WO2005022147A1 - Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network - Google Patents
Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network Download PDFInfo
- Publication number
- WO2005022147A1 WO2005022147A1 PCT/US2004/028213 US2004028213W WO2005022147A1 WO 2005022147 A1 WO2005022147 A1 WO 2005022147A1 US 2004028213 W US2004028213 W US 2004028213W WO 2005022147 A1 WO2005022147 A1 WO 2005022147A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cell
- cells
- optical switch
- flow
- channel
- Prior art date
Links
- 230000003287 optical effect Effects 0.000 title claims abstract description 157
- 238000000034 method Methods 0.000 title abstract description 32
- 238000001514 detection method Methods 0.000 claims description 44
- 239000012530 fluid Substances 0.000 claims description 13
- 238000005286 illumination Methods 0.000 claims description 10
- 239000004033 plastic Substances 0.000 abstract description 5
- 229920003023 plastic Polymers 0.000 abstract description 5
- 238000004806 packaging method and process Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 260
- 239000000523 sample Substances 0.000 description 31
- 239000000872 buffer Substances 0.000 description 29
- 239000000758 substrate Substances 0.000 description 27
- 238000013461 design Methods 0.000 description 24
- 238000013459 approach Methods 0.000 description 22
- 239000002245 particle Substances 0.000 description 13
- 239000011521 glass Substances 0.000 description 11
- 230000001960 triggered effect Effects 0.000 description 10
- 238000003384 imaging method Methods 0.000 description 9
- 230000005284 excitation Effects 0.000 description 8
- 238000000206 photolithography Methods 0.000 description 8
- 239000002699 waste material Substances 0.000 description 7
- 238000010586 diagram Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 230000002123 temporal effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000001917 fluorescence detection Methods 0.000 description 5
- 230000005484 gravity Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- -1 e.g. Substances 0.000 description 4
- 230000010287 polarization Effects 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000004973 liquid crystal related substance Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000009416 shuttering Methods 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005530 etching Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 239000010954 inorganic particle Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011146 organic particle Substances 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920002972 Acrylic fiber Polymers 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 244000007835 Cyamopsis tetragonoloba Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000004720 dielectrophoresis Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000005370 electroosmosis Methods 0.000 description 1
- 238000004049 embossing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Polymers C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 description 1
- 229960004359 iodixanol Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000011527 multiparameter analysis Methods 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZEYOIOAKZLALAP-UHFFFAOYSA-M sodium amidotrizoate Chemical compound [Na+].CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I ZEYOIOAKZLALAP-UHFFFAOYSA-M 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/1456—Optical investigation techniques, e.g. flow cytometry without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals
- G01N15/1459—Optical investigation techniques, e.g. flow cytometry without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals the analysis being performed on a sample stream
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
- B01L3/502776—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for focusing or laminating flows
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0636—Focussing flows, e.g. to laminate flows
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0809—Geometry, shape and general structure rectangular shaped
- B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
- B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
- B01L2400/0454—Moving fluids with specific forces or mechanical means specific forces radiation pressure, optical tweezers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/04—Moving fluids with specific forces or mechanical means
- B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/149—Optical investigation techniques, e.g. flow cytometry specially adapted for sorting particles, e.g. by their size or optical properties
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
- Y10T436/2575—Volumetric liquid transfer
Definitions
- This invention relates to methods and apparatus for the use of optical forces in a microfluidic channel network to provide an optical switch that enables selective routing of target cells through the network to sort them from non-target cells and collect them.
- FACS fluorescent activated cell sorters
- Microfabricated cytometers have the potential to sort with as few as 1,000 cells while concomitantly consuming less reagents in an easy to use, closed system. The latter is important because, unlike conventional FACS instruments, aerosols are not created, r ,-. 2 reducing the risks of contamination of the sorted cells and of working with biohazardous materials.
- Several microfabricated cell sorters have been described, but mostly as "proof of concept”. Fu, et al. 2 reported 30-fold enrichment of E. coli at a throughput of 17 cells/s.
- the force exerted on a particle by an optical beam is a function of the optical power and the relative optical properties of the particle and its surrounding fluid medium. Forces on the order of 1 pN/mW can be achieved for biological cells approximately 10 ⁇ m in diameter. While the optical force is small, the force necessary to deflect a cell into an adjacent flowstream is also small, e.g. 900 pN to move a 10 ⁇ m diameter cell, 20 - 40 ⁇ m laterally across the flow in a few milliseconds. This is the force necessary to overcome the viscous drag force on the cell at the velocity implied by this lateral motion. [0006] The principles behind the optical forces and general background technology may be found in U.S. Patent 6,744,038, which is incorporated herein by reference as if fully set forth herein. Summary of the Invention
- optical switch is triggered by detection of a fluorescence signal from target cells flowing in the microfluidic channel network upstream of the optical switch position, although other detection modalities such as light scattering could equally be used for activation of the optical switch.
- the optical switch is used to direct cells or particles into one of a multiple number of output channel flow streams without modifying the underlying flow, whereby the desired cells are collected for further use. It is important that the flow in a microfluidic channel is typically laminar at a very low Reynolds number.
- the optical switch utilizes optical forces on a cell to accomplish just this, the transport of cells transverse to the lamina to move the cells from a flow stream that exits a bifurcation junction through one output channel to a flow stream that exits the bifurcation junction through the second output channel.
- the invention described in the following paragraphs details the methodology used to create an optical switch and the approaches used to optimize the optical switch, the design of the microfluidic channel network and the properties of the flow of cells or particles in the microfluidic network in order to achieve enhanced sorting performance.
- the optical switch generally works by projecting an optical illumination field into the microfluidic channel network in the vicinity of the cell's trajectory in an established flow in a microfluidic channel.
- the interaction ofthe cell with the optical field produce forces on the cell that transport it transverse to the established flow such that it moves from one flowstream to another flowstream in the established flow, without trapping the cell or significantly altering its motion in the primary flow.
- cells and particles both will be understood to mean any of biological cells, biological particles, natural organic or inorganic particles and man- made organic or inorganic particles.
- the size range of the cells sorted in the microfluidic channel network is typically that of biological cells, with diameters ranging from approximately 1 ⁇ m to approximately 50 ⁇ m. More generally, cells with diameters ranging from approximately 100 nm to approximately 100 ⁇ m are candidates for sorting by means of an optical switch in a microfluidic channel network.
- a laser has been used to produce the optical beam used in the optical switch.
- the laser currently used for the optical switch is a near-IR, continuous wave laser that is known not to harm the viability of biological cells at the power densities and exposure times used to demonstrate optical switching.
- Alternate laser sources may be considered for different applications, including visible or near-UV wavelength lasers if damage to the particles is not an issue, or pulsed lasers where a large flux of light can be used to move the particle very quickly.
- the source of the optical beam does not need to be limited to a laser, even though further discussion ofthe invention uses a laser to produce the optical switch.
- FIG 1 is a plan view of a "Y" shaped sorting junction in a microfluidic channel network.
- FIG 2 is a plan view of a microfluidic channel network that incorporates both a sheath flow pinch junction and a "Y" shaped sorting junction connected by a main channel, with 50/50 splitting of cells in the flow, collectively referred to as a 50/50 optical switch network.
- FIG 3 is a plan view of a microfluidic channel network that incorporates both a sheath flow pinch junction and a "Y" shaped sorting junction connected by a main channel, with skewed splitting of cells in the flow via differential sheath flow, collectively referred to as a sheath flow skewed optical switch network, with an optical switch.
- FIG 4 is a plan view of a microfluidic channel network that incorporates both a sheath flow pinch junction and a "Y" shaped sorting junction connected by a main channel, with skewed splitting of cells in the flow via differential outlet channel width, collectively referred to as an outlet flow skewed optical switch network, with an optical switch.
- FIG 5 is a 50/50 optical switch network with a bi-directional laser line optical switch.
- FIG 6 is a 50/50 optical switch network with a bi-directional laser spot optical switch.
- FIG 7 is a plan view of laser line optical switches in larger microfluidic channel networks with more than two outlet channels.
- FIG 8 shows possible optical designs for modulation and/or shuttering of the optical switch.
- FIG 9 is a plan view of a sheath flow skewed optical switch network with a laser spot optical switch that is translated parallel to the cell flow or at an angle to the cell flow.
- FIG 10 shows a detector arrangement and timing/trigger diagram using a single laser source for the cell detection and trigger decision method.
- FIG 11 shows a detector arrangement and timing/trigger diagram using two laser sources for the cell detection and trigger decision method.
- FIG 12 is a schematic of a representative design for photolithography masks for microfluidic channel networks in both bottom and top glass substrates that provides a 2- dimensional sheath flow pinch of the cell flow in the main channel when these substrates are bonded to form a single network.
- FIG 13 shows a 3-dimensional illustration ofthe design described in FIG. 12.
- FIG 14 is an illustration of the side view of a microfluidic channel network that provides sequential sheath flow pinch of the cell flow in the vertical direction and then in the horizontal direction, resulting in full 2-dimensional sheath flow pinch of the cell flow in the main channel.
- FIG 15 is a 3-dimensional illustration of the microfluidic channel network described in FIG. 14.
- FIG 16 is a schematic of a representative photolithography mask design for both bottom and top glass substrates that when bonded together form the microfluidic channel network illustrated in FIGs. 14 and 15.
- FIG 17 is a representative embodiment of a photolithography mask for a complete microfluidic channel network, with a T-pinch junction and a T-bifurcation junction to the outlet channels, to implement the optical switch based cell sort method.
- FIG 18 is a representative embodiment of a photolithography mask for a complete microfluidic channel network, with a triangle-pinch junction and a Y-bifurcation junction to the outlet channels, to implement the optical switch based cell sort method.
- FIG 19 shows a preferred embodiment of a microfluidic channel network in a completed microfluidic cell sorting chip.
- FIG 20 shows a preferred embodiment for a self-contained disposable cartridge for the optical switch based microfluidic channel network cell sorter.
- FIG 21 shows a preferred embodiment ofthe optical system for the optical switch based microfluidic channel network cell sorter.
- FIG 22 shows representative performance of the optical switch based microfluidic channel network cell sorter for various implementations ofthe optical switch.
- FIG. 1 shows one embodiment of an optical switch 10 that serves to sort cells in a 1x2 microfluidic channel network, i.e. a network with one main input channel 11 and two output channels 12 and 13 extending from a bifurcation junction.
- a "Y" geometry for the bifurcation junction is shown in Fig. 1, but other bifurcations such as a "T" geometry may also be used.
- these microfluidic channels are produced in optically transparent substrates to enable projection ofthe optical switch and other cell detection optics into the channel.
- This substrate is typically, but not limited to, glass, quartz, plastics, e.g., polymethylmethacrylate (PMMA), etc., and other castable or workable polymers (e.g.
- the depth ofthe microfluidic channels is typically in, but not limited to, the range lO ⁇ m to 100 ⁇ m.
- the width of the microfluidic channels is typically, but not limited to, 1 to 5 times the depth.
- the cross section is typically rectangular, or rectangular with quarter-round corners in the case of microfluidic channels produced by photolithograpic masking of glass substrate followed by isotropic etching of the channels.
- the flow conditions are set such that when the optical beam, in this case from a laser, is turned off or blocked so that the beam does not impinge on the junction region, all cells will preferentially flow into one of the output channels, for example the right output channel 13.
- the optical beam is turned on or unblocked, the beam strikes the junction region and optical forces generated by the interaction of the cells with the optical beam direct the cells into the left output channel 12.
- the optical pattern chosen for directing the cells is a long, thin line of laser illumination at some angle relative to the direction of fluid flow.
- Optical gradient forces displace the cells laterally, away from the main stream line of cells, such that switched cells then exit the main channel into one output channel, for example 12 while unswitched cells from the main stream of cells exit into the other output channel, for example 13.
- the setting and control of the flow conditions in the microfluidic channel network can be achieved by direct drive pumping, pneumatic pumping, electro-kinetics, capillary action, gravity, or other means to generate fluidic flow.
- the performance of the sorting mechanism in terms of throughput (the temporal rate of cells entering the sorting region at the top of the bifurcation junction), yield efficiency (the fraction of target cells in the target output channel, 12), and purity (the ratio of the number of target cells to the total number of cells in the target output channel, 12), are impacted by various factors, each of which affects the implementation of the optical switch.
- the optical switch can be characterized by several parameters such as the shape of the optical pattern projected into the sorting junction region of the microfluidic channel network, the position of the pattern with respect to the bifurcation junction, any motion of the optical pattern with respect to its initial position and shape, the duration of activation of the optical switch, the wavelength and power of the laser source used to produce the optical switch pattern, etc.
- the selection of particular values of these parameters for the optical switch is a critical function of, among other things, the topology and geometry of the microfluidic channel system, the flow rates (cell velocities) within the microchannel system, the ability to control the position of cells flowing in the main channel (whether they are flowing in the center of the main channel or off-set to one side), the amount of displacement of the cells necessary to achieve reliable switching, the depth of the channels, the shape ofthe channels, and the forces produced by the cells' interactions with the optical switch.
- 1 -dimensional focusing of cells (horizontally in the planar view shown) into a single file in the center of the main channel is achieved by pinching the cell input channel flow 20 with added flow of buffer from both the left 21 and right 22 sides, using a sheath flow approach as shown in FIG. 2. Maintaining the cells in the center of the main channel is achieved by having equal flow from each side. This flow effectively creates a fluidic splitting plane 23, as shown in FIG. 2, and this ultimately will result in a 50/50 splitting of the fluid and cells at the bifurcation junction.
- the focused line of cells can be positioned off-set from the center of the main channel by putting unequal flows into the side sheath flow channels, FIG. 3a-b.
- the side ofthe main channel to which the cell flow is skewed will be opposite to the side in which the sheath flow has the higher flow rate. That is, when the right sheath buffer 32 flows faster than the left sheath buffer 31, the line of cells is skewed toward the left of the flow in the main channel, as shown in FIG. 3a-b.
- FIG. 3a-b Also shown in FIG. 3a-b are a fluorescence detector 34 and an optical switch 35.
