[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2001085341A1 - Dispositifs microfluidiques - Google Patents

Dispositifs microfluidiques Download PDF

Info

Publication number
WO2001085341A1
WO2001085341A1 PCT/GB2001/002119 GB0102119W WO0185341A1 WO 2001085341 A1 WO2001085341 A1 WO 2001085341A1 GB 0102119 W GB0102119 W GB 0102119W WO 0185341 A1 WO0185341 A1 WO 0185341A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
particles
flow
beads
reaction chamber
Prior art date
Application number
PCT/GB2001/002119
Other languages
English (en)
Inventor
Helen Andersson
Göran Stemme
Wouter Van Der Wijngaart
Original Assignee
Pyrosequencing Ab
Piesold, Alexander, James
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
Application filed by Pyrosequencing Ab, Piesold, Alexander, James filed Critical Pyrosequencing Ab
Priority to JP2001581990A priority Critical patent/JP2003532400A/ja
Priority to EP01928128A priority patent/EP1280601A1/fr
Priority to AU54992/01A priority patent/AU5499201A/en
Publication of WO2001085341A1 publication Critical patent/WO2001085341A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/4077—Concentrating samples by other techniques involving separation of suspended solids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/18—Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0039—Inorganic membrane manufacture
    • B01D67/0053—Inorganic membrane manufacture by inducing porosity into non porous precursor membranes
    • B01D67/0058—Inorganic membrane manufacture by inducing porosity into non porous precursor membranes by selective elimination of components, e.g. by leaching
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/02—Inorganic material
    • B01D71/0213—Silicon
    • 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
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • 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
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0825—Test strips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L3/502753—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 bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation

