5,482,867, 5,491,074, 5,527,681, 5,550,215, 5,571,639, 5,578,832, 5,593,839, 5,599,695, 5,624,711, 5,631,734, 5,795,716, 5,831,070, 5,837,832, 5,856,101, 5,858,659, 5,936,324, 5,968,740, 5,974,164, 5,981,185, 5,981,956, 6,025,601, 6,033,860, 6,040,193, 6,090,555, 6,136,269, 6,269,846 and 6,428,752, in PCT Applications Nos. PCT/US99/00730 (International Publication Number WO 99/36760) and PCT/US01/04285 (International Publication Number WO 01/58593), which are all incorporated herein by reference in their entirety for all purposes.
- Patents that describe synthesis techniques in specific embodiments include U.S. Patent Nos. 5,412,087, 6,147,205, 6,262,216, 6,310,189, 5,889,165, and 5,959,098.
- Nucleic acid arrays are described in many of the above patents, but the same techniques are applied to polypeptide arrays.
- Nucleic acid arrays that are useful in the present invention include those that are commercially available from Affymetrix (Santa Clara, Calif.) under the brand name GeneChip®. Example arrays are shown on the website at affymetrix.com.
- The present invention also contemplates many uses for polymers attached to solid substrates. These uses include gene expression monitoring, profiling, library screening, genotyping and diagnostics. Gene expression monitoring and profiling methods can be shown in U.S. Pat. Nos. 5,800,992, 6,013,449, 6,020,135, 6,033,860, 6,040,138, 6,177,248 and 6,309,822. Genotyping and uses therefore are shown in U.S. Ser. Nos. 15 10/442,021, 10/013,598 (U.S. Patent Application Publication 20030036069), and U.S. Pat. Nos. 5,856,092, 6,300,063, 5,858,659, 6,284,460, 6,361,947, 6,368,799 and 6,333,179. Other uses are embodied in U.S. Pat. Nos. 5,871,928, 5,902,723, 6,045,996, 5,541,061, and 6,197,506.
- The present invention also contemplates sample preparation methods in certain preferred embodiments. Prior to or concurrent with genotyping, the genomic sample may be amplified by a variety of mechanisms, some of which may employ PCR. See, e.g., PCR Technology: Principles and Applications for DNA Amplification (Ed. H.A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattila et al., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methods and
Applications 1, 17 (1991); PCR (Eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. Nos. 4,683,202, 4,683,195, 4,800,159 4,965,188, and 5,333,675, and each of which is incorporated herein by reference in their entireties for all purposes. The sample may be amplified on the array. See, for example, U.S. Pat. No. 6,300,070 and U.S. Ser. No. 09/513,300, which are incorporated herein by reference. - Other suitable amplification methods include the ligase chain reaction (LCR) (e.g., Wu and Wallace,
Genomics 4, 560 (1989), Landegren et al., Science 241, 1077 (1988) and Barringer et al. Gene 89:117 (1990)), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86, 1173 (1989) and WO88/10315), self-sustained sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990) and WO90/06995), selective amplification of target polynucleotide sequences (U.S. Pat. No. 6,410,276), consensus sequence primed polymerase chain reaction (CP-PCR) (U.S. Pat. No. 4,437,975), arbitrarily primed polymerase chain reaction (AP-PCR) (U.S. Pat. Nos. 5,413,909, 5,861,245) and nucleic acid based sequence amplification (NABSA). (See, U.S. Pat. Nos. 5,409,818, 5,554,517, and 6,063,603, each of which is incorporated herein by reference). Other amplification methods that may be used are described in U.S. Pat. Nos. 5,242,794, 5,494,810, 4,988,617 and in U.S. Ser. No. 09/854,317, each of which is incorporated herein by reference. - Additional methods of sample preparation and techniques for reducing the complexity of a nucleic sample are described in Dong et al.,
Genome Research 11, 1418 (2001), in U.S. Pat. No. 6,361,947, 6,391,592 and U.S. Ser. Nos. 09/916,135, 09/920,491 (U.S. Patent Application Publication 20030096235), Ser. No. 09/910,292 (U.S. Patent Application Publication 20030082543), and Ser. No. 10/013,598. - Methods for conducting polynucleotide hybridization assays have been well developed in the art. Hybridization assay procedures and 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 (2nd Ed. Cold Spring Harbor, N.Y., 1989); Berger and Kimmel Methods in Enzymology, Vol. 152, Guide to Molecular Cloning Techniques (Academic Press, Inc., San Diego, Calif., 1987); Young and Davism, P.N.A.S. 80: 1194 (1983). Methods and apparatus for carrying out repeated and controlled hybridization reactions have been described in U.S. Pat. Nos. 5,871,928, 5,874,219, 6,045,996 and 6,386,749, 6,391,623 each of which are incorporated herein by reference.
- The present invention also contemplates signal detection of hybridization between ligands in certain preferred embodiments. See U.S. Pat. Nos. 5,143,854, 5,578,832; 5,631,734; 5,834,758; 5,936,324; 5,981,956; 6,025,601; 6,141,096; 6,185,030; 6,201,639; 6,218,803; and 6,225,625, in U.S. Ser. No. 10/389,194 and in PCT Application PCT/US99/06097 (published as WO99/47964), each of which also is hereby incorporated by reference in its entirety for all purposes.
- Methods and apparatus for signal detection and processing of intensity data are disclosed in, for example, U.S. Pat. Nos. 5,143,854, 5,547,839, 5,578,832, 5,631,734, 5,800,992, 5,834,758; 5,856,092, 5,902,723, 5,936,324, 5,981,956, 6,025,601, 6,090,555, 6,141,096, 6,185,030, 6,201,639; 6,218,803; and 6,225,625, in U.S. Ser. Nos. 10/389,194, 60/493,495 and in PCT Application PCT/US99/06097 (published as WO99/47964), each of which also is hereby incorporated by reference in its entirety for all purposes.
- The practice of the present invention may also employ conventional biology methods, software and systems. Computer software products of the invention typically include computer readable medium having computer-executable instructions for performing the logic steps of the method of the invention. Suitable computer readable medium include floppy disk, CD-ROM/DVD/DVD-ROM, hard-disk drive, flash memory, ROM/RAM, magnetic tapes and etc. The computer executable instructions may be written in a suitable computer language or combination of several languages. Basic computational biology methods are described in, e.g. Setubal and Meidanis et al., Introduction to Computational Biology Methods (PWS Publishing Company, Boston, 1997); Salzberg, Searles, Kasif, (Ed.), Computational Methods in Molecular Biology, (Elsevier, Amsterdam, 1998); Rashidi and Buehler, Bioinformatics Basics: Application in Biological Science and Medicine (CRC Press, London, 2000) and Ouelette and Bzevanis Bioinformatics: A Practical Guide for Analysis of Gene and Proteins (Wiley & Sons, Inc., 2nd ed., 2001). See U.S. Pat. No. 6,420,108.
- The present invention may also make use of various computer program products and software for a variety of purposes, such as probe design, management of data, analysis, and instrument operation. See, U.S. Pat. Nos. 5,593,839, 5,795,716, 5,733,729, 5,974,164, 6,066,454, 6,090,555, 6,185,561, 6,188,783, 6,223,127, 6,229,911 and 6,308,170.
- Additionally, the present invention may have preferred embodiments that include methods for providing genetic information over networks such as the Internet as shown in U.S. Ser. Nos. 10/197,621, 10/063,559 (United States Publication No. 20020183936), Ser. Nos. 10/065,856, 10/065,868, 10/328,818, 10/328,872, 10/423,403, and 60/482,389.
- An “array” is an intentionally created collection of molecules which can be prepared either synthetically or biosynthetically. The molecules in the array can be identical or different from each other. The array can assume a variety of formats, e.g., libraries of soluble molecules; libraries of compounds tethered to resin beads, silica chips, or other solid supports.
- Nucleic acid library or array is an intentionally created collection of nucleic acids which can be prepared either synthetically or biosynthetically and screened for biological activity in a variety of different formats (e.g., libraries of soluble molecules; and libraries of oligos tethered to resin beads, silica chips, or other solid supports). Additionally, the term “array” is meant to include those libraries of nucleic acids which can be prepared by spotting nucleic acids of essentially any length (e.g., from 1 to about 1000 nucleotide monomers in length) onto a substrate. The term “nucleic acid” as used herein refers to a polymeric form of nucleotides of any length, either ribonucleotides, deoxyribonucleotides or peptide nucleic acids (PNAs), that comprise purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of the polynucleotide can comprise sugars and phosphate groups, as may typically be found in RNA or DNA, or modified or substituted sugar or phosphate groups. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. Thus the terms nucleoside, nucleotide, deoxynucleoside and deoxynucleotide generally include analogs such as those described herein. These analogs are those molecules having some structural features in common with a naturally occurring nucleoside or nucleotide such that when incorporated into a nucleic acid or oligonucleoside sequence, they allow hybridization with a naturally occurring nucleic acid sequence in solution. Typically, these analogs are derived from naturally occurring nucleosides and nucleotides by replacing and/or modifying the base, the ribose or the phosphodiester moiety. The changes can be tailor made to stabilize or destabilize hybrid formation or enhance the specificity of hybridization with a complementary nucleic acid sequence as desired.
- Biopolymer or biological polymer: is intended to mean repeating units of biological or chemical moieties. Representative biopolymers include, but are not limited to, nucleic acids, oligonucleotides, amino acids, proteins, peptides, hormones, oligosaccharides, lipids, glycolipids, lipopolysaccharides, phospholipids, synthetic analogues of the foregoing, including, but not limited to, inverted nucleotides, peptide nucleic acids, Meta-DNA, and combinations of the above. “Biopolymer synthesis” is intended to encompass the synthetic production, both organic and inorganic, of a biopolymer.
- Related to a bioploymer is a “biomonomer” which is intended to mean a single unit of biopolymer, or a single unit which is not part of a biopolymer. Thus, for example, a nucleotide is a biomonomer within an oligonucleotide biopolymer, and an amino acid is a biomonomer within a protein or peptide biopolymer; avidin, biotin, antibodies, antibody fragments, etc., for example, are also biomonomers. initiation Biomonomer: or “initiator biomonomer” is meant to indicate the first biomonomer which is covalently attached via reactive nucleophiles to the surface of the polymer, or the first biomonomer which is attached to a linker or spacer arm attached to the polymer, the linker or spacer arm being attached to the polymer via reactive nucleophiles.
- Complementary: Refers to the hybridization or base pairing between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer binding site on a single stranded nucleic acid to be sequenced or amplified. Complementary nucleotides are, generally, A and T (or A and U), or C and G. Two single stranded RNA or DNA molecules are said to be complementary when the nucleotides of one strand, optimally aligned and compared and with appropriate nucleotide insertions or deletions, pair with at least about 80% of the nucleotides of the other strand, usually at least about 90% to 95%, and more preferably from about 98 to 100%. Alternatively, complementarity exists when an RNA or DNA strand will hybridize under selective hybridization conditions to its complement. Typically, selective hybridization will occur when there is at least about 65% complementary over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% complementary. See, M. Kanehisa Nucleic Acids Res. 12:203 (1984), incorporated herein by reference.
- Combinatorial Synthesis Strategy: A combinatorial synthesis strategy is an ordered strategy for parallel synthesis of diverse polymer sequences by sequential addition of reagents which may be represented by a reactant matrix and a switch matrix, the product of which is a product matrix. A reactant matrix is a 1 column by m row matrix of the building blocks to be added. The switch matrix is all or a subset of the binary numbers, preferably ordered, between 1 and m arranged in columns. A “binary strategy” is one in which at least two successive steps illuminate a portion, often half, of a region of interest on the substrate. In a binary synthesis strategy, all possible compounds which can be formed from an ordered set of reactants are formed. In most preferred embodiments, binary synthesis refers to a synthesis strategy which also factors a previous addition step. For example, a strategy in which a switch matrix for a masking strategy halves regions that were previously illuminated, illuminating about half of the previously illuminated region and protecting the remaining half (while also protecting about half of previously protected regions and illuminating about half of previously protected regions). It will be recognized that binary rounds may be interspersed with non-binary rounds and that only a portion of a substrate may be subjected to a binary scheme. A combinatorial “masking” strategy is a synthesis which uses light or other spatially selective deprotecting or activating agents to remove protecting groups from materials for addition of other materials such as amino acids.
- Effective amount refers to an amount sufficient to induce a desired result.
- Genome is all the genetic material in the chromosomes of an organism. DNA derived from the genetic material in the chromosomes of a particular organism is genomic DNA.
- A genomic library is a collection of clones made from a set of randomly generated overlapping DNA fragments representing the entire genome of an organism. Hybridization conditions will typically include salt concentrations of less than about 1M, more usually less than about 500 mM and preferably less than about 200 mM. Hybridization temperatures can be as low as 5.degree. C., but are typically greater than 22.degree. C., more typically greater than about 30.degree. C., and preferably in excess of about 37.degree. C. Longer fragments may require higher hybridization temperatures for specific hybridization. As other factors may affect the stringency of hybridization, including base composition and length of the complementary strands, presence of organic solvents and extent of base mismatching, the combination of parameters is more important than the absolute measure of any one alone.
- Hybridizations, e.g., allele-specific probe hybridizations, are generally performed under stringent conditions. For example, conditions where the salt concentration is no more than about 1 Molar (M) and a temperature of at least 25 degrees Celsius (° C.), e.g., 750 mM NaCl, 50 mM NaPhosphate, 5 mM EDTA, pH 7.4 (5×SSPE) and a temperature of from about 25 to about 30° C.
- Hybridizations are usually performed under stringent conditions, for example, at a salt concentration of no more than 1 M and a temperature of at least 25° C. For example, conditions of 5×SSPE (750 mM NaCl, 50 mM NaPhosphate, 5 mM EDTA, pH 7.4) and a temperature of 25-30° C. are suitable for allele-specific probe hybridizations. For stringent conditions, see, for example, Sambrook, Fritsche and Maniatis. “Molecular Cloning A laboratory Manual” 2nd Ed. Cold Spring Harbor Press (1989) which is hereby incorporated by reference in its entirety for all purposes above.
- The term “hybridization” refers to the process in which two single-stranded polynucleotides bind non-covalently to form a stable double-stranded polynucleotide; triple-stranded hybridization is also theoretically possible. The resulting (usually) double-stranded polynucleotide is a “hybrid.” The proportion of the population of polynucleotides that forms stable hybrids is referred to herein as the “degree of hybridization.”
