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WO1998013683A1 - Detection parallele a partir de plusieurs sites - Google Patents

Detection parallele a partir de plusieurs sites Download PDF

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Publication number
WO1998013683A1
WO1998013683A1 PCT/US1997/017930 US9717930W WO9813683A1 WO 1998013683 A1 WO1998013683 A1 WO 1998013683A1 US 9717930 W US9717930 W US 9717930W WO 9813683 A1 WO9813683 A1 WO 9813683A1
Authority
WO
WIPO (PCT)
Prior art keywords
light
detection
sites
detection site
site
Prior art date
Application number
PCT/US1997/017930
Other languages
English (en)
Inventor
Paul J. Stabile
David Norman Ludington
Pamela Kay York
Arye Rosen
Satyam Choudary Cherukuri
Peter John Zanzucchi
Paul Heaney
Original Assignee
Sarnoff Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/721,427 external-priority patent/US5872623A/en
Priority claimed from US08/721,432 external-priority patent/US5854684A/en
Application filed by Sarnoff Corporation filed Critical Sarnoff Corporation
Priority to AU46071/97A priority Critical patent/AU4607197A/en
Publication of WO1998013683A1 publication Critical patent/WO1998013683A1/fr

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    • 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
    • B01L3/505—Containers for the purpose of retaining a material to be analysed, e.g. test tubes flexible containers not provided for above
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/251—Colorimeters; Construction thereof
    • G01N21/253—Colorimeters; Construction thereof for batch operation, i.e. multisample apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00279—Features relating to reactor vessels
    • B01J2219/00306—Reactor vessels in a multiple arrangement
    • B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315—Microtiter plates
    • B01J2219/00317—Microwell devices, i.e. having large numbers of wells
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00427—Means for dispensing and evacuation of reagents using masks
    • B01J2219/00434—Liquid crystal masks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00351—Means for dispensing and evacuation of reagents
    • B01J2219/00436—Maskless processes
    • B01J2219/00448—Maskless processes using microlens arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/0061—The surface being organic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00612—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00614—Delimitation of the attachment areas
    • B01J2219/00621—Delimitation of the attachment areas by physical means, e.g. trenches, raised areas
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00686—Automatic
    • B01J2219/00689—Automatic using computers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • B01J2219/00707—Processes involving means for analysing and characterising the products separated from the reactor apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0654—Lenses; Optical fibres
    • 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
    • B01L2300/0819—Microarrays; Biochips
    • 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
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00—Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries

Definitions

  • the present invention relates to a detection device to detect in parallel light emitted from or transmitted from a plate containing a plurality of detection sites, preferably detection wells containing a liquid sample.
  • the present invention solves the detection problem by providing a detector array that can collect in parallel, in a spatially addressable manner, light from a plurality of sites.
  • a detector array that can collect in parallel, in a spatially addressable manner, light from a plurality of sites.
  • light from 2,500 separate sites can concurrently be collected on an array containing 2,500 separate light responsive pixels that convert the light to an electrical charge, each such pixel being uniquely aligned for receiving light from one of the sites.
  • the separate charges can be separately addressed, measured and converted to a digitally storable, electronic form.
  • the invention provides an apparatus for measuring the amount of light emitted from or transmitted through two or more detection sites of a first set of detection sites on a planar substrate while spatially resolving the measurements for each detection site of the first set, the apparatus comprising: (a) for each detection site of the first set, an addressable source of a light beam directed to that detection site at a first angle; and (b) an array detector comprising a plurality of light responsive pixels, wherein for each detection site of the first set there is at least one light responsive pixel that receives light emitted , from or transmitted through that detection site at a second angle that can be the same as the first angle.
  • the apparatus further comprises a controller for controlling the addressable beams of light.
  • the controller preferably, is programmed to operate the light beams so that the light beams for any two adjacent detection sites on the substrate are not simultaneously illuminated during an experimental measurement.
  • the controller is programmed to operate the beams of light so each detection site of the first set is illuminated in the course of measuring the light emitted from or transmitted through all of the detection sites of the first set.
  • FIGS 1A and IB depict detection devices of the invention.
  • Figure 2 shows another detection device of the invention.
  • FIGS 3A and 3B depict another detection device of the invention.
  • Figure shows another detection device of the invention.
  • Figure 5 depicts another detection device of the invention.
  • Figure 6 depicts another detection device of the invention.
  • Figure 7 depicts another detection device of the invention.
  • Figure 8 shows some illustrative formats for the planar substrate used with the invention.
  • Figure 9 shows three detection site geometries.
  • Figure 10 shows the arrangement of alignment tools on a planar substrate.
  • Addressable sources of light beams are: produced by a number of light-emitting devices that can be sequentially powered in sub-groups (which can include only one such device) until all of the light-emitting devices have been powered; or are light beams that are divided out of one or more broader light beams by mechanically moving a mask between the planar substrate and the one or more broader beams of light; or are beams that are divided out of one or more broader beams by interposing, between the one or more broader beams of collimated light and the planar substrate, a device having a plurality of windows with electrically operated shutters.