Definitions

  • the present invention relates to microfluidic devices and particularly, although not exclusively, to microfluidic devices for manipulating microbeads.
  • Microspheres also known as beads, are routinely used as the mobile solid phase in medical diagnostics, microbiology, cancer research, immunology and molecular biology for separation, synthesis and detection of molecules.
  • the uniformity of the beads and their precisely defined size ensure that each bead has identical chemical and physical properties. Beads are available in several different materials and sizes (a few nanometers to millimeters in diameter).
  • the surface chemistry of the beads can be modified with various functional groups rendering the beads hydrophobic, hydrophilic, fluorescent, or active towards special ligand binding proteins. In order to perform and detect chemical reactions on beads, they must be confined to a limited volume.
  • Microfluidic devices for manipulating microspheres have, to date, mainly involved magnetic microspheres and have primarily focused on magnetically activated separations, see for example P. Telleman, TJ. Larsen, J. Philip, G. Blankenstein, and A. Wolff, Cell sorting in microfluidic systems, Micro Total Analysis Systems '98, Banff Canada, Oct 13-16, 1998, 39-44.
  • Paramagnetic beads i.e. beads with a magnetite (Fe 3 O 4 ) core sealed in a polymer shell, are extensively used today because they can be conveniently separated by applying external magnets.
  • magnetic principles are not always advantageous in micro total analysis systems ( ⁇ -TAS) applications. External magnetic systems complicate precision handling and result in a bulky system. Incorporation of magnetic components on wafer level is also a very complicated process.
  • the invention provides a microfluidic reaction apparatus for trapping one or more particles of predetermined nominal size or range of sizes, comprising a flow inlet and a reaction zone having an enlarged cross-sectional area in comparison to said flow inlet, said reaction zone comprising a filter means having a plurality of holes defined therein, the holes being smaller than said nominal size or range of sizes and arranged so as to trap said particles while a fluid flows from the flow inlet through the filter means.
  • the apparatus may be used to implement multi-step reactions at a single location.
  • the enhanced flow characteristics which may be achieved in accordance with the invention, in particular a reduced tendency to clog are beneficial in whichever stage of a process it is required to pass fluid over the filter and not necessarily during the reaction itself.
  • the apparatus whilst some preferred applications of an apparatus in accordance with the invention involve flowing a reaction fluid over the particles in a through-flow process, it is equally possible for the apparatus to be used for 'stop-flow' measurements in which there is not a significant flow of reaction fluid through the filter. In such cases the improved fluid characteristics mentioned above are still beneficial when charging the filter with the particles using a fluid in which the particles are suspended and/or in performing washing steps between the respective stages of a multi-stage reaction.
  • the filter means could extend laterally across the flow zone, i.e. normal to the direction of liquid flow.
  • the filter means extends around the flow axis, i.e. it has at least some extent in a plane whose normal is not parallel with the flow axis. This is beneficial since it enhances the concentration of the trapped particles into a smaller space which aids detection of the reaction. This is important, for example, when the reaction is one which emits light since it will increase the intensity and thus ease of measurement of the potentially low level of light.
  • the filter means extends substantially completely around the flow axis so as to form a porous reaction chamber. This enables the particles to be trapped in a compact arrangement whilst still allowing good porosity for the fluid passing through.
  • the chamber is shaped so as to conform to the shape of a reaction monitoring device.
  • the enclosure is substantially rectangular to match the rectangular shape of a charge coupled device.
  • the charge-coupled device may not be rectangular - e.g. it may be hexagonal in which case the chamber would preferably be hexagonal too.
  • the chamber could be circular or partly or substantially spherical.
  • the invention provides a reaction apparatus comprising a porous reaction chamber for trapping one or more particles therein and a reaction monitoring means arranged to monitor the particles trapped in the reaction chamber; wherein the reaction chamber is arranged so as substantially to correspond in shape to the reaction monitoring means.
  • the holes may be of any convenient size or shape as long as they are smaller in at least one dimension than the nominal size or range of sizes of the particles. It should be understood that where particles are non-spherical it is the minimum dimension that is taken to represent the 'size' of the particle. The important criterion is that the particles are trapped by the holes without passing through.
  • the holes are elongate, most preferably rectangular. This promotes a substantially lateral flow with minimal 'dead spaces' i.e. regions with low or no flow.
  • the holes could be defined as apertures in a wall or between the elements of a mesh, but preferably are defined between a plurality of preferably substantially parallel discrete wall elements which are preferably rectangular. Such wall elements preferably extend normally from a substrate to form pillars.
  • Apparatus in accordance with the invention could be open on one side, but are preferably closed to prevent contamination.
  • at least the reaction zone of the apparatus is closed by a substantially transparent cover. This allows reactions generating light or modifying incident light, for example fluorescence resulting from shining laser light onto the particles, to be monitored.
  • the apparatus is preferably formed on substantially planar substrate. Also preferred is that a flow outlet is provided, preferably substantially colinearly with the flow inlet and the reaction zone.
  • Apparatus in accordance with the invention can be manufactured using standard photolithographic procedures and bulk micromachining of silicon.
  • a mask fabrication process is used involving a deep reactive ion etching (DRIE).
  • DRIE deep reactive ion etching
  • a two stage process is used to form respective faces from a substantially planar substrate.
  • the bond is preferably effected by heating the mouth of the channel so as partially to melt the end of the tube.
  • the strength of the bond is enhanced by applying an adhesive around the base of the tube.
  • the adhesive is an epoxy glue.
  • the mouth of the channel is roughened prior to bonding the tube thereto. This enhances the strength of the bond.
  • the apparatus of the invention may be used for many different purposes.
  • a preferred use of the apparatus is in the analysis or sequencing of nucleic acid (i.e. DNA, RNA or cDNA).
  • a particularly preferred nucleic acid sequencing application is in sequencing-by-synthesis. Any suitable method of detecting nucleotide incorporation in sequencing by synthesis reactions may be used, i.e. use of fluorescently labelled nucleotides, colourimetric detection, radiolabels, or use of enzymatic detection systems.