- the fluorescence detector is used as a means to decide which cells to sort, and will be discussed in further detail later. It is evident from FIG. 3b that an effective sort involves moving a cell across the splitting plane from a flow stream that exits the bifurcation junction to the fluorescence-negative non-target cell microfluidic channel 36 into a flow stream that exits the bifurcation junction to the fluorescence-positive, target cell microfluidic channel 37.
- Manipulation of the sheath buffer flow rate can be achieved either by separately controlling the flow rate in the respective side channels using direct drive pumping, pneumatic pumping, electrokinetics, capillary action, gravity, or other means to generate fluidic flow, or by specifically designing the microfluidic sheath network to ensure that central flow (50/50 splitting) or off-set flow occurs, through careful balancing ofthe pressure drops in each of the microfluidic channels.
- An alternative approach to achieve the preferential flow of all cells from the input flow 40 in the main channel into one output microfluidic channel, say the fluorescence- negative channel 46, prior to fluorescence detection 44, is to obtain central pinching using equal sheath buffer flow rates 41 and 42, but then preferentially bias the cell flow into fluorescence-negative channel by having a larger volumetric fluid flow out of the bifurcation junction into the fluorescence-negative output channel 46 relative to the fluorescence-positive output channel 47. This is demonstrated in FIG. 4a-b, in which the left output channel 46 is wider than the right output channel 47. This configuration effectively places the splitting plane 43 to the right of the centrally located cell stream.
- the optical switch 45 is then used to translate the target cells across the splitting plane into the target cell, fluorescence- positive., right output channel.
- This approach is equally effective by having the right output channel wider than the left output channel, whereby target cells are translated by the optical switch across the splitting plane, which is now located to the left of the centrally located cell stream, and are consequently sorted into the left output channel.
- the flow of cells into a desired output channel can be controlled.
- An alternative to this design is to use a bi-directional optical switch which utilizes two laser lines.
- one laser line sorts the desired cells to one output channel, and the other laser line sorts all other cells into the other output channel.
- This approach can be used with either the 50/50, FIG. 2, or the offset, FIG. 3 and 4, splitting configuration. In the latter case when a cell is not in the switching zone, one may choose to leave the laser on in either of its two positional states, or one may also shutter the laser during this time.
- the optical switch can also be made bi-directional by having two mirror- image laser lines impinging on the switching region, located just above the bifurcation ,. . . 10
- junction which independently turn on to direct cells to either ofthe two outputs stemming from the bifurcation junction.
- FIG. 5 A schematic of the bi-directional optical switch using laser lines in a 1x2 microfluidic network is shown in FIG. 5.
- a similar bi-directional optical switch has also be achieved with laser spots directed to either side ofthe channel, as shown in FIG. 6.
- a single laser source can be used in the bidirectional optical switch, or alternatively the bi-directional optical switch can use two independent laser sources.
- the bi-directional design potentially offers some performance advantages versus the mono-directional design. The first is that purity is potentially maximized because every cell is directed by the laser. Secondly, the fluid flow is simplified because equal flow can be directed out each of the two output ports, instead of some predetermined ratio of flow.
- microfluidic networks with IxN, or MxN, outputs can be utilized. Optical switching can be achieved in these larger networks by having an arbitrarily large number of independently modulated laser lines. Some embodiments are shown in FIG. 7a-c. Furthermore, cells can also be fed back multiple times through the same sorter to increase the purity of the sort, or alternatively, channels can also be arranged in a cascade for multiple levels of sorting. [0044] Two different activation modes can be considered when operating the optical switch in a mono-directional or bi-directional arrangement; a passive mode or an active mode.
- the passive mode is such that the state of the optical switch is either on or off, regardless of what cell may be flowing through the channel. In this case knowledge of when or how many cells are entering the switching region is not required, and consequently, depending on the state of the laser, all cells within the switching region are switched.
- the active mode the cells are first detected as they enter a detection/selection region, and then are switched based on some decision process.
- FIG. 3a-b and FIG. 4a-b show examples of this mode that use a fluorescence detector placed just prior to the switching region. In this case, all fluorescent cells were directed to one output channel, and all non-fluorescent cells were directed to the other output channel.
- Non-fluorescent detection/selection techniques for the decision process include Time-Of-Flight, scatter, imaging, capacitance, or any detection modality that can identify a desired cell. Regardless of the detection/selection method, switching using the active mode can be utilized to sort one population of cells from another based on some decision process.
- the optical beam In order to utilize the active mode, the optical beam must be modulated on or off in response to the decision process. Regardless ofthe number of lasers used, or whether the optical switch is mono-directional or bi-directional, the lasers can be modulated in many ways, including using an electro-optic modulator, modulating the laser power, shuttering the laser, using a liquid crystal modulator, using a galvanometer, and using an acousto- optic modulator.
- the separate lasers can be turned on and off independently; however, when using a single laser source the two different orientations of the optical switch line can be achieved by using a polarization rotator (such as a liquid crystal modulator) and having each of the two different line patterns be each of two separate polarizations.
- a polarization rotator such as a liquid crystal modulator
- an acoustic-optic modulator or a galvanometer mirror can be used to modulate the position of a single spot used as the optical switch, or a two-axis acousto-optic modulator or two-axis galvanometer mirror can be used to draw two different line shapes to be used as the bi-directional optical switch.
- FIG. 8a shows three different possible optical designs for performing the modulation and/or shuttering of the optical switch.
- the bi-directional optical switch is created from a single optical beam (laser) directed toward and passing through a Liquid Crystal Modulator (LCM).
- the LCM is a polarization rotator and therefore if the beam is polarized in one direction it will pass straight through the Polarizing Beam Splitter (PBS), through a cylindrical lens creating a line shape, through another PBS, and then through some focusing optics which focus the line onto the microfluidic switching region.
- PBS Polarizing Beam Splitter
- To switch cells into the other output channel a mirror image line must be created.
- an Acousto-Optic Modulator can be used to create the lines or spots used in the bi-directional optical switch.
- FIG. 8c shows the combination of the systems described in FIG. 8a and FIG. 8b.
- a galvanometer mirror either one-axis or two-axis, depending on the desired beam motion, may be used in place ofthe AOM.
- Many variations for the optical pattern can be considered when optimizing switching efficiency for mono- or bi-directional optical switches. As mentioned above a laser line has been used as the optical switch pattern.
- the line might be generated by a cylindrical lens, by scanning a galvanometer mirror or an acousto-optic modulator, by a diffractive optic, by a custom refractive optic, or by any other technique. To date the line has been generated using a cylindrical lens, by scanning a galvanometer or by using an acousto-optic modulator.
- the length of the line can be arbitrarily long or as short as a single point.
- the line can have higher intensity at the top of the line and gradually taper down in intensity toward the end of the line.
- the line might be a curved arc which optimizes the output direction of the cells.
- the angle of the line or the shape of the line might vary (i.e. swivel to optimize output). For implementations with multiple output channels, any arbitrary pattern of lines in 2D space might be generated to optimize the direction of each output cell. Alternatively, the line might be created by an array of discrete spots.
- the optical switch has been configured such that the laser spot is swept alongside a selected cell as it flows down the main channel toward the bifurcation junction, thereby increasing the total interaction time between the cell and the laser.
- the optical switch utilizes a laser spot which is translated, in a straight line, down the length of the main channel toward the bifurcation junction.
- the line swept by the spot can be parallel with the walls of the main channel (FIG. 9a), or can be at some angle relative to the cell flow stream (FIG. 9b). Therefore, the angle can range from 0-90 degrees.
- the ability to sweep the spot is achieved using either an AOM or scanning galvanometer mirrors.
- the optical switch is triggered to sweep by a decision based on detection of the desired cell using fluorescence or other detection modality that can identify a desired cell; for example Time-Of-Flight, scatter, imaging, or capacitance.
- the cell position can be either off-set or centered in the main channel, which dictates the length of the line swept by the spot and the laser power used to achieve efficient switching/sorting.
- the optical switch is turned on, and the spot appears alongside the desired cell.
- the spot then tracks alongside the selected cell and uses optical forces to direct the selected cell into the desired output channel.
- Typical to both methods is the use of a temporal signal to analyze the moving cell, and use this information to generate a decision to switch, or not to switch.
- This temporal signal is essentially a measure of a signal as a function of time, which can yield a distinctive temporal fingerprint in terms of both peak intensity and peak width.
- the signal may be fluorescence, scatter (for instance, forward scatter), capacitance, imaging, or any detection modality that can identify a desired cell.
- One approach is to utilize a single laser source coupled with two or more detectors to accomplish both cell detection and cell identification.
- FIG. lOa-d show this approach using one laser source combined with a fluorescence detector and a forward scatter detector. The temporal signals from these detectors are used as the information for the switch decision.
- the presence of a cell is verified by the forward scatter signal and when this signal is coupled with a fluorescence signal intensity which is within a predetermined range; this "gating" information is then used to trigger the optical switch.
- the cell stream is centrally located by using equal flow rate sheath buffers, with output channels having different widths used to create a splitting plane to the right ofthe cell stream.
- any configuration used to manipulate the position ofthe cell stream and splitting plane can be used.
- common to both configurations is the presence of an error checking detector, which verifies whether a cell has been switched or not.
- FIG. lOa-b show the detector arrangement and the timing/trigger diagram for when the sort parameter is negative and the optical switch is not triggered.
- the cells enter the main fluidic channel and are focused into a single file by sheath buffer flowing from both sides. As a cell passes the through the laser in the detection/selection region, both fluorescence and forward scatter signals are detected simultaneously, or nearly simultaneously. Although the presence of a cell is successfully detected via the forward scatter signal (at time t ), the fluorescence signal is below the gating level and the optical switch is not triggered (at time t ).
- FIG. lOc-d show the detector arrangement and the timing/trigger diagram for when the sort parameter is positive and the optical switch is triggered.
- both fluorescence and forward scatter signals are again detected (at time ti simultaneously, or nearly simultaneously, but the fluorescence signal is within the gating level and the optical switch is triggered (at time t ).
- An error check signal (at time t 3 ) is obtained since a cell was switched.
- the trigger time (at time t 2 ) is a preset value ( ⁇ t) measured from the initial detection time (t]), and this ⁇ t value is determined by the speed ofthe cells and the position of the optical switch relative to the detection/selection region.
- FIG. lla-d shows this second approach, in which two laser sources are used instead of one. Also, as with the single laser approach described above, the temporal signals from these detectors are used as the information for the switch decision.
- One laser is used in a detection zone to separately accomplish cell detection prior to the identification selection region.
- the detection in this case can be based on fluorescence, scatter (for instance forward scatter), capacitance, imaging, or any detection modality that can identify a desired cell.
- the second laser is coupled with two or more detectors and is used to accomplish cell detection and cell identification. Again, identification in this case can be based on fluorescence, scatter (for instance forward scatter), capacitance, imaging, or any detection modality that can identify a desired cell.
- FIG. lla-b shows the detector arrangement and the timing/trigger diagram for when the sort parameter is negative and the optical switch is not triggered.
- the cells enter the main fluidic channel and are focused into a single file by sheath buffer flowing from both sides.
- the presence of a cell is verified by the forward scatter signal (at time t ⁇ ) as it passes through the detection window region.
- a second forward scatter signal is obtained (at time t 2 ), however, this signal is coupled with a fluorescence signal intensity (at time t 2 ) which is not within the gating level and the optical switch is not triggered (at time t 3 ).
- No error check signal (at time t ) is obtained since no cell was switched.
- the flow rate (v) of the cell stream is obtained using (t ⁇ ), (t 2 ) and the known distance (d) between the detection and identification windows.
- FIG. llc-d show the detector arrangement and the timing/trigger diagram for when the sort parameter is positive and the optical switch is triggered.
- the presence of a cell is again verified by the forward scatter signal (at time t ) as it passes through the detection window region.
- a second forward scatter signal is obtained (at time t 2 ), and this signal is coupled with a fluorescence signal intensity (at time t ) which is within the gating level and the optical switch is triggered (at time t 3 ).
- An error check signal (at time t 4 ) is now obtained since a cell was switched.
- This approach allows for more efficient sorting as it can account for fluctuations in cell flow rate, and therefore more accurately trigger the optical switch.
- An added benefit of this approach is, for each individual cell, the possibility of adjusting the rate at which the laser spot is translated - - 16
- Another approach to improving the sorting efficiency, while incorporating the triggering approaches described above, is to centralize the cells in the main channel using channel designs which create a true sample core, whereby the core is completely surrounded by the sheath buffer. Variability in the location of a cell along the channel height can cause variability in cell detection and fluorescence intensity.
- FIG. 12a-b and FIG. 13 show one method to accomplish this, in which the channel design on one substrate is the mirror image ofthe design on the other substrate.
- the channel networks overlay and form complete fluidic conduits.
- Fig 12a-b show one type of design used in this approach, with the sample channel shown as a dashed line.
- the key feature of this approach is to ensure that the sample channels are shallower than the sheath channels, such that when the substrates are brought together the sample conduit appears to enter the junction as a hole. This is shown in FIG. 13, where the cells can be seen to enter the junction, and then are pinched from all sides creating a sample core which flows in the center ofthe main channel.
- the channels can be formed by wet chemical etch or laser etch of glass or quartz, by molding or embossing in plastics or polymers.
- Another method involves having a series of intersecting channels arranged such that in the first junction/intersection the cells are pushed vertically toward one wall of the main channel, the next junction/intersection forces this cell stream vertically into the center of the main channel, and then a final pinch flow from both sides at a third junction/intersection creates the complete sheath buffer shroud around a sample core flowing in the main channel.
- This is shown in FIG. 14 and FIG. 15, with one possible channel schematic shown in FIG. 16.
- junction (A) sample flows from the top substrate into the junction and down into the channel in the bottom substrate, where the side sheath buffer flows into the junction from the sides.
- the sample is slightly focused and pushed to the top wall of the bottom channel as it continues to flow toward the next junction (B).
- the sample flows along the top of the bottom channel from junction A to junction (B).
- a second sheath buffer flows into the junction (B) from the top substrate and the sample is pushed down to the middle of the channel in the bottom substrate.