  • each light source can separately illuminated or all the light sources of about whole number subsets (such as subsets of about 1/2, 1/3, 1/4, 1/5, 1/6, 1/7, 1/8, etc. of the light sources) can be illuminated in concert.
  • a detection site is adjacent to any reference detection site if a straight line joining the center of the detection site to the reference detection site is no more than about 1.5 times the length of the line joining the center of the reference detection site to the center of the nearest detection site. • alignment of detection sites or detection areas with light responsive pixels
  • a detection site or detection area is aligned if all the light of the second angle, transmission angle or detection angle (excepting nominal transmission loses) emitted or transmitted therefrom intercepts the aligned light responsive pixels. • angle of light
  • the "angle of light” is measured by comparing the angle of a reference vector with a vector describing the motion of the light.
  • One or more lenses or other optical devices through which a beam of collimated (parallel) light of a first cross-sectional area is expanded to a beam of collimated light having a greater, second cross-sectional area.
  • An area or volume on a substrate on or in which a chemistry or biochemistry has been conducted that either (a) will produce a substance that is directly or indirectly (for instance, a radioisotope detected with a scintillate or fluorophore) detected optically or (b) will or will not produce such a substance depending on such circumstances as whether a material used in the chemistry or biochemistry contains a substance which the user of the apparatus of the invention seeks to analyze, whether the materials used in the chemistry or biochemistry inhibit production of the substance, whether the chemistry or biochemistry functioned as anticipated, and the like.
  • An addressable source of a light beam directly focuses a light beam if, after any optical devices needed to collimate the light, no other optical devices other than light filters intervene between the device producing the light and the substrate.
  • a measurement of the light transmitted through or emitted from a detection site to determine a data point for instance for a chemical or biochemical procedure conducted on the planar substrate, as opposed to an initial, calibration or alignment measurement used to establish that a light detection apparatus is properly aligned and in good working order.
  • light responsive pixel A defined area of material that, when exposed to light energy, generates a corresponding collection of charge.
  • Linearly aligned detection sites each have an equivalent volume or surface area having geometrical centers aligned along a straight line.
  • photon-based imaging device Any device that converts impinging photons to a charge or voltage, preferably wherein data from the device can be used to determine the number of photons impinging the device.
  • a material that when struck with an appropriate particle or photon such as a nuclear decay particle, for instance an appropriate alpha, beta or gamma particle, emits a light particle.
  • An array detector receives substantially no light from the light source if the light- source light intercepting light-responsive portions of the pixels of the array detector is no more than about 5%, preferably no more than about 1%, more preferably no more than about 0.1%, yet more preferably no more than about 0.01%, of the pixel-intercepting light that originates from the planar substrate.
  • the invention provides an apparatus for measuring the amount of light emitted or reflected from a first set of two or more detection sites on a planar substrate while spatially resolving the measurements from each first set detection site, the apparatus comprising: a source of a light beam directed towards the planar substrate at a first angle; one or more lenses for focusing light emitted or reflected from each of the first set detection sites and having a second angle having an angle offset from the first angle, onto a unique area of an array detector; and the array detector comprising a plurality of light responsive pixels, wherein for each first detection site there is at least one light responsive pixel that receives light emitted or reflected from that detection site and substantially no cross-talk from another detection site, and wherein substantially none of the light from the light source intersects with the array detector.
  • the offset second angle is also offset from the angle at which light of the first angle reflects off the planar substrate.
  • the apparatus is designed for use where the emitted or reflected light has a different wavelength than light from the source of light and the apparatus further comprises a filter interposed between the detection sites and the array detector, which filter selectively absorbs the light from the light beam source and transmits light emitted or reflected from the detection sites.
  • the source of light comprises a beam expander, such as a lens, for expanding the cross-sectional area of the light.
  • the source of light comprises at least one light producing device per detection site.
  • the one or more focusing lenses comprise a separate lenslet overlaid on the light responsive pixels aligned with each first set detection site.
  • the invention also provides assay systems made up of the above-described apparatus and reaction plates having a substantial number of densely arrayed reaction cells, as described below, for which the apparatus is designed to make optical measurements.
  • the invention provides such and apparatus and a plate having a first edge and a second edge and having at least about 1,000 uniformly sized reaction cells formed in its upper surface, wherein the density of the reaction cells is at least about 10 cells per cm , wherein the apparatus is designed to detect light emitted or reflected from the uniformly sized reaction cells.
  • the invention further provides an apparatus for measuring the amount of light emitted from a first set of two or more detection sites on a planar substrate while spatially resolving the measurements from each first set detection site, the apparatus comprising: a source of a light beam having a first wavelength directed towards the planar substrate at a first angle; one or more lenses for focusing light emitted from each of the first set detection sites and having a second angle onto a unique area of an array detector; a filter interposed between the detection sites and the array detector, which filter selectively absorbs light of the first wavelength and transmits light emitted from the detection sites having a wavelength differing from the first wavelength; and the array detector comprising a plurality of light responsive pixels, wherein for each first detection site there is at least one light responsive pixel that receives light emitted from that detection site and substantially no cross-talk from another detection site, wherein substantially none of the light from the light source intersects with the array detector.