  • Most preferably the apparatus is used in the Applicant's PyroSequencingTM sequencing-by-synthesis technique full details of which are given in WO98/13523.
  • the analyte in question comprises a nucleic acid, i.e. DNA fragment and that the liquid comprises a nucleotide.
  • the nucleic acid fragment is single-stranded.
  • Apparatus in accordance with the invention are particularly beneficial in such techniques since they allow different nucleotides to be cyclically pumped over the particles, preferably microbeads such as DynabeadsTM (available from Dynal Biotech ASA, Norway), which remain in the same position and thus are easy to monitor for the generation of light associated with the technique.
  • nucleotide will be understood to cover both deoxy and dideoxy nucleotide triphosphates (dNTPs and ddNTPs).
  • dNTPs and ddNTPs deoxy and dideoxy nucleotide triphosphates
  • analogues of dNTPs and ddNTPs which are normally incorporated into a growing DNA chain by a polymerase are also included.
  • a through-flow system for such techniques is novel and inventive in its own right and thus when viewed from a further aspect the invention provides a method of sequencing by synthesis comprising trapping a target immobilised on a plurality of beads, on a filter means provided in a through-flow channel and passing at least one nucleotide over said trapped beads.
  • Figure 2 shows schematically a plan view of an embodiment of an apparatus in accordance with the present invention using the filter arrangement of Fig. lc;
  • Figure 3 shows a scanning electron microscope (SEM) view of an embodiment of a device in accordance with the present invention
  • Figures 4a and 4b show SEM images of an embodiment of a reaction chamber in accordance with the present invention
  • Figure 5 shows a SEM view of pillars in the reaction chamber of figure 5;
  • Figures 6a-6d show respective stages in a method in accordance with an invention disclosed herein for attaching fluid connectors;
  • Figure 7 illustrates the principle of allele specific pyro-extension on a SNP
  • Figure 8 shows a plot of total collected light versus time
  • Figures 9a and 9b show snapshots of respectively match and mis-match pyro- extension.
  • FIG. la shows a known filter arrangement in which a planar filter A is placed laterally across a uniform channel B. This arrangement is prone to clogging when packed with beads C, thus impeding the free flow of liquid through the channel.
  • Fig. lb shows a filter arrangement in accordance with the invention.
  • the fluid inlet channel 2 opens into a zone 2a of enlarged cross section, compared to the inlet channel, in which a filter 4' is disposed laterally across it.
  • a filter 4' is disposed laterally across it.
  • a greater number of holes is provided than the arrangement of Fig. la. This significantly reduces the tendency for the filter 4' to clog in comparison with Fig. la, and results in more homogeneous flow characteristics over it.
  • Fig. lb is an improvement over that in Fig. la from the point of view of fluid flow characteristics.
  • the beads 6 may be more spread out than in the Fig. la arrangement, e.g. where the reaction which takes place on surface of the beads generates a low level of light.
  • the arrangement shown in Fig. lc overcomes this problem.
  • the filter 4 is similarly disposed in a zone 2a of enlarged cross-section.
  • the filter 4 extends all the way around the flow axis 8 to form a porous reaction chamber 10.
  • FIG. 2 A more detailed plan view of the preferred embodiment is shown in Fig. 2.
  • the microfluidic reaction apparatus is described in a substantially planar, rectangular substrate 12. The method of fabrication is described in greater detail hereinafter. Fluid and particles are introduced to the apparatus by means of a vertically disposed inlet tube 14, extending normally from the other surface of the substrate 12. A similar exit tube 16 is disposed at the other end of the apparatus.
  • the inlet tube 14 is in fluid communication with the inlet channel 2.
  • the inlet channel 2 opens out into a reaction zone 2a of enlarged cross-section.
  • the filter 4 extends all the way around the flow axis 8 to form a box-like reaction chamber 10.
  • the remainder of the enlarged zone 2a forms a waste chamber 18 for collecting fluid that has passed through the filter 4.
  • the waste fluid is channeled into an outlet channel 16 of similar dimensions to the inlet channel 2 and which is in fluid communication with the exit tube 16.
  • FIGs. 3, 4a, 4b and 5 there may be seen various scanning electron microscope (SEM) images of the embodiment depicted in Fig. 2. From these it may be seen that the filter 4 is made up of a series of parallel vertical pillars 22 extending vertically from the floor of the enlarged zone 2a etched out of the substrate 12. The gaps between the pillars 22 define the holes which must be smaller than the beads or other particles which it is desired to trap.
  • the apparatus shown in Figs. 2 to 5 is fabricated as follows. First, one hundred millimetre diameter 525 ⁇ m thick p-doped silicon (100 off)-wafers are used as the starting material. Photoresist (1.5 ⁇ m thick) is used for two etch masks. First, the front side is patterned and etched with the first mask using deep reactive ion etching (DRIE) (Surface Technology Systems, UK) to define the inlet channel 2, reaction chamber 10, filter 4, waste chamber 18 and outlet channel 20. Gas switching in the DRIE process gives rise to the undulating surface pattern on the pillars 22 which may be observed in Fig. 5.
  • DRIE deep reactive ion etching
  • a 170, 300 or 500 ⁇ m thick Pyrex glass wafer is anodically bonded to the front side.
  • the backside is then patterned in a second DRIE step with the second mask to create fluid connectors for the inlet and outlet tubes 14, 16.
  • the silicon-glass stack is then sawn into 9x5 mm chips.
  • External polyethylene (PE) tubes are used as the inlet and outlet tubes 14, 16 and are fixed to the chip in a multi-step procedure as schematically shown in Figs. 6a to 6d.
  • a mask-defined silicon surface roughening is performed around the fluid openings 26 by the second DRIE step to ensure good adhesion of the PE tubes (Fig. 6a).
  • a guide wire 24 is used to align the PE tubes 14, 16 with the respective fluid openings on the chip during the tube fixing process (Fig. 5b).
  • the silicon-glass stack 28 is briefly heated to generate a local melting of the PE tube 14, 16 onto the chip (Fig. 6c).
  • the interface between the chip and the PE tubes 14, 16 is then covered with epoxy glue.
  • Several exemplary apparatus of the form shown in Fig. 2 were fabricated with varying sizes. The dimensions of these are shown in rows 1 to 8 of Table 1 below. Row 9 relates to a design similar to that in Fig. la and is included for the purposes of comparison.
  • Table 1 A summary of the different designs of the flow-through micromachmed device where is the filter chamber volume, Wthe pillar width, E the pillar length, and H the pillar height.
  • the dimensions of the micromachmed structures were measured using a scanning electron microscope and compared with the original specifications. The consistency of the filter pillar dimensions within a reaction chamber and between different reaction chambers was measured.
  • the dimensions of the measured structures were found to be in good agreement with the original specifications.