- Hybridization probes are oligonucleotides capable of binding in a base-specific manner to a complementary strand of nucleic acid. Such probes include peptide nucleic acids, as described in Nielsen et al., Science 254, 1497-1500 (1991), and other nucleic acid analogs and nucleic acid mimetics.
- Hybridizing specifically to: refers to the binding, duplexing, or hybridizing of a molecule only to a particular nucleotide sequence or sequences under stringent conditions when that sequence is present in a complex mixture (e.g., total cellular) DNA or RNA.
- Isolated nucleic acid is an object species invention that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). Preferably, an isolated nucleic acid comprises at least about 50, 80 or 90% (on a molar basis) of all macromolecular species present. Most preferably, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods).
- Ligand: A ligand is a molecule that is recognized by a particular receptor. The agent bound by or reacting with a receptor is called a “ligand,” a term which is definitionally meaningful only in terms of its counterpart receptor. The term “ligand” does not imply any particular molecular size or other structural or compositional feature other than that the substance in question is capable of binding or otherwise interacting with the receptor. Also, a ligand may serve either as the natural ligand to which the receptor binds, or as a functional analogue that may act as an agonist or antagonist. Examples of ligands 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., opiates, steroids, etc.), hormone receptors, peptides, enzymes, enzyme substrates, substrate analogs, transition state analogs, cofactors, drugs, proteins, and antibodies. Linkage disequilibrium or allelic association means the preferential association of a particular allele or genetic marker with a specific allele, or genetic marker at a nearby chromosomal location more frequently than expected by chance for any particular allele frequency in the population. For example, if locus X has alleles a and b, which occur equally frequently, and linked locus Y has alleles c and d, which occur equally frequently, one would expect the combination ac to occur with a frequency of 0.25. If ac occurs more frequently, then alleles a and c are in linkage disequilibrium. Linkage disequilibrium may result from natural selection of certain combination of alleles or because an allele has been introduced into a population too recently to have reached equilibrium with linked alleles.
- Mixed population or complex population: refers to any sample containing both desired and undesired nucleic acids. As a non-limiting example, a complex population of nucleic acids may be total genomic DNA, total genomic RNA or a combination thereof. Moreover, a complex population of nucleic acids may have been enriched for a given population but include other undesirable populations. For example, a complex population of nucleic acids may be a sample which has been enriched for desired messenger RNA (mRNA) sequences but still includes some undesired ribosomal RNA sequences (rRNA).
- Monomer: refers to any member of the set of molecules that can be joined together to form an oligomer or polymer. The set of monomers useful in the present invention includes, but is not restricted to, for the example of (poly)peptide synthesis, the set of L-amino acids, D-amino acids, or synthetic amino acids. As used herein, “monomer” refers to any member of a basis set for synthesis of an oligomer. For example, dimers of L-amino acids form a basis set of 400 “monomers” for synthesis of polypeptides. Different basis sets of monomers may be used at successive steps in the synthesis of a polymer.
- The term “monomer” also refers to a chemical subunit that can be combined with a different chemical subunit to form a compound larger than either subunit alone. mRNA or mRNA transcripts: as used herein, include, but not limited to pre-mRNA transcript(s), transcript processing intermediates, mature mRNA(s) ready for translation and transcripts of the gene or genes, or nucleic acids derived from the mRNA transcript(s). Transcript processing may include splicing, editing and degradation. As used herein, a nucleic acid derived from an mRNA transcript refers to a nucleic acid for whose synthesis the mRNA transcript or a subsequence thereof has ultimately served as a template. Thus, a cDNA reverse transcribed from an mRNA, an RNA transcribed from that cDNA, a DNA amplified from the cDNA, an RNA transcribed from the amplified DNA, etc., are all derived from the mRNA transcript and detection of such derived products is indicative of the presence and/or abundance of the original transcript in a sample. Thus, mRNA derived samples include, but are not limited to, mRNA transcripts of the gene or genes, cDNA reverse transcribed from the mRNA, cRNA transcribed from the cDNA, DNA amplified from the genes, RNA transcribed from amplified DNA, and the like.
- Nucleic acid library or array is an intentionally created collection of nucleic acids which can be prepared either synthetically or biosynthetically and screened for biological activity in a variety of different formats (e.g., libraries of soluble molecules; and libraries of oligos tethered to resin beads, silica chips, or other solid supports). Additionally, the term “array” is meant to include those libraries of nucleic acids which can be prepared by spotting nucleic acids of essentially any length (e.g., from 1 to about 1000 nucleotide monomers in length) onto a substrate. The term “nucleic acid” as used herein refers to a polymeric form of nucleotides of any length, either ribonucleotides, deoxyribonucleotides or peptide nucleic acids (PNAs), that comprise purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of the polynucleotide can comprise sugars and phosphate groups, as may typically be found in RNA or DNA, or modified or substituted sugar or phosphate groups. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides may be interrupted by non-nucleotide components. Thus the terms nucleoside, nucleotide, deoxynucleoside and deoxynucleotide generally include analogs such as those described herein. These analogs are those molecules having some structural features in common with a naturally occurring nucleoside or nucleotide such that when incorporated into a nucleic acid or oligonucleoside sequence, they allow hybridization with a naturally occurring nucleic acid sequence in solution. Typically, these analogs are derived from naturally occurring nucleosides and nucleotides by replacing and/or modifying the base, the ribose or the phosphodiester moiety. The changes can be tailor made to stabilize or destabilize hybrid formation or enhance the specificity of hybridization with a complementary nucleic acid sequence as desired.
- Nucleic acids according to the present invention may include any polymer or oligomer of pyrimidine and purine bases, preferably cytosine, thymine, and uracil, and adenine and guanine, respectively. See Albert L. Lehninger, PRINCIPLES OF BIOCHEMISTRY, at 793-800 (Worth Pub. 1982). Indeed, the present invention contemplates any deoxyribonucleotide, ribonucleotide or peptide nucleic acid component, and any chemical variants thereof, such as methylated, hydroxymethylated or glucosylated forms of these bases, and the like. The polymers or oligomers may be heterogeneous or homogeneous in composition, and may be isolated from naturally-occurring sources or may be artificially or synthetically produced. In addition, the nucleic acids may be DNA or RNA, or a mixture thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states.
- An “oligonucleotide” or “polynucleotide” is a nucleic acid ranging from at least 2, preferable at least 8, and more preferably at least 20 nucleotides in length or a compound that specifically hybridizes to a polynucleotide. Polynucleotides of the present invention include sequences of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) which may be isolated from natural sources, recombinantly produced or artificially synthesized and mimetics thereof. A further example of a polynucleotide of the present invention may be peptide nucleic acid (PNA). The invention also encompasses situations in which there is a nontraditional base pairing such as Hoogsteen base pairing which has been identified in certain tRNA molecules and postulated to exist in a triple helix. “Polynucleotide” and “oligonucleotide” are used interchangeably in this application.
- Probe: A probe is a surface-immobilized molecule that can be recognized by a particular target. See U.S. Pat. No. 6,582,908 for an example of arrays having all possible combinations of probes with 10, 12, and more bases. 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, nucleic acids, oligosaccharides, proteins, and monoclonal antibodies.
- Primer is a single-stranded oligonucleotide capable of acting as a point of initiation for template-directed DNA synthesis under suitable conditions e.g., buffer and temperature, in the presence of four different nucleoside triphosphates and an agent for polymerization, such as, for example, DNA or RNA polymerase or reverse transcriptase. The length of the primer, in any given case, depends on, for example, the intended use of the primer, and generally ranges from 15 to 30 nucleotides. Short primer molecules generally require cooler temperatures to form sufficiently stable hybrid complexes with the template. A primer need not reflect the exact sequence of the template but must be sufficiently complementary to hybridize with such template. The primer site is the area of the template to which a primer hybridizes. The primer pair is a set of primers including a 5′ upstream primer that hybridizes with the 5′ end of the sequence to be amplified and a 3′ downstream primer that hybridizes with the complement of the 3′ end of the sequence to be amplified.
- Polymorphism refers to the occurrence of two or more genetically determined alternative sequences or alleles in a population. A polymorphic marker or site is the locus at which divergence occurs. Preferred markers have at least two alleles, each occurring at frequency of greater than 1%, and more preferably greater than 10% or 20% of a selected population. A polymorphism may comprise one or more base changes, an insertion, a repeat, or a deletion. A polymorphic locus may be as small as one base pair. Polymorphic markers include restriction fragment length polymorphisms, variable number of tandem repeats (VNTR's), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats, simple sequence repeats, and insertion elements such as Alu. The first identified allelic form is arbitrarily designated as the reference form and other allelic forms are designated as alternative or variant alleles. The allelic form occurring most frequently in a selected population is sometimes referred to as the wildtype form. Diploid organisms may be homozygous or heterozygous for allelic forms. A diallelic polymorphism has two forms. A triallelic polymorphism has three forms. Single nucleotide polymorphisms (SNPs) are included in polymorphisms.
- Receptor: A molecule that has an affinity for a given ligand. Receptors may be naturally-occurring or manmade molecules. Also, they can be employed in their unaltered state or as aggregates with other species. Receptors may be attached, covalently or noncovalently, to a binding member, either directly or via a specific binding substance. Examples of receptors 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, polynucleotides, nucleic acids, peptides, cofactors, lectins, sugars, polysaccharides, cells, cellular membranes, and organelles. Receptors are sometimes referred to in the art as anti-ligands. As the term receptors is used herein, no difference in meaning is intended. A “Ligand Receptor Pair” is formed when two macromolecules have combined through molecular recognition to form a complex. Other examples of receptors which can be investigated by this invention include but are not restricted to those molecules shown in U.S. Pat. No. 5,143,854, which is hereby incorporated by reference in its entirety.
- “Solid support”, “support”, and “substrate” are used interchangeably and refer to a material or group of materials having a rigid or semi-rigid surface or surfaces. In many embodiments, at least one surface of the solid support will be substantially flat, although in some embodiments it may be desirable to physically separate synthesis regions for different compounds with, for example, wells, raised regions, pins, etched trenches, or the like. According to other embodiments, the solid support(s) will take the form of beads, resins, gels, microspheres, or other geometric configurations. See U.S. Pat. No. 5,744,305 for exemplary substrates.
- Target: A molecule that has an affinity for a given probe. Targets may be naturally occurring or man-made 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, nucleic acids, peptides, cofactors, lectins, sugars, polysaccharides, cells, cellular membranes, and organelles. Targets are sometimes referred to in the art as anti-probes. 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.