  • the second embodiment apparatus further comprises: a first polarizing filter for polarizing the source light beam to a first polarity; and a second polarizing filter for polarizing the light emitted from the detection sites to a second polarity, which is offset from the first polarity, preferably by about 90°.
  • a first polarizing filter for polarizing the source light beam to a first polarity
  • a second polarizing filter for polarizing the light emitted from the detection sites to a second polarity, which is offset from the first polarity, preferably by about 90°.
  • the invention further provides a method for measuring and spatially resolving the amount of light transmitted through a first set of two or more detection chambers or the amount of light emitted from the first set detection sites as a result of their illumination, wherein each chamber is separated by a blocking material that is opaque to the light and the density of first set detection sites is at least about 10 per cm *- preferably at least about 20 per cm , more preferably at least about 40 per cm , still more preferably at least
  • the method comprising (1) providing an apparatus comprising: a source of light directed towards the planar substrate at a transmission angle; one or more lenses for focusing light from each first set detection chamber onto a unique area of an array detector; and the array detector comprising a plurality of light responsive pixels, wherein for each first set detection chamber there is at least one light responsive pixel that receives light transmitted through that detection chamber and substantially no cross-talk from another detection chamber, and (2) measuring light transmitted through the detection sites using the apparatus.
  • the source of light is operated to direct a pulse of light towards the first set detection sites and thereafter a light response is collected in the array detector while the source of light is not producing light.
  • the apparatus is designed for use with planar substrates having detection sites are concave depressions for holding liquid, wherein the surfaces on the depressions have a coating of one or more layers of material, wherein the coating is designed either to reflect the light emitted from the detection sites or light from the source of light.
  • the invention further provides an apparatus for measuring and spatially resolving the amount of light emitted from a first set of two or more detection sites arranged on a planar substrate with a density of at least about 10 detection sites per cm 2 , the apparatus comprising: one or more lenses for focusing light emitted from the first set detection sites, which light has a detection angle, onto an array detector; and the array detector comprising a plurality of light responsive pixels, wherein for each detection site there is at least one light responsive pixel that receives light emitted from that detection site and substantially no cross-talk from another detection site.
  • the density of detection sites is at least about 20 per cm , more preferably at least about 40 per cm , yet more preferably at least about 100 per cm .
  • the planar substrate incorporates a scintillate adjacent to each detection site or the detection sites comprise chambers suitable for holding a fluid containing a scintillate.
  • the source of collimated light is depicted, for example, as a laser 101, that emits light beam 102A.
  • Light beam
  • 102A is bent by mirror 103 and off-axis lens 104 to create a broader beam 102B having an angle ex relative to a line A-B that is perpendicular to the planar substrate 105. Portions of light beam 102B intercept the detection sites 106 where the light from the beam 102B can be absorbed by molecules at the detection sites, and portions of light beam 102B intercept areas 107 that are covered with optical blocking material.
  • Light 110 emitted from the detection sites 106 at an angle ⁇ relative to line A-B (in the illustration, ⁇ is 0 degrees) passes through filter 108.
  • Filter 108 is coated on first side 109A and second side 109B with an optical coating. Filter 108 is selected to absorb light of the wavelength of beam
  • Light beam 110 is focused by lens 111 onto array detector 112, which is illustrated as a charge- coupled device (CCD).
  • CCD charge- coupled device
  • the lens 111 fails to focus light of angle ⁇ onto the array detector 112.
  • Figure IB shows an alternative embodiment wherein the light beam source
  • 201 is located on the same side of planar substrate 205 as the array detector 212. Interposed in front of the array detector is a filter 208 and a lens 211. The data from the array detector 212 is processed by image processor 250 and analyzed by analyzer 260.
  • Light source 1 can for instance be a Xenon Short Arc Lamp available from Oriel Instruments Corp. (Stratford, CT, e.g., the 300W lamp Model Number 6259) and suitable for emitting large amounts of excitation energy.
  • Colliminating lens 4A also serves to redirect light from the light source 1 towards assay plate 5.
  • An light filter and polarizer 4B is located between the colliminating lens 4A and the assay plate 5, and serves to select light of an excitation wavelength and of a first polarity.
  • a set of fresnel lenses 4C is located between the light filter and polarizer 4B and the assay plate 5.
  • the fresnel lenses serve to focus the excitation energy onto each individual well in the assay plate. -Another set of lenses can be used to collect the emission light from the assay plate and focus it on the CCD camera.
  • a filter and crosspolarizer 8 is located between the assay plate 5 and a CCD 12, and serves to select light of an emission wavelength and a second polarity offset from the first polarity.