- the sample continues to flow along the middle of the bottom channel toward the next junction (C).
- a third sheath buffer flows into junction (C) from both sides, and the sample is pinched into single file.
- the sample is now surrounded by sheath buffer as it continues to flow, as a sample core, centered both horizontally and vertically within the main input channel.
- microfluidic channel network designs described in Figs. 1-16 have been produced in glass substrate utilizing conventional photolithographic masking and isotropic etching of the masked glass substrates.
- the bottom profile of the channel has a quarter-round contour of radius d e at each edge due to the isotropic etch and the top of the etched channel is open.
- a glass substrate typically a glass cover slip, is thermally bonded to the substrate with the etched microfluidic channels to seal the tops ofthe channels and complete a microfluidic channel network. Holes are typically drilled in the top substrate prior to the thermal bonding to provide vias for ingress and egress of fluid flow to the microfluidic channel network.
- the depth d e ofthe channels depends on the rate ofthe chemical etch process and the duration of the etch step.
- the depth of the microfluidic channels is typically in, but not limited to, the range 10 ⁇ m to 100 ⁇ m.
- the width of the microfluidic channels is typically, but not limited to, 2 to 5 times the depth.
- the microfluidic channels typically have rectangular cross sections, but otherwise are similar to the channels in the glass substrates.
- the size of the glass substrate in which the microfluidic channel network is produced is typically in, but not limited to, the range of 5 mm x 5 mm to 25 mm x 50 mm with a total thickness in, but not limited to, the range 500 ⁇ m to 2 mm.
- the top substrate is typically the same size, with thickness in, but not limited to, the range 300 ⁇ m to 1 mm.
- the vias are typically, but not limited to, 200 ⁇ m to 600 ⁇ m in diameter.
- the completed substrate, with a microfluidic channel network and a bonded cover plate with vias for fluidic ports for ingress and egress of fluid flow, is termed a microfluidic sorting chip or chip for brevity.
- the microfluidic channels networks shown in Figs. 1-16 typically have only described the local geometries of the inlet microfluidic channel, the sheath buffer pinch junction channels, the cell identification and optical switch main channel, and the bifurcation of the main channel to the outlet channel.
- This description needs to be expanded to provide for regions in each channel to make the connections to reservoirs in a macro-scale fluidic device or cartridge that provides the interface to the vias described above to provide ingress and egress ofthe fluid flow from the network.
- the cross section and length of each of these microfluidic channels typically needs to be adjusted to assure appropriate controlled flow within the entire microfluidic channel network, depending on the technique selected to achieve the flow in the channels. Both the cross section and the length of these channels are determined by the pattern used to produce the photolithography mask.
- Fig. 17 shows one embodiment of a mask for a complete microfluidic channel network that has an inlet channel, two sheath channels to a T-pinch junction and two outlet' channels from a T-bifurcation junction.
- This mask was designed to provide a 7:1 volumetric pinch ratio (the sheath flow rate is seven times greater than the cell inlet flow rate).
- the length ofthe channels was designed to provide both sufficient pressure drop to enable the use of either standard low flow syringe pumps or low pressure pneumatic controllers to establish the flow.
- the design also reflects the balance of pressures needed to enable use of only two pumps, one for the cell inlet channel and one for the two sheath channels, with the outlets maintained at atmospheric pressure.
- the sheath channel inlet is at the termination at the top ofthe design, the cell inlet channel originates below this in the center of the two sheath channels and is long enough to provide the appropriate pressure drop to set the 7:1 pinch ratio, and the two outlets are located at the termini at the bottom left and right.
- Fig. 18 shows another embodiment that incorporates a triangular junction for the pinch junction and a Y-bifurcation junction, in a design that provides a 10:1 volumetric pinch ratio. Otherwise the design is geometrically similar to that of Fig. 17. Many other designs are clearly possible, but they all share the common features of needing to provide for fluidic ingress and egress and to provide appropriate pressure drops and pressure balances for the method chosen to establish the fluid flow. Similar design conditions are used to produce the photolithography masks used to make the microfluidic channel networks for 2-dimensional pinch flow networks described previously.
- Fig. 19 shows a preferred embodiment of a microfluidic channel network in a completed microfluidic sorting chip.
- the two inlet ports, for the cell sample flow and for the sheath buffer flow are identified, as are the two outlet ports, for the fluorescence- positive target cells and for the fluorescence-negative non-target cells, the waste stream.
- the chip is 24 mm by 40 mm.
- the thickness of the etched substrate is 1.1 mm.
- the thickness ofthe bonded cover plate is 550 ⁇ m.
- the microfluidic channels are 50 ⁇ m deep.
- the cell inlet microfluidic channel is 110 ⁇ m wide.
- the sheath flow and outlet microfluidic channels are 150 ⁇ m wide, as is the main microfluidic channel.
- the sheath flow pinch junction is an inverted equilateral triangle, 300 ⁇ m per side, connecting the cell inlet channel through the base of the triangle, at the top of the junction, with the two sheath flow pinch channels from each side to the main channel through the apex of the triangle, at the bottom of the junction.
- This microfluidic channel network design is optimized to use pneumatic control of the flow at all four ports to establish the network flow.
- Microfluidic connections to the chip may be made in a variety of ways. One method is to use flexible microfluidic tubing directly connected to the ports, either by gluing or using various tubing adapters that can be attached to the surface ofthe chip at the ports.
- This tubing can be connected directly to syringe pumps or similar systems that provide volumes for handling both the cell sample and the sheath buffers and provide the pressure to flow these volumes through the chip.
- syringe pumps for handling the sample volume requires that the pump be cleaned and reloaded for each sample and introduces the possibility for carry over or contamination from one sample to the next.
- An improved method for microfluidic connections to the chip utilizes a cartridge that is directly adhered to the chip using a UV-curable adhesive, a PSA bonding sheet, or other conventional bonding methods.
- the cartridge has four built-in reservoirs that separately provide interface connections to the cell inlet channel, the two sheath channels (from one reservoir), and each of the two outlet channels.
- Such a cartridge provides the possibility of sterile handling of both the cell sample and the sorted target cells and waste stream, since they can be completely confined to the volumes of the cartridge before and after the cell sort.
- the flow for such a cartridge and chip system can be provided by using two pneumatic pressure controllers that separately pressurize the cell inlet and sheath buffer reservoirs to induce flow through the microfluidic channel network of the chip to the outlet reservoirs that are at atmospheric pressure.
- FIG. 20 shows a preferred embodiment of a self-contained disposable cartridge that provides fluidic reservoirs for the cell sample volume, the sheath buffer volume and the two outlet collection volumes for target cells and waste respectively.
- the cartridge is manufactured from acrylic plastic and may either be machined or cast.
- the cell sample volume is typically conical in shape, tapering towards the port to the inlet microfluidic channel.
- the inlet reservoir contains a polypropylene insert to minimize cell adhesion and consequently maximize cell yield.
- the chip is bonded with UV adhesive to the optical window region, and the outlet ports from the chip interface with their respective reservoir volumes.
- the reservoir volumes are sealed with the snap-on lid that has drilled ports for connection between the pneumatic controllers and the individual reservoirs.
- the lid contains a silicone gasket to aid in sealing against the cartridge body. It also incorporates a 0.1 ⁇ m polypropylene filter to create a gas permeable, liquid tight interface between the cartridge volumes and the external environment. This maintains aseptic conditions on the cartridge and minimizes any biohazard contamination to the user or the instrument.
- the cartridge is prepared for a cell sorting run by first priming the microfluidic channel network through the sheath port with sheath buffer solution, using an ordinary syringe with a luer fitting. In this way the channels are primed and the sheath reservoir is filled with 800 ⁇ l and each outlet reservoir is filled with 200 ⁇ l.
- the cell sample reservoir is aspirated of excess buffer liquid and then 5 - 25 ⁇ l of cell sample is placed into the sample input reservoir using a pipette.
- the cartridge lid is then applied and snapped into place, providing a self-contained system in which to perform the cell sorting run.
- the cartridge is designed to be placed in a holder that positions the main channel ofthe chip such that the optical imaging system that projects the optical switch beam into the channel is appropriately aligned and focused into the channel.
- the cartridge holder also includes a pressure manifold plate that has four ports, connected by external tubing to the four pneumatic controllers. Each manifold port is sealed to its respective cartridge lid port with an o-ring, and these seals are made leak free by pressing the manifold against the cartridge lid with a cam-lock mechanism.
- a preferred embodiment of the optical system for the optical switch is shown in FIG. 21.
- the cartridge with the pneumatic manifold connecting to the snap-on lid, is positioned such that the optical switch region is at the focus of both a lens system viewing from above the cartridge and a lens system viewing from below.
- the output beam from a 488 nm laser is projected through the imaging system into the main channel just upstream of the sorting region, as shown in FIGs. 3-7 and 9-11, to provide excitation for the detection of fluorescence from fluorescence-positive target cells.
- the fluorescence emission is collected by the same lens and imaged through a dichroic mirror and an appropriate fluorescence emission filter to a photomultiplier tube.
- the signal from the photomultiplier tube is processed by the electronics to measure the level of the fluorescence from the cells and determine the presence of fluorescence-positive target cells in the flow stream in the main channel.
- the fluorescence excitation is not limited to the 488 nm wavelength, but can be at any wavelength that is appropriate for the fluorophores used to identify the target cells. If a different excitation illumination is used, the wavelength of the fluorescence emission filter must be changed accordingly.
- the electronics triggers the AOM to direct the beam from the IR-laser, typically a 1070 nm laser operation between 5 W and 20 W output power, into the main channel at the optical switch position. In the preferred embodiment, the AOM is controlled to produce an optical switch pattern as described in FIG.
- the lens below the cartridge images the 488 nm excitation illumination onto a photodiode.
- the signal detected by this photodiode is used to help distinguish fluorescently labeled cells from smaller debris that may carry the fluorescent label, and also to identify clumps of cells that might have formed. These events are rejected as candidates for sorting to the target output charmel.
- Yet another preferred embodiment would incorporate appropriate imaging and optical filtering to provide a forward scattering signal based on the illumination of the cell by the 488 nm laser that is used to excite the fluorescence.
- the optics would provide a range of angular sensitivity, such as, but not limited to this range, 0.8° to 10°, for the detection of the forward scattering signal. This signal can help characterize cells in addition to the fluorescence signal, as well as help distinguish cells from debris.
- the forward scattering illumination is not limited to the fluorescence excitation laser, but could be at any other wavelength provided by an additional light source that is properly imaged into the main channel.
- Yet another preferred embodiment would incorporate additional fluorescence detection channels that are sensitive to fluorescence emissions at different wavelength, typically using a single excitation wavelength, such as, but not limited to, 488 nm.
- Each detection channel would incorporate a PMT with an appropriate dichroic mirror and emission filter for the fluorescence emission wavelength of the additional fluorophore. From two to four fluorescence detection channels are readily accommodated in this manner. Using more than one fluorophore in this manner provides the ability for multiple detection criteria to identify the target cells for sorting with the optical switch.
- Yet another preferred embodiment would incorporate an error checking capability that provides optical illumination, typically as a narrow line across one of the channels in the network, and typically at a longer wavelength, perhaps, but not limited to, 785 nm from a solid state laser, that is outside the range of wavelengths used for fluorescence detection and forward scatter detection, but is shorter than the optical switch wavelength that is typically at 1070 nm.
- This source can be appropriately imaged into the microfluidic channel network to provide lines that can be used to detect passage of particles through any vertical plane in the network. This provides additional ability to check the performance of the optical switch performance and provides additional capability for the timing ofthe trigger ofthe optical switch, as described in FIG. 11.
- Yet another preferred embodiment of the optical system would incorporate an additional optical illumination path at, but not restricted to, 750 nm, e.g., as produced by band pass filtering the light from an LED, and illuminating a region of the microfluidic channels with that light. That region would be imaged through a 750 nm pass filter onto a CCD camera to provide visualization of the performance of the cells flowing in the microfluidic channel network at the bifurcation junction and/or at the pinch junction.
- the filters before the camera would be adequate to block any shorter wavelength radiation associated with the excitation or detection of fluorescence and with the forward/side scatter optics and the error detection optics.
- the filters would also block the longer wavelength, 1070 nm light from the optical switch.
- the preferred embodiment ofthe cartridge shown in Fig. 20 is designed to hold the microfluidic channel network in a horizontal configuration, so that all of the channels and inlet/outlet ports are at the same vertical level. This minimizes the effects of gravity on the pressure drops through the microfluidic channels, leading to more stable and controllable flow in the network. However, gravity will still have an effect on the cells in the flow, particularly as the cells pass from the cell sample reservoir into the cell inlet microfluidic channel.
- Another preferred embodiment of the sorter to help control the effects of gravity on settling of the cells in this reservoir and on their settling in the relatively slower flow in the inlet microfluidic channel before the cells flow speeds up at the pinch junction, is to enhance the buoyancy ofthe cells, such that settling ofthe cells is minimized. Increasing the buoyancy can be achieved by using additives in the sample buffer.
- rheological control additives particularly those that are either pseudoplastic or shear thinning, or both, are xanthan gum, carageenan, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl guar, Gum Arabic, Gum Tragacanth, Alginate, polyacrylates,carbomer.
- Other additives include HistopaqueTM, which is a mixture of polysucrose and sodium diatrizoate, and OptiprepTM, which is a 60% w/v solution of iodixanol in water. The concentration of these additives used depends on the density of the cell being sorted.
- the buffers that are used for the cell sample volume and for the sheath flow can be any buffers that are biologically compatible with the cells that are being sorted, and are compatible with optical illumination that is used both for the fluorescence detection modality and for the optical switch, i.e., the buffer has sufficiently low absorbance at the fluorescence excitation detection wavelengths and the optical switch wavelength.
- a preferred embodiment of the sheath buffer uses PBS/BSA, phosphate buffered saline (PBS) at pH 7.2 with 1% bovine serum albumin (BSA) fraction 5.