-
FIGS. 1-4 show a simplified fluidic system for processing biological sensors according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications. Thesystem 100 includes afluidic component 110, asupport component 120, and an electrical andmechanical component 130. Although the above has been shown using a selected group of components for thesystem 100, there can be many alternatives, modifications, and variations. For example, some of the components may be expanded and/or combined. Other components may be inserted to those noted above. Depending upon the embodiment, the arrangement of components may be interchanged with others replaced. Further details of these components are found throughout the present specification and more particularly below. - The
fluidic component 110 includes at least some containers. Each of these containers includes one or more fluids for processing at least one biological sensor. For example, each container is a well. In another example, the wells are grouped into one or more plate and/or one or more strip. As shown inFIGS. 1-4 , the wells are grouped into at least awell plate 112 and awell strip 114. In one embodiment, thewell plate 112 includes 96 wells, and thewell strip 114 includes 4 wells. In another embodiment, each well contains one or more fluids, and different wells contain the same or different fluids. In yet another embodiment, different wells have the same or different depths. - FIGS. 5(A) and (B) show a
simplified well strip 114 influidic system 100 for processing biological sensors according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications. Thewell strip 114 includes a plurality oftubes 510, aheater 512, and athermometer 514 such as a thermocouple. Although the above has been shown using a selected group of components for thewell strip 114, there can be many alternatives, modifications, and variations. For example, some of the components may be expanded and/or combined. Other components may be inserted to those noted above. Depending upon the embodiment, the arrangement of components may be interchanged with others replaced. Further details of these components are found throughout the present specification and more particularly below. - The plurality of
tubes 510 provides a plurality of wells for the one or more sensors. For example, each of the plurality oftubes 510 includes at least one fluid. The fluid is heated by theheater 512, and the temperature of the fluid is monitored, directly or indirectly, by thethermocouple 514. In response, thethermocouple 514 sends a signal to a temperature controller. In one embodiment, the temperature controller is also a component of thefluidic system 100. The temperature controller processes the received signal in light of a target temperature and adjusts the power of theheater 512 in order to achieve the targeted temperature for the fluid. As shown inFIG. 1 , the targeted temperature is provided to thefluidic system 100 by the user through atemperature interface 140 according to an embodiment of the present invention. Thetemperature interface 140 is a component of thefluidic system 100. -
FIG. 6 is a simplified diagram showing temperature as function of time forwell strip 114 influidic system 100 for processing biological sensors according to an embodiment of the present invention. This diagram is merely an example, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications. As shown inFIG. 6 , acurve 610 represents the temperature measured by thethermometer 514 as a function of time.Curves 620 represent temperatures for fluids in the plurality oftubes 510, such as wells, as functions of time. The temperatures for fluids have been measured by other thermometers, such as thermocouples, in the plurality of tubes.Curves 620 show that at a given time the fluid temperatures in different tubes are close to each other, and the fluid temperatures stabilize at about 50° C. after a period of time. - As shown in
FIGS. 1-4 , thefluidic component 110 also includes holder strips 116 and 118. In one embodiment, theholder strip 116 is used to transport the one or more sensors to thefluidic system 100 after a hybridization process is performed. For example, theholder strip 116 is a hybridization tray. In another embodiment, theholder strip 118 is used to transport the one or more sensors out of thefluidic system 100. For example, theholder strip 118 includes at least a cuvette holder. - The
support component 120 includes at least apanel 122. For example, thepanel 122 is placed horizontally. As shown inFIGS. 1-4 , thefluidic component 110 is placed on thepanel 122. For example, thefluidic component 110 is fixed at a predetermined position, directly or indirectly, on thepanel 122. In another example, the one or more wells of the fluidic component are substantially perpendicular to thepanel 122. - As shown in
FIGS. 1-4 , thewell plate 112 includes a plurality of wells arranged into a plurality of rows and a plurality of columns. For example, the number of rows is equal to or larger than the number of columns. In another example, each of the plurality of rows extends from a first side of the well plate to a second side of the well plate. In one embodiment, thewell strip 114 and twoholder strips well plate 112. In yet another example, the plurality of rows is perpendicular to the plurality of columns. Additionally, thewell strip 114 includes a row of wells. The holder strips 116 and 118 each include a row of wells capable of holding the one or more sensors. In one embodiment, the plurality of rows is parallel to the rows of wells for thewell strip 114 and the holder strips 116 and 118. In another embodiment, the plurality of columns is parallel to the rows of wells for thewell strip 114 and the holder strips 116 and 118. - According to an embodiment, the
well plate 112, thewell strip 114, theholder strip 116, and/or theholder strip 118 include a plurality of wells. At least one of the plurality of wells contains one or more fluids. For example, the volume of the one or more fluids in each well is equal to or smaller than 3 ml or 5 ml. In one embodiment, the volume of the one or more fluids for low stringency wash or stain is about 1.9 ml, and for high stringency wash is about 3.7 ml. In another embodiment, different wells have the same or different depths. - The electrical and
mechanical component 130 can move each of the one or more sensors from one position to another position. For example, the one or more sensors are not parts of the electrical andmechanical component 130. In another example, the electrical andmechanical component 130 is used as a transport component. In yet another example, the movement of the sensors can be made in one, two, or three dimensions. In yet another example, the movement of the sensors is made at various speed. As shown inFIGS. 1-4 , the electrical andmechanical component 130 moves each of the one or more sensors from one well to another well of thefluidic component 110. Additionally, the electrical andmechanical component 130 can move each of the one or more sensors within a corresponding well of thefluidic component 110, and/or move each of the one or more sensors into and/or out of a corresponding well of thefluidic component 110. - According to an embodiment of the present invention, the electrical and
mechanical component 130 includes at least agripper 132, andmotors motors motor 134 can move the one or more sensors in two opposite directions that are perpendicular to thepanel 122. In another example, themotors panel 122. In one embodiment, themotor 136 can move the one or more sensors in directions that are parallel to thewell strip 114. In another embodiment, themotor 138 can move the one or more sensors in directions that are perpendicular to thewell strip 114. - Additionally, the electrical and
mechanical component 130 includes other components. For example, the electrical andmechanical component 130 includes at least a high-voltage power supply and a low-voltage power supply. In one embodiment, the power suppliers are used to provide voltages at predetermined values and/or within predetermined ranges to, for example, themotors - FIGS. 7(A) and (B) show a
simplified gripper 132 influidic system 100 for processing biological sensors according to an embodiment of the present invention. These diagrams are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications. Thegripper 132 includes anactuator 710, and twoarms gripper 132, there can be many alternatives, modifications, and variations. For example, some of the components may be expanded and/or combined. Other components may be inserted to those noted above. Depending upon the embodiment, the arrangement of components may be interchanged with others replaced. Further details of these components are found throughout the present specification and more particularly below. - The
actuator 710 is used to move thearms actuator 710 is an electrical actuator. In another embodiment, theactuator 710 is a pneumatic actuator. For example, the pneumatic actuator receives a gas at a first pressure from a gas regulator, and the gas regulator converts the gas at a second pressure to the gas at the first pressure. In another example, the gas is clean dry air. As shown inFIG. 1 , the first pressure is monitored by apressure meter 150, which is a component of thefluidic system 100. Additionally, thearm 720 includes a plurality of fingers, such asfingers FIG. 7 (A). Similarly, thearm 730 also includes a plurality of fingers. As shown inFIG. 7 (B), thegripper 132 is used to grip the one or more sensors. For example, the one or more sensors are not parts of thesystem 100. - As discussed above and further emphasized here,
FIGS. 1-4 are merely examples, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications. For example, thewell plate 112 can be replaced by a well strip with a single row or a single column. In another example, thestrips fluidic component 110. -
FIG. 8 shows a simplified fluidic system for processing biological sensors according to another embodiment of the present invention. This diagram is merely an example, which should not unduly limit the scope of the claims. One of ordinary skill in the art would recognize many variations, alternatives, and modifications. Thesystem 800 includes a fluidic component, a support component, and an electrical and mechanical component. The fluidic component, the support component, and the electrical and mechanical component are either the same as or modified from thefluidic component 110, thesupport component 120, and the electrical andmechanical component 130 respectively. - For example, the fluidic component of the
system 800 is either partially or completely enclosed by acover 810. In another example, the fluidic component of thesystem 800 includes a well plate, a well strip, and two holder strips. The well plate includes a plurality of wells arranged into a plurality of rows and a plurality of columns. For example, the number of rows is equal to or larger than the number of columns. In another example, each of the plurality of columns extends from a first side of the well plate to a second side of the well plate. In one embodiment, the well strip and two holder strips all are placed next to the first side of the well plate. In yet another example, the plurality of rows is perpendicular to the plurality of columns. Additionally, the well strip includes a row of wells, and each of the holder strips includes a row of wells that are capable of holding the one or more sensors. In one embodiment, the plurality of rows is parallel to the rows of wells for the well strip and the holder strips. In another embodiment, the plurality of columns is parallel to the rows of wells for the well strip and the holder strips. - As discussed above and further emphasized here, a fluidic system for processing biological sensors according to certain embodiments of the present invention includes a fluidic component, a support component, and an electrical and mechanical component. For example, the fluidic system is the
system - According to an embodiment of the present invention, the movement of the one or more sensors into, within, and/or out of the
fluidic system -
FIG. 9 shows a simplified fluidic method for processing biological sensors that is performed byfluidic system method 900 includes aprocess 910 for low stringency wash, aprocess 920 for high stringency wash, aprocess 930 for Streptavidin Phycoerythrin (SAPE) stain, aprocess 940 for low stringency wash, aprocess 950 for antibody (AB) stain, aprocess 960 for low stringency wash, aprocess 970 for SAPE stain, and aprocess 980 for low stringency wash. Although the above has been shown using a selected sequence of processes, there can be many alternatives, modifications, and variations. For example, some of the processes may be expanded and/or combined. Other processes may be inserted to those noted above. Depending upon the embodiment, the specific sequence of processes may be interchanged with others replaced. Further details of these processes are found throughout the present specification and more particularly below. - At each of the
processes - At the
process 920 for high stringency wash, each of the one or more sensors is washed in at least one well. Within each well, the fluid is at an elevated temperature, and the corresponding sensor is mixed with the fluid for a period of time. For example, the elevated temperature is 48° C., and the period of time is 25 minutes. In another example, the elevated temperature is 41° C., and the period of time is also 25 minutes. - At each of the
processes - At the
process 950 for AB stain, each of the one or more sensors is stained in at least one well at room temperature. For each well, the corresponding sensor is mixed with the fluid for a period of time. As an example, the period of time is 10 minutes. - As discussed above and further emphasized here, the
processes fluidic system process 910, the one or more sensors are processed for hybridization. For example, the hybridization process is performed at 48° C. for 16 hours. Following theprocess 980, the one or more sensors are scanned. - FIGS. 10(A)-(V) are simplified diagrams showing movement of one or more sensors made by
fluidic system - According to one embodiment, each of FIGS. 10(A)-(V) shows the
well plate 112, thewell strip 114, and theholder strip row 1 is intended for SAPE stain, therow 3 is intended for AB stain, and rows 5-12 are intended for low stringency wash. In another example, thewell strip 112 is intended for high stringency wash. In yet another example, theholder strip 116 is a hybridization tray that is intended to transport the one or more sensors to thefluidic system 100 after a hybridization process is performed. In yet another embodiment, theholder strip 118 includes a cuvette holder and is intended to transport the one or more microarrays out of thefluidic system 100. - In order to describe movement of the one or more sensors, when a well is being used or after a well has been used, the well is marked with a square with hatch pattern. As shown in
FIG. 10 (A), the one or more sensors are transported to thefluidic system 100 by theholder strip 116. Afterwards, the one or more sensors are processed with low stringency wash according to theprocess 910 as shown in FIGS. 10(B)-(E). Each sensor is washed in four wells inrows process 920, the one or more sensors are moved to thewell strip 114 and processed with high stringency wash as shown inFIG. 10 (F). -
FIG. 10 (G) shows the one or more sensors are moved from thewell strip 114 to therow 1 of thewell plate 112. At therow 1, the one or more sensors are stained with SAPE according to theprocess 930. At theprocess 940, another low stringency wash is performed on the one or more sensors as shown in FIGS. 10(H)-(K). Each sensor is washed in four wells inrows - Following the
process 940, the one or more sensors are moved to therow 3 of thewell plate 112 as shown inFIG. 10 (L). At therow 3, the one or more sensors are stained with AB according to theprocess 950. Afterwards, the one or more sensors are processed with low stringency wash according to theprocess 960 as shown in FIGS. 10(M)-(P). Each sensor is washed in four wells inrows process 910. At each well, the sensor is agitated substantially parallel to the well depth in order to achieve a plurality of times of mixture with the fluid within the well. -
FIG. 10 (Q) shows the one or more sensors are moved from therow 9 to therow 1 of thewell plate 112. At therow 1, the one or more sensors are stained with SAPE according to theprocess 970. None of the wells used in theprocess 970 has been used in theprocess 930. At theprocess 980, another low stringency wash is performed on the one or more sensors as shown in FIGS. 10(R)-(U). Each sensor is washed in four wells inrows process 940. At each well, the sensor is agitated substantially parallel to the well depth in order to achieve a plurality of times of mixture with the fluid within the well. After theprocess 980, the one or more sensors are placed into theholder strip 118 as shown inFIG. 10 (V). These sensors can be transported from thefluidic system 100 to a scanner. - As discussed above and further emphasized here, the
fluidic system method 900. In another example, the biological sensors can be various types. See U.S. patent application Ser. Nos. 10/826,577 filed Apr. 16, 2004 and Ser. No. 11/243,621 filed Oct. 4, 2005, each of which is incorporated by reference herein. In yet another example, each of the one or more biological sensors is a biological microarray. In one embodiment, the biological microarray has a sensor length, a sensor width, and a sensor thickness. For example, the sensor length is equal to or shorter than 10 mm, the sensor width is equal to or narrower than 10 mm, and the sensor thickness is equal to or thinner than 1000 μm. In another example, the sensor length is equal to about 6.3 mm, the sensor width is equal to about 6.3 mm, and the sensor thickness is equal to about 700 μm. - In one embodiment, each biological sensor is a biological microarray. In another embodiment, each biological sensor is attached to a support component. For example, the support component is a peg. FIGS. 11(A) and (B) are simplified microarrays on pegs that can be processed by
fluidic system FIG. 11 (A), a biological microarray is attached to one peg, and each biological microarray can be manipulated individually by thefluidic system FIG. 11 (B), a plurality of biological microarrays is attached to a plurality of pegs respectively, and the plurality of pegs is connected by a base component. For example, the plurality of pegs includes four pegs, and the plurality of biological microarrays includes four microarrays. In another example, the plurality of pegs includes eight pegs, and the plurality of biological microarrays includes eight microarrays. In yet another example, the plurality of microarrays is manipulated together by thefluidic system - Also as discussed above and further emphasized here, the
fluidic system method 900. In another embodiment, the scanner for scanning the processed biological sensors can be of various types. For example, the scanner is made by Axon. Alternatively, see U.S. Provisional Application Ser. Nos. 60/648,309 filed Jan. 27, 2005 and 60/673,969 filed Apr. 22, 2005, each of which is incorporated by reference herein. - According to another embodiment of the present invention, a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container. The first container is capable of holding a first volume of a first fluid, and the second container is capable of holding a second volume of a second fluid. Additionally, the fluidic system includes a support component configured to support at least the first container and the second container. The first container and the second container are substantially stationary with respect to the support component. Moreover, the fluidic system includes a transport component configured to move a first sensor, with respect to the support component, into the first container and in contact with the first volume of the first fluid, and move a second sensor, with respect to the support component, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously. For example, the fluidic system is implemented according the
system 100 and/or thesystem 800. - According to yet another embodiment, a fluidic system for processing biological sensors includes a fluidic component including at least a first container and a second container. The first container is capable of holding a first volume of a first fluid, and the second container is capable of holding a second volume of a second fluid. Additionally, the fluidic system includes a support component including a panel for supporting at least the first container and the second container. The first container and the second container are substantially stationary with respect to the panel. Moreover, the fluidic system includes a transport component including a gripper and at least one motor. The gripper is capable of gripping the first sensor and the second sensor substantially simultaneously and of releasing the first sensor and the second sensor substantially simultaneously. The at least one motor is configured to move the gripped first sensor, with respect to the panel, into the first container and in contact with the first volume of the first fluid. The at least one motor is further configured to move the gripped second sensor, with respect to the panel, into the second container and in contact with the second volume of the second fluid. The first sensor and the second sensor are moved substantially simultaneously. For example, the fluidic system is implemented according the
system 100 and/or thesystem 800. - According to yet another embodiment, a method for processing biological sensors includes performing a hybridization process on at least a first sensor and a second sensor, and after the hybridization process, transferring the first sensor and the second sensor into a fluidic system. The fluidic system includes at least a first container and a second container, the first container holds a first volume of a first fluid, and the second container holds a second volume of a second fluid. Additionally, the method includes moving the first sensor into the first container and in contact with the first volume of the first fluid, and moving the second sensor into the second container and in contact with the second volume of the second fluid. The moving the first sensor and the moving the second sensor are performed substantially simultaneously. For example, the fluidic system is implemented according the
system 100 and/or thesystem 800. - The present invention has various applications. For example, the
fluidic system 100 or thefluidic system 800 is used as a fluidic station. In one embodiment, the fluidic station, as shown inFIG. 1 , has a footprint of 19.5-inch width and 17.5-inch depth. Additionally, the fluidic station has a height of 15 inch. In another example, certain embodiments of the present invention are used for personal and portable instruments as well as methods for processing biological microarrays. - The present invention has various advantages. Certain embodiments of the present invention provide an automated fluidic system. Some embodiments of the present invention provide a low-cost fluidic system. Certain embodiments of the present invention can improve throughput of the fluidic system. For example, a plurality of biological sensors, such as microarrays, is processed in parallel. Some embodiments of the present invention can reduce cross-contamination between different processes performed on one or more biological sensors. For example, at a given process, different sensors are washed, stained, and/or held in different wells. In another example, a given sensor is washed, stained, and/or held in different wells for different processes respectively. In yet another example, each well is used for at most a single process for at most a single sensor, such as a microarray.
- Although specific embodiments of the present invention have been described, it will be understood by those of skill in the art that there are other embodiments that are equivalent to the described embodiments. Accordingly, it is to be understood that the invention is not to be limited by the specific illustrated embodiments, but only by the scope of the appended claims.