  • the detection device 300 of Figure 3A differs in having an addressable window array 313 interposed between (a) the light source 301, mirror 303 and lens 304 and (b) the planar substrate 305.
  • the addressable window array 313 has closable transmission windows 314. Illustrated are first transmission window 314A, second transmission window 314B and third transmission window 314C. First transmission window 314A and second transmission window 314B are illustrated as closed, while third transmission window 314C is illustrated as open.
  • Figure 3B shows three-dimensional aspects of detection device 300, and illustrates that a patterned array transmission windows 314 can be opened at a given moment. As illustrated, only a subset of detection sites are illuminated at any given moment. Thus, for instance, all concurrently illuminated detection sites can be separated by one un-illuminated detection site such that a total of four illuminations are needed to illuminate all the detection sites. If the illuminated detection sites are separated by two un-illuminated detections sites, then nine separate illuminations are needed to illuminate all of the detection sites; if the illuminated detection sites are separated by three un-illuminated detections sites, then 16 separate illuminations are needed to illuminate all of the detection sites; and so on. The effect of cross-talk can be minimized by reinitializing the array detector if needed between illuminations.
  • FIG. 4 shows a detection device 400 which provides an individual, addressable light source 415 for each of all or a subset of the detection sites 406.
  • the light sources 415 are set in a light source support substrate 418.
  • Each light source 415 which for instance are light-emitting diodes (LEDs), emits collimated light 402 of angle ⁇ .
  • the light can be collimated using individual collimating lenses 416 (not shown) overlaid onto each light source 415. As illustrated, each lens can be overlaid with an optical doubler 417.
  • the individually activatable light sources 415 can be used to minimize cross-talk in the same way that individual illumination reduces cross-talk in detection device 300.
  • Figure 5 shows a detection device 500 which provides an individual, addressable light source 515 for each of a subset of the detection sites 506.
  • the light source support substrate 518 has light sources 515 for each detection site 506 located in a row on the planar substrate 505.
  • Detection device 500 can operate without making use of offset angles for the source and emitted light illustrated in detection devices 100, 300 and 400. Instead, detection device 500 relies on individual illumination of the detection sites to minimize cross-talk.
  • the plate is moved relative to the light sources 515 and the detector array 512, and the associated electronics are operated at each alignment of the light sources 515 and detector array 512 with a row of detection sites 506, until data has been collected from all detections sites 506.
  • ten light source substrates 518 each with 100 light sources can be used to illuminate all 10,000 detection sites after 10 separate physical alignments of the detection sites 506.
  • Figure 6 shows a detection device 600 having a 2-dimensional array 618 of individually addressable light sources 615, each aligned with a separate detection site 606, preferably via an intervening optical device 604 which further separates the light beams 602 emitted by the light sources 615.
  • the planar substrate 605 can contain a 100 X 100 array of detection sites;
  • the detector array 612 can be a 1024 X 1024 CCD having 10 X 10 light-responsive 18 ⁇ m pixels per the average area on the planar substrate 605 occupied by a detection site 606 (where the detection sites 606 are laid out in columns and rows, this average area is the area defined by the multiplication product of (1) the pitch between reaction cells in separate rows and (2) the pitch between reaction cells in separate columns); and the detector array 612 can have 5 X 5 pixels aligned with each detection site.
  • Figure 7 shows a detection device 700 where light sources 715 are provided by separate waveguides 722 (such as gratings) that direct light from a laser diode 701.
  • Each pixel 723 in this embodiment has an overlaid lens 711 for selecting light of the second angle.
  • Broad beamed light sources such as the Xenon Arc Lamp flood the entire Assay plate with one beam of light.
  • each light beam typically corresponds to a detection site in the assay plate.
  • Each beam is addressable (can be turned on or off separately from the other beams).
  • Individually addressable LEDs can be constructed by packaging individual LEDs of suitable dimensions on a circuit board allowing the individual illumination either of each LED or a subset of the LEDs.
  • the semiconductor laser diodes visible and infrared wavelengths
  • available from Opto Power Corporation (Tucson, AZ) or SDL, Inc. (San Jose, CA) can be so packaged.
  • the center-to-center dimension used in the present application ranges from about 0.5 mm to about 1.2 mm. In various embodiments, preferred ranges are from about 1.0 mm to about 1.2 mm, from about 0.7 mm to about 0.9 mm, or from about 0.5 mm to about 0.7 mm.
  • the array detector can be, for example, a charge coupled device (CCD, such as that available from DALSA, Inc. (Easton CT), David Sarnoff Research Center (Princeton, NJ) or Princeton Instruments (Trenton, NJ)), an intensified CCD array (such as that available from Princeton Instruments, Hamamatsu Corp. (Bridgewater, NJ) or Photometries Ltd. of Arlington, AR), a focal plane array (such as that available from Scientific Imaging Technologies, Inc. (Beaverton, OR), Eastman Kodak Co., Inc. (Rochester, NY) or David Sarnoff Research Center), a photodiode array (such as that available from Reticon Corp. (Sunnyvale, CA), Sensors Unlimited, Inc.