- a preferred embodiment of the cell buffer uses PBS/BSA with 14.5% Optiprep for live cell samples and 27% Optiprep for a variety of formalin fixed cell samples.
- the performance of the optical switch method of cell sorting in a microfluidic channel network is evaluated by the throughput, purity and recovery of the sort as previously described.
- the cartridge described in FIG. 20 is optimized to allow measurement ofthe performance, since it is made of acrylic, the bottoms ofthe target and waste collection reservoirs are transparent and the cells that are sorted into these reservoirs can be quantified as to both number and fluorescence labeling using an inverted fluorescence microscope.
- FIGs. 3-11 were evaluated. These evaluations were performed using a 50:50 mix of live HeLa:HeLa- GFP cells that was sorted using either a 1- or 2-sided stationary laser spot, or a 0° or 8° 1- sided laser sweep.
- the laser was swept at 240 Hz.
- the laser ON time was 4 msec and the laser power was 20 W for all switch modes.
- the focused IR laser spot was translated about 70 ⁇ m along the main channel.
- FIG. 22 shows the performance ofthe 1 -sided switching methods, described in FIG. 9, with a stationary laser spot or a spot that is translated in the direction of flow, either parallel or at a slight angle to the flow.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Fluid Mechanics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2004800281349A CN1860363B (en) | 2003-08-28 | 2004-08-27 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
EP04782647A EP1668355A4 (en) | 2003-08-28 | 2004-08-27 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
CA2536360A CA2536360C (en) | 2003-08-28 | 2004-08-27 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
JP2006524942A JP4533382B2 (en) | 2003-08-28 | 2004-08-27 | Integrated structure for microfluidic analysis and sorting |
AU2004269406A AU2004269406B2 (en) | 2003-08-28 | 2004-08-27 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US49929403P | 2003-08-28 | 2003-08-28 | |
US60/499,294 | 2003-08-28 | ||
US57489704P | 2004-05-26 | 2004-05-26 | |
US60/574,897 | 2004-05-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005022147A1 true WO2005022147A1 (en) | 2005-03-10 |
Family
ID=34278657
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/028213 WO2005022147A1 (en) | 2003-08-28 | 2004-08-27 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
Country Status (7)
Country | Link |
---|---|
US (2) | US7745221B2 (en) |
EP (1) | EP1668355A4 (en) |
JP (1) | JP4533382B2 (en) |
CN (1) | CN1860363B (en) |
AU (1) | AU2004269406B2 (en) |
CA (1) | CA2536360C (en) |
WO (1) | WO2005022147A1 (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007009983A1 (en) * | 2005-07-19 | 2007-01-25 | Commissariat A L'energie Atomique | Method of calibrating a particle flux sorting device |
FR2901717A1 (en) * | 2006-05-30 | 2007-12-07 | Centre Nat Rech Scient | METHOD FOR TREATING DROPS IN A MICROFLUIDIC CIRCUIT |
WO2008130871A2 (en) | 2007-04-20 | 2008-10-30 | Cellula, Inc. | Cell sorting system and methods |
WO2010023596A1 (en) * | 2008-08-25 | 2010-03-04 | Koninklijke Philips Electronics N.V. | Reconfigurable microfluidic filter |
JP2010513876A (en) * | 2006-12-19 | 2010-04-30 | フィオ コーポレイション | Microfluidic system and method for testing target molecules in biological samples |
WO2010075459A1 (en) * | 2008-12-22 | 2010-07-01 | Celula, Inc. | Methods and genotyping panels for detecting alleles, genomes, and transcriptomes |
CN102175590A (en) * | 2011-03-23 | 2011-09-07 | 重庆天海医疗设备有限公司 | Disposable counting board for microscopic detection |
CN103175950A (en) * | 2011-12-20 | 2013-06-26 | 中国科学院深圳先进技术研究院 | Hemocyte analysis chip and system for using chip thereof |
WO2012094325A3 (en) * | 2011-01-03 | 2013-09-06 | Cytonome/St. Llc | Method and apparatus for monitoring and optimizing particle sorting |
WO2016050837A1 (en) | 2014-09-30 | 2016-04-07 | Foss Analytical A/S | Method, device and system for hydrodynamic flow focusing |
US9849456B2 (en) | 2013-12-04 | 2017-12-26 | Clearbridge Mfluidics Pte. Ltd. | Microfluidic device |
US10543992B2 (en) | 2003-10-30 | 2020-01-28 | Cytonome/St, Llc | Multilayer hydrodynamic sheath flow structure |
US10583439B2 (en) | 2013-03-14 | 2020-03-10 | Cytonome/St, Llc | Hydrodynamic focusing apparatus and methods |
GB2547349B (en) * | 2014-08-29 | 2020-09-30 | Synaptive Medical Barbados Inc | System and method for intraoperative cell storage, processing and imaging |
US11471885B2 (en) | 2016-11-14 | 2022-10-18 | Orca Biosystems, Inc. | Methods and apparatuses for sorting target particles |
Families Citing this family (176)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006507921A (en) * | 2002-06-28 | 2006-03-09 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | Method and apparatus for fluid dispersion |
US11243494B2 (en) | 2002-07-31 | 2022-02-08 | Abs Global, Inc. | Multiple laminar flow-based particle and cellular separation with laser steering |
US7699767B2 (en) | 2002-07-31 | 2010-04-20 | Arryx, Inc. | Multiple laminar flow-based particle and cellular separation with laser steering |
ES2375724T3 (en) | 2002-09-27 | 2012-03-05 | The General Hospital Corporation | MICROFLUDE DEVICE FOR SEPERATION OF CELLS AND ITS USES. |
US20060078893A1 (en) | 2004-10-12 | 2006-04-13 | Medical Research Council | Compartmentalised combinatorial chemistry by microfluidic control |
GB0307428D0 (en) | 2003-03-31 | 2003-05-07 | Medical Res Council | Compartmentalised combinatorial chemistry |
GB0307403D0 (en) | 2003-03-31 | 2003-05-07 | Medical Res Council | Selection by compartmentalised screening |
JP2006523142A (en) | 2003-04-10 | 2006-10-12 | プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ | Formation and control of fluid species |
RU2005139384A (en) * | 2003-05-16 | 2006-05-10 | Юниверсити Оф Чикаго (Us) | METHOD AND DEVICE OF OPTICAL FRACTIONATION |
EP2662135A3 (en) | 2003-08-27 | 2013-12-25 | President and Fellows of Harvard College | Method for mixing droplets in a microchannel |
CN1860363B (en) * | 2003-08-28 | 2011-12-28 | 赛路拉公司 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
US20050221339A1 (en) | 2004-03-31 | 2005-10-06 | Medical Research Council Harvard University | Compartmentalised screening by microfluidic control |
US9477233B2 (en) | 2004-07-02 | 2016-10-25 | The University Of Chicago | Microfluidic system with a plurality of sequential T-junctions for performing reactions in microdroplets |
CA2600899C (en) * | 2004-07-16 | 2014-04-01 | Simon Fraser University | Microfluidic device and method of using same |
US7968287B2 (en) | 2004-10-08 | 2011-06-28 | Medical Research Council Harvard University | In vitro evolution in microfluidic systems |
US9492400B2 (en) | 2004-11-04 | 2016-11-15 | Massachusetts Institute Of Technology | Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals |
US8951746B2 (en) * | 2004-11-05 | 2015-02-10 | Southwest Research Institute | Method and devices for screening cervical cancer |
US7615762B2 (en) * | 2004-12-03 | 2009-11-10 | Nano Science Diagnostics, Inc. | Method and apparatus for low quantity detection of bioparticles in small sample volumes |
US20070054119A1 (en) * | 2005-03-04 | 2007-03-08 | Piotr Garstecki | Systems and methods of forming particles |
AU2006220816A1 (en) | 2005-03-04 | 2006-09-14 | President And Fellows Of Harvard College | Method and apparatus for forming multiple emulsions |
US20070196820A1 (en) | 2005-04-05 | 2007-08-23 | Ravi Kapur | Devices and methods for enrichment and alteration of cells and other particles |
WO2006108087A2 (en) * | 2005-04-05 | 2006-10-12 | Cellpoint Diagnostics | Devices and methods for enrichment and alteration of circulating tumor cells and other particles |
US7574076B2 (en) * | 2005-04-08 | 2009-08-11 | Arryx, Inc. | Apparatus for optically-based sorting within liquid core waveguides |
US8921102B2 (en) | 2005-07-29 | 2014-12-30 | Gpb Scientific, Llc | Devices and methods for enrichment and alteration of circulating tumor cells and other particles |
WO2007102839A2 (en) * | 2005-10-27 | 2007-09-13 | Applera Corporation | Optoelectronic separation of biomolecules |
US9267937B2 (en) | 2005-12-15 | 2016-02-23 | Massachusetts Institute Of Technology | System for screening particles |
JP2009536313A (en) | 2006-01-11 | 2009-10-08 | レインダンス テクノロジーズ, インコーポレイテッド | Microfluidic devices and methods for use in nanoreactor formation and control |
EP2004316B8 (en) * | 2006-01-27 | 2011-04-13 | President and Fellows of Harvard College | Fluidic droplet coalescence |
WO2008105773A2 (en) | 2006-03-31 | 2008-09-04 | Massachusetts Institute Of Technology | System for targeted delivery of therapeutic agents |
US9562837B2 (en) | 2006-05-11 | 2017-02-07 | Raindance Technologies, Inc. | Systems for handling microfludic droplets |
EP2021113A2 (en) | 2006-05-11 | 2009-02-11 | Raindance Technologies, Inc. | Microfluidic devices |
EP2019691B1 (en) | 2006-05-15 | 2020-08-12 | Massachusetts Institute of Technology | Polymers for functional particles |
JP2007301534A (en) * | 2006-05-15 | 2007-11-22 | Ebara Corp | Atomizer |
JP5032792B2 (en) * | 2006-05-22 | 2012-09-26 | 浜松ホトニクス株式会社 | Cell sorter |
US8137912B2 (en) | 2006-06-14 | 2012-03-20 | The General Hospital Corporation | Methods for the diagnosis of fetal abnormalities |
US20080050739A1 (en) | 2006-06-14 | 2008-02-28 | Roland Stoughton | Diagnosis of fetal abnormalities using polymorphisms including short tandem repeats |
US8372584B2 (en) | 2006-06-14 | 2013-02-12 | The General Hospital Corporation | Rare cell analysis using sample splitting and DNA tags |
WO2007147074A2 (en) | 2006-06-14 | 2007-12-21 | Living Microsystems, Inc. | Use of highly parallel snp genotyping for fetal diagnosis |
WO2007150030A2 (en) * | 2006-06-23 | 2007-12-27 | Massachusetts Institute Of Technology | Microfluidic synthesis of organic nanoparticles |
WO2008021123A1 (en) | 2006-08-07 | 2008-02-21 | President And Fellows Of Harvard College | Fluorocarbon emulsion stabilizing surfactants |
US7676122B2 (en) * | 2006-12-11 | 2010-03-09 | Jiahua James Dou | Apparatus, system and method for particle manipulation using waveguides |
WO2008097559A2 (en) | 2007-02-06 | 2008-08-14 | Brandeis University | Manipulation of fluids and reactions in microfluidic systems |
WO2008098165A2 (en) | 2007-02-09 | 2008-08-14 | Massachusetts Institute Of Technology | Oscillating cell culture bioreactor |
CN102014871A (en) * | 2007-03-28 | 2011-04-13 | 哈佛大学 | Emulsions and techniques for formation |
WO2008124639A2 (en) | 2007-04-04 | 2008-10-16 | Massachusetts Institute Of Technology | Poly (amino acid) targeting moieties |
CN101765762B (en) * | 2007-04-16 | 2013-08-14 | 通用医疗公司以马萨诸塞州通用医疗公司名义经营 | Systems and methods for particle focusing in microchannels |
US8592221B2 (en) | 2007-04-19 | 2013-11-26 | Brandeis University | Manipulation of fluids, fluid components and reactions in microfluidic systems |
US20090042737A1 (en) * | 2007-08-09 | 2009-02-12 | Katz Andrew S | Methods and Devices for Correlated, Multi-Parameter Single Cell Measurements and Recovery of Remnant Biological Material |
EP2620157A3 (en) | 2007-10-12 | 2013-10-16 | Massachusetts Institute of Technology | Vaccine nanotechnology |
JP4539707B2 (en) * | 2007-10-25 | 2010-09-08 | ソニー株式会社 | Microparticle sorting device, microparticle sorting substrate, and microparticle sorting method |
US8585916B2 (en) * | 2008-01-24 | 2013-11-19 | Sandia Corporation | Micropores and methods of making and using thereof |
US8942458B2 (en) | 2008-06-27 | 2015-01-27 | Furukawa Electric Co., Ltd. | Method for distinguishing and sorting of cells and device therefor |
WO2010009365A1 (en) | 2008-07-18 | 2010-01-21 | Raindance Technologies, Inc. | Droplet libraries |
US12038438B2 (en) | 2008-07-18 | 2024-07-16 | Bio-Rad Laboratories, Inc. | Enzyme quantification |
LT2334812T (en) | 2008-09-20 | 2017-04-25 | The Board Of Trustees Of The Leland Stanford Junior University | Noninvasive diagnosis of fetal aneuploidy by sequencing |
US8343498B2 (en) | 2008-10-12 | 2013-01-01 | Massachusetts Institute Of Technology | Adjuvant incorporation in immunonanotherapeutics |
US8343497B2 (en) | 2008-10-12 | 2013-01-01 | The Brigham And Women's Hospital, Inc. | Targeting of antigen presenting cells with immunonanotherapeutics |
US8591905B2 (en) | 2008-10-12 | 2013-11-26 | The Brigham And Women's Hospital, Inc. | Nicotine immunonanotherapeutics |