  • the micromachmed structures were found to have high uniformity indicating a uniform and reproducible fabrication process.
  • the melt-on method for fixing the external P ⁇ tubes to the chip was found to be very convenient and reliable. It resulted in robust, precisely positioned interconnections to the macroscopic world with low dead volumes. It is believed that the epoxy glue is important in giving the assembly the robustness.
  • the fluid behaviour of the flow-through micromachmed device was investigated.
  • streptavidin coated beads of two different materials and sizes were used, i.e. polystyrene beads with a diameter of 5.50 ⁇ m (Bangs Laboratories, IN, USA) and magnetic Dynabeads with a diameter of 2.8 ⁇ m (Dynal Biotech ASA, Norway).
  • the bead solutions were applied manually with a pipette under a standard light microscope with 40X objective.
  • the beads were applied at a low concentration (10 000 beads/mL). Samples at the outlet were collected and controlled under the microscope to confirm that beads do not pass through the filter.
  • the smallest reaction chamber (design 1, 5, 6) has a volume of 0.5 nL and can hold about 50 beads with a diameter of 5.50 ⁇ m.
  • the flow-through volume of liquid or gas There is no upper limitation of the flow-through volume of liquid or gas, which is important when working with very- low sample concentrations.
  • the smallest volume required to fill the device is 3.0 nL (the volume of the inlet channel and reaction chamber).
  • Equation 1 is valid when 2 ⁇ L/D h ⁇ 50 where L is the length of the channel [8].
  • Design 9 is a channel with only 20 pillars constituting the filter compared to 70-790 pillars for design 1-8. 12
  • the beads can easily be removed out of the reaction chamber by applying back-pressure. After removing the beads and carefully cleaning of the micromachmed flow-through device, it can be reused.
  • the flow-through micromachined reaction chamber presented here collects both nonmagnetic and magnetic beads.
  • Nonmagnetic beads have lower density resulting in improved fluid dynamic behaviour in ⁇ -TAS compared to magnetic beads.
  • the batch fabrication process of the flow-through microfluidic device is simple and reproducible, involving only two masks and two different processing techniques. These are important factors in terms of parallellization and producing cost effective economical ⁇ -TAS.
  • the chip dimensions (9x5 mm) were chosen to simplify practical handling and can be further reduced if required.
  • the smallest reaction chamber of 0.5 nL, collecting approximate 50 beads, can also be further miniaturized if a reduced number of beads or flow-through volume are of interest.
  • an apparatus as shown in Fig. 2 was used in the Applicant's PyrosequencingTM sequencing-by-synthesis technique. This technique is performed by hybridizing a sequencing primer to the single-stranded nucleic acid template and incubation with the enzymes DNA poiymerase, ATP sulfurylase and luciferase. A specific deoxynucleotide triphosphate (dNTP, nucleotide) is added to the reaction. DNA poiymerase catalyses the 13
  • SNP single nucleotide polymorphisms
  • the outer PCR was followed by an inner PCR generating ⁇ 80 bp fragments.
  • One of the inner primers was biotinylated at the 5 '-end to allow immobilization. Biotinylated inner PCR product was immobilized onto the streptavidin coated beads. Single-stranded DNA was obtained by incubating the immobilized PCR product in NaOH. The immobilized strand was resuspended in H 2 O and annealing buffer was added to the single-stranded templates. The solution was then divided into two wells and primers were added in each well. The primers vary in their 3 '-ends and have the sequence 5'- GCTGCTGGTGCAGGGGCCACGG-3' and 5'-
  • sample flow-through rate is adjustable, which is important when performing chemical reactions on beads [10]. Effectively unlimited flow- through volumes of gas and liquid are possible allowing detection of rare molecules or biological species (at or below 100 copies/mL) [11].
  • the flow-through microfluidic reaction chamber reduces the accumulation of by-products resulting in increased reaction and detection sensitivity compared to a closed system (i.e. microtiter plates).
  • reaction chamber of designs 1-8 included in the study do not significantly affect the device performance (i.e., bead capture, air bubble sensitivity, pressure drop) for bead assays as long as the pillars constitute a mechanical barrier. Analytical calculations showed that the largest pressure drop is located across the inlet and outlet channels.
  • the reaction chamber and filter dimensions can therefore be optimized for bead size and chemical reaction parameters.
  • the filter dimensions are important. For example, when filtering cells it is important that the cells pass through the filter as quickly as possible to reduce cell activation, stiction and cell rupture [12].
  • the flow resistance remains low when the reaction chamber is packed with beads. Otherwise, it is difficult to pump the reactants through the reaction chamber.
  • the flow rate decreases with 40% when the reaction chamber is packed with beads. This corresponds to a flow of about 2 ⁇ L/min, which still is well within the margins for ⁇ -TAS. 15
  • At least preferred embodiments of the present invention can be used for solid- phase DNA sequencing, automatic introduction of beads by using micropumps, parallellization and device fabrication using plastic replication techniques.
  • the filter has been described as being made up of discrete pillars it is also conceivable to form a filter of walls which have slits which have openings which are narrower than the diameters of the beads being filtered. It is also possible to have one or several laterally arranged slits along the perimeter of the reaction chamber. These lateral slits should be narrower than the diameters of the beads being filtered.
  • the pillar filter design creates vertical filter openings which provides a substantially lateral flow with minimal "dead volumes" in the fluidic device (i.e. no or small volumes with low or zero flow). This is a very attractive feature since it improves the quality of the chemical and biochemical analysis.
  • the beads in the reaction chamber are collected in a "point" configuration (e.g.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Water Supply & Treatment (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biochemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Manufacturing & Machinery (AREA)
  • Fluid Mechanics (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne un dispositif microfluidique destiné à piéger des billes (6) non magnétiques et magnétiques (6), le dispositif comprenant une entrée (2), une sortie (20) et un filtre de piégeage de bille (4) ce filtre comportant une paroi dotée de fentes dont les ouvertures sont plus petites que le diamètre des billes. Le filtre (4) est disposé dans une zone plus large (2a) et peut s'étendre autour de l'axe d'écoulement, par exemple sous une forme de type boîte. Le dispositif peut être utilisé dans un procédé de séquençage par synthèse.
PCT/GB2001/002119 2000-05-12 2001-05-14 Dispositifs microfluidiques WO2001085341A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2001581990A JP2003532400A (ja) 2000-05-12 2001-05-14 微小流体装置
EP01928128A EP1280601A1 (fr) 2000-05-12 2001-05-14 Dispositifs microfluidiques
AU54992/01A AU5499201A (en) 2000-05-12 2001-05-14 Microfluidic devices