  • CCD charge coupled device
  • an intensified CCD array such as that available from Princeton Instruments, Hamamatsu Corp. (Bridgewater, NJ) or Photometries Ltd. of Arlington, AR
  • a focal plane array such as that available from Scientific Imaging Technologies, Inc. (Beavert
  • the light responsive pixels are maintained at a temperature of about 10 °C or less, more preferably a temperature from about -30 °C to about 0 °C.
  • the detector preferably has the following performance features:
  • Masks such as those incorporated into the planar substrate to optically separate the various detection sites can for instance be manufactured by forming the planar substrate of two layers of material.
  • the top layer is formed of a material that is opaque to the relevant wavelengths, while the second is translucent to light of the wavelength to be detected.
  • the top layer is chemically etched or formed by laser ablation to define open areas that will define wells that serve as light-transmitting apertures. After such structures have been formed, this top masking layer is bonded to the lower, translucent layer.
  • a method for forming such a bond are set forth in "Field-Assisted Sealing," U.S. Application P- 89,876, filed November 7, 1995, which patent application is incorporated by reference, in its entirety, into this specification.
  • Additional sealing methods are described, for example, in Jobling-Purser, U.S. Patent 2,620,598, Curlee et al., U.S. Patent 5,009,690, Kleiman, U.S. Patent 4,643,532, Pomerantz, U.S. Patent 3,506,424, Pomerantz et al., U.S. Patent 3,417,459, Home, U.S. Patent 4,294,602 and Wohltjen et al., U.S. Patent 4,452,624.
  • LCD masks are described, for example, in Stewart et al., U.S. Patent No. 5,076,667 and Roach et al., U.S. Patent No. 5,337,068.
  • the planar substrate 105, 305, 405, 505 or 605 (for convenience, hereafter 105) used with the invention is formed of a substrate that is an organic or inorganic material that is suitable for forming the fine structures described herein.
  • the planar substrate 105 should be formed of a material that is resistant to the types of materials it is anticipated will be encountered in use. Thus, for instance, in diagnostic settings the planar substrate 105 typically encounters aqueous materials and can, accordingly, be manufactured of a broad range of materials.
  • the planar substrate 105 is designed for use in synthetic reactions, often the planar substrate 105 should be constructed of a material that is resistant to acids, bases and solvents.
  • the planar substrate 105 is constructed of glass, particularly borosilicate glass.
  • a basic parameter for the planar substrate 105 is the spacing between the centers of adjacent detection sites 106, which spacing is termed the "pitch.”
  • Four cell formats for plates are illustrated in Figure 8; these formats are the IK, 4K, 10K and 100K formats.
  • the IK format has a pitch of 2260 ⁇ m; the 4K format has a pitch of 1488 ⁇ m; the 10K format has a pitch of 965 ⁇ m; and the 100K format has a pitch of 558 ⁇ m.
  • Illustrative parameters for these formats are set forth below:
  • detection site volume and depth are selected to help accommodate the insertion of beads on which synthetic or other chemistries are conducted.
  • the pitch is the 2260 ⁇ m distance illustrated in Figure 8.
  • the area defined by the pitch further defines the amount of surface area that a given detection site 106 resides within.
  • the product of the pitch between detection sites 106 in a row and the pitch between detection sites 106 in a column determines the size of the surface area on which an individual detection site 106 sits.
  • the percentage of this surface area taken up by the area of each of the cell apertures is the area of the cell openings divided by the above-described product, times 100%. It is useful in understanding how the planar substrate 106 is used to refer to Zanzucchi et al., "Liquid Distribution System," U.S. Patent Application No.
  • LDS liquid distribution system
  • the liquid distribution device is designed for use in applications requiring a high density of reaction cells detection sites.
  • the device uses electrode-based pumps that have no moving parts to transport fluid from the reservoirs to the reaction cells.
  • the reaction cells or detection sites are preferably found on a planar substrate 105 that is separable from the portion of the liquid distribution system containing reservoirs and pumps.
  • the separable planar substrate 105 docks with the liquid distribution system, typically with a gasket material (that has openings at appropriate locations) interposed between the two, so that the cells are aligned underneath the appropriate outlet for delivering liquid from the liquid distribution system.
  • the spacing between detection sites 106 i.e., pitch
  • the area of each of the openings of the detection sites 106 which will be referred to as the cell aperture
  • the row-column arrangement which will be referred to as the matrix layout.
  • the depth of a detection site 106 can be made to vary according to the application for which the planar substrate 106 is used. Structures required for support functions can be formed on the area between detection site apertures.
  • Format 1 K is a 1024 cell array symmetrically formed into 32 rows and 32 columns and having a reaction cell volume of at least about 120 nanoliter per detection site 106.
  • a detection site pitch of 2260 ⁇ m can be accommodated.
  • a detection site configuration that satisfies volumetric and surface area requirements for fluid delivery, synthesis, assay and detection is 890 ⁇ m x 890 ⁇ m.