US8277812B2 (en) | 2008-10-12 | 2012-10-02 | Massachusetts Institute Of Technology | Immunonanotherapeutics that provide IgG humoral response without T-cell antigen |
KR101023040B1 (en) * | 2008-11-13 | 2011-03-24 | 한국항공대학교산학협력단 | Apparatus for high throughput particle separation and method thereof |
US8162149B1 (en) | 2009-01-21 | 2012-04-24 | Sandia Corporation | Particle sorter comprising a fluid displacer in a closed-loop fluid circuit |
US9134221B2 (en) | 2009-03-10 | 2015-09-15 | The Regents Of The University Of California | Fluidic flow cytometry devices and particle sensing based on signal-encoding |
US9645010B2 (en) | 2009-03-10 | 2017-05-09 | The Regents Of The University Of California | Fluidic flow cytometry devices and methods |
WO2010111231A1 (en) | 2009-03-23 | 2010-09-30 | Raindance Technologies, Inc. | Manipulation of microfluidic droplets |
US8689981B2 (en) | 2009-04-10 | 2014-04-08 | President And Fellows Of Harvard College | Manipulation of particles in channels |
CN102460154B (en) * | 2009-04-13 | 2015-10-07 | 华盛顿大学 | Ensemble-decision aliquot ranking |
AU2010257118B2 (en) | 2009-06-04 | 2014-08-28 | Lockheed Martin Corporation | Multiple-sample microfluidic chip for DNA analysis |
US8535536B1 (en) * | 2009-07-04 | 2013-09-17 | University Of Utah Research Foundation | Cross-flow split-thin-flow cell |
EP2462245B1 (en) * | 2009-08-06 | 2016-10-05 | Cornell University | Device and methods for epigenetic analysis |
US8202486B2 (en) * | 2009-08-12 | 2012-06-19 | Caliper Life Sciences, Inc. | Pinching channels for fractionation of fragmented samples |
CN102574078B (en) | 2009-09-02 | 2016-05-18 | 哈佛学院院长等 | Use and spray the multiple emulsion producing with other technology |
EP2486409A1 (en) | 2009-10-09 | 2012-08-15 | Universite De Strasbourg | Labelled silica-based nanomaterial with enhanced properties and uses thereof |
WO2011140627A1 (en) | 2009-11-04 | 2011-11-17 | The University Of British Columbia | Nucleic acid-containing lipid particles and related methods |
US10837883B2 (en) | 2009-12-23 | 2020-11-17 | Bio-Rad Laboratories, Inc. | Microfluidic systems and methods for reducing the exchange of molecules between droplets |
EP2534267B1 (en) | 2010-02-12 | 2018-04-11 | Raindance Technologies, Inc. | Digital analyte analysis |
US9366632B2 (en) | 2010-02-12 | 2016-06-14 | Raindance Technologies, Inc. | Digital analyte analysis |
US9399797B2 (en) | 2010-02-12 | 2016-07-26 | Raindance Technologies, Inc. | Digital analyte analysis |
US10351905B2 (en) | 2010-02-12 | 2019-07-16 | Bio-Rad Laboratories, Inc. | Digital analyte analysis |
KR101120137B1 (en) * | 2010-03-10 | 2012-05-17 | 주식회사 넥스비보 | Selective Particle Capture and Release Device |
US8774488B2 (en) | 2010-03-11 | 2014-07-08 | Cellscape Corporation | Method and device for identification of nucleated red blood cells from a maternal blood sample |
ITTO20100068U1 (en) * | 2010-04-20 | 2011-10-21 | Eltek Spa | MICROFLUID AND / OR EQUIPMENT DEVICES FOR MICROFLUID DEVICES |
EP3447155A1 (en) | 2010-09-30 | 2019-02-27 | Raindance Technologies, Inc. | Sandwich assays in droplets |
US8969071B2 (en) * | 2010-10-13 | 2015-03-03 | Lawrence Livermore National Security, Llc | Passive chip-based droplet sorting |
GB2497501A (en) | 2010-10-15 | 2013-06-12 | Lockheed Corp | Micro fluidic optic design |
WO2012054904A2 (en) | 2010-10-21 | 2012-04-26 | The Regents Of The University Of California | Microfluidics with wirelessly powered electronic circuits |
CN102019277B (en) * | 2010-10-29 | 2013-05-22 | 北京惟馨雨生物科技有限公司 | Sorter and sorting method for separating cells and particles |
JP2012095603A (en) * | 2010-11-02 | 2012-05-24 | Univ Of Fukui | System for tracking expression state of gene |
US10908066B2 (en) | 2010-11-16 | 2021-02-02 | 1087 Systems, Inc. | Use of vibrational spectroscopy for microfluidic liquid measurement |
US8822207B2 (en) * | 2011-01-21 | 2014-09-02 | Owl biomedical, Inc. | Cartridge for MEMS particle sorting system |
EP2673614B1 (en) | 2011-02-11 | 2018-08-01 | Raindance Technologies, Inc. | Method for forming mixed droplets |
EP2675819B1 (en) | 2011-02-18 | 2020-04-08 | Bio-Rad Laboratories, Inc. | Compositions and methods for molecular labeling |
EP2490005A1 (en) * | 2011-02-18 | 2012-08-22 | Koninklijke Philips Electronics N.V. | Microfluidic resistance network and microfluidic device |
US8528582B2 (en) | 2011-04-28 | 2013-09-10 | The United States Of America As Represented By The Secretary Of The Navy | Method of changing fluid flow by using an optical beam |
BR112013029729A2 (en) | 2011-05-23 | 2017-01-24 | Basf Se | emulsion control including multiple emulsions |
US8841071B2 (en) | 2011-06-02 | 2014-09-23 | Raindance Technologies, Inc. | Sample multiplexing |
EP3709018A1 (en) | 2011-06-02 | 2020-09-16 | Bio-Rad Laboratories, Inc. | Microfluidic apparatus for identifying components of a chemical reaction |
WO2013006661A2 (en) | 2011-07-06 | 2013-01-10 | President And Fellows Of Harvard College | Multiple emulsions and techniques for the formation of multiple emulsions |
WO2013010134A2 (en) * | 2011-07-14 | 2013-01-17 | Celula, Inc. | Systems, apparatus and methods for biochemical analysis |
US8658430B2 (en) | 2011-07-20 | 2014-02-25 | Raindance Technologies, Inc. | Manipulating droplet size |
US9841367B2 (en) * | 2011-09-16 | 2017-12-12 | The University Of North Carolina At Charlotte | Methods and devices for optical sorting of microspheres based on their resonant optical properties |
US9242248B2 (en) * | 2011-09-16 | 2016-01-26 | The University Of North Carolina At Charlotte | Methods and devices for optical sorting of microspheres based on their resonant optical properties |
EP2770980A4 (en) | 2011-10-25 | 2015-11-04 | Univ British Columbia | Limit size lipid nanoparticles and related methods |
US9108196B1 (en) * | 2012-01-24 | 2015-08-18 | Stratedigm, Inc. | Method and apparatus for control of fluid flow or fluid suspended particle flow in a microfluidic channel |
US9322054B2 (en) | 2012-02-22 | 2016-04-26 | Lockheed Martin Corporation | Microfluidic cartridge |
RU2510509C1 (en) * | 2012-07-16 | 2014-03-27 | Федеральное государственное бюджетное учреждение науки Институт цитологии и генетики Сибирского отделения Российской академии наук | Microfluid system for immunoassay |
US11898954B2 (en) * | 2012-08-01 | 2024-02-13 | Owl biomedical, Inc. | Particle manipulation system with camera/classifier confirmation and deep learning algorithm |
US9194786B2 (en) * | 2012-08-01 | 2015-11-24 | Owl biomedical, Inc. | Particle manipulation system with cytometric capability |
US9168568B2 (en) | 2012-08-01 | 2015-10-27 | Owl biomedical, Inc. | Particle manipulation system with cytometric confirmation |
US9372144B2 (en) * | 2013-10-01 | 2016-06-21 | Owl biomedical, Inc. | Particle manipulation system with out-of-plane channel |
EP2906928A4 (en) | 2012-10-15 | 2016-11-09 | Nanocellect Biomedical Inc | Systems, apparatus, and methods for sorting particles |
TWI498593B (en) | 2012-11-06 | 2015-09-01 | Ind Tech Res Inst | Projection lens, projection device and optically-induced microparticle device |
US10215687B2 (en) | 2012-11-19 | 2019-02-26 | The General Hospital Corporation | Method and system for integrated mutliplexed photometry module |
EP2920574B1 (en) * | 2012-11-19 | 2021-06-16 | The General Hospital Corporation | System and method for integrated multiplexed photometry module |
CN103105352A (en) * | 2013-01-28 | 2013-05-15 | 大连海事大学 | Device and method for rapidly detecting surviving unicellular organisms in ship ballast water |
US20160016180A1 (en) * | 2013-03-08 | 2016-01-21 | Duke University | Devices, systems, and methods for acoustically-enhanced magnetophoresis |
BR112015023155B1 (en) * | 2013-03-14 | 2022-09-20 | Inguran, Llc | HIGH PERFORMANCE SPERM SCREENING DEVICE AND METHODS |
EP2971279B1 (en) | 2013-03-15 | 2019-11-13 | The Trustees of Princeton University | Methods and devices for high throughput purification |
US20150064153A1 (en) | 2013-03-15 | 2015-03-05 | The Trustees Of Princeton University | High efficiency microfluidic purification of stem cells to improve transplants |
EP2971013B1 (en) | 2013-03-15 | 2020-08-19 | The University Of British Columbia | Lipid nanoparticles for transfection and related methods |
WO2014145152A2 (en) | 2013-03-15 | 2014-09-18 | Gpb Scientific, Llc | On-chip microfluidic processing of particles |
KR101412777B1 (en) | 2013-03-29 | 2014-07-01 | 성원기 | Lateral flow device for simultaneous quantitative analysis of multi-component |
CN105518464B (en) | 2013-07-05 | 2019-12-03 | 华盛顿大学商业中心 | Method, composition and the system of microfluid analysis |
US8961904B2 (en) | 2013-07-16 | 2015-02-24 | Premium Genetics (Uk) Ltd. | Microfluidic chip |
US9604214B2 (en) * | 2013-10-01 | 2017-03-28 | Owl biomedical, Inc. | Cell sorting system using microfabricated components |
US9863865B2 (en) | 2013-10-01 | 2018-01-09 | Owl biomedical, Inc. | Cell sorting system using electromagnetic solenoid |
US9404838B2 (en) * | 2013-10-01 | 2016-08-02 | Owl biomedical, Inc. | Particle manipulation system with out-of-plane channel and focusing element |
US11901041B2 (en) | 2013-10-04 | 2024-02-13 | Bio-Rad Laboratories, Inc. | Digital analysis of nucleic acid modification |
US11796449B2 (en) | 2013-10-30 | 2023-10-24 | Abs Global, Inc. | Microfluidic system and method with focused energy apparatus |
US9944977B2 (en) | 2013-12-12 | 2018-04-17 | Raindance Technologies, Inc. | Distinguishing rare variations in a nucleic acid sequence from a sample |
US11193176B2 (en) | 2013-12-31 | 2021-12-07 | Bio-Rad Laboratories, Inc. | Method for detecting and quantifying latent retroviral RNA species |
US9453787B2 (en) * | 2014-03-05 | 2016-09-27 | Owl biomedical, Inc. | MEMS-based single particle separation system |
US8820538B1 (en) | 2014-03-17 | 2014-09-02 | Namocell LLC | Method and apparatus for particle sorting |
EP4253936A3 (en) | 2014-03-18 | 2024-03-20 | The Regents of The University of California | Parallel flow cytometer using radiofrequency mulitplexing, and method |
CN103911275B (en) * | 2014-04-03 | 2015-08-05 | 河北工业大学 | A kind of micro-fluidic chip for cell screening |
KR20170039250A (en) | 2014-08-28 | 2017-04-10 | 시스멕스 가부시키가이샤 | Particle image-capturing device and particle image-capturing method |
US10456767B2 (en) * | 2014-10-22 | 2019-10-29 | Hitachi High-Technologies Corporation | Cytometric mechanism, cell culture device comprising same, and cytometric method |
US10180388B2 (en) | 2015-02-19 | 2019-01-15 | 1087 Systems, Inc. | Scanning infrared measurement system |
US10976232B2 (en) | 2015-08-24 | 2021-04-13 | Gpb Scientific, Inc. | Methods and devices for multi-step cell purification and concentration |
DK3341116T3 (en) * | 2015-08-27 | 2022-05-02 | Harvard College | SORTING PROCEDURE USING ACOUSTIC WAVES |
US10647981B1 (en) | 2015-09-08 | 2020-05-12 | Bio-Rad Laboratories, Inc. | Nucleic acid library generation methods and compositions |
WO2017066404A1 (en) | 2015-10-13 | 2017-04-20 | Omega Biosystems Incorporated | Multi-modal fluorescence imaging flow cytometry system |
AU2017212067A1 (en) * | 2016-01-26 | 2018-08-02 | Ricoh Company, Ltd. | Droplet forming device and dispensing device |
US10688493B2 (en) * | 2016-03-09 | 2020-06-23 | Texas Tech University System | Integrated microfluidic rectifier for various bioanalytical applications |
CA3018065A1 (en) | 2016-03-17 | 2017-09-21 | Bd Biosciences | Cell sorting using a high throughput fluorescence flow cytometer |
US10935485B2 (en) * | 2016-05-12 | 2021-03-02 | Bd Biosciences | Fluorescence imaging flow cytometry with enhanced image resolution |
US11291756B2 (en) | 2016-07-28 | 2022-04-05 | The Charles Stark Draper Laboratory, Inc. | Acoustic separation for bioprocessing |
US20190290829A1 (en) * | 2016-07-28 | 2019-09-26 | The Charles Stark Draper Laboratory, Inc. | Acoustic separation for bioprocessing |
EP4242631A3 (en) | 2016-09-13 | 2024-03-06 | Becton, Dickinson and Company | Flow cytometer with optical equalization |
US10272431B2 (en) | 2017-02-18 | 2019-04-30 | Owl biomedical, Inc. | Microfabricated cell sorter using pressure pulse |
WO2018201034A1 (en) | 2017-04-28 | 2018-11-01 | The Charles Stark Draper Laboratory, Inc. | Acoustic separation of particles for bioprocessing |
TWI677464B (en) * | 2017-05-10 | 2019-11-21 | 上準微流體股份有限公司 | Microfluidic chip, apparatus for enriching cells and method for enriching cells in a microfluidic chip |
CN111246943B (en) * | 2017-08-15 | 2021-06-22 | 通用医疗公司 | Method and system for integrated multiplexed modular light metering |