Claims (55)
1. A fluidic system for processing biological sensors, the fluidic system comprising:
a fluidic component including at least a first container and a second container, the first container capable of holding a first volume of a first fluid, the second container capable of holding a second volume of a second fluid;
a support component configured to support at least the first container and the second container, the first container and the second container being substantially stationary with respect to the support component;
a transport component configured to:
move a first sensor, with respect to the support component, into the first container and in contact with the first volume of the first fluid;
move a second sensor, with respect to the support component, into the second container and in contact with the second volume of the second fluid;
wherein the first sensor and the second sensor are moved substantially simultaneously.
2. The fluidic system of claim 1 wherein the fluidic system is configured to process the first sensor and the second sensor so that the processed first sensor and the processed second sensor are ready for scan.
3. The fluidic system of claim 1 wherein:
when the first sensor is inside the first container and in contact with the first volume of the first fluid, the first volume of the first fluid remains completely within the first container;
when the second sensor is inside the second container and in contact with the second volume of the second fluid, the second volume of the second fluid remains completely within the second container.
4. The fluidic system of claim 1 wherein the first sensor is attached to a first support member.
5. The fluidic system of claim 4 wherein the first support member is a peg.
6. The fluidic system of claim 4 wherein the second sensor is attached to a second support member.
7. The fluidic system of claim 6 wherein each of the first support member and the second support member is a part of a plate.
8. The fluidic system of claim 1 wherein:
the first sensor is associated with a sensor length, a sensor width, and a sensor thickness;
the sensor length is equal to or shorter than 10 mm;
the sensor width is equal to or narrower than 10 mm;
the sensor thickness is equal to or thinner than 1000 μm.
9. The fluidic system of claim 1 wherein the first sensor is a biological sensor.
10. The fluidic system of claim 9 wherein the biological sensor includes a microarray.
11. The fluidic system of claim 1 wherein the first volume of the first fluid sensor is equal to or smaller than 5 ml.
12. The fluidic system of claim 1 wherein the support component is further configured to support, directly, at least the first container and the second container.
13. The fluidic system of claim 1 wherein the support component is further configured to support, indirectly through another object, at least the first container and the second container.
14. The fluidic system of claim 1 wherein the first fluid and the second fluid are the same or different in kind.
15. The fluidic system of claim 1 wherein the first volume and the second volume are the same or different in size.
16. The fluidic system of claim 1 wherein each of the first container and the second container is a well.
17. The fluidic system of claim 1 wherein the first container and the second container are two of a plurality of containers, the plurality of containers being attached, directly or indirectly, to a common component.
18. The fluidic system of claim 17 wherein the plurality of containers are arranged in one or more rows and one or more columns.
19. A fluidic system for processing biological sensors, the fluidic system comprising:
a fluidic component including at least a first container and a second container, the first container capable of holding a first volume of a first fluid, the second container capable of holding a second volume of a second fluid;
a support component including a panel for supporting at least the first container and the second container, the first container and the second container being substantially stationary with respect to the panel;
a transport component including a gripper and at least one motor;
wherein:
the gripper is capable of gripping the first sensor and the second sensor substantially simultaneously and of releasing the first sensor and the second sensor substantially simultaneously;
the at least one motor is configured to move the gripped first sensor, with respect to the panel, into the first container and in contact with the first volume of the first fluid;
the at least one motor is further configured to move the gripped second sensor, with respect to the panel, into the second container and in contact with the second volume of the second fluid;
wherein the first sensor and the second sensor are moved substantially simultaneously.
20. The fluidic system of claim 19 wherein the gripper includes an actuator.
21. The fluidic system of claim 20 wherein the actuator is a pneumatic actuator.
22. The fluidic system of claim 20 wherein the actuator is an electrical actuator.
23. The fluidic system of claim 19 wherein:
the at least one motor is capable of moving the gripped first sensor in at lest six directions;
each of the six directions is opposite to another direction of the six directions and is perpendicular to four directions of the six directions;
the four directions of the six directions are different from the another direction.
24. The fluidic system of claim 19 wherein the fluidic component is at least partially enclosed by a cover.
25. The fluidic system of claim 19 wherein:
the first container and the second container are attached to an object associated with a temperature;
the object includes a heater configured to heat up the first volume of the first fluid and the second volume of the second fluid;
the object further includes a thermometer configured to measure the temperature.
26. The fluidic system of claim 19 , and further comprising a temperature controller coupled to the heater and the thermometer and configured to heat the temperature to a predetermined value.
27. The fluidic system of claim 19 wherein the transport component is coupled to a processing system, the processing system configured to provide instructions to the transport component for gripping, releasing, or moving the first sensor and the second sensor.
28. The fluidic system of claim 27 wherein the processing system includes a computer.
29. The fluidic system of claim 19 wherein the fluidic system is configured to process the first sensor and the second sensor so that the processed first sensor and the processed second sensor are ready for scan.
30. The fluidic system of claim 19 wherein:
when the first sensor is inside the first container and in contact with the first volume of the first fluid, the first volume of the first fluid remains completely within the first container;
when the second sensor is inside the second container and in contact with the second volume of the second fluid, the second volume of the second fluid remains completely within the second container.
31. The fluidic system of claim 19 wherein the first sensor is attached to a first support member.
32. The fluidic system of claim 31 wherein the first support member is a peg.
33. The fluidic system of claim 31 wherein the second sensor is attached to a second support member.
34. The fluidic system of claim 32 wherein each of the first support member and the second support member is a part of a plate.
35. The fluidic system of claim 19 wherein:
the first sensor is associated with a sensor length, a sensor width, and a sensor thickness;
the sensor length is equal to or shorter than 10 mm;
the sensor width is equal to or narrower than 10 mm;
the sensor thickness is equal to or thinner than 1000 μm.
36. The fluidic system of claim 19 wherein the first sensor is a biological sensor.
37. The fluidic system of claim 36 wherein the biological sensor includes a microarray.
38. The fluidic system of claim 19 wherein the first volume of the first fluid sensor is equal to or smaller than 5 ml.
39. The fluidic system of claim 19 wherein the support component is further configured to support, directly, at least the first container and the second container.
40. A method for processing biological sensors, the method comprising:
performing a hybridization process on at least a first sensor and a second sensor;
after the hybridization process, transferring the first sensor and the second sensor into a fluidic system, the fluidic system including at least a first container and a second container, the first container holding a first volume of a first fluid, the second container holding a second volume of a second fluid;
moving the first sensor into the first container and in contact with the first volume of the first fluid;
moving the second sensor into the second container and in contact with the second volume of the second fluid;
wherein the moving the first sensor and the moving the second sensor are performed substantially simultaneously.
41. The method of claim 40 wherein:
the fluidic system includes a support component configured to support at least the first container and the second container, the first container and the second container being substantially stationary with respect to the support component;
the moving the first sensor includes moving the first sensor with respect to the support component;
the moving the second sensor includes moving the second sensor with respect to the support component.
42. The method of claim 40 , and further comprising after the moving the first sensor and the moving the second sensor, processing the first sensor and the second sensor so that the processed first sensor and the processed second sensor are ready for scan.
43. The method of claim 42 wherein the processing the first sensor and the second sensor includes performing at least a low stringency wash, at least a high stringency wash, and at least a stain process to the first sensor and the second sensor.
44. The method of claim 42 , and further comprising:
transferring the processed first sensor and the processed second sensor out of the fluidic system;
performing a scanning process on the processed first sensor and the processed second sensor.
45. The method of claim 44 wherein between the transferring the first sensor and the second sensor-into a fluidic system and the transferring the processed first sensor and the processed second sensor out of the fluidic system:
the first volume of the first fluid is not in contact with any sensor other than the first sensor;
the second volume of the second fluid is not in contact with any sensor other than the second sensor.
46. The method of claim 44 wherein between the transferring the first sensor and the second sensor into a fluidic system and the transferring the processed first sensor and the processed second sensor out of the fluidic system:
the first container is not provided with any volume of any fluid that is different from the first volume of the first fluid and is not provided by the first sensor;
the second container is not provided with any volume of any fluid that is different from the second volume of the second fluid and is not provided by the second sensor.
47. The method of claim 40 wherein:
the moving the first sensor includes when the first sensor is inside the first container and in contact with the first volume of the first fluid, keeping the first volume of the first fluid completely within the first container;
the moving the second sensor includes when the second sensor is inside the second container and in contact with the second volume of the second fluid, keeping the second volume of the second fluid completely within the second container.
48. The method of claim 40 wherein the first sensor is attached to a first support member.
49. The method of claim 48 wherein the first support member is a peg.
50. The method of claim 48 wherein the second sensor is attached to a second support member.
51. The method of claim 50 wherein each of the first support member and the second support member is a part of a plate.
52. The method of claim 40 wherein the first sensor is a biological sensor.
53. The method of claim 52 wherein the biological sensor includes a microarray.
54. The method of claim 40 wherein the first fluid and the second fluid are the same or different.
55. The method of claim 40 wherein the first volume and the second volume are the same or different in size.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/388,762 US20060246576A1 (en) | 2005-04-06 | 2006-03-23 | Fluidic system and method for processing biological microarrays in personal instrumentation |
US12/632,429 US20100081583A1 (en) | 2005-04-06 | 2009-12-07 | Fludic system and method for processing biological microarrays in personal instrumentation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US66913005P | 2005-04-06 | 2005-04-06 | |
US11/388,762 US20060246576A1 (en) | 2005-04-06 | 2006-03-23 | Fluidic system and method for processing biological microarrays in personal instrumentation |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/632,429 Continuation US20100081583A1 (en) | 2005-04-06 | 2009-12-07 | Fludic system and method for processing biological microarrays in personal instrumentation |
Publications (1)
Publication Number | Publication Date |
---|---|
US20060246576A1 true US20060246576A1 (en) | 2006-11-02 |
Family
ID=37077485
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/388,762 Abandoned US20060246576A1 (en) | 2005-04-06 | 2006-03-23 | Fluidic system and method for processing biological microarrays in personal instrumentation |
US11/389,549 Abandoned US20060234371A1 (en) | 2005-04-06 | 2006-03-24 | System and method for processing large number of biological microarrays |
US12/481,852 Active 2027-09-05 US8796186B2 (en) | 2005-04-06 | 2009-06-10 | System and method for processing large number of biological microarrays |