  • the detection sites 106 have a fluid capacity of a minimum of about 120 nanoliters.
  • Format 4K is a 4096 cell array symmetrically formed into 64 rows and 64 columns and having a reaction cell volume capacity of at least about 120 nanoliter per detection site 106. For this size and array configuration, in a typical case, a detection site pitch of 1488 ⁇ m can be accommodated. The detection site configuration of 890 ⁇ m square of the IK format is maintained. Using typical micromachining techniques suitable for production, the detection sites 106 have a fluid capacity of a minimum of about 120 nanoliters. Format 10K
  • 10K is a 10,000 cell array symmetrically formed into 100 rows and 100 columns. Micromachined features are reduced in size from the 4K cell format.
  • the associated liquid distribution system for instance a liquid distribution system according to Zanzucchi et al. /'Liquid Distribution
  • U.S. Patent Application No. 08/556,036, filed November 9, 1995 is also fabricated with a correspondingly dense layout of fluid delivery capillaries.
  • a detection site pitch of 965 ⁇ m in the planar substrate 106 can be accommodated.
  • the detection site configuration is adjusted for the more demanding requirements created by the higher density of detection sites.
  • a 635 ⁇ m x 635 ⁇ m detection site aperture is used.
  • the detection sites 106 have a fluid capacity of a minimum of about 50 nanoliters.
  • the pitch of the individually addressable light sources is the same as that of the detection site pitch of one of the preferred planar substrate formates, or the pitch of the light sources is a whole-number multiple of detection site pitch such as a 2-fold, 3-fold, 4-fold, etc. multiple.
  • the detection site aperture is preferably substantially square or rectangular in profile to best accommodate an array format.
  • the aperture can have rounded corners to accommodate the micromachining or molding/replication techniques used.
  • substantially in this context means no more than the amount of rounding or irregularity in shape that can be expected when such structures are formed in glass by chemical etching, as predominately practiced commercially in 1995.
  • the circular features formed at the edges of the "rectangular" or “square” cells have radii no greater than the depth of the cell and the edges of the aperture of the cell are longer than the cell depth.
  • first detection site 106A illustrates the relatively sharp edge lines obtained by chemically etching a silicon substrate.
  • second detection site 106B illustrates the relatively sharp edge lines obtained by laser etching a glass substrate. When chemically etching a glass substrate, the lines obtained are typically less sharp, as illustrated for detection site 106C.
  • the detection site 106 cross-sectional profile can be of various shapes depending on the micromachining or replication technique but should preferably meet a minimum fluid volume capacity and must provide enough depth to accommodate experiments that require a bead 121 for use in syntheses or assays that require a solid support. Although a number of beads 121 per cell may be used, and although beads 121 of different sizes may be used depending on the experiment, the preferred design is based on providing adequate space for synthesis or other reaction on a single bead 121 of a defined maximum specified swollen diameter.
  • cell depths sufficient to accommodate swollen beads 121 of 200 ⁇ m diameter are used in formats IK, 4K,10K; and depths sufficient to accommodate swollen beads of 100 ⁇ m diameter are used in format 100K.
  • the detection site profile is achieved with micromachining, replicating, molding, or like fabrication methods, cells in a single substrate, or is achieved by combining multiple layers of substrates.
  • the combining of layers can be achieved by known methods or, with appropriate substrates, with the field-assist sealing method described in Zhonghui H. Fan et al., U.S. Provisional Application No. P- 89,876, titled "Field Assisted Glass-Glass Sealing," filed November 7, 1995, which is incorporated herein in its entirety by reference.
  • optical requirements are important variables in the selection of cell construction, cross-sectional profile, and material.
  • the planar substrate allows for the space between detection sites to be used to provide for fluid conduits and drains, electrical vias, sealing features, and the like.
  • the planar substrate can be constructed of any material, material combinations, substrate thicknesses, and fabrication techniques, that suit the application.
  • mechanical alignment using three-pin registry is acceptable, and the edge alignment locations specified in Figure 10 can be used.
  • the preferred method is to grind first edge notch 119A, second edge notch 119B and third edge notch 119C, for instance at the locations shown in Figure 10.
  • the use of such notches obviates the need to accurately machine all the edges of the planar substrate 105 and provides for a method of mechanically identifying the top and bottom of the planar substrate 105.
  • the location of the center of the detection site patterns is defined in Figure 10 by the intersection of lines D and E.
  • the use of comparable notches in the manufacture of a liquid distribution system with which the planar substrate 105 allows equipment and tool manufacturers to coordinate their designs.
  • examples of the distances represented by Rl, R2, R3, Cm and Co are:
  • optical alignment is preferable.
  • the preferred location for the optical fiducials such as first fiducial 120A, second fiducial 120B and third fiducial 120C, are illustrated in Figure 10.
  • the preferred support material will be one that has shown itself susceptible to microfabrication methods, such as a microfabrication method that can form channels having cross-sectional dimensions between about 50 microns and about 250 microns.