JP6871116B2 (en) * | 2017-09-15 | 2021-05-12 | 株式会社東芝 | Cell sorter |
US20210031201A1 (en) * | 2018-04-15 | 2021-02-04 | Optofluidic Bioassay, Llc | Differential pressure assisted drainage system |
WO2020018074A1 (en) | 2018-07-17 | 2020-01-23 | Hewlett-Packard Development Company, L.P. | Droplet ejectors to provide fluids to droplet ejectors |
US11925932B2 (en) | 2018-04-24 | 2024-03-12 | Hewlett-Packard Development Company, L.P. | Microfluidic devices |
WO2020018073A1 (en) | 2018-07-17 | 2020-01-23 | Hewlett-Packard Development Company, L.P. | Droplet ejectors with target media |
WO2019209374A1 (en) * | 2018-04-24 | 2019-10-31 | Hewlett-Packard Development Company, L.P. | Sequenced droplet ejection to deliver fluids |
WO2019226790A1 (en) | 2018-05-23 | 2019-11-28 | Abs Global, Inc. | Systems and methods for particle focusing in microchannels |
WO2020011193A1 (en) * | 2018-07-11 | 2020-01-16 | The University Of Hong Kong | Automatic microfluidic system for continuous and quantitive collection of droplets |
WO2020146425A1 (en) * | 2019-01-07 | 2020-07-16 | Elegen Corporation | Methods of using microfluidic positional encoding devices |
WO2020215011A1 (en) | 2019-04-18 | 2020-10-22 | Abs Global, Inc. | System and process for continuous addition of cryoprotectant |
EP3997439A4 (en) | 2019-07-10 | 2023-07-19 | Becton, Dickinson and Company | Reconfigurable integrated circuits for adjusting cell sorting classification |
US11701658B2 (en) | 2019-08-09 | 2023-07-18 | President And Fellows Of Harvard College | Systems and methods for microfluidic particle selection, encapsulation, and injection using surface acoustic waves |
US11161109B2 (en) | 2019-09-19 | 2021-11-02 | Invidx Corp. | Point-of-care testing cartridge with sliding cap |
US11327084B2 (en) * | 2019-09-19 | 2022-05-10 | Invidx Corp. | Joint hematology and biochemistry point-of-care testing system |
WO2021142133A1 (en) * | 2020-01-07 | 2021-07-15 | Elegen Corporation | Dna assembly in microfluidics device having integrated solid-phase columns |
US11628439B2 (en) | 2020-01-13 | 2023-04-18 | Abs Global, Inc. | Single-sheath microfluidic chip |
EP4154365A4 (en) | 2020-05-19 | 2023-11-08 | Becton, Dickinson and Company | Methods for modulating an intensity profile of a laser beam and systems for same |
CN111644212B (en) * | 2020-05-22 | 2022-05-24 | 华东理工大学 | Micro-fluidic chip and nano-particle separation device |
EP4172592A4 (en) | 2020-06-26 | 2023-12-06 | Becton, Dickinson and Company | Dual excitation beams for irradiating a sample in a flow stream and methods for using same |
US11200446B1 (en) | 2020-08-31 | 2021-12-14 | Element Biosciences, Inc. | Single-pass primary analysis |
WO2023154874A2 (en) * | 2022-02-10 | 2023-08-17 | University Of Virginia Patent Foundation | Buffer exchange of biological samples in-line with separation and measurement operations |
WO2023177601A1 (en) * | 2022-03-18 | 2023-09-21 | Owl biomedical, Inc. | Microfabricated droplet dispensor with hydrogel |
CN114693646B (en) * | 2022-03-31 | 2023-04-11 | 中山大学中山眼科中心 | Corneal endothelial cell active factor analysis method based on deep learning |
WO2024158708A1 (en) * | 2023-01-23 | 2024-08-02 | Beckman Coulter, Inc. | Flow cell for a flow cytometer |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020132315A1 (en) * | 2000-11-13 | 2002-09-19 | Genoptix | Methods and apparatus for measurement of dielectric constants of particles |
US20020181837A1 (en) * | 2000-11-28 | 2002-12-05 | Mark Wang | Optical switching and sorting of biological samples and microparticles transported in a micro-fluidic device, including integrated bio-chip devices |
Family Cites Families (191)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US520654A (en) * | 1894-05-29 | Method of making chairs for railroad-rails | ||
US3638139A (en) * | 1964-09-29 | 1972-01-25 | Bell Telephone Labor Inc | Frequency-selective laser devices |
US3558877A (en) * | 1966-12-19 | 1971-01-26 | Gca Corp | Method and apparatus for mass separation by selective light absorption |
US3628182A (en) | 1969-03-20 | 1971-12-14 | Bell Telephone Labor Inc | Ring-type parametric oscillator |
US3826899A (en) * | 1969-08-15 | 1974-07-30 | Nuclear Res Ass Inc | Biological cell analyzing system |
US3710279A (en) * | 1969-12-15 | 1973-01-09 | Bell Telephone Labor Inc | Apparatuses for trapping and accelerating neutral particles |
US3778612A (en) | 1969-12-15 | 1973-12-11 | A Ashkin | Neutral particle beam separator and velocity analyzer using radiation pressure |
US3808550A (en) * | 1969-12-15 | 1974-04-30 | Bell Telephone Labor Inc | Apparatuses for trapping and accelerating neutral particles |
CA944466A (en) * | 1970-01-26 | 1974-03-26 | Western Electric Company, Incorporated | Guided raman devices |
US3808432A (en) * | 1970-06-04 | 1974-04-30 | Bell Telephone Labor Inc | Neutral particle accelerator utilizing radiation pressure |
US3662183A (en) * | 1970-12-28 | 1972-05-09 | Bell Telephone Labor Inc | Continuously tunable optical parametric oscillator |
US3725810A (en) * | 1971-04-23 | 1973-04-03 | Bell Telephone Labor Inc | Optical stimulated emission devices employing split optical guides |
US3761721A (en) | 1972-07-06 | 1973-09-25 | Trw Inc | Matter wave interferometric apparatus |
US4127329A (en) | 1976-12-21 | 1978-11-28 | Northeast Utilities Service Company | Raman scattering system and method for aerosol monitoring |
US4092535A (en) * | 1977-04-22 | 1978-05-30 | Bell Telephone Laboratories, Incorporated | Damping of optically levitated particles by feedback and beam shaping |
US4063106A (en) | 1977-04-25 | 1977-12-13 | Bell Telephone Laboratories, Incorporated | Optical fiber Raman oscillator |
US4247815A (en) * | 1979-05-22 | 1981-01-27 | The United States Of America As Represented By The Secretary Of The Army | Method and apparatus for physiologic facsimile imaging of biologic targets based on complex permittivity measurements using remote microwave interrogation |
US4253846A (en) * | 1979-11-21 | 1981-03-03 | Technicon Instruments Corporation | Method and apparatus for automated analysis of fluid samples |
US4327288A (en) * | 1980-09-29 | 1982-04-27 | Bell Telephone Laboratories, Incorporated | Method for focusing neutral atoms, molecules and ions |
US4386274A (en) * | 1980-11-10 | 1983-05-31 | Saul Altshuler | Isotope separation by standing waves |
US4453805A (en) * | 1981-02-19 | 1984-06-12 | Bell Telephone Laboratories, Incorporated | Optical grating using a liquid suspension of dielectric particles |
FR2506530A1 (en) * | 1981-05-22 | 1982-11-26 | Thomson Csf | COHERENT RADIATION SOURCE GENERATING AN ADJUSTABLE SPREAD DIRECTION BEAM |
US4390403A (en) * | 1981-07-24 | 1983-06-28 | Batchelder J Samuel | Method and apparatus for dielectrophoretic manipulation of chemical species |
FR2519777A1 (en) * | 1982-01-12 | 1983-07-18 | Thomson Csf | METHOD FOR MANUFACTURING DIFFRACTANT PHASE STRUCTURES |
US4440638A (en) * | 1982-02-16 | 1984-04-03 | U.T. Board Of Regents | Surface field-effect device for manipulation of charged species |
FR2537768A1 (en) * | 1982-12-08 | 1984-06-15 | Commissariat Energie Atomique | METHOD AND DEVICE FOR OBTAINING SPATIALLY MODULATED DENSITY PARTICLE BEAMS, APPLICATION TO ION ETCHING AND IMPLANTATION |
US4632517A (en) | 1983-12-08 | 1986-12-30 | University Of Pittsburgh | Crystalline colloidal narrow band radiation filter |
US4627689A (en) | 1983-12-08 | 1986-12-09 | University Of Pittsburgh | Crystalline colloidal narrow band radiation filter |
EP0177718B1 (en) | 1984-09-11 | 1989-12-06 | Partec AG | Method and device for sorting microscopic particles |
US4758427A (en) * | 1985-08-08 | 1988-07-19 | Ciba-Geigy Corporation | Enhanced absorption of psychoactive 2-aryl-pyrazolo quinolines as a solid molecular dispersion in polyvinylpyrrolidone |
GB8623072D0 (en) | 1986-09-25 | 1986-10-29 | Amersham Int Plc | Particle analysis |
US4827125A (en) * | 1987-04-29 | 1989-05-02 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Confocal scanning laser microscope having no moving parts |
US4939081A (en) * | 1987-05-27 | 1990-07-03 | The Netherlands Cancer Institute | Cell-separation |
US4893886A (en) * | 1987-09-17 | 1990-01-16 | American Telephone And Telegraph Company | Non-destructive optical trap for biological particles and method of doing same |
US4887721A (en) | 1987-11-30 | 1989-12-19 | The United States Of America As Represented By The United States Department Of Energy | Laser particle sorter |
US4908112A (en) * | 1988-06-16 | 1990-03-13 | E. I. Du Pont De Nemours & Co. | Silicon semiconductor wafer for analyzing micronic biological samples |
US5100627A (en) * | 1989-11-30 | 1992-03-31 | The Regents Of The University Of California | Chamber for the optical manipulation of microscopic particles |
FR2655435B1 (en) * | 1989-12-01 | 1992-02-21 | Thomson Csf | COHERENT ADDITION DEVICE OF LASER BEAMS. |
CA2031716C (en) * | 1989-12-07 | 1996-06-18 | Hiroaki Misawa | Laser microprocessing and the device therefor |
US5795457A (en) * | 1990-01-30 | 1998-08-18 | British Technology Group Ltd. | Manipulation of solid, semi-solid or liquid materials |
US5029791A (en) * | 1990-03-08 | 1991-07-09 | Candela Laser Corporation | Optics X-Y positioner |
US5198369A (en) * | 1990-04-25 | 1993-03-30 | Canon Kabushiki Kaisha | Sample measuring method using agglomeration reaction of microcarriers |
US5079169A (en) * | 1990-05-22 | 1992-01-07 | The Regents Of The Stanford Leland Junior University | Method for optically manipulating polymer filaments |
US5338930A (en) * | 1990-06-01 | 1994-08-16 | Research Corporation Technologies | Frequency standard using an atomic fountain of optically trapped atoms |
US5245466A (en) | 1990-08-15 | 1993-09-14 | President And Fellows Of Harvard University And Rowland Institute | Optical matter |
US5113286A (en) * | 1990-09-27 | 1992-05-12 | At&T Bell Laboratories | Diffraction grating apparatus and method of forming a surface relief pattern in diffraction grating apparatus |
US6149789A (en) | 1990-10-31 | 2000-11-21 | Fraunhofer Gesellschaft Zur Forderung Der Angewandten Forschung E.V. | Process for manipulating microscopic, dielectric particles and a device therefor |
US5170890A (en) | 1990-12-05 | 1992-12-15 | Wilson Steven D | Particle trap |
CA2057506C (en) * | 1990-12-13 | 2003-05-13 | Keiji Sasaki | Laser trapping and method for applications thereof |
JP3129471B2 (en) * | 1991-06-01 | 2001-01-29 | 科学技術振興事業団 | Multi-beam particle operation method |
US5206504A (en) * | 1991-11-01 | 1993-04-27 | The United States Of America As Represented By The Administrator, National Aeronautics And Space Administration | Sample positioning in microgravity |
JP3018687B2 (en) * | 1991-12-12 | 2000-03-13 | 松下電器産業株式会社 | Scanning laser microscope |
JPH05203878A (en) | 1992-01-27 | 1993-08-13 | Jeol Ltd | Scanning type laser microscope |
US5495105A (en) * | 1992-02-20 | 1996-02-27 | Canon Kabushiki Kaisha | Method and apparatus for particle manipulation, and measuring apparatus utilizing the same |
EP0556748B1 (en) | 1992-02-20 | 1998-10-28 | Canon Kabushiki Kaisha | Method and apparatus for particle manipulation, and measuring apparatus utilizing the same |
US5274231A (en) | 1992-04-14 | 1993-12-28 | Board Of Trustees, Leland Stanford Jr. University | Method and apparatus for manipulating atoms, ions or molecules and for measuring physical quantities using stimulated Raman transitions |
US5486335A (en) * | 1992-05-01 | 1996-01-23 | Trustees Of The University Of Pennsylvania | Analysis based on flow restriction |
JPH0693038B2 (en) * | 1992-06-11 | 1994-11-16 | 東京工業大学長 | Method and apparatus for controlling the motion of a small number of neutral atoms |
US5189294A (en) * | 1992-07-08 | 1993-02-23 | The United States Of America As Represented By The Secretary Of The Air Force | Transform lens with a plurality of sliced lens segments |
US5374556A (en) | 1992-07-23 | 1994-12-20 | Cell Robotics, Inc. | Flexure structure for stage positioning |
US5364744A (en) | 1992-07-23 | 1994-11-15 | Cell Robotics, Inc. | Method for the manufacture of an optical manipulation chamber |
JP3292515B2 (en) | 1992-09-07 | 2002-06-17 | オリンパス光学工業株式会社 | Fine adjustment method and fine adjustment device for microscope observation |
US6399397B1 (en) * | 1992-09-14 | 2002-06-04 | Sri International | Up-converting reporters for biological and other assays using laser excitation techniques |