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0001768A SE0001768D0 (sv) 2000-05-12 2000-05-12 Mikrofluidisk flödescell för manipulering av partiklar
SE0001768-1 2000-05-12

Publications (1)

Publication Number Publication Date
WO2001085341A1 true WO2001085341A1 (fr) 2001-11-15

Family

ID=20279654

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2001/002119 WO2001085341A1 (fr) 2000-05-12 2001-05-14 Dispositifs microfluidiques

Country Status (5)

Country Link
EP (1) EP1280601A1 (fr)
JP (1) JP2003532400A (fr)
AU (1) AU5499201A (fr)
SE (1) SE0001768D0 (fr)
WO (1) WO2001085341A1 (fr)

Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003068373A2 (fr) * 2002-02-13 2003-08-21 Hospira, Inc. Filtre antimicrobien microfluidique
EP1359228A1 (fr) * 2002-04-23 2003-11-05 Accenture Global Services GmbH Authentification d'acide nucléique selon la détection de la lumière diffusée
WO2003090930A1 (fr) * 2002-04-24 2003-11-06 Battelle Memorial Institute Procede pour separations a haut rendement dans des systemes microfluidiques a petites particules
WO2003099438A1 (fr) * 2002-05-24 2003-12-04 The Governors Of The University Of Alberta Appareil et procede de piegeage de reactifs a base de billes dans des systemes d'analyse microfluidiques
WO2004046695A3 (fr) * 2002-11-15 2004-07-22 Eksigent Technologies Llc Traitement de particules
WO2004074169A1 (fr) * 2003-02-24 2004-09-02 Microtechnology Centre Management Limited Filtre microfluidique
EP1499706A2 (fr) * 2002-04-01 2005-01-26 Fluidigm Corporation Systemes d'analyse de particules microfluidiques
WO2005036167A1 (fr) * 2003-10-15 2005-04-21 National University Of Singapore Procede et appareil de detection d'un analyte avec un filtre
WO2005060345A2 (fr) * 2003-12-22 2005-07-07 Biotage Ab Nouveau procede de sequençage par synthese
WO2005102528A1 (fr) * 2004-03-26 2005-11-03 Corning Incorporated Capillaires transparents filtres
US7077175B2 (en) 2004-04-09 2006-07-18 Hongfeng Yin Particle packing of microdevice
WO2007008223A2 (fr) * 2004-09-20 2007-01-18 3M Innovative Properties Company Systemes et procedes de biodetection et capteurs a microresonateur a utiliser dans ceux-ci
US7175810B2 (en) 2002-11-15 2007-02-13 Eksigent Technologies Processing of particles
WO2007031152A1 (fr) * 2005-09-09 2007-03-22 Gesellschaft zur Förderung der Analytischen Wissenschaften e.V. Procede et dispositif pour produire des membranes artificielles spheriques ou tubulaires
DE102005062723A1 (de) * 2005-12-22 2007-07-05 INSTITUT FüR MIKROTECHNIK MAINZ GMBH Probenaufarbeitungschip, Reaktionskammer und Verwendung des Probenaufarbeitungschips
US7259855B2 (en) 2003-10-14 2007-08-21 3M Innovative Properties Company Porous microsphere resonators
US7271379B2 (en) 2004-05-27 2007-09-18 3M Innovative Properties Company Dielectric microcavity fluorosensors excited with a broadband light source
US7312611B1 (en) 1999-11-26 2007-12-25 The Governors Of The University Of Alberta Apparatus and method for trapping bead based reagents within microfluidic analysis systems
WO2008024070A1 (fr) * 2006-08-22 2008-02-28 Agency For Science, Technology And Research Unité, dispositif et procédés de filtration microfluidique
US7352933B2 (en) 2004-05-27 2008-04-01 3M Innovative Properties Company Dielectric microcavity sensors
US7389025B2 (en) 2006-03-29 2008-06-17 3M Innovative Properties Company Coupling light into microresonators
US7444045B2 (en) 2003-10-14 2008-10-28 3M Innovative Properties Company Hybrid sphere-waveguide resonators
US7532790B2 (en) 2006-03-29 2009-05-12 3M Innovative Properties Company Method of coupling light into microresonators
WO2009069023A2 (fr) * 2007-11-29 2009-06-04 International Business Machines Corporation Appareil et procédé de détection d'un analyte dans un échantillon
WO2009125067A1 (fr) * 2008-04-10 2009-10-15 Valtion Teknillinen Tutkimuskeskus Dispositifs à puce microfluidique et leur utilisation
US7745207B2 (en) 2006-02-03 2010-06-29 IntegenX, Inc. Microfluidic devices
US7749365B2 (en) 2006-02-01 2010-07-06 IntegenX, Inc. Optimized sample injection structures in microfluidic separations
US7766033B2 (en) 2006-03-22 2010-08-03 The Regents Of The University Of California Multiplexed latching valves for microfluidic devices and processors
US7799553B2 (en) 2004-06-01 2010-09-21 The Regents Of The University Of California Microfabricated integrated DNA analysis system
WO2010111509A1 (fr) 2009-03-25 2010-09-30 Life Technologies Corporation Adn témoin de discrimination positive/d'extraction
US20110027916A1 (en) * 2008-04-11 2011-02-03 Koninklijke Philips Electronics N.V. Detection apparatus for detecting particles
USRE43122E1 (en) 1999-11-26 2012-01-24 The Governors Of The University Of Alberta Apparatus and method for trapping bead based reagents within microfluidic analysis systems
EP2458011A1 (fr) 2005-10-03 2012-05-30 Life Technologies Corporation Compositions, procédés et kits pour l'amplification d'acides nucléiques
US8388908B2 (en) 2009-06-02 2013-03-05 Integenx Inc. Fluidic devices with diaphragm valves
US8394642B2 (en) 2009-06-05 2013-03-12 Integenx Inc. Universal sample preparation system and use in an integrated analysis system
US8431390B2 (en) 2004-09-15 2013-04-30 Integenx Inc. Systems of sample processing having a macro-micro interface
US8454906B2 (en) 2007-07-24 2013-06-04 The Regents Of The University Of California Microfabricated droplet generator for single molecule/cell genetic analysis in engineered monodispersed emulsions
US8512538B2 (en) 2010-05-28 2013-08-20 Integenx Inc. Capillary electrophoresis device
US8557518B2 (en) 2007-02-05 2013-10-15 Integenx Inc. Microfluidic and nanofluidic devices, systems, and applications
US8584703B2 (en) 2009-12-01 2013-11-19 Integenx Inc. Device with diaphragm valve
US8672532B2 (en) 2008-12-31 2014-03-18 Integenx Inc. Microfluidic methods
US8748165B2 (en) 2008-01-22 2014-06-10 Integenx Inc. Methods for generating short tandem repeat (STR) profiles
US8763642B2 (en) 2010-08-20 2014-07-01 Integenx Inc. Microfluidic devices with mechanically-sealed diaphragm valves
EP2774677A2 (fr) 2013-03-05 2014-09-10 Robert Bosch Gmbh Dispositif de réalisation de processus chimiques et/ou biochimiques
US8841116B2 (en) 2006-10-25 2014-09-23 The Regents Of The University Of California Inline-injection microdevice and microfabricated integrated DNA analysis system using same
CN104583752A (zh) * 2012-07-13 2015-04-29 生物梅里埃公司 溶解存在于样品中的微生物、提取并提纯所述微生物的核酸以用于分析目的的自动化系统
US9121058B2 (en) 2010-08-20 2015-09-01 Integenx Inc. Linear valve arrays
US9304065B2 (en) 2012-02-29 2016-04-05 Fluidigm Corporation Methods, systems and devices for multiple single-cell capturing and processing using microfluidics
US9644623B2 (en) 2002-12-30 2017-05-09 The Regents Of The University Of California Fluid control structures in microfluidic devices
US10191071B2 (en) 2013-11-18 2019-01-29 IntegenX, Inc. Cartridges and instruments for sample analysis
US10208332B2 (en) 2014-05-21 2019-02-19 Integenx Inc. Fluidic cartridge with valve mechanism
US10525467B2 (en) 2011-10-21 2020-01-07 Integenx Inc. Sample preparation, processing and analysis systems
WO2020113237A1 (fr) 2018-11-30 2020-06-04 Caris Mpi, Inc. Profilage moléculaire de nouvelle génération
US10690627B2 (en) 2014-10-22 2020-06-23 IntegenX, Inc. Systems and methods for sample preparation, processing and analysis
US10865440B2 (en) 2011-10-21 2020-12-15 IntegenX, Inc. Sample preparation, processing and analysis systems
US11813610B2 (en) 2018-07-09 2023-11-14 Hewlett-Packard Development Company, L.P. Microfluidic devices
US11842805B2 (en) 2019-12-02 2023-12-12 Caris Mpi, Inc. Pan-cancer platinum response predictor

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4050971B2 (ja) * 2002-10-08 2008-02-20 株式会社島津製作所 ダイアフラムを用いフィルタ機能を有するバルブ
JP2005257597A (ja) * 2004-03-15 2005-09-22 Japan Science & Technology Agency ビーズ担体充填式マイクロチップおよびそれを用いたビーズ担体の配置方法
JP4849278B2 (ja) * 2009-03-27 2012-01-11 セイコーエプソン株式会社 細胞処理デバイス、細胞処理カートリッジおよび体液処理システム
JP5663985B2 (ja) * 2009-12-16 2015-02-04 ソニー株式会社 マイクロビーズ検査用のセル及びマイクロビーズの解析方法
WO2016203807A1 (fr) * 2015-06-18 2016-12-22 ソニー株式会社 Sonde d'analyse
KR101726064B1 (ko) * 2015-08-06 2017-04-13 한양대학교 산학협력단 진동자를 구비하는 미세입자 분리소자
TWI677464B (zh) * 2017-05-10 2019-11-21 上準微流體股份有限公司 微流體晶片、用於富集細胞的裝置及方法
JP7299071B2 (ja) * 2019-06-04 2023-06-27 株式会社日立プラントサービス 固相合成装置