  • Such support materials include glass, fused silica, quartz, silicon wafer or suitable plastics. Glass, quartz, silicon and plastic support materials are preferably surface treated with a suitable treatment reagent such as a siliconizing agent, which minimizes the reactive sites on the material, including reactive sites that bind to biological molecules such as proteins or nucleic acids.
  • a non-conducting support material such as a suitable glass, is preferred.
  • Preferred glasses include borosilicate glasses, low-alkali lime-silica glasses, vitreous silica (quartz) or other glasses of like durability when subjected to a variety of chemicals.
  • Borosilicate glasses such as Corning 0211, 1733, 1737 or 7740 glasses, available from Corning Glass Co.,
  • Corning, NY are among the preferred glasses.
  • materials having a low fluorescent background at the relevant excitation and emissions wavelengths are preferred.
  • the detection sites and horizontal channels and other structures of the planar substrates can be made by the following procedure.
  • a plate is coated sequentially on both sides with, first, a thin chromium layer of about 500A thickness and, second, a gold film about 2000 angstroms thick in known manner, as by evaporation or sputtering, to protect the plate from subsequent etchants.
  • a two micron layer of a photoresist such as Dynakem EPA of Hoechst-Celanese Corp., Bridgewater, NJ, is spun on and the photoresist is exposed, either using a mask or using square or rectangular images, suitably using the MRS 4500 panel stepper available from MRS Technology, Inc., Acton, MA.
  • the gold layer in the openings is etched away using a standard etch of 4 grams of potassium iodide and 1 gram of iodine (I2) in 25 ml of water.
  • the underlying chromium layer is then separately etched using an acid chromium etch, such as
  • the gasket used to reversibly seal the planar substrate to a liquid distribution instrument that functions with the planar substrate can be affixed to the planar substrate, leaving openings for the detection sites and other structures, as needed.
  • One method of attaching the gasket is screen-printing.
  • the printed gasket can be made of silicone or another chemically-resistant, resilient material.
  • a multi-step compression-molding process that utilizes photolithography can be applied to affix the gasket.
  • the top surface of the planar substrate, on which generally detection sites and other structures have been formed is coated with a photoresist.
  • the photoresist layer is about 1 mil in thickness.
  • the photoresist layer is treated by standard photolithography techniques to remove photoresist from those areas (the "gasket areas") away from the apertures of the cells where gasket material is desired.
  • a layer of a flowable gasket material that can be cured to a resilient, elastomeric solid is applied.
  • the gasket material is now cured.
  • the photoresist is then dissolved, leaving the plate with a patterned gasket.
  • the gasket material is "substantially" cleared if it is sufficiently cleared to allow the underlying photoresist to be dissolved.
  • the gasket material is any elastomeric material that is suitable for use in the above-described compression molding technique, that is, when cured, compatible with the chemistries that are to be practiced in the plate on which the gasket is formed, and that is, when cured, resistant to the solvents used to remove the photoresist.
  • the gasket material is preferably silicone, such as RTV type silicone rubber (e.g., Silastic J, RTV Silicone Rubber available from Dow Corning, Midland, Michigan).
  • the photoresist can be a film-type photoresist such that typically the structures on the plate will not be filled during the compression- molding process or a liquid-type photoresist such that the structures will temporarily be filled during the compression-molding process and etched away at the completion of the process.
  • a primer for promoting the adhesion of the gasket material such as 1200 RTV Prime Coat from Dow Corning, Midland, Michigan.
  • the planar substrate can also be roughened to promote the adhesion of the gasket material to the plate. For example, 5 micron roughness can be produced by lapping.
  • the platen is preferably treated with a release-promoter, or a release promoter is incorporated into the gasket material, as it is in Silastic J silicone rubber.
  • the compression-molding process can leave thin residues of gasket material at unwanted locations. These residues are laser cut away from the plate or, in some cases, are removed using a timed exposure to a solvent that dissolves the thin film of exposed gasket material residue without having substantial effect on the thicker layer of gasket material found at desired locations.
  • This gasket can also be used as the optical blocking material of areas 107.
  • the corresponding array detector will preferably have pixels of about 10 X 10 ⁇ m to about 100 X 100 ⁇ m dimensions, and 1 to about 25 pixels per detection site.
  • a 256 X 256 pixels array detector will have in excess of 25 pixels per each of 1000 detection sites, namely 65 pixels per detection site.
  • the corresponding array detector will preferably have pixels of about 10 X 10 ⁇ m to about 100 X 100 ⁇ m dimensions, and 1 to about 25 pixels per detection site.
  • a 512 X 512 pixels array detector will have in excess of 25 pixels per each of 4000 detection sites, namely 65 pixels per detection site.