GB9220564D0 (en) | 1992-09-29 | 1992-11-11 | Univ London | The method of rheological investigation |
LU88184A1 (en) * | 1992-10-28 | 1994-09-09 | Europ Communities | Optical modulator |
US5452123A (en) | 1992-12-30 | 1995-09-19 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Method of making an optically nonlinear switched optical device and related devices |
DE4300698A1 (en) | 1993-01-13 | 1994-07-14 | Raimund Schuetze | Device and method for handling, processing and observing small particles, in particular biological particles |
US5327515A (en) * | 1993-01-14 | 1994-07-05 | At&T Laboratories | Method for forming a Bragg grating in an optical medium |
GB9301122D0 (en) * | 1993-01-21 | 1993-03-10 | Scient Generics Ltd | Method of analysis/separation |
US5360764A (en) | 1993-02-16 | 1994-11-01 | The United States Of America, As Represented By The Secretary Of Commerce | Method of fabricating laser controlled nanolithography |
GB9306729D0 (en) | 1993-03-31 | 1993-05-26 | British Tech Group | Improvements in separators |
US5473471A (en) | 1993-04-16 | 1995-12-05 | Matsushita Electric Industrial Co., Ltd. | Complex lens with diffraction grating |
US5366559A (en) | 1993-05-27 | 1994-11-22 | Research Triangle Institute | Method for protecting a substrate surface from contamination using the photophoretic effect |
EP0635994B1 (en) | 1993-07-08 | 1998-09-23 | Canon Kabushiki Kaisha | Method and apparatus for separating particles |
DE69415019T2 (en) * | 1993-07-22 | 1999-06-24 | Btg International Ltd., London | INTELLIGENT OPTICAL SENSOR FOR OPTICAL NEAR FIELD DEVICE |
JPH08512003A (en) | 1993-07-27 | 1996-12-17 | フィジィカル オプティクス コーポレーション | Light source disassembly molding device |
DE4326181A1 (en) | 1993-08-04 | 1995-02-09 | Europ Lab Molekularbiolog | Method and device for luminescence spectroscopy and material microprocessing of fixed and moving molecules, particles and objects |
ATE271125T1 (en) | 1993-08-25 | 2004-07-15 | Asahi Chemical Ind | NOVEL TYROSINE KINASE |
US5445011A (en) * | 1993-09-21 | 1995-08-29 | Ghislain; Lucien P. | Scanning force microscope using an optical trap |
US5900160A (en) * | 1993-10-04 | 1999-05-04 | President And Fellows Of Harvard College | Methods of etching articles via microcontact printing |
US5512745A (en) * | 1994-03-09 | 1996-04-30 | Board Of Trustees Of The Leland Stanford Jr. University | Optical trap system and method |
JP3355021B2 (en) * | 1994-03-26 | 2002-12-09 | 科学技術振興事業団 | Micro memory and micro sensor |
DE4411268C2 (en) * | 1994-03-31 | 2001-02-01 | Danfoss As | Analysis method and device |
US6071394A (en) * | 1996-09-06 | 2000-06-06 | Nanogen, Inc. | Channel-less separation of bioparticles on a bioelectronic chip by dielectrophoresis |
US5637458A (en) * | 1994-07-20 | 1997-06-10 | Sios, Inc. | Apparatus and method for the detection and assay of organic molecules |
US6001229A (en) * | 1994-08-01 | 1999-12-14 | Lockheed Martin Energy Systems, Inc. | Apparatus and method for performing microfluidic manipulations for chemical analysis |
JP3474652B2 (en) * | 1994-11-11 | 2003-12-08 | 株式会社モリテックス | Multi-point laser trapping apparatus and method |
US5629802A (en) * | 1995-01-05 | 1997-05-13 | The United States Of America As Represented By The Secretary Of The Air Force | Spatially multiplexed optical signal processor |
US5795782A (en) * | 1995-03-17 | 1998-08-18 | President & Fellows Of Harvard College | Characterization of individual polymer molecules based on monomer-interface interactions |
US5793485A (en) * | 1995-03-20 | 1998-08-11 | Sandia Corporation | Resonant-cavity apparatus for cytometry or particle analysis |
US5608519A (en) * | 1995-03-20 | 1997-03-04 | Gourley; Paul L. | Laser apparatus and method for microscopic and spectroscopic analysis and processing of biological cells |
US5953166A (en) | 1995-03-22 | 1999-09-14 | Moritex Corporation | Laser trapping apparatus |
US5677286A (en) | 1995-04-27 | 1997-10-14 | The University Of Michigan | Glycosylated analogs of camptothecin |
US6797942B2 (en) | 2001-09-13 | 2004-09-28 | University Of Chicago | Apparatus and process for the lateral deflection and separation of flowing particles by a static array of optical tweezers |
US5631141A (en) * | 1995-05-05 | 1997-05-20 | The Regents Of The University Of California | High resolution biosensor for in-situ microthermometry |
US5776674A (en) * | 1995-06-05 | 1998-07-07 | Seq, Ltd | Chemical biochemical and biological processing in thin films |
US5659561A (en) * | 1995-06-06 | 1997-08-19 | University Of Central Florida | Spatial solitary waves in bulk quadratic nonlinear materials and their applications |
US5620857A (en) * | 1995-06-07 | 1997-04-15 | United States Of America, As Represented By The Secretary Of Commerce | Optical trap for detection and quantitation of subzeptomolar quantities of analytes |
US5950071A (en) | 1995-11-17 | 1999-09-07 | Lightforce Technology, Inc. | Detachment and removal of microscopic surface contaminants using a pulsed detach light |
WO1997021832A1 (en) | 1995-12-08 | 1997-06-19 | Evotec Biosystems Gmbh | Process for determination of low concentration of nucleic acid molecules |
US5888370A (en) * | 1996-02-23 | 1999-03-30 | Board Of Regents, The University Of Texas System | Method and apparatus for fractionation using generalized dielectrophoresis and field flow fractionation |
US5993630A (en) | 1996-01-31 | 1999-11-30 | Board Of Regents The University Of Texas System | Method and apparatus for fractionation using conventional dielectrophoresis and field flow fractionation |
US6641708B1 (en) | 1996-01-31 | 2003-11-04 | Board Of Regents, The University Of Texas System | Method and apparatus for fractionation using conventional dielectrophoresis and field flow fractionation |
US6078681A (en) | 1996-03-18 | 2000-06-20 | Marine Biological Laboratory | Analytical imaging system and process |
NZ331865A (en) | 1996-03-18 | 1999-04-29 | Univ Wales Bangor Change Of Na | Apparatus with electrode arrays for carrying out chemical, physical or physico-chemical reactions |
US5942443A (en) | 1996-06-28 | 1999-08-24 | Caliper Technologies Corporation | High throughput screening assay systems in microscale fluidic devices |
US5760395A (en) * | 1996-04-18 | 1998-06-02 | Universities Research Assoc., Inc. | Method and apparatus for laser-controlled proton beam radiology |
US5694216A (en) | 1996-04-25 | 1997-12-02 | University Of Central Florida | Scanning heterodyne acousto-optical interferometers |
US5752606A (en) * | 1996-05-23 | 1998-05-19 | Wilson; Steve D. | Method for trapping, manipulating, and separating cells and cellular components utilizing a particle trap |
US5726404A (en) | 1996-05-31 | 1998-03-10 | University Of Washington | Valveless liquid microswitch |
US5952651A (en) | 1996-06-10 | 1999-09-14 | Moritex Corporation | Laser manipulation apparatus and cell plate used therefor |
JP3688820B2 (en) | 1996-08-26 | 2005-08-31 | 株式会社モリテックス | Laser trapping device and micromanipulator using the same |
CA2258489C (en) | 1996-06-28 | 2004-01-27 | Caliper Technologies Corporation | High-throughput screening assay systems in microscale fluidic devices |
JPH1048102A (en) | 1996-07-31 | 1998-02-20 | Hitachi Ltd | Optical tweezers |
US5804436A (en) * | 1996-08-02 | 1998-09-08 | Axiom Biotechnologies, Inc. | Apparatus and method for real-time measurement of cellular response |
US6280967B1 (en) * | 1996-08-02 | 2001-08-28 | Axiom Biotechnologies, Inc. | Cell flow apparatus and method for real-time of cellular responses |
DE69709377T2 (en) | 1996-09-04 | 2002-08-14 | Scandinavian Micro Biodevices A/S, Lyngby | MICROFLOWING SYSTEM FOR PARTICLE ANALYSIS AND SEPARATION |
US6221654B1 (en) * | 1996-09-25 | 2001-04-24 | California Institute Of Technology | Method and apparatus for analysis and sorting of polynucleotides based on size |
US5858192A (en) * | 1996-10-18 | 1999-01-12 | Board Of Regents, The University Of Texas System | Method and apparatus for manipulation using spiral electrodes |
US6008010A (en) | 1996-11-01 | 1999-12-28 | University Of Pittsburgh | Method and apparatus for holding cells |
DE19649048C1 (en) * | 1996-11-27 | 1998-04-09 | Evotec Biosystems Gmbh | Particle identification method for enzyme-linked immunoassay using fast Fourier transform |
US6534308B1 (en) * | 1997-03-27 | 2003-03-18 | Oncosis, Llc | Method and apparatus for selectively targeting specific cells within a mixed cell population |
US5874266A (en) | 1997-03-27 | 1999-02-23 | Palsson; Bernhard O. | Targeted system for removing tumor cells from cell populations |
US5939716A (en) | 1997-04-02 | 1999-08-17 | Sandia Corporation | Three-dimensional light trap for reflective particles |
US6215134B1 (en) * | 1997-05-09 | 2001-04-10 | California Institute Of Technology | Semiconductor surface lenses and shaped structures |
GB2326229A (en) | 1997-06-13 | 1998-12-16 | Robert Jeffrey Geddes Carr | Detecting and analysing submicron particles |
US6111398A (en) | 1997-07-03 | 2000-08-29 | Coulter International Corp. | Method and apparatus for sensing and characterizing particles |
US6143558A (en) | 1997-07-08 | 2000-11-07 | The Regents Of The University Of Michigan | Optical fiberless sensors for analyzing cellular analytes |
US6540895B1 (en) * | 1997-09-23 | 2003-04-01 | California Institute Of Technology | Microfabricated cell sorter for chemical and biological materials |
US6833242B2 (en) * | 1997-09-23 | 2004-12-21 | California Institute Of Technology | Methods for detecting and sorting polynucleotides based on size |
JPH11119800A (en) * | 1997-10-20 | 1999-04-30 | Fujitsu Ltd | Method and device for voice encoding and decoding |
US6121603A (en) | 1997-12-01 | 2000-09-19 | Hang; Zhijiang | Optical confocal device having a common light directing means |
ES2350702T3 (en) * | 1998-01-12 | 2011-01-26 | Massachusetts Institute Of Technology | SYSTEM TO ANALYZE A PLURALITY OF SAMPLES. |
DE19801139B4 (en) * | 1998-01-14 | 2016-05-12 | Till Photonics Gmbh | Point Scanning Luminescence Microscope |
US6485905B2 (en) | 1998-02-02 | 2002-11-26 | Signature Bioscience, Inc. | Bio-assay device |
US6287874B1 (en) * | 1998-02-02 | 2001-09-11 | Signature Bioscience, Inc. | Methods for analyzing protein binding events |
US6287776B1 (en) | 1998-02-02 | 2001-09-11 | Signature Bioscience, Inc. | Method for detecting and classifying nucleic acid hybridization |
US6338968B1 (en) * | 1998-02-02 | 2002-01-15 | Signature Bioscience, Inc. | Method and apparatus for detecting molecular binding events |
US6395480B1 (en) * | 1999-02-01 | 2002-05-28 | Signature Bioscience, Inc. | Computer program and database structure for detecting molecular binding events |
KR20010040559A (en) | 1998-02-02 | 2001-05-15 | 시그나츄어 바이오사이언스 인코포레이티드 | Method and apparatus for detecting molecular binding events |
US6055106A (en) | 1998-02-03 | 2000-04-25 | Arch Development Corporation | Apparatus for applying optical gradient forces |
JPH11218691A (en) | 1998-02-04 | 1999-08-10 | Hitachi Ltd | Method and device for operating liquid drop |
US6082205A (en) * | 1998-02-06 | 2000-07-04 | Ohio State University | System and device for determining particle characteristics |
US5974901A (en) | 1998-02-06 | 1999-11-02 | The Cleveland Clinic Foundation | Method for determining particle characteristics |
US6156576A (en) | 1998-03-06 | 2000-12-05 | The Regents Of The University Of California | Fast controllable laser lysis of cells for analysis |
US6740497B2 (en) * | 1998-03-06 | 2004-05-25 | The Regents Of The University Of California | Method and apparatus for detecting cancerous cells using molecules that change electrophoretic mobility |
US5998152A (en) | 1998-03-09 | 1999-12-07 | Tularik Inc. | High-throughput screening assays for modulators of nucleic acid topoisomerases |
US6088376A (en) * | 1998-03-16 | 2000-07-11 | California Institute Of Technology | Vertical-cavity-surface-emitting semiconductor devices with fiber-coupled optical cavity |
US6642018B1 (en) | 1998-03-27 | 2003-11-04 | Oncosis Llc | Method for inducing a response in one or more targeted cells |
ES2207203T3 (en) * | 1998-04-17 | 2004-05-16 | Rigel Pharmaceuticals, Inc. | TESTS WITH MULTIPLE FACS PARAMETERS TO DETECT ALTERATIONS IN CELLULAR PARAMETERS. |
AU763433B2 (en) | 1998-05-22 | 2003-07-24 | California Institute Of Technology | Microfabricated cell sorter |
US6139831A (en) | 1998-05-28 | 2000-10-31 | The Rockfeller University | Apparatus and method for immobilizing molecules onto a substrate |