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5726026A (en) * 1992-05-01 1998-03-10 Trustees Of The University Of Pennsylvania Mesoscale sample preparation device and systems for determination and processing of analytes
WO1999009042A2 (fr) * 1997-08-13 1999-02-25 Cepheid Microstructures permettant de manipuler des echantillons fluides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5726026A (en) * 1992-05-01 1998-03-10 Trustees Of The University Of Pennsylvania Mesoscale sample preparation device and systems for determination and processing of analytes
WO1999009042A2 (fr) * 1997-08-13 1999-02-25 Cepheid Microstructures permettant de manipuler des echantillons fluides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANDERSSON H ET AL: "Micromachined flow-through filter-chamber for chemical reactions on beads", SENSORS AND ACTUATORS B,ELSEVIER SEQUOIA S.A., LAUSANNE,CH, vol. 67, no. 1-2, 10 August 2000 (2000-08-10), pages 203 - 208, XP004213496, ISSN: 0925-4005 *

Cited By (104)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE43122E1 (en) 1999-11-26 2012-01-24 The Governors Of The University Of Alberta Apparatus and method for trapping bead based reagents within microfluidic analysis systems
US7312611B1 (en) 1999-11-26 2007-12-25 The Governors Of The University Of Alberta Apparatus and method for trapping bead based reagents within microfluidic analysis systems
US8034628B2 (en) 1999-11-26 2011-10-11 The Governors Of The University Of Alberta Apparatus and method for trapping bead based reagents within microfluidic analysis systems
US9926521B2 (en) 2000-06-27 2018-03-27 Fluidigm Corporation Microfluidic particle-analysis systems
WO2003068373A3 (fr) * 2002-02-13 2003-11-20 Abbott Lab Filtre antimicrobien microfluidique
US7201846B2 (en) 2002-02-13 2007-04-10 Hospira, Inc. Micro-fluidic anti-microbial filter
WO2003068373A2 (fr) * 2002-02-13 2003-08-21 Hospira, Inc. Filtre antimicrobien microfluidique
EP1499706A2 (fr) * 2002-04-01 2005-01-26 Fluidigm Corporation Systemes d'analyse de particules microfluidiques
EP2666849A3 (fr) * 2002-04-01 2014-05-28 Fluidigm Corporation Systèmes d'analyse de particules microfluidiques
EP1499706A4 (fr) * 2002-04-01 2010-11-03 Fluidigm Corp Systemes d'analyse de particules microfluidiques
EP1359228A1 (fr) * 2002-04-23 2003-11-05 Accenture Global Services GmbH Authentification d'acide nucléique selon la détection de la lumière diffusée
WO2003090930A1 (fr) * 2002-04-24 2003-11-06 Battelle Memorial Institute Procede pour separations a haut rendement dans des systemes microfluidiques a petites particules
WO2003099438A1 (fr) * 2002-05-24 2003-12-04 The Governors Of The University Of Alberta Appareil et procede de piegeage de reactifs a base de billes dans des systemes d'analyse microfluidiques
JP2006506646A (ja) * 2002-11-15 2006-02-23 エクシジェント テクノロジーズ， エルエルシー 粒子の処理方法
US7175810B2 (en) 2002-11-15 2007-02-13 Eksigent Technologies Processing of particles
WO2004046695A3 (fr) * 2002-11-15 2004-07-22 Eksigent Technologies Llc Traitement de particules
US7220592B2 (en) 2002-11-15 2007-05-22 Eksigent Technologies, Llc Particulate processing system
US9644623B2 (en) 2002-12-30 2017-05-09 The Regents Of The University Of California Fluid control structures in microfluidic devices
US9651039B2 (en) 2002-12-30 2017-05-16 The Regents Of The University Of California Fluid control structures in microfluidic devices
WO2004074169A1 (fr) * 2003-02-24 2004-09-02 Microtechnology Centre Management Limited Filtre microfluidique
US7595890B2 (en) 2003-10-14 2009-09-29 3M Innovative Properties Company Porous microsphere resonators
US7259855B2 (en) 2003-10-14 2007-08-21 3M Innovative Properties Company Porous microsphere resonators
US7444045B2 (en) 2003-10-14 2008-10-28 3M Innovative Properties Company Hybrid sphere-waveguide resonators
WO2005036167A1 (fr) * 2003-10-15 2005-04-21 National University Of Singapore Procede et appareil de detection d'un analyte avec un filtre
WO2005060345A2 (fr) * 2003-12-22 2005-07-07 Biotage Ab Nouveau procede de sequençage par synthese
WO2005060345A3 (fr) * 2003-12-22 2006-05-11 Biotage Ab Nouveau procede de sequençage par synthese
WO2005102528A1 (fr) * 2004-03-26 2005-11-03 Corning Incorporated Capillaires transparents filtres
US7077175B2 (en) 2004-04-09 2006-07-18 Hongfeng Yin Particle packing of microdevice
US7352933B2 (en) 2004-05-27 2008-04-01 3M Innovative Properties Company Dielectric microcavity sensors
US7271379B2 (en) 2004-05-27 2007-09-18 3M Innovative Properties Company Dielectric microcavity fluorosensors excited with a broadband light source
US7622705B2 (en) 2004-05-27 2009-11-24 3M Innovative Properties Company Dielectric microcavity fluorosensors excited with a broadband light source
US7799553B2 (en) 2004-06-01 2010-09-21 The Regents Of The University Of California Microfabricated integrated DNA analysis system
US8551714B2 (en) 2004-09-15 2013-10-08 Integenx Inc. Microfluidic devices
US8476063B2 (en) 2004-09-15 2013-07-02 Integenx Inc. Microfluidic devices
US8431340B2 (en) 2004-09-15 2013-04-30 Integenx Inc. Methods for processing and analyzing nucleic acid samples
US8431390B2 (en) 2004-09-15 2013-04-30 Integenx Inc. Systems of sample processing having a macro-micro interface
US9752185B2 (en) 2004-09-15 2017-09-05 Integenx Inc. Microfluidic devices
KR101245925B1 (ko) * 2004-09-20 2013-03-20 쓰리엠 이노베이티브 프로퍼티즈 컴파니 바이오 센싱하기 위한 시스템 및 방법과, 이를 위한마이크로 공진기 센서
WO2007008223A2 (fr) * 2004-09-20 2007-01-18 3M Innovative Properties Company Systemes et procedes de biodetection et capteurs a microresonateur a utiliser dans ceux-ci
US7257279B2 (en) 2004-09-20 2007-08-14 3M Innovative Properties Company Systems and methods for biosensing and microresonator sensors for same
WO2007008223A3 (fr) * 2004-09-20 2007-07-05 3M Innovative Properties Co Systemes et procedes de biodetection et capteurs a microresonateur a utiliser dans ceux-ci
EP2293046A1 (fr) * 2004-09-20 2011-03-09 3M Innovative Properties Co. Systèmes et procédés pour la biocapture et capteurs microrésonateurs correspondants
WO2007031152A1 (fr) * 2005-09-09 2007-03-22 Gesellschaft zur Förderung der Analytischen Wissenschaften e.V. Procede et dispositif pour produire des membranes artificielles spheriques ou tubulaires
EP2458011A1 (fr) 2005-10-03 2012-05-30 Life Technologies Corporation Compositions, procédés et kits pour l'amplification d'acides nucléiques
DE102005062723B4 (de) * 2005-12-22 2007-11-22 INSTITUT FüR MIKROTECHNIK MAINZ GMBH Probenaufarbeitungschip, Reaktionskammer und Verwendung des Probenaufarbeitungschips
DE102005062723A1 (de) * 2005-12-22 2007-07-05 INSTITUT FüR MIKROTECHNIK MAINZ GMBH Probenaufarbeitungschip, Reaktionskammer und Verwendung des Probenaufarbeitungschips