US12/632,429 Abandoned US20100081583A1 (en) | 2005-04-06 | 2009-12-07 | Fludic system and method for processing biological microarrays in personal instrumentation |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/389,549 Abandoned US20060234371A1 (en) | 2005-04-06 | 2006-03-24 | System and method for processing large number of biological microarrays |
US12/481,852 Active 2027-09-05 US8796186B2 (en) | 2005-04-06 | 2009-06-10 | System and method for processing large number of biological microarrays |
US12/632,429 Abandoned US20100081583A1 (en) | 2005-04-06 | 2009-12-07 | Fludic system and method for processing biological microarrays in personal instrumentation |
Country Status (2)
Country | Link |
---|---|
US (4) | US20060246576A1 (en) |
CN (4) | CN201040757Y (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060234371A1 (en) * | 2005-04-06 | 2006-10-19 | Affymetrix, Inc. | System and method for processing large number of biological microarrays |
US20100328732A1 (en) * | 2006-11-21 | 2010-12-30 | Illumina Inc. | Hexagonal site line scanning method and system |
US8351026B2 (en) | 2005-04-22 | 2013-01-08 | Affymetrix, Inc. | Methods and devices for reading microarrays |
US11302417B2 (en) | 2013-03-15 | 2022-04-12 | Affymetrix, Inc. | Systems and methods for SNP characterization and identifying off target variants |
US11692220B2 (en) | 2012-07-31 | 2023-07-04 | Gen-Probe Incorporated | Apparatus for applying thermal energy to a receptacle and detecting an emission signal from the receptacle |
Families Citing this family (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080003667A1 (en) * | 2006-05-19 | 2008-01-03 | Affymetrix, Inc. | Consumable elements for use with fluid processing and detection systems |
DE102010028769A1 (en) | 2010-05-07 | 2011-11-10 | Pvt Probenverteiltechnik Gmbh | System for transporting containers between different stations and container carriers |
EP2589968A1 (en) * | 2011-11-04 | 2013-05-08 | Roche Diagnostics GmbH | Laboratory sample distribution system, laboratory system and method of operating |
EP2589967A1 (en) | 2011-11-04 | 2013-05-08 | Roche Diagnostics GmbH | Laboratory sample distribution system and corresponding method of operation |
EP2589966A1 (en) | 2011-11-04 | 2013-05-08 | Roche Diagnostics GmbH | Laboratory sample distribution system and corresponding method of operation |
ITRE20130096A1 (en) * | 2013-12-27 | 2015-06-28 | Spire S R L | AUTOMATIC DIAGNOSTIC MACHINE AND METHOD OF LOADING THE SAME |
DE102014202838B3 (en) | 2014-02-17 | 2014-11-06 | Roche Pvt Gmbh | Transport device, sample distribution system and laboratory automation system |
DE102014202843B3 (en) | 2014-02-17 | 2014-11-06 | Roche Pvt Gmbh | Transport device, sample distribution system and laboratory automation system |
EP2927695B1 (en) | 2014-03-31 | 2018-08-22 | Roche Diagniostics GmbH | Sample distribution system and laboratory automation system |
EP2927167B1 (en) | 2014-03-31 | 2018-04-18 | F. Hoffmann-La Roche AG | Dispatch device, sample distribution system and laboratory automation system |
EP2927168A1 (en) | 2014-03-31 | 2015-10-07 | Roche Diagniostics GmbH | Transport device, sample distribution system and laboratory automation system |
EP2927163B1 (en) | 2014-03-31 | 2018-02-28 | Roche Diagnostics GmbH | Vertical conveyor, sample distribution system and laboratory automation system |
EP2927625A1 (en) | 2014-03-31 | 2015-10-07 | Roche Diagniostics GmbH | Sample distribution system and laboratory automation system |
EP2957914B1 (en) | 2014-06-17 | 2018-01-03 | Roche Diagnostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP2977766A1 (en) | 2014-07-24 | 2016-01-27 | Roche Diagniostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP2995960B1 (en) | 2014-09-09 | 2020-07-15 | Roche Diagniostics GmbH | Laboratory sample distribution system and method for calibrating magnetic sensors |
EP2995580A1 (en) | 2014-09-09 | 2016-03-16 | Roche Diagniostics GmbH | Laboratory sample distribution system and laboratory automation system |
US9952242B2 (en) | 2014-09-12 | 2018-04-24 | Roche Diagnostics Operations, Inc. | Laboratory sample distribution system and laboratory automation system |
EP2995958A1 (en) | 2014-09-15 | 2016-03-16 | Roche Diagniostics GmbH | Method of operating a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
EP3006943B1 (en) | 2014-10-07 | 2020-04-22 | Roche Diagniostics GmbH | Module for a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
EP3016116A1 (en) | 2014-11-03 | 2016-05-04 | Roche Diagniostics GmbH | Printed circuit board arrangement, coil for a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
EP3070479B1 (en) | 2015-03-16 | 2019-07-03 | Roche Diagniostics GmbH | Transport carrier, laboratory cargo distribution system and laboratory automation system |
EP3073270B1 (en) | 2015-03-23 | 2019-05-29 | Roche Diagniostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP3096145B1 (en) | 2015-05-22 | 2019-09-04 | Roche Diagniostics GmbH | Method of operating a laboratory automation system and laboratory automation system |
EP3096146A1 (en) | 2015-05-22 | 2016-11-23 | Roche Diagniostics GmbH | Method of operating a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
EP3095739A1 (en) | 2015-05-22 | 2016-11-23 | Roche Diagniostics GmbH | Method of operating a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
EP3112874A1 (en) | 2015-07-02 | 2017-01-04 | Roche Diagnostics GmbH | Storage module, method of operating a laboratory automation system and laboratory automation system |
EP3121603A1 (en) | 2015-07-22 | 2017-01-25 | Roche Diagnostics GmbH | Sample container carrier, laboratory sample distribution system and laboratory automation system |
CA3171618A1 (en) | 2015-07-23 | 2017-01-26 | Meso Scale Technologies, Llc. | Integrated consumable data management system & platform |
WO2017027643A1 (en) | 2015-08-10 | 2017-02-16 | Essenlix Corp. | Bio/chemical assay devices and methods for simplified steps, small samples, accelerated speed, and ease-of-use |
EP3139175B1 (en) | 2015-09-01 | 2021-12-15 | Roche Diagnostics GmbH | Laboratory cargo distribution system, laboratory automation system and method of operating a laboratory cargo distribution system |
KR20190057445A (en) | 2015-09-14 | 2019-05-28 | 에센릭스 코프. | Device and system for analyzing a sample, particularly blood, as well as methods of using the same |
CA2998635C (en) | 2015-09-14 | 2021-08-24 | Essenlix Corporation | Device and system for collecting and analyzing vapor condensate, particularly exhaled breath condensate, as well as method of using the same |
EP3153866A1 (en) | 2015-10-06 | 2017-04-12 | Roche Diagnostics GmbH | Method of determining a handover position and laboratory automation system |
EP3153867B1 (en) | 2015-10-06 | 2018-11-14 | Roche Diagniostics GmbH | Method of configuring a laboratory automation system, laboratory sample distribution system and laboratory automation system |
EP3156352B1 (en) | 2015-10-13 | 2019-02-27 | Roche Diagniostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP3156353B1 (en) | 2015-10-14 | 2019-04-03 | Roche Diagniostics GmbH | Method of rotating a sample container carrier, laboratory sample distribution system and laboratory automation system |
EP3211430A1 (en) | 2016-02-26 | 2017-08-30 | Roche Diagnostics GmbH | Transport device with base plate modules |
EP3211429A1 (en) | 2016-02-26 | 2017-08-30 | Roche Diagnostics GmbH | Transport device having a tiled driving surface |
EP3211428A1 (en) | 2016-02-26 | 2017-08-30 | Roche Diagnostics GmbH | Transport device unit for a laboratory sample distribution system |
CN115754322A (en) * | 2016-04-22 | 2023-03-07 | 贝克顿·迪金森公司 | Automatic diagnostic analyzer and method of operating the same |
EP3465225B1 (en) | 2016-06-03 | 2021-03-10 | Roche Diagnostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP3255519B1 (en) | 2016-06-09 | 2019-02-20 | Roche Diagniostics GmbH | Laboratory sample distribution system and method of operating a laboratory sample distribution system |
EP3260867A1 (en) | 2016-06-21 | 2017-12-27 | Roche Diagnostics GmbH | Method of setting a handover position and laboratory automation system |
EP3494398B1 (en) | 2016-08-04 | 2022-04-06 | Roche Diagnostics GmbH | Laboratory sample distribution system and laboratory automation system |
RU2743388C2 (en) * | 2016-11-23 | 2021-02-17 | Иллюмина, Инк. | System and method of fixing flow cell assembly |
US10718786B2 (en) * | 2016-11-23 | 2020-07-21 | Illumina, Inc. | Flow cell assembly securement system and method |
EP3330717B1 (en) | 2016-12-01 | 2022-04-06 | Roche Diagnostics GmbH | Laboratory sample distribution system and laboratory automation system |
CN110312473B (en) | 2016-12-21 | 2023-04-07 | 艾森利克斯公司 | Apparatus and method for authenticating a sample and use thereof |
EP3343232B1 (en) | 2016-12-29 | 2021-09-15 | Roche Diagnostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP3355065B1 (en) | 2017-01-31 | 2021-08-18 | Roche Diagnostics GmbH | Laboratory sample distribution system and laboratory automation system |
EP3357842B1 (en) | 2017-02-03 | 2022-03-23 | Roche Diagnostics GmbH | Laboratory automation system |
CA3052786A1 (en) | 2017-02-07 | 2018-08-16 | Essenlix Corporation | Compressed open flow assay and use |
CN111316096B (en) | 2017-02-08 | 2023-08-11 | Essenlix公司 | Biological/chemical material extraction and assay |
CN110998325A (en) | 2017-02-09 | 2020-04-10 | Essenlix公司 | Amplification assay |
JP2020507770A (en) | 2017-02-09 | 2020-03-12 | エッセンリックス コーポレーション | Colorimetric assay |
CN111433606A (en) | 2017-02-09 | 2020-07-17 | Essenlix公司 | Using determination of different pitch heights |
US11523752B2 (en) | 2017-02-16 | 2022-12-13 | Essenlix Corporation | Assay for vapor condensates |
US10671969B2 (en) | 2017-05-03 | 2020-06-02 | Summate Technologies, Inc. | Operating room situated, parts-inventory control system and supervisory arrangement for accurately tracking the use of and accounting for the ultimate disposition of an individual component part of a complete implant which is then being surgically engrafted in-vivo upon or into the body of a living subject |
EP3410123B1 (en) | 2017-06-02 | 2023-09-20 | Roche Diagnostics GmbH | Method of operating a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
EP3428653B1 (en) | 2017-07-13 | 2021-09-15 | Roche Diagnostics GmbH | Method of operating a laboratory sample distribution system, laboratory sample distribution system and laboratory automation system |
HUE061474T2 (en) | 2017-08-01 | 2023-07-28 | Mgi Tech Co Ltd | Nucleic acid sequencing method |
CN111492222A (en) | 2017-08-01 | 2020-08-04 | Essenlix公司 | Sample collection, retention and assay |
US11725227B2 (en) | 2017-08-01 | 2023-08-15 | Essenlix Corporation | Devices and methods for examining drug effects on microorganisms |
US11280706B2 (en) | 2017-08-01 | 2022-03-22 | Essenlix Corporation | Dilution calibration |
CN107656042A (en) * | 2017-08-21 | 2018-02-02 | 深圳市锦瑞生物科技有限公司 | Immunity analysis instrument charging appliance |
EP3456415B1 (en) | 2017-09-13 | 2021-10-20 | Roche Diagnostics GmbH | Sample container carrier, laboratory sample distribution system and laboratory automation system |
EP3457144B1 (en) | 2017-09-13 | 2021-10-20 | Roche Diagnostics GmbH | Sample container carrier, laboratory sample distribution system and laboratory automation system |
US10816562B2 (en) | 2017-10-04 | 2020-10-27 | Leica Biosystems Imaging, Inc. | Slide inventory and reinsertion system |
US11393561B2 (en) | 2017-10-13 | 2022-07-19 | Essenlix Corporation | Devices and methods for authenticating a medical test and use of the same |
US11609224B2 (en) | 2017-10-26 | 2023-03-21 | Essenlix Corporation | Devices and methods for white blood cell analyses |
US11237113B2 (en) | 2017-10-26 | 2022-02-01 | Essenlix Corporation | Rapid pH measurement |
US10807095B2 (en) | 2017-10-26 | 2020-10-20 | Essenlix Corporation | Making and tracking assay card |
EP3625571B1 (en) | 2017-11-30 | 2024-04-10 | Leica Biosystems Imaging, Inc. | Slide rack gripper apparatus |
WO2019118652A1 (en) | 2017-12-12 | 2019-06-20 | Essenlix Corporation | Sample manipulation and assay with rapid temperature change |
US11510608B2 (en) | 2017-12-14 | 2022-11-29 | Essenlix Corporation | Devices, systems, and methods for monitoring hair |
WO2019140334A1 (en) | 2018-01-11 | 2019-07-18 | Essenlix Corporation | Homogeneous assay (ii) |
EP3540443B1 (en) | 2018-03-16 | 2023-08-30 | Roche Diagnostics GmbH | Laboratory system, laboratory sample distribution system and laboratory automation system |
US10470809B1 (en) * | 2018-06-19 | 2019-11-12 | Summate Technologies, Inc. | Automated screw identification system and method |
US10786331B2 (en) | 2018-06-19 | 2020-09-29 | Summate Technologies, Inc. | Automated implant identification system and method with combined machine-readable and human-readable markers |
US11885952B2 (en) | 2018-07-30 | 2024-01-30 | Essenlix Corporation | Optics, device, and system for assaying and imaging |
US10909343B1 (en) | 2019-07-12 | 2021-02-02 | Summate Technologies, Inc. | Automated screw identification system and method with labeled pegs |
CN111004706B (en) * | 2019-12-23 | 2023-06-16 | 长春长光辰英生物科学仪器有限公司 | High-flux receiving system used in micro-size target sorting instrument |
WO2021252735A1 (en) * | 2020-06-11 | 2021-12-16 | Chan Zuckerberg Biohub, Inc. | Methods and compositions related to lanthanide-encoded microbeads |
US11747356B2 (en) | 2020-12-21 | 2023-09-05 | Roche Diagnostics Operations, Inc. | Support element for a modular transport plane, modular transport plane, and laboratory distribution system |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4731335A (en) * | 1985-09-13 | 1988-03-15 | Fisher Scientific Company | Method for treating thin samples on a surface employing capillary flow |