CA2345961A1 (en) | 1998-09-30 | 2000-04-27 | Michael J. Renn | Laser-guided manipulation of non-atomic particles |
JP2002533142A (en) * | 1998-12-23 | 2002-10-08 | メディスペクトラ, インコーポレイテッド | Systems and methods for optical testing of samples |
US6929925B1 (en) | 1999-01-27 | 2005-08-16 | The Regents Of The University Of California | Assays for sensory modulators using a sensory cell specific G-protein beta subunit |
WO2000045179A2 (en) | 1999-01-27 | 2000-08-03 | The Regents Of The University Of California | Screening for modulators of g-protein subunit beta 3 |
WO2000045160A1 (en) | 1999-02-01 | 2000-08-03 | Signature Bioscience Inc. | Method and apparatus for detecting molecular binding events |
US6294063B1 (en) | 1999-02-12 | 2001-09-25 | Board Of Regents, The University Of Texas System | Method and apparatus for programmable fluidic processing |
US6507400B1 (en) * | 1999-02-27 | 2003-01-14 | Mwi, Inc. | Optical system for multi-part differential particle discrimination and an apparatus using the same |
US6067859A (en) * | 1999-03-04 | 2000-05-30 | The Board Of Regents, The University Of Texas System | Optical stretcher |
CN1185492C (en) * | 1999-03-15 | 2005-01-19 | 清华大学 | Single-point gating type micro-electromagnetic unit array chip, electromagnetic biochip and application |
US6518056B2 (en) * | 1999-04-27 | 2003-02-11 | Agilent Technologies Inc. | Apparatus, systems and method for assaying biological materials using an annular format |
US6485690B1 (en) * | 1999-05-27 | 2002-11-26 | Orchid Biosciences, Inc. | Multiple fluid sample processor and system |
EP1194693B1 (en) * | 1999-06-28 | 2006-10-25 | California Institute Of Technology | Microfabricated elastomeric valve and pump systems |
US6818395B1 (en) * | 1999-06-28 | 2004-11-16 | California Institute Of Technology | Methods and apparatus for analyzing polynucleotide sequences |
GB9916848D0 (en) | 1999-07-20 | 1999-09-22 | Univ Wales Bangor | Travelling wave dielectrophoretic apparatus and method |
AU1471001A (en) | 1999-11-04 | 2001-05-14 | California Institute Of Technology | Methods and apparatus for analyzing polynucleotide sequences |
WO2001040454A1 (en) * | 1999-11-30 | 2001-06-07 | Oncosis | Method and apparatus for selectively targeting specific cells within a cell population |
DE20022966U1 (en) | 1999-12-02 | 2002-08-22 | Evotec OAI AG, 22525 Hamburg | High-throughput screening device for the optical detection of samples |
DE19960583A1 (en) | 1999-12-15 | 2001-07-05 | Evotec Biosystems Ag | Method and device for microscopy |
US6915679B2 (en) | 2000-02-23 | 2005-07-12 | Caliper Life Sciences, Inc. | Multi-reservoir pressure control system |
US6287758B1 (en) | 2000-03-23 | 2001-09-11 | Axiom Biotechnologies, Inc. | Methods of registering trans-membrane electric potentials |
WO2002022774A1 (en) | 2000-09-12 | 2002-03-21 | Oncosis Llc | Chamber for laser-based processing |
ATE448875T1 (en) | 2000-09-14 | 2009-12-15 | Caliper Life Sciences Inc | MICROFLUIDIC DEVICES AND METHODS FOR CARRYING OUT TEMPERATURE-MEDIATED REACTIONS |
EP1334347A1 (en) * | 2000-09-15 | 2003-08-13 | California Institute Of Technology | Microfabricated crossflow devices and methods |
US6833542B2 (en) | 2000-11-13 | 2004-12-21 | Genoptix, Inc. | Method for sorting particles |
US6784420B2 (en) | 2000-11-13 | 2004-08-31 | Genoptix, Inc. | Method of separating particles using an optical gradient |
US6936811B2 (en) | 2000-11-13 | 2005-08-30 | Genoptix, Inc. | Method for separating micro-particles |
US20030007894A1 (en) * | 2001-04-27 | 2003-01-09 | Genoptix | Methods and apparatus for use of optical forces for identification, characterization and/or sorting of particles |
WO2002044689A2 (en) * | 2000-11-28 | 2002-06-06 | The Regents Of The University Of California | Storing microparticles in optical switch which is transported by micro-fluidic device |
AU3053002A (en) * | 2000-11-28 | 2002-06-11 | Univ California | Optical switching and sorting of biological samples and microparticles transported in a micro-fluidic device, including integrated bio-chip devices |
EP1421365A1 (en) * | 2001-07-19 | 2004-05-26 | Tufts University | Optical array device and methods of use thereof for screening, analysis and manipulation of particles |
US7318902B2 (en) | 2002-02-04 | 2008-01-15 | Colorado School Of Mines | Laminar flow-based separations of colloidal and cellular particles |
US6808075B2 (en) * | 2002-04-17 | 2004-10-26 | Cytonome, Inc. | Method and apparatus for sorting particles |
WO2004038363A2 (en) | 2002-05-09 | 2004-05-06 | The University Of Chicago | Microfluidic device and method for pressure-driven plug transport and reaction |
US7041481B2 (en) | 2003-03-14 | 2006-05-09 | The Regents Of The University Of California | Chemical amplification based on fluid partitioning |
GB0307233D0 (en) * | 2003-03-28 | 2003-04-30 | Medical Res Council | Improvements in biosensor electrodes |
CN1860363B (en) | 2003-08-28 | 2011-12-28 | 赛路拉公司 | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network |
US20080213821A1 (en) | 2004-05-06 | 2008-09-04 | Nanyang Technological University | Microfluidic Cell Sorter System |
FR2888932A1 (en) | 2005-07-19 | 2007-01-26 | Commissariat Energie Atomique | METHOD FOR CALIBRATING A PARTICLE FLOW SORTING DEVICE |
US7726561B2 (en) * | 2006-07-21 | 2010-06-01 | Intuit Inc. | System and method for reconciling credit card payments with corresponding transactions |
-
2004
- 2004-08-27 CN CN2004800281349A patent/CN1860363B/en not_active Expired - Lifetime
- 2004-08-27 US US10/928,650 patent/US7745221B2/en not_active Expired - Fee Related
- 2004-08-27 CA CA2536360A patent/CA2536360C/en not_active Expired - Fee Related
- 2004-08-27 JP JP2006524942A patent/JP4533382B2/en not_active Expired - Fee Related
- 2004-08-27 EP EP04782647A patent/EP1668355A4/en not_active Withdrawn
- 2004-08-27 WO PCT/US2004/028213 patent/WO2005022147A1/en active Application Filing
- 2004-08-27 AU AU2004269406A patent/AU2004269406B2/en not_active Ceased
-
2010
- 2010-06-28 US US12/825,037 patent/US8426209B2/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020132315A1 (en) * | 2000-11-13 | 2002-09-19 | Genoptix | Methods and apparatus for measurement of dielectric constants of particles |
US20020181837A1 (en) * | 2000-11-28 | 2002-12-05 | Mark Wang | Optical switching and sorting of biological samples and microparticles transported in a micro-fluidic device, including integrated bio-chip devices |
Non-Patent Citations (1)
Title |
---|
See also references of EP1668355A4 * |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11873173B2 (en) | 2003-10-30 | 2024-01-16 | Cytonome/St, Llc | Multilayer hydrodynamic sheath flow structure |
US11634286B2 (en) | 2003-10-30 | 2023-04-25 | Cytonome/St, Llc | Multilayer hydrodynamic sheath flow structure |
US10689210B2 (en) | 2003-10-30 | 2020-06-23 | Cytonome/St, Llc | Multilayer hydrodynamic sheath flow structure |
US10543992B2 (en) | 2003-10-30 | 2020-01-28 | Cytonome/St, Llc | Multilayer hydrodynamic sheath flow structure |
FR2888932A1 (en) * | 2005-07-19 | 2007-01-26 | Commissariat Energie Atomique | METHOD FOR CALIBRATING A PARTICLE FLOW SORTING DEVICE |
WO2007009983A1 (en) * | 2005-07-19 | 2007-01-25 | Commissariat A L'energie Atomique | Method of calibrating a particle flux sorting device |
US8206994B2 (en) | 2006-05-30 | 2012-06-26 | Centre National De La Recherche Scientifique | Method for treating drops in a microfluid circuit |
FR2901717A1 (en) * | 2006-05-30 | 2007-12-07 | Centre Nat Rech Scient | METHOD FOR TREATING DROPS IN A MICROFLUIDIC CIRCUIT |
WO2007138178A3 (en) * | 2006-05-30 | 2008-07-24 | Centre Nat Rech Scient | Method for treating drops in a microfluid circuit |
JP2010513876A (en) * | 2006-12-19 | 2010-04-30 | フィオ コーポレイション | Microfluidic system and method for testing target molecules in biological samples |
WO2008130871A2 (en) | 2007-04-20 | 2008-10-30 | Cellula, Inc. | Cell sorting system and methods |
EP2139984A4 (en) * | 2007-04-20 | 2011-06-29 | Cellula Inc | Cell sorting system and methods |
EP2139984A2 (en) * | 2007-04-20 | 2010-01-06 | Cellula, Inc. | Cell sorting system and methods |
WO2010023596A1 (en) * | 2008-08-25 | 2010-03-04 | Koninklijke Philips Electronics N.V. | Reconfigurable microfluidic filter |
US9994902B2 (en) | 2008-12-22 | 2018-06-12 | Progenity, Inc. | Methods and genotyping panels for detecting alleles, genomes, and transcriptomes |
US9051602B2 (en) | 2008-12-22 | 2015-06-09 | Celula, Inc. | Methods and genotyping panels for detecting alleles, genomes, and transcriptomes |
WO2010075459A1 (en) * | 2008-12-22 | 2010-07-01 | Celula, Inc. | Methods and genotyping panels for detecting alleles, genomes, and transcriptomes |
EP2661614A2 (en) * | 2011-01-03 | 2013-11-13 | Cytonome/ST, LLC | Method and apparatus for monitoring and optimizing particle sorting |
WO2012094325A3 (en) * | 2011-01-03 | 2013-09-06 | Cytonome/St. Llc | Method and apparatus for monitoring and optimizing particle sorting |
US10481069B2 (en) | 2011-01-03 | 2019-11-19 | Cytonome/St, Llc | Method and apparatus for monitoring and optimizing microfluidic particle sorting |
CN102175590A (en) * | 2011-03-23 | 2011-09-07 | 重庆天海医疗设备有限公司 | Disposable counting board for microscopic detection |
CN103175950B (en) * | 2011-12-20 | 2015-04-22 | 中国科学院深圳先进技术研究院 | Hemocyte analysis chip and system for using chip thereof |
CN103175950A (en) * | 2011-12-20 | 2013-06-26 | 中国科学院深圳先进技术研究院 | Hemocyte analysis chip and system for using chip thereof |
US10583439B2 (en) | 2013-03-14 | 2020-03-10 | Cytonome/St, Llc | Hydrodynamic focusing apparatus and methods |
US11446665B2 (en) | 2013-03-14 | 2022-09-20 | Cytonome/St, Llc | Hydrodynamic focusing apparatus and methods |
US9849456B2 (en) | 2013-12-04 | 2017-12-26 | Clearbridge Mfluidics Pte. Ltd. | Microfluidic device |
GB2547349B (en) * | 2014-08-29 | 2020-09-30 | Synaptive Medical Barbados Inc | System and method for intraoperative cell storage, processing and imaging |
WO2016050837A1 (en) | 2014-09-30 | 2016-04-07 | Foss Analytical A/S | Method, device and system for hydrodynamic flow focusing |
US11471885B2 (en) | 2016-11-14 | 2022-10-18 | Orca Biosystems, Inc. | Methods and apparatuses for sorting target particles |
Also Published As
Publication number | Publication date |
---|---|
US7745221B2 (en) | 2010-06-29 |
CN1860363A (en) | 2006-11-08 |
US20050207940A1 (en) | 2005-09-22 |
AU2004269406A1 (en) | 2005-03-10 |
AU2004269406B2 (en) | 2010-12-16 |
EP1668355A4 (en) | 2011-11-09 |
EP1668355A1 (en) | 2006-06-14 |
CA2536360A1 (en) | 2005-03-10 |
CA2536360C (en) | 2013-08-06 |
US8426209B2 (en) | 2013-04-23 |
JP2007504446A (en) | 2007-03-01 |
US20100304429A1 (en) | 2010-12-02 |
CN1860363B (en) | 2011-12-28 |
JP4533382B2 (en) | 2010-09-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7745221B2 (en) | Methods and apparatus for sorting cells using an optical switch in a microfluidic channel network | |
US8691164B2 (en) | Cell sorting system and methods | |
Chung et al. | Recent advances in miniaturized microfluidic flow cytometry for clinical use | |
Wolff et al. | Integrating advanced functionality in a microfabricated high-throughput fluorescent-activated cell sorter | |
US6540895B1 (en) | Microfabricated cell sorter for chemical and biological materials | |
US7214298B2 (en) | Microfabricated cell sorter | |
US20080070311A1 (en) | Microfluidic flow cytometer and applications of same | |
WO1999061888A9 (en) | Microfabricated cell sorter | |
US11733152B2 (en) | Microfluidic system with combined electrical and optical detection for high accuracy particle sorting and methods thereof | |
WO2008036083A1 (en) | Microfluidic flow cytometer and applications of same | |
CN101743303B (en) | cell sorting system and method | |
Tu et al. | Microfluidic cell analysis and sorting using photonic forces | |
MXPA00011492A (en) | Microfabricated cell sorter |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200480028134.9 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2536360 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006524942 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004269406 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004782647 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2004269406 Country of ref document: AU Date of ref document: 20040827 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004269406 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 2004782647 Country of ref document: EP |