US7749365B2 (en) 2006-02-01 2010-07-06 IntegenX, Inc. Optimized sample injection structures in microfluidic separations
US7745207B2 (en) 2006-02-03 2010-06-29 IntegenX, Inc. Microfluidic devices
US7766033B2 (en) 2006-03-22 2010-08-03 The Regents Of The University Of California Multiplexed latching valves for microfluidic devices and processors
US8286665B2 (en) 2006-03-22 2012-10-16 The Regents Of The University Of California Multiplexed latching valves for microfluidic devices and processors
CN101416362B (zh) * 2006-03-29 2010-11-03 3M创新有限公司 将光耦合进微谐振器
US7532790B2 (en) 2006-03-29 2009-05-12 3M Innovative Properties Company Method of coupling light into microresonators
US7389025B2 (en) 2006-03-29 2008-06-17 3M Innovative Properties Company Coupling light into microresonators
WO2008024070A1 (fr) * 2006-08-22 2008-02-28 Agency For Science, Technology And Research Unité, dispositif et procédés de filtration microfluidique
US8841116B2 (en) 2006-10-25 2014-09-23 The Regents Of The University Of California Inline-injection microdevice and microfabricated integrated DNA analysis system using same
US8557518B2 (en) 2007-02-05 2013-10-15 Integenx Inc. Microfluidic and nanofluidic devices, systems, and applications
US8454906B2 (en) 2007-07-24 2013-06-04 The Regents Of The University Of California Microfabricated droplet generator for single molecule/cell genetic analysis in engineered monodispersed emulsions
US9005887B2 (en) 2007-11-29 2015-04-14 International Business Machines Corporation Detection of an analyte in a sample
CN101896273B (zh) * 2007-11-29 2014-10-01 国际商业机器公司 用于检测样本中的被分析物的设备和方法
WO2009069023A2 (fr) * 2007-11-29 2009-06-04 International Business Machines Corporation Appareil et procédé de détection d'un analyte dans un échantillon
CN101896273A (zh) * 2007-11-29 2010-11-24 国际商业机器公司 用于检测样本中的被分析物的设备和方法
US9594082B2 (en) 2007-11-29 2017-03-14 International Business Machines Corporation Apparatus and method for detection of an analyte in a sample
US9012136B2 (en) 2007-11-29 2015-04-21 International Business Machines Corporation Detection of an analyte in a sample
WO2009069023A3 (fr) * 2007-11-29 2009-07-16 Ibm Appareil et procédé de détection d'un analyte dans un échantillon
US8748165B2 (en) 2008-01-22 2014-06-10 Integenx Inc. Methods for generating short tandem repeat (STR) profiles
WO2009125067A1 (fr) * 2008-04-10 2009-10-15 Valtion Teknillinen Tutkimuskeskus Dispositifs à puce microfluidique et leur utilisation
US8895292B2 (en) 2008-04-10 2014-11-25 Valtion Teknillinen Tutkimuskeskus Microfluidic chip devices and their use
US20110027916A1 (en) * 2008-04-11 2011-02-03 Koninklijke Philips Electronics N.V. Detection apparatus for detecting particles
US8672532B2 (en) 2008-12-31 2014-03-18 Integenx Inc. Microfluidic methods
WO2010111509A1 (fr) 2009-03-25 2010-09-30 Life Technologies Corporation Adn témoin de discrimination positive/d'extraction
US8388908B2 (en) 2009-06-02 2013-03-05 Integenx Inc. Fluidic devices with diaphragm valves
US8562918B2 (en) 2009-06-05 2013-10-22 Integenx Inc. Universal sample preparation system and use in an integrated analysis system
US8394642B2 (en) 2009-06-05 2013-03-12 Integenx Inc. Universal sample preparation system and use in an integrated analysis system
US9012236B2 (en) 2009-06-05 2015-04-21 Integenx Inc. Universal sample preparation system and use in an integrated analysis system
US8584703B2 (en) 2009-12-01 2013-11-19 Integenx Inc. Device with diaphragm valve
US8512538B2 (en) 2010-05-28 2013-08-20 Integenx Inc. Capillary electrophoresis device
US9121058B2 (en) 2010-08-20 2015-09-01 Integenx Inc. Linear valve arrays
US9731266B2 (en) 2010-08-20 2017-08-15 Integenx Inc. Linear valve arrays
US8763642B2 (en) 2010-08-20 2014-07-01 Integenx Inc. Microfluidic devices with mechanically-sealed diaphragm valves
US11684918B2 (en) 2011-10-21 2023-06-27 IntegenX, Inc. Sample preparation, processing and analysis systems
US10865440B2 (en) 2011-10-21 2020-12-15 IntegenX, Inc. Sample preparation, processing and analysis systems
US12168798B2 (en) 2011-10-21 2024-12-17 Integenx. Inc. Sample preparation, processing and analysis systems
US10525467B2 (en) 2011-10-21 2020-01-07 Integenx Inc. Sample preparation, processing and analysis systems
US9304065B2 (en) 2012-02-29 2016-04-05 Fluidigm Corporation Methods, systems and devices for multiple single-cell capturing and processing using microfluidics
US9506845B2 (en) 2012-02-29 2016-11-29 Fluidigm Corporation Methods, systems and devices for multiple single-cell capturing and processing using microfluidics
US9952126B2 (en) 2012-02-29 2018-04-24 Fluidigm Corporation Methods for multiple single-cell capturing and processing using micro fluidics
US9429500B2 (en) 2012-02-29 2016-08-30 Fluidigm Corporation Methods, systems and devices for multiple single-cell capturing and processing using microfluidics
CN104583752A (zh) * 2012-07-13 2015-04-29 生物梅里埃公司 溶解存在于样品中的微生物、提取并提纯所述微生物的核酸以用于分析目的的自动化系统
DE102013203682A1 (de) 2013-03-05 2014-09-11 Robert Bosch Gmbh Vorrichtung zur Durchführung von chemischen und/oder biochemischen Prozessen
EP2774677A2 (fr) 2013-03-05 2014-09-10 Robert Bosch Gmbh Dispositif de réalisation de processus chimiques et/ou biochimiques
US10191071B2 (en) 2013-11-18 2019-01-29 IntegenX, Inc. Cartridges and instruments for sample analysis
US10989723B2 (en) 2013-11-18 2021-04-27 IntegenX, Inc. Cartridges and instruments for sample analysis
US11891650B2 (en) 2014-05-21 2024-02-06 IntegenX, Inc. Fluid cartridge with valve mechanism
US10961561B2 (en) 2014-05-21 2021-03-30 IntegenX, Inc. Fluidic cartridge with valve mechanism
US12152272B2 (en) 2014-05-21 2024-11-26 Integenx Inc. Fluidic cartridge with valve mechanism
US10208332B2 (en) 2014-05-21 2019-02-19 Integenx Inc. Fluidic cartridge with valve mechanism
US12099032B2 (en) 2014-10-22 2024-09-24 IntegenX, Inc. Systems and methods for sample preparation, processing and analysis
US10690627B2 (en) 2014-10-22 2020-06-23 IntegenX, Inc. Systems and methods for sample preparation, processing and analysis
US11813610B2 (en) 2018-07-09 2023-11-14 Hewlett-Packard Development Company, L.P. Microfluidic devices
US11315673B2 (en) 2018-11-30 2022-04-26 Caris Mpi, Inc. Next-generation molecular profiling
WO2020113237A1 (fr) 2018-11-30 2020-06-04 Caris Mpi, Inc. Profilage moléculaire de nouvelle génération
EP4369356A2 (fr) 2018-11-30 2024-05-15 Caris MPI, Inc. Profilage moléculaire de nouvelle génération
US12165759B2 (en) 2018-11-30 2024-12-10 Caris Mpi, Inc. Classifying an entity for FOLFOX treatment
US11842805B2 (en) 2019-12-02 2023-12-12 Caris Mpi, Inc. Pan-cancer platinum response predictor