US5601650A (en) * | 1991-05-29 | 1997-02-11 | Medite Gesellschaft Fur Medizintechnik Mbh | Process and device for dyeing histological preparations arranged on microscope slides |
US6361940B1 (en) * | 1996-09-24 | 2002-03-26 | Qiagen Genomics, Inc. | Compositions and methods for enhancing hybridization and priming specificity |
US20040185483A1 (en) * | 1998-12-28 | 2004-09-23 | Illumina, Inc. | Composite arrays utilizing microspheres with a hybridization chamber |
US20060234371A1 (en) * | 2005-04-06 | 2006-10-19 | Affymetrix, Inc. | System and method for processing large number of biological microarrays |
Family Cites Families (276)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US751084A (en) * | 1904-02-02 | Electric switch | ||
US2371061A (en) * | 1941-09-10 | 1945-03-06 | Maryland Plastics Inc | Method of making dies |
US2610419A (en) * | 1947-08-13 | 1952-09-16 | Irvin Frey | Marking garments for identification |
US3281860A (en) | 1964-11-09 | 1966-10-25 | Dick Co Ab | Ink jet nozzle |
DE1617732C2 (en) | 1966-03-01 | 1972-12-21 | Promoveo-Sobioda & Cie, Seyssinet (Frankreich) | Device for examining living cells of microorganisms |
US3802966A (en) | 1969-08-22 | 1974-04-09 | Ethyl Corp | Apparatus for delivering a fluid suspension to a forming unit clear reactor power plant |
BE793185A (en) | 1971-12-23 | 1973-04-16 | Atomic Energy Commission | APPARATUS FOR QUICKLY ANALYZING AND SORTING PARTICLES SUCH AS BIOLOGICAL CELLS |
JPS6112373B2 (en) | 1974-09-04 | 1986-04-08 | Hitachi Ltd | |
US4121222A (en) | 1977-09-06 | 1978-10-17 | A. B. Dick Company | Drop counter ink replenishing system |
US4200110A (en) | 1977-11-28 | 1980-04-29 | United States Of America | Fiber optic pH probe |
US4204929A (en) | 1978-04-18 | 1980-05-27 | University Patents, Inc. | Isoelectric focusing method |
US4325910A (en) * | 1979-07-11 | 1982-04-20 | Technicraft, Inc. | Automated multiple-purpose chemical-analysis apparatus |
US4349510A (en) | 1979-07-24 | 1982-09-14 | Seppo Kolehmainen | Method and apparatus for measurement of samples by luminescence |
US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US4373071A (en) | 1981-04-30 | 1983-02-08 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4707454A (en) | 1981-08-10 | 1987-11-17 | Bio-Diagnostics, Inc. | Fluorescent chlorophyll labeled assay reagents |
US4499052A (en) | 1982-08-30 | 1985-02-12 | Becton, Dickinson And Company | Apparatus for distinguishing multiple subpopulations of cells |
AU567440B2 (en) | 1982-11-20 | 1987-11-19 | Thomas Paterson Whitehead | Dispensing device and recording apparatus |
NZ207394A (en) | 1983-03-08 | 1987-03-06 | Commw Serum Lab Commission | Detecting or determining sequence of amino acids |
US4672040A (en) | 1983-05-12 | 1987-06-09 | Advanced Magnetics, Inc. | Magnetic particles for use in separations |
CA1230552A (en) * | 1983-11-07 | 1987-12-22 | Howard M. Chandler | Device and method for performing qualitative enzyme immunoassays |
FI71768C (en) | 1984-02-17 | 1987-02-09 | Orion Yhtymae Oy | Enhanced nucleic acid reagents and process for their preparation. |
DE3565986D1 (en) | 1984-05-02 | 1988-12-08 | Brendan James Hamill | An apparatus for the chemical synthesis of oligonucleotides |
GB8429212D0 (en) | 1984-11-19 | 1984-12-27 | Vincent Patents Ltd | Exhaust systems for ic engines |
JPH0823558B2 (en) | 1984-11-27 | 1996-03-06 | オ−ジエニクス リミテツド | Verification device |
FR2583772B1 (en) | 1985-06-20 | 1987-08-28 | Roussel Uclaf | NEW MEDIA, THE PREPARATION OF SUCH MEDIA, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION TO THE SYNTHESIS OF OLIGONUCLEOTIDES AND THE NEW NUCLEOSIDES AND OLIGONUCLEOTIDES RELATED TO THE MEDIA THUS OBTAINED |
FR2584090B1 (en) | 1985-06-27 | 1987-08-28 | Roussel Uclaf | NEW SUPPORTS, THEIR PREPARATION AND THE INTERMEDIATES OBTAINED, THEIR APPLICATION TO THE SYNTHESIS OF OLIGONUCLEOTIDES AND THE NEW NUCLEOSIDES AND OLIGONUCLEOTIDES RELATED TO THE SUPPORTS OBTAINED |
US4963498A (en) | 1985-08-05 | 1990-10-16 | Biotrack | Capillary flow device |
US5164598A (en) | 1985-08-05 | 1992-11-17 | Biotrack | Capillary flow device |
US4682895A (en) | 1985-08-06 | 1987-07-28 | Texas A&M University | Fiber optic probe for quantification of colorimetric reactions |
US5595908A (en) * | 1985-09-26 | 1997-01-21 | University Of Southern Mississipi | Piezoelectric device for detection of polynucleotide hybridization |
WO1987003966A1 (en) * | 1985-12-23 | 1987-07-02 | Beckman Instruments, Inc. | Automatic immunochemistry analyzing apparatus and method |
US4940670A (en) | 1986-01-24 | 1990-07-10 | Rhodes Buck A | Method for compounding and testing patient specific monoclonal antibodies and monoclonal antibody fragments for in vivo use |
US5256549A (en) | 1986-03-28 | 1993-10-26 | Chiron Corporation | Purification of synthetic oligomers |
US5153319A (en) | 1986-03-31 | 1992-10-06 | University Patents, Inc. | Process for preparing polynucleotides |
US4824789B1 (en) | 1986-10-10 | 1996-08-13 | Minnesota Mining & Mfg | Gas sensor |
US4798738A (en) | 1986-10-10 | 1989-01-17 | Cardiovascular Devices, Inc. | Micro sensor |
US5143853A (en) | 1986-06-25 | 1992-09-01 | Trustees Of Tufts College | Absorbance modulated fluorescence detection methods and sensors |
US5254477A (en) | 1986-06-25 | 1993-10-19 | Trustees Of Tufts College | Flourescence intramolecular energy transfer conjugate compositions and detection methods |
US5252494A (en) | 1986-06-25 | 1993-10-12 | Trustees Of Tufts College | Fiber optic sensors, apparatus, and detection methods using controlled release polymers and reagent formulations held within a polymeric reaction matrix |
US4822746A (en) | 1986-06-25 | 1989-04-18 | Trustees Of Tufts College | Radiative and non-radiative energy transfer and absorbance modulated fluorescence detection methods and sensors |
US5114864A (en) | 1986-06-25 | 1992-05-19 | Trustees Of Tufts College | Fiber optic sensors, apparatus, and detection methods using fluid erodible controlled release polymers for delivery of reagent formulations |
EP0260965B2 (en) | 1986-09-18 | 2002-01-16 | Pacific Biotech Inc. | Immunodiagnostic device |
US4764671A (en) * | 1986-10-03 | 1988-08-16 | Kollmorgen Corporation | Fiber optic fluid sensor using coated sensor tip |
US5021550A (en) | 1986-10-07 | 1991-06-04 | Thomas Jefferson University | Method for preventing deletion sequences in solid phase synthesis |
US5698450A (en) | 1986-10-14 | 1997-12-16 | Ringrose; Anthony | Method for measuring antigens or antibodies in biological fluids |
US4895706A (en) | 1986-10-28 | 1990-01-23 | Costar Corporation | Multi-well filter strip and composite assemblies |
US4877745A (en) | 1986-11-17 | 1989-10-31 | Abbott Laboratories | Apparatus and process for reagent fluid dispensing and printing |
US4922092A (en) | 1986-11-26 | 1990-05-01 | Image Research Limited | High sensitivity optical imaging apparatus |
ATE66695T1 (en) | 1986-12-01 | 1991-09-15 | Molecular Biosystems Inc | PROCEDURE FOR INCREASING THE SENSITIVITY OF NUCLEIC ACID HYBRIDIZATION TESTS. |
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 |
US4859419A (en) * | 1987-02-27 | 1989-08-22 | American Bionetics, Inc. | Diagnostic manifold apparatus |
US4829010A (en) * | 1987-03-13 | 1989-05-09 | Tanox Biosystems, Inc. | Immunoassay device enclosing matrixes of antibody spots for cell determinations |
JPH0736274Y2 (en) | 1987-05-15 | 1995-08-16 | ベックマン インスツルメンツ インコーポレーテッド | Improved flow cell |
SE458968B (en) | 1987-06-16 | 1989-05-22 | Wallac Oy | BIOSPECIFIC ANALYTICAL PROCEDURE FOR MULTIPLE ANALYTICS WHICH DO NOT INCLUDE PARTICULAR COATING AND LABELING WITH FLUORESCING LABEL SUBSTANCES |
US5132242A (en) | 1987-07-15 | 1992-07-21 | Cheung Sau W | Fluorescent microspheres and methods of using them |
US5194300A (en) | 1987-07-15 | 1993-03-16 | Cheung Sau W | Methods of making fluorescent microspheres |
US5447837A (en) | 1987-08-05 | 1995-09-05 | Calypte, Inc. | Multi-immunoassay diagnostic system for antigens or antibodies or both |
US4785814A (en) | 1987-08-11 | 1988-11-22 | Cordis Corporation | Optical probe for measuring pH and oxygen in blood and employing a composite membrane |
US4853335A (en) | 1987-09-28 | 1989-08-01 | Olsen Duane A | Colloidal gold particle concentration immunoassay |
US5219712A (en) * | 1987-11-28 | 1993-06-15 | Thorn Emi Plc | Method of forming a solid article |
US5322799A (en) | 1988-02-03 | 1994-06-21 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University | Observation cell and mixing chamber |
US5100775A (en) | 1988-03-16 | 1992-03-31 | Smyczek Peter J | Method for conducting nucleic acid hybridization in chamber with precise fluid delivery |
US4988617A (en) | 1988-03-25 | 1991-01-29 | California Institute Of Technology | Method of detecting a nucleotide change in nucleic acids |
US4965725B1 (en) | 1988-04-08 | 1996-05-07 | Neuromedical Systems Inc | Neural network based automated cytological specimen classification system and method |
US5002867A (en) | 1988-04-25 | 1991-03-26 | Macevicz Stephen C | Nucleic acid sequence determination by multiple mixed oligonucleotide probes |
US5188963A (en) | 1989-11-17 | 1993-02-23 | Gene Tec Corporation | Device for processing biological specimens for analysis of nucleic acids |
US5075077A (en) | 1988-08-02 | 1991-12-24 | Abbott Laboratories | Test card for performing assays |
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 |
US5320808A (en) | 1988-08-02 | 1994-06-14 | Abbott Laboratories | Reaction cartridge and carousel for biological sample analyzer |
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 |
US5104808A (en) * | 1988-08-26 | 1992-04-14 | Laska Paul F | Method and apparatus for effecting a plurality of assays on a plurality of samples in an automatic analytical device |
US5278048A (en) | 1988-10-21 | 1994-01-11 | Molecular Devices Corporation | Methods for detecting the effect of cell affecting agents on living cells |
US5683916A (en) * | 1988-10-31 | 1997-11-04 | Hemasure Inc. | Membrane affinity apparatus and purification methods related thereto |
US5200051A (en) | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US5575849A (en) | 1988-11-25 | 1996-11-19 | Canon Kabushiki Kaisha | Apparatus for producing a substrate having a surface with a plurality of spherical dimples for photoconductive members |
US5047524A (en) | 1988-12-21 | 1991-09-10 | Applied Biosystems, Inc. | Automated system for polynucleotide synthesis and purification |
GB8829942D0 (en) | 1988-12-22 | 1989-02-15 | Isis Innovations Ltd | Method |
US5229297A (en) * | 1989-02-03 | 1993-07-20 | Eastman Kodak Company | Containment cuvette for PCR and method of use |
WO1990010875A1 (en) | 1989-03-07 | 1990-09-20 | Idemitsu Petrochemical Company Limited | Analyzer of liquid sample and analyzing method of liquid sample using said analyzer |
JPH02299598A (en) | 1989-04-14 | 1990-12-11 | Ro Inst For Molecular Genetics & Geneteic Res | Determination by means of hybridization, together with oligonucleotide probe of all or part of extremely short sequence in sample of nucleic acid connecting with separate particle of microscopic size |
US5087820A (en) | 1989-05-31 | 1992-02-11 | Digital Diagnostic Corp. | Radiometric analysis system for solid support samples |
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 |
US5800992A (en) | 1989-06-07 | 1998-09-01 | Fodor; Stephen P.A. | Method of detecting nucleic acids |
US5744101A (en) * | 1989-06-07 | 1998-04-28 | Affymax Technologies N.V. | Photolabile nucleoside protecting groups |
US5424186A (en) * | 1989-06-07 | 1995-06-13 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis |
US6040138A (en) * | 1995-09-15 | 2000-03-21 | Affymetrix, Inc. | Expression monitoring by hybridization to high density oligonucleotide arrays |
US5176881A (en) | 1989-08-11 | 1993-01-05 | The University Of Tennessee Research Corporation | Fiber optic-based regenerable biosensor |
US5302509A (en) | 1989-08-14 | 1994-04-12 | Beckman Instruments, Inc. | Method for sequencing polynucleotides |
US5141813A (en) | 1989-08-28 | 1992-08-25 | Clontech Laboratories, Inc. | Multifunctional controlled pore glass reagent for solid phase oligonucleotide synthesis |
EP0416148A1 (en) | 1989-09-07 | 1991-03-13 | RSM ANALYTISCHE INSTRUMENTE GmbH | Arrangement for simultaneously measuring particle or quantum radiation from multiple samples |
US5346672A (en) | 1989-11-17 | 1994-09-13 | Gene Tec Corporation | Devices for containing biological specimens for thermal processing |
US5104792A (en) * | 1989-12-21 | 1992-04-14 | The United States Of America As Represented By The Department Of Health And Human Services | Method for amplifying unknown nucleic acid sequences |
US5073029A (en) | 1990-02-16 | 1991-12-17 | Eqm Research, Inc. | Multisource device for photometric analysis and associated chromogens |
ATE154981T1 (en) * | 1990-04-06 | 1997-07-15 | Perkin Elmer Corp | AUTOMATED MOLECULAR BIOLOGY LABORATORY |
US5326692B1 (en) | 1992-05-13 | 1996-04-30 | Molecular Probes Inc | Fluorescent microparticles with controllable enhanced stokes shift |
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 |
JP3010057B2 (en) * | 1990-08-24 | 2000-02-14 | オリンパス光学工業株式会社 | Cup cleaning equipment |
DE69125441T2 (en) | 1990-09-28 | 1997-11-06 | Toshiba Kawasaki Kk | Gene detection method |
US5154888A (en) * | 1990-10-25 | 1992-10-13 | Eastman Kodak Company | Automatic sealing closure means for closing off a passage in a flexible cuvette |
US5105305A (en) | 1991-01-10 | 1992-04-14 | At&T Bell Laboratories | Near-field scanning optical microscope using a fluorescent probe |
US5244636A (en) | 1991-01-25 | 1993-09-14 | Trustees Of Tufts College | Imaging fiber optic array sensors, apparatus, and methods for concurrently detecting multiple analytes of interest in a fluid sample |
US5250264A (en) | 1991-01-25 | 1993-10-05 | Trustees Of Tufts College | Method of making imaging fiber optic sensors to concurrently detect multiple analytes of interest in a fluid sample |