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Abstract

La présente invention concerne des appareils de détection de lumière à partir, par exemple, de sites de détection rapprochés. Selon une réalisation, l'invention fournit un appareil mesurant la quantité de lumière émise par deux ou plusieurs sites de détection d'un premier ensemble de sites de détection ou transmise par l'intermédiaire desdits sites de détection sur un substrat plan (305). En l'occurrence, les mesures se font avec une résolution spatiale pour chaque site de détection du premier ensemble. Ledit appareil comporte pour chaque site de détection du premier ensemble: une source adressable d'un faisceau de lumière (301) orienté vers ce site de détection selon un premier angle, une matrice de détecteur comprenant une pluralité de pixels photosensibles (312). Pour chaque site de détection de ce premier ensemble, le système comporte au moins un pixel qui reçoit la lumière émise depuis ce site de détection ou transmise par l'intermédiaire de ce site de détection selon un second angle qui peut être le même que le premier.
PCT/US1997/017930 1996-09-26 1997-09-25 Detection parallele a partir de plusieurs sites WO1998013683A1 (fr)

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US6007690A (en) * 1996-07-30 1999-12-28 Aclara Biosciences, Inc. Integrated microfluidic devices
US6056860A (en) * 1996-09-18 2000-05-02 Aclara Biosciences, Inc. Surface modified electrophoretic chambers
US9671342B2 (en) 1998-05-16 2017-06-06 Life Technologies Corporation Instrument for monitoring polymerase chain reaction of DNA
US9823195B2 (en) 1998-05-16 2017-11-21 Life Technologies Corporation Optical instrument comprising multi-notch beam splitter
US9273353B2 (en) 1998-05-16 2016-03-01 Life Technologies Corporation Instrument for monitoring polymerase chain reaction of DNA
EP1619491A1 (fr) * 1998-05-16 2006-01-25 Applera Corporation Instrument optique servant à surveiller des réactions de polymérase en chaîne d'ADN
WO2000013017A3 (fr) * 1998-08-28 2000-07-20 Febit Ferrarius Biotech Gmbh Procede et dispositif de fabrication et/ou d'analyse de supports de reaction biochimiques
WO2000013018A3 (fr) * 1998-08-28 2000-09-14 Febit Ferrarius Biotech Gmbh Support pour un procede de determination d'analyte et procede de fabrication du support
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EP1742058A3 (fr) * 1998-08-28 2008-12-10 febit holding GmbH Substrats pour procédés de détermination d'analytes et méthodes de fabrication de tels substrats
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WO2000014514A1 (fr) * 1998-09-08 2000-03-16 Motorola, Inc. Analyseur de biomolecules comprenant une mosaique de detecteurs et un filtre
EP1151280A4 (fr) * 1998-11-24 2004-05-26 Cambridge Res & Instrmnt Inc Systeme et technique de dosage a polarisation de fluorescence
DE19858443A1 (de) * 1998-12-17 2000-07-06 Inst Mikrotechnik Mainz Gmbh Verfahren zum Abgeben eines Fluids, fluidisches Bauteil sowie Vorrichtung zur Handhabung solcher Bauteile
US6942771B1 (en) 1999-04-21 2005-09-13 Clinical Micro Sensors, Inc. Microfluidic systems in the electrochemical detection of target analytes
US8883424B2 (en) 1999-05-21 2014-11-11 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US9289766B2 (en) 1999-05-21 2016-03-22 Illumina, Inc. Use of microfluidic systems in the detection of target analytes using microsphere arrays
US6875619B2 (en) 1999-11-12 2005-04-05 Motorola, Inc. Microfluidic devices comprising biochannels
US6960467B2 (en) 1999-11-12 2005-11-01 Clinical Micro Sensors, Inc. Biochannel assay for hybridization with biomaterial
US7312087B2 (en) 2000-01-11 2007-12-25 Clinical Micro Sensors, Inc. Devices and methods for biochip multiplexing
US7470540B2 (en) 2000-10-17 2008-12-30 Febit Ag Method and device for the integrated synthesis and analysis of analytes on a support
GB2368903A (en) * 2000-11-08 2002-05-15 Proimmune Ltd Analysis of biological and biochemical assays
EP1509622A4 (fr) * 2002-05-23 2008-01-23 Perkin Elmer Life Science Inc Detection de la polarisation de fluorescence d'acides nucleiques
JP2005526975A (ja) * 2002-05-23 2005-09-08 パーキン・エルマー・ライフ・サイエンスィズ・インコーポレーテッド 核酸の蛍光偏光検出
WO2004050244A1 (fr) * 2002-11-29 2004-06-17 The National Blood Authority Ouverture de conteneurs d'echantillons a l'aide d'un laser
US7473551B2 (en) 2004-05-21 2009-01-06 Atonomics A/S Nano-mechanic microsensors and methods for detecting target analytes
WO2006056168A1 (fr) * 2004-11-24 2006-06-01 Heinrich Heine Universität Düsseldorf Dispositif et procede de mesure de fluorescence dans plusieurs espaces de reaction
US10222349B2 (en) 2007-02-05 2019-03-05 Qiagen Sciences, Llc Methods and devices for sequencing nucleic acids in smaller batches
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