Also Published As

Publication number Publication date
JP2003532400A (ja) 2003-11-05
AU5499201A (en) 2001-11-20
EP1280601A1 (fr) 2003-02-05
SE0001768D0 (sv) 2000-05-12

Similar Documents

Publication Publication Date Title
EP1280601A1 (fr) Dispositifs microfluidiques
Andersson et al. Micromachined flow-through filter-chamber for chemical reactions on beads
AU674685B2 (en) Fluid handling in microfabricated analytical devices
US5304487A (en) Fluid handling in mesoscale analytical devices
Andersson et al. Micromachined filter‐chamber array with passive valves for biochemical assays on beads
CN101498630B (zh) 一种样品预处理集成芯片
US7759112B2 (en) Apparatus, system, and method for purifying nucleic acids
US10596522B2 (en) Hemolysis-free blood plasma separation
US7188731B2 (en) Variable flexure-based fluid filter
EP3725409A1 (fr) Dispositif de diagnostic de microtamis dans l'isolation et l'analyse de cellules uniques
US9034196B2 (en) Microfluidic device with a filter
AU2006299414A1 (en) Microfluidic device for purifying a biological component using magnetic beads
Blattert et al. Separation of blood in microchannel bends
GB2392977A (en) A fluidic dielectrophoretic system and method for analysing biomolecules
CN110913988B (zh) 使用致动的表面附接柱来处理细胞的系统、流体盒及方法
US7220592B2 (en) Particulate processing system
JP7030361B2 (ja) 微小液滴生成装置
Malic et al. Current state of intellectual property in microfluidic nucleic acid analysis
KR100550515B1 (ko) 생체분자 필터 및 그 제조방법
CN109746058B (zh) 微液滴检测芯片
Andersson et al. Micromachined flow-through filter-chamber for solid phase DNA analysis
Cardoso et al. Micro total analysis systems
NL1040089C2 (en) Micro well plate to distribute single cells in single wells, and methods to use such plate.
NL1039638C2 (en) Diagnostic device with a filtration membrane for on spot microscopic diagnostic analysis and methods.
Archibong et al. Modular microfluidic filters based on transparent membranes

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ CZ DE DE DK DK DM DZ EC EE EE ES FI 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 NO NZ PL PT RO RU SD SE SG SI SK SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2001928128

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2001928128

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2001928128

Country of ref document: EP