US5320814A (en) | 1991-01-25 | 1994-06-14 | Trustees Of Tufts College | Fiber optic array sensors, apparatus, and methods for concurrently visualizing and chemically detecting multiple analytes of interest in a fluid sample |
US5244813A (en) | 1991-01-25 | 1993-09-14 | Trustees Of Tufts College | Fiber optic sensor, apparatus, and methods for detecting an organic analyte in a fluid or vapor sample |
US5230866A (en) * | 1991-03-01 | 1993-07-27 | Biotrack, Inc. | Capillary stop-flow junction having improved stability against accidental fluid flow |
US5380489A (en) | 1992-02-18 | 1995-01-10 | Eastman Kodak Company | Element and method for nucleic acid amplification and detection using adhered probes |
US5133374A (en) * | 1991-04-01 | 1992-07-28 | Druding Kevin W | Apparatus and method for purging medical instruments and disposing of infectious waste |
US5170659A (en) | 1991-04-08 | 1992-12-15 | Kemp Development Corporation | Apparatus and method for detecting fluid leakage |
FR2678950B1 (en) * | 1991-07-09 | 1993-11-05 | Bertin Et Cie | CARTRIDGE, DEVICE AND METHOD FOR EXTRACTING NUCLEIC ACIDS SUCH AS DNA FROM A SAMPLE OF BLOOD OR TISSUE CELLS. |
US5726010A (en) * | 1991-07-31 | 1998-03-10 | Idexx Laboratories, Inc. | Reversible flow chromatographic binding assay |
US5639603A (en) | 1991-09-18 | 1997-06-17 | Affymax Technologies N.V. | Synthesizing and screening molecular diversity |
IL102486A (en) | 1991-10-04 | 1997-11-20 | Orgenics Ltd | Method and apparatus for detection of nucleic acid sequences with a nucleic acid probe |
DE69223980T2 (en) | 1991-10-15 | 1998-05-28 | Multilyte Ltd | BINDING TEST USING A MARKED REAGENT |
US5215131A (en) * | 1991-11-14 | 1993-06-01 | Poy George L | Automatic liquid delivery system |
US5324633A (en) | 1991-11-22 | 1994-06-28 | Affymax Technologies N.V. | Method and apparatus for measuring binding affinity |
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 |
JP3007469B2 (en) * | 1992-01-30 | 2000-02-07 | 東北パイオニア株式会社 | Speaker magnetic circuit |
US5888723A (en) | 1992-02-18 | 1999-03-30 | Johnson & Johnson Clinical Diagnostics, Inc. | Method for nucleic acid amplification and detection using adhered probes |
AU3728093A (en) | 1992-02-19 | 1993-09-13 | Public Health Research Institute Of The City Of New York, Inc., The | Novel oligonucleotide arrays and their use for sorting, isolating, sequencing, and manipulating nucleic acids |
US5445970A (en) | 1992-03-20 | 1995-08-29 | Abbott Laboratories | Magnetically assisted binding assays using magnetically labeled binding members |
US5376313A (en) | 1992-03-27 | 1994-12-27 | Abbott Laboratories | Injection molding a plastic assay cuvette having low birefringence |
US5258781A (en) * | 1992-04-08 | 1993-11-02 | Xerox Corporation | One-step encapsulation, air gap sealing and structure bonding of thermal ink jet printhead |
EP0565999A2 (en) | 1992-04-16 | 1993-10-20 | Siemens Aktiengesellschaft | Optical coupling device for two groups of waveguides |
US5486335A (en) * | 1992-05-01 | 1996-01-23 | Trustees Of The University Of Pennsylvania | Analysis based on flow restriction |
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 |
US5587128A (en) | 1992-05-01 | 1996-12-24 | The Trustees Of The University Of Pennsylvania | Mesoscale polynucleotide amplification devices |
US5304487A (en) * | 1992-05-01 | 1994-04-19 | Trustees Of The University Of Pennsylvania | Fluid handling in mesoscale analytical devices |
SE9201929D0 (en) | 1992-06-23 | 1992-06-23 | Pharmacia Lkb Biotech | METHOD AND SYSTEM FOR MOLECULAR-BIOLOGICAL DIAGNOSTICS |
DE69313611T2 (en) | 1992-07-02 | 1998-01-08 | Erkki Soini | BIOS-SPECIFIC MULTIPARAMETER ANALYSIS PROCEDURE |
DK0660936T3 (en) | 1992-09-14 | 1999-05-25 | Stanford Res Inst Int | Up-converting reporter molecule for biological and other assays using laser excitation technique |
US5674698A (en) | 1992-09-14 | 1997-10-07 | Sri International | Up-converting reporters for biological and other assays using laser excitation techniques |
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 |
US5565324A (en) | 1992-10-01 | 1996-10-15 | The Trustees Of Columbia University In The City Of New York | Complex combinatorial chemical libraries encoded with tags |
US5288463A (en) * | 1992-10-23 | 1994-02-22 | Eastman Kodak Company | Positive flow control in an unvented container |
US5422271A (en) * | 1992-11-20 | 1995-06-06 | Eastman Kodak Company | Nucleic acid material amplification and detection without washing |
US5543329A (en) * | 1992-11-03 | 1996-08-06 | Intelligent Monitoring Systems And Advanced Global Technologies | Sensor for antigen-antibody reactions |
SE9203320D0 (en) | 1992-11-06 | 1992-11-06 | Pharmacia Lkb Biotech | A METHOD OF PROCESSING NUCLEIC ACID SAMPLES |
US5500187A (en) * | 1992-12-08 | 1996-03-19 | Westinghouse Electric Corporation | Disposable optical agglutination assay device and method for use |
US5314829A (en) | 1992-12-18 | 1994-05-24 | California Institute Of Technology | Method for imaging informational biological molecules on a semiconductor substrate |
US5298741A (en) | 1993-01-13 | 1994-03-29 | Trustees Of Tufts College | Thin film fiber optic sensor array and apparatus for concurrent viewing and chemical sensing of a sample |
IL108497A0 (en) * | 1993-02-01 | 1994-05-30 | Seq Ltd | Methods and apparatus for dna sequencing |
US5364790A (en) * | 1993-02-16 | 1994-11-15 | The Perkin-Elmer Corporation | In situ PCR amplification system |
CA2102884A1 (en) | 1993-03-04 | 1994-09-05 | James J. Wynne | Dental procedures and apparatus using ultraviolet radiation |
US5279721A (en) * | 1993-04-22 | 1994-01-18 | Peter Schmid | Apparatus and method for an automated electrophoresis system |
US5395587A (en) * | 1993-07-06 | 1995-03-07 | Smithkline Beecham Corporation | Surface plasmon resonance detector having collector for eluted ligate |
JP3598123B2 (en) * | 1993-07-15 | 2004-12-08 | 浜松ホトニクス株式会社 | Nucleic acid denaturation detector |
JP3302458B2 (en) | 1993-08-31 | 2002-07-15 | 富士通株式会社 | Integrated optical device and manufacturing method |
JP3106874B2 (en) * | 1993-09-29 | 2000-11-06 | 松下電器産業株式会社 | Disk recording and playback device |
US5374395A (en) | 1993-10-14 | 1994-12-20 | Amoco Corporation | Diagnostics instrument |
JP3488465B2 (en) | 1993-10-28 | 2004-01-19 | ヒューストン・アドバンスド・リサーチ・センター | Microfabricated flow-through porosity device for separately detecting binding reactions |
US6165778A (en) | 1993-11-02 | 2000-12-26 | Affymax Technologies N.V. | Reaction vessel agitation apparatus |
US5494798A (en) | 1993-12-09 | 1996-02-27 | Gerdt; David W. | Fiber optic evanscent wave sensor for immunoassay |
US5496997A (en) | 1994-01-03 | 1996-03-05 | Pope; Edward J. A. | Sensor incorporating an optical fiber and a solid porous inorganic microsphere |
US5578832A (en) * | 1994-09-02 | 1996-11-26 | Affymetrix, Inc. | Method and apparatus for imaging a sample on a device |
US5591384A (en) * | 1994-03-31 | 1997-01-07 | Modern Technologies Corp. | Method for molding parts |
SE9401594D0 (en) | 1994-05-06 | 1994-05-06 | Pharmacia Lkb Biotech | Method of nucleic acid transfer |
US5571639A (en) * | 1994-05-24 | 1996-11-05 | Affymax Technologies N.V. | Computer-aided engineering system for design of sequence arrays and lithographic masks |
US6287850B1 (en) | 1995-06-07 | 2001-09-11 | Affymetrix, Inc. | Bioarray chip reaction apparatus and its manufacture |
DE69527585T2 (en) * | 1994-06-08 | 2003-04-03 | Affymetrix Inc | Method and device for packaging chips |
US5807522A (en) | 1994-06-17 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for fabricating microarrays of biological samples |
US5549974A (en) | 1994-06-23 | 1996-08-27 | Affymax Technologies Nv | Methods for the solid phase synthesis of thiazolidinones, metathiazanones, and derivatives thereof |
US5512490A (en) | 1994-08-11 | 1996-04-30 | Trustees Of Tufts College | Optical sensor, optical sensing apparatus, and methods for detecting an analyte of interest using spectral recognition patterns |
US5627041A (en) * | 1994-09-02 | 1997-05-06 | Biometric Imaging, Inc. | Disposable cartridge for an assay of a biological sample |
US5695934A (en) | 1994-10-13 | 1997-12-09 | Lynx Therapeutics, Inc. | Massively parallel sequencing of sorted polynucleotides |
JPH08178926A (en) | 1994-10-25 | 1996-07-12 | Sumitomo Pharmaceut Co Ltd | Immunoassay plate and use thereof |
US5585069A (en) | 1994-11-10 | 1996-12-17 | David Sarnoff Research Center, Inc. | Partitioned microelectronic and fluidic device array for clinical diagnostics and chemical synthesis |
US5866434A (en) * | 1994-12-08 | 1999-02-02 | Meso Scale Technology | Graphitic nanotubes in luminescence assays |
US5784152A (en) | 1995-03-16 | 1998-07-21 | Bio-Rad Laboratories | Tunable excitation and/or tunable detection microplate reader |
US5609826A (en) | 1995-04-17 | 1997-03-11 | Ontogen Corporation | Methods and apparatus for the generation of chemical libraries |
DE19514638C2 (en) * | 1995-04-20 | 1998-06-04 | Peter Dr Med Boekstegers | Device for the selective suction and retroinfusion of a fluid from or into body veins controlled by venous pressure |
US6340588B1 (en) | 1995-04-25 | 2002-01-22 | Discovery Partners International, Inc. | Matrices with memories |
US5690894A (en) | 1995-05-23 | 1997-11-25 | The Regents Of The University Of California | High density array fabrication and readout method for a fiber optic biosensor |
US5628849A (en) * | 1995-05-26 | 1997-05-13 | International Business Machines Corporation | Method for in-situ environment sensitive sealing and/or product controlling |
US6074614A (en) | 1995-06-07 | 2000-06-13 | Molecular Devices Corporation | Multi-assay plate cover for elimination of meniscus |
US5545531A (en) | 1995-06-07 | 1996-08-13 | Affymax Technologies N.V. | Methods for making a device for concurrently processing multiple biological chip assays |
US5856174A (en) | 1995-06-29 | 1999-01-05 | Affymetrix, Inc. | Integrated nucleic acid diagnostic device |
JP3561891B2 (en) | 1995-08-25 | 2004-09-02 | 株式会社三菱化学ヤトロン | Microplate light shielding means and luminescence measuring device |
US5658802A (en) * | 1995-09-07 | 1997-08-19 | Microfab Technologies, Inc. | Method and apparatus for making miniaturized diagnostic arrays |
US5656241A (en) | 1995-09-07 | 1997-08-12 | Optical Sensors Incorporated | Method for manufacturing fiber optic sensors |
US5981180A (en) | 1995-10-11 | 1999-11-09 | Luminex Corporation | Multiplexed analysis of clinical specimens apparatus and methods |
US5716825A (en) * | 1995-11-01 | 1998-02-10 | Hewlett Packard Company | Integrated nucleic acid analysis system for MALDI-TOF MS |
US5633972A (en) | 1995-11-29 | 1997-05-27 | Trustees Of Tufts College | Superresolution imaging fiber for subwavelength light energy generation and near-field optical microscopy |
US5814524A (en) | 1995-12-14 | 1998-09-29 | Trustees Of Tufts College | Optical sensor apparatus for far-field viewing and making optical analytical measurements at remote locations |
US6660233B1 (en) | 1996-01-16 | 2003-12-09 | Beckman Coulter, Inc. | Analytical biochemistry system with robotically carried bioarray |
US5837196A (en) | 1996-01-26 | 1998-11-17 | The Regents Of The University Of California | High density array fabrication and readout method for a fiber optic biosensor |
US5649576A (en) | 1996-02-26 | 1997-07-22 | Pharmacopeia, Inc. | Partitioning device |
US6114122A (en) * | 1996-03-26 | 2000-09-05 | Affymetrix, Inc. | Fluidics station with a mounting system and method of using |
US5840256A (en) | 1996-04-09 | 1998-11-24 | David Sarnoff Research Center Inc. | Plate for reaction system |
WO1998001760A2 (en) * | 1996-07-05 | 1998-01-15 | Beckman Coulter, Inc. | Automated sample processing system |
EP0910790A1 (en) | 1996-07-10 | 1999-04-28 | Cambridge Imaging Limited | Improvements in and relating to imaging |
GB2315131B (en) | 1996-07-10 | 2000-11-29 | Cambridge Imaging Ltd | Improvements in and relating to imaging |
US5854684A (en) | 1996-09-26 | 1998-12-29 | Sarnoff Corporation | Massively parallel detection |
US5900481A (en) | 1996-11-06 | 1999-05-04 | Sequenom, Inc. | Bead linkers for immobilizing nucleic acids to solid supports |
US5804384A (en) | 1996-12-06 | 1998-09-08 | Vysis, Inc. | Devices and methods for detecting multiple analytes in samples |
WO1998029736A1 (en) | 1996-12-31 | 1998-07-09 | Genometrix Incorporated | Multiplexed molecular analysis apparatus and method |
US5837860A (en) | 1997-03-05 | 1998-11-17 | Molecular Tool, Inc. | Covalent attachment of nucleic acid molecules onto solid-phases via disulfide bonds |
US6327410B1 (en) | 1997-03-14 | 2001-12-04 | The Trustees Of Tufts College | Target analyte sensors utilizing Microspheres |
US6023540A (en) | 1997-03-14 | 2000-02-08 | Trustees Of Tufts College | Fiber optic sensor with encoded microspheres |
US6143496A (en) | 1997-04-17 | 2000-11-07 | Cytonix Corporation | Method of sampling, amplifying and quantifying segment of nucleic acid, polymerase chain reaction assembly having nanoliter-sized sample chambers, and method of filling assembly |
US6406845B1 (en) | 1997-05-05 | 2002-06-18 | Trustees Of Tuft College | Fiber optic biosensor for selectively detecting oligonucleotide species in a mixed fluid sample |
US5985214A (en) * | 1997-05-16 | 1999-11-16 | Aurora Biosciences Corporation | Systems and methods for rapidly identifying useful chemicals in liquid samples |
US5876946A (en) | 1997-06-03 | 1999-03-02 | Pharmacopeia, Inc. | High-throughput assay |
US5869004A (en) * | 1997-06-09 | 1999-02-09 | Caliper Technologies Corp. | Methods and apparatus for in situ concentration and/or dilution of materials in microfluidic systems |
US6037186A (en) | 1997-07-16 | 2000-03-14 | Stimpson; Don | Parallel production of high density arrays |
US6071748A (en) | 1997-07-16 | 2000-06-06 | Ljl Biosystems, Inc. | Light detection device |
US7115884B1 (en) | 1997-10-06 | 2006-10-03 | Trustees Of Tufts College | Self-encoding fiber optic sensor |
DE19745373A1 (en) | 1997-10-14 | 1999-04-15 | Bayer Ag | Optical measuring system for the detection of luminescence or fluorescence signals |
US6090553A (en) * | 1997-10-29 | 2000-07-18 | Beckman Coulter, Inc. | Use of uracil-DNA glycosylase in genetic analysis |
US5922617A (en) | 1997-11-12 | 1999-07-13 | Functional Genetics, Inc. | Rapid screening assay methods and devices |
US6268131B1 (en) | 1997-12-15 | 2001-07-31 | Sequenom, Inc. | Mass spectrometric methods for sequencing nucleic acids |
US6232066B1 (en) | 1997-12-19 | 2001-05-15 | Neogen, Inc. | High throughput assay system |
US6458533B1 (en) | 1997-12-19 | 2002-10-01 | High Throughput Genomics, Inc. | High throughput assay system for monitoring ESTs |
US6269846B1 (en) | 1998-01-13 | 2001-08-07 | Genetic Microsystems, Inc. | Depositing fluid specimens on substrates, resulting ordered arrays, techniques for deposition of arrays |
US6210910B1 (en) | 1998-03-02 | 2001-04-03 | Trustees Of Tufts College | Optical fiber biosensor array comprising cell populations confined to microcavities |
US6519032B1 (en) | 1998-04-03 | 2003-02-11 | Symyx Technologies, Inc. | Fiber optic apparatus and use thereof in combinatorial material science |
ATE423314T1 (en) | 1998-06-24 | 2009-03-15 | Illumina Inc | DECODING OF MATRIXED SENSORS BY MICROPARTICLES |
US6608671B2 (en) | 1998-07-17 | 2003-08-19 | Vertex Pharmaceuticals (San Diego) Llc | Detector and screening device for ion channels |
US6132685A (en) | 1998-08-10 | 2000-10-17 | Caliper Technologies Corporation | High throughput microfluidic systems and methods |
JP2002522065A (en) * | 1998-08-10 | 2002-07-23 | ジェノミック ソリューションズ インコーポレイテッド | Heat and fluid circulation device for nucleic acid hybridization |
US6050278A (en) * | 1998-09-24 | 2000-04-18 | Minntech Corporation | Dialyzer precleaning system |
US6100084A (en) * | 1998-11-05 | 2000-08-08 | The Regents Of The University Of California | Micro-sonicator for spore lysis |
WO2000029619A2 (en) * | 1998-11-13 | 2000-05-25 | Mosaic Technologies | Multielement analytical device for assay of nucleic acid sequences and uses therefore |
DE19852982C1 (en) * | 1998-11-17 | 2000-03-16 | Braun Melsungen Ag | Cartridge holder for dialysis machine has lower cheek with outlet connection and upper cheek with inflow connection, with cartridge being insertable between cheeks |
US6887693B2 (en) * | 1998-12-24 | 2005-05-03 | Cepheid | Device and method for lysing cells, spores, or microorganisms |
US6429027B1 (en) | 1998-12-28 | 2002-08-06 | Illumina, Inc. | Composite arrays utilizing microspheres |
US20020150909A1 (en) | 1999-02-09 | 2002-10-17 | Stuelpnagel John R. | Automated information processing in randomly ordered arrays |
ATE556149T1 (en) * | 1999-02-23 | 2012-05-15 | Caliper Life Sciences Inc | MANIPULATION OF MICROPARTICLES IN MICROFLUIDIC SYSTEMS |
US6235479B1 (en) * | 1999-04-13 | 2001-05-22 | Bio Merieux, Inc. | Methods and devices for performing analysis of a nucleic acid sample |
US20030108867A1 (en) | 1999-04-20 | 2003-06-12 | Chee Mark S | Nucleic acid sequencing using microsphere arrays |
US6355431B1 (en) | 1999-04-20 | 2002-03-12 | Illumina, Inc. | Detection of nucleic acid amplification reactions using bead arrays |
US6261523B1 (en) | 1999-04-27 | 2001-07-17 | Agilent Technologies Inc. | Adjustable volume sealed chemical-solution-confinement vessel |
DE19923821A1 (en) * | 1999-05-19 | 2000-11-23 | Zeiss Carl Jena Gmbh | Method and device for recording the position of a surface to be scanned with a laser scanner includes a microscope beam input directed through a microscope lens onto a lens with a biochip to pick up fluorescent samples. |
US6544732B1 (en) | 1999-05-20 | 2003-04-08 | Illumina, Inc. | Encoding and decoding of array sensors utilizing nanocrystals |
CA2374596A1 (en) | 1999-05-20 | 2000-11-30 | Illumina, Inc. | Method and apparatus for retaining and presenting at least one microsphere array to solutions and/or to optical imaging systems |
WO2000075373A2 (en) | 1999-05-20 | 2000-12-14 | Illumina, Inc. | Combinatorial decoding of random nucleic acid arrays |
JP4316050B2 (en) * | 1999-05-31 | 2009-08-19 | ボールセミコンダクター株式会社 | Micromachine manufacturing method |
US6170494B1 (en) * | 1999-11-12 | 2001-01-09 | Advanced Micro Devices, Inc. | Method for automatically cleaning resist nozzle |
ATE527053T1 (en) | 1999-12-13 | 2011-10-15 | Illumina Inc | SYNTHESIS DEVICE FOR OLIGONUCLEOTIDES USING CENTRIFLY FORCE |
US20010039014A1 (en) * | 2000-01-11 | 2001-11-08 | Maxygen, Inc. | Integrated systems and methods for diversity generation and screening |
US7582420B2 (en) | 2001-07-12 | 2009-09-01 | Illumina, Inc. | Multiplex nucleic acid reactions |
JP2003521252A (en) | 2000-02-07 | 2003-07-15 | イルミナ インコーポレイテッド | Nucleic acid detection method using universal priming |
US6770441B2 (en) | 2000-02-10 | 2004-08-03 | Illumina, Inc. | Array compositions and methods of making same |
FR2806166B1 (en) * | 2000-03-09 | 2002-11-15 | Genomic Sa | AUTOMATON FOR PROCESSING, SIGNAL ACQUISITION AND ANALYSIS OF BIOCHIPS |
US6511277B1 (en) | 2000-07-10 | 2003-01-28 | Affymetrix, Inc. | Cartridge loader and methods |
US6422249B1 (en) * | 2000-08-10 | 2002-07-23 | Affymetrix Inc. | Cartridge washing system and methods |
US8048386B2 (en) * | 2002-02-25 | 2011-11-01 | Cepheid | Fluid processing and control |
US20030096239A1 (en) | 2000-08-25 | 2003-05-22 | Kevin Gunderson | Probes and decoder oligonucleotides |
AU2001288751A1 (en) | 2000-09-05 | 2002-03-22 | Illumina, Inc. | Cellular arrays comprising encoded cells |
EP1330306A2 (en) * | 2000-10-10 | 2003-07-30 | BioTrove, Inc. | Apparatus for assay, synthesis and storage, and methods of manufacture, use, and manipulation thereof |
WO2002040634A2 (en) * | 2000-11-14 | 2002-05-23 | Genetag Technology, Inc. | Expression miniarrays and uses thereof |
US6905816B2 (en) * | 2000-11-27 | 2005-06-14 | Intelligent Medical Devices, Inc. | Clinically intelligent diagnostic devices and methods |
KR100991573B1 (en) * | 2000-12-11 | 2010-11-04 | 프레지던트 앤드 펠로우즈 오브 하버드 칼리지 | Nanosensors |
US6869792B2 (en) * | 2001-03-16 | 2005-03-22 | Irm, Llc | Method and apparatus for performing multiple processing steps on a sample in a single vessel |
WO2003006164A1 (en) * | 2001-07-11 | 2003-01-23 | Universisty Of Southern California | Dna probe synthesis on chip on demand by mems ejector array |
WO2003008943A1 (en) | 2001-07-19 | 2003-01-30 | Tufts University | Optical array device and methods of use thereof for screening, analysis and manipulation of particles |
US6998094B2 (en) * | 2001-09-06 | 2006-02-14 | Genetix Limited | Apparatus for and methods of handling biological sample containers |
US20030148362A1 (en) * | 2002-02-07 | 2003-08-07 | Eastern Virginia Medical School Of The Medical College Of Hampton Roads | Diagnostic microarray and method of use thereof |
EP1380337B1 (en) * | 2002-07-12 | 2012-11-14 | Tosoh Corporation | Fine channel device and a chemically operating method for fluid using the device |
US20040120861A1 (en) * | 2002-10-11 | 2004-06-24 | Affymetrix, Inc. | System and method for high-throughput processing of biological probe arrays |
US7402279B2 (en) * | 2002-10-31 | 2008-07-22 | Agilent Technologies, Inc. | Device with integrated microfluidic and electronic components |
US20040191807A1 (en) * | 2002-12-13 | 2004-09-30 | Affymetrix, Inc. | Automated high-throughput microarray system |
US7043939B2 (en) * | 2003-08-14 | 2006-05-16 | Imac Business Corporation | Band-like ring |
US7476360B2 (en) * | 2003-12-09 | 2009-01-13 | Genefluidics, Inc. | Cartridge for use with electrochemical sensor |
US20060034913A1 (en) | 2004-08-13 | 2006-02-16 | James Gaede | Multiplex drug delivery device |
US20080311585A1 (en) | 2005-11-02 | 2008-12-18 | Affymetrix, Inc. | System and method for multiplex liquid handling |
US20080038714A1 (en) * | 2005-11-02 | 2008-02-14 | Affymetrix, Inc. | Instrument to Pneumatically Control Lab Cards and Method Thereof |
US20070099288A1 (en) * | 2005-11-02 | 2007-05-03 | Affymetrix, Inc. | Microfluidic Methods, Devices, and Systems for Fluid Handling |
US8007267B2 (en) | 2005-11-02 | 2011-08-30 | Affymetrix, Inc. | System and method for making lab card by embossing |
US8075852B2 (en) | 2005-11-02 | 2011-12-13 | Affymetrix, Inc. | System and method for bubble removal |
KR100772893B1 (en) * | 2006-05-02 | 2007-11-05 | 삼성전자주식회사 | Oligomer probe array with improved signal to noise ratio and assay intensity and fabrication method thereof |
US20080003667A1 (en) | 2006-05-19 | 2008-01-03 | Affymetrix, Inc. | Consumable elements for use with fluid processing and detection systems |
-
2006
- 2006-03-23 US US11/388,762 patent/US20060246576A1/en not_active Abandoned
- 2006-03-24 US US11/389,549 patent/US20060234371A1/en not_active Abandoned
- 2006-04-06 CN CNU2006201000508U patent/CN201040757Y/en not_active Expired - Lifetime
- 2006-04-06 CN CNU2006201000512U patent/CN201006877Y/en not_active Expired - Lifetime
- 2006-04-06 CN CNA2006100737225A patent/CN1876800A/en active Pending
- 2006-04-06 CN CN2006100737210A patent/CN1847848B/en active Active
-
2009
- 2009-06-10 US US12/481,852 patent/US8796186B2/en active Active
- 2009-12-07 US US12/632,429 patent/US20100081583A1/en not_active Abandoned
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4731335A (en) * | 1985-09-13 | 1988-03-15 | Fisher Scientific Company | Method for treating thin samples on a surface employing capillary flow |
US4731335B1 (en) * | 1985-09-13 | 1991-07-09 | Fisher Scientific Co | |
US5601650A (en) * | 1991-05-29 | 1997-02-11 | Medite Gesellschaft Fur Medizintechnik Mbh | Process and device for dyeing histological preparations arranged on microscope slides |
US6361940B1 (en) * | 1996-09-24 | 2002-03-26 | Qiagen Genomics, Inc. | Compositions and methods for enhancing hybridization and priming specificity |
US20040185483A1 (en) * | 1998-12-28 | 2004-09-23 | Illumina, Inc. | Composite arrays utilizing microspheres with a hybridization chamber |
US20060234371A1 (en) * | 2005-04-06 | 2006-10-19 | Affymetrix, Inc. | System and method for processing large number of biological microarrays |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060234371A1 (en) * | 2005-04-06 | 2006-10-19 | Affymetrix, Inc. | System and method for processing large number of biological microarrays |
US8796186B2 (en) | 2005-04-06 | 2014-08-05 | Affymetrix, Inc. | System and method for processing large number of biological microarrays |
US8351026B2 (en) | 2005-04-22 | 2013-01-08 | Affymetrix, Inc. | Methods and devices for reading microarrays |
US20100328732A1 (en) * | 2006-11-21 | 2010-12-30 | Illumina Inc. | Hexagonal site line scanning method and system |
US8023162B2 (en) * | 2006-11-21 | 2011-09-20 | Illumina, Inc. | Hexagonal site line scanning method and system |
US11692220B2 (en) | 2012-07-31 | 2023-07-04 | Gen-Probe Incorporated | Apparatus for applying thermal energy to a receptacle and detecting an emission signal from the receptacle |
US11788128B2 (en) | 2012-07-31 | 2023-10-17 | Gen-Probe Incorporated | Apparatus for applying thermal energy to a receptacle and detecting an emission signal from the receptacle |
US11302417B2 (en) | 2013-03-15 | 2022-04-12 | Affymetrix, Inc. | Systems and methods for SNP characterization and identifying off target variants |
Also Published As
Publication number | Publication date |
---|---|
CN201006877Y (en) | 2008-01-16 |
CN201040757Y (en) | 2008-03-26 |
US20060234371A1 (en) | 2006-10-19 |
CN1847848B (en) | 2012-10-10 |
US20100081583A1 (en) | 2010-04-01 |
CN1876800A (en) | 2006-12-13 |
CN1847848A (en) | 2006-10-18 |
US8796186B2 (en) | 2014-08-05 |
US20100069265A1 (en) | 2010-03-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20060246576A1 (en) | Fluidic system and method for processing biological microarrays in personal instrumentation | |
EP1458486B1 (en) | Array plates and method for constructing array plates | |
EP1647600A2 (en) | Methods for identifying biological samples by addition of nucleic acid bar-code tags | |
US20040191810A1 (en) | Immersed microarrays in conical wells | |
US20050221351A1 (en) | Methods and devices for microarray image analysis | |
US20050208555A1 (en) | Methods of genotyping | |
US20040023247A1 (en) | Quality control methods for microarray production | |
US20050023672A1 (en) | Device and method for immersed array packaging and processing | |
US20040161779A1 (en) | Methods, compositions and computer software products for interrogating sequence variations in functional genomic regions | |
US20040115794A1 (en) | Methods for detecting transcriptional factor binding sites | |
US20060147957A1 (en) | Methods for high throughput sample preparation for microarray analysis | |
US7629164B2 (en) | Methods for genotyping polymorphisms in humans | |
US20050032102A1 (en) | Mapping genomic rearrangements | |
US20040191807A1 (en) | Automated high-throughput microarray system | |
US20040115644A1 (en) | Methods of direct amplification and complexity reduction for genomic DNA | |
US20040171167A1 (en) | Chip-in-a-well scanning | |
US20040259124A1 (en) | Methods for oligonucleotide probe design | |
US20060147940A1 (en) | Combinatorial affinity selection | |
US20040096837A1 (en) | Non-contiguous oligonucleotide probe arrays | |
US20050074799A1 (en) | Use of guanine analogs in high-complexity genotyping | |
US7117097B2 (en) | Methods, computer software products and systems for correlating gene lists | |
US20040110132A1 (en) | Method for concentrate nucleic acids | |
US20060216831A1 (en) | Methods for automated collection of small volume of liquid | |
US8815510B2 (en) | Combinatorial affinity selection | |
US20040191809A1 (en) | Methods for registration at the nanometer scale |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: AFFYMETRIX, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SHIRAZI, MOHSEN;REEL/FRAME:018021/0789 Effective date: 20060605 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |