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WO2014071258A1 - Dispositifs et procédés d'échantillonnage biologique pour réponse et d'analyse - Google Patents

Dispositifs et procédés d'échantillonnage biologique pour réponse et d'analyse Download PDF

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Publication number
WO2014071258A1
WO2014071258A1 PCT/US2013/068171 US2013068171W WO2014071258A1 WO 2014071258 A1 WO2014071258 A1 WO 2014071258A1 US 2013068171 W US2013068171 W US 2013068171W WO 2014071258 A1 WO2014071258 A1 WO 2014071258A1
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WO
WIPO (PCT)
Prior art keywords
cartridge
container
containers
reaction chamber
sample
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2013/068171
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English (en)
Inventor
Imran R. Malik
Erika R. GARCIA
Xiomara Linnette Madero
Axel Scherer
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California Institute of Technology
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California Institute of Technology
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Publication of WO2014071258A1 publication Critical patent/WO2014071258A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • 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
    • B01L2200/0684—Venting, avoiding backpressure, avoid gas bubbles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • 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
    • B01L2300/06—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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0864—Configuration of multiple channels and/or chambers in a single devices comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877—Flow chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0896—Nanoscaled
    • 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
    • B01L2300/12—Specific details about materials
    • B01L2300/123—Flexible; Elastomeric
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/168—Specific optical properties, e.g. reflective coatings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B01L2400/0421—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic electrophoretic flow
    • 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
    • B01L2400/0478—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure pistons
    • 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
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/0644—Valves, specific forms thereof with moving parts rotary valves
    • 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
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0633—Valves, specific forms thereof with moving parts
    • B01L2400/065—Valves, specific forms thereof with moving parts sliding valves
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1002—Reagent dispensers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1095—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices for supplying the samples to flow-through analysers
    • G01N35/1097—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices for supplying the samples to flow-through analysers characterised by the valves

Definitions

  • BIOLOGICAL SAMPLE PREPARATION DEVICES (Attorney Docket P1323-US), US Patent Application No. "INSTRUMENTS FOR BIOLOGICAL SAMPLE-TO-
  • the present disclosure relates to biomolecular analysis. More particularly, it relates to devices and methods for biological sample-to-answer and analysis.
  • a cartridge comprising: a first part, wherein the first part is transparent to electromagnetic waves of a desired wavelength range and has an inner surface defining a first surface of at least one reaction chamber; a central part, attached to the first part, wherein the central part has an inner surface defining sidewalls of the at least one reaction chamber; and a metal back plate, attached to the central part, wherein the metal back plate has an inner surface defining a second surface of the at least one reaction chamber, wherein the first part comprises: a transparent top layer configured to act as a waveguide and focus or direct electromagnetic waves onto the at least one reaction chamber; at least one prism, attached to a side of the transparent top layer and configured to focus or direct electromagnetic waves onto the transparent top layer; at least one handle; at least one opening in the transparent top layer; and at least one fluidics channel connecting the at least one opening to the at least one reaction chamber.
  • FIG. 1 depicts an exemplary sample preparation device.
  • FIG. 42 illustrates an exemplary sealing arrangement between a sample holder and a container structure.
  • FIG. 43 illustrates an exemplary sealing arrangement in details.
  • FIG. 44 illustrates some details of an embodiment of a sample-to-answer device.
  • FIG. 45 illustrates an exemplary set of cylinders which a protecting structure.
  • FIG. 46 illustrates an exemplary sample insertion attachment for pipettes.
  • FIG. 47 illustrates an exemplary embodiment of a reaction cartridge.
  • FIG. 48 illustrates a top cross sectional view of an exemplary optical analysis instrument.
  • FIG. 49 illustrates a perspective view of an exemplary optical analysis instrument.
  • FIG. 50 illustrates another perspective view of an exemplary optical analysis instrument.
  • FIG. 51 illustrates some details of an exemplary optical analysis instrument.
  • FIG. 62 illustrates an exemplary pen-shaped device.
  • FIG. 63 illustrates different fabrication methods for a reaction chamber. DETAILED DESCRIPTION
  • a portable device in the present disclosure may be able to accept a biological sample, such as blood or other human bodily fluid, and prepare the sample for further processing, for example by extracting nucleic acid or other target analyte of interest.
  • a biological sample such as blood or other human bodily fluid
  • Another portable device may also contain one or more reaction chambers, where a specific reaction can take place after the sample has been prepared in the rest of the device.
  • the device may be able to prepare a biological sample and then perform PCR.
  • a system in the present disclosure may be an automated instrument that can accept a portable device such as those described in the present disclosure. The system may be able to operate the portable device in an automatic rather than manual manner.
  • PCR Polymerase chain reaction
  • lysis comprises breaking down the cell walls or membranes, thereby causing the liberation of intracellular molecules.
  • PCR and other techniques, are often only available through the use of expensive instruments or qualified operators.
  • the systems and devices of the present disclosure can have the advantage of being portable and of being cheaper and easier to operate than more traditional realizations. These advantages can allow their use in less technological areas of the world, thereby enabling their use for disease detection, for example malaria detection.
  • the present disclosure also describes methods of operation of such devices and systems, as well as methods of fabrication for said devices.
  • FIG. 1 illustrates an embodiment of a fluidics device of the present disclosure for sample preparation.
  • a housing (105) provides a supporting structure for the various components of the device.
  • housing (105) and other components may be fabricated with transparent acrylic materials or other kinds of plastic materials.
  • a number of cylindrical structures, containers, container structures, reservoirs or cylinders (1 10) are affixed to the housing (105).
  • the cylinders (1 10) may have plungers (1 15) or other similar sealing structures that permit the movement of fluids into and out of the cylinders (1 10).
  • plungers (1 15), or other similar structures operate in a manner similar to a syringe.
  • the diameter and size of the cylinders (1 10) may be different.
  • each cylinder (1 10) may have a different function.
  • a sample may be inserted in a first cylinder (125), subsequently moved onto a lysing solution or buffer cylinder (130), then in a washing cylinder (135) and finally in an elution cylinder (120).
  • the cylinders (1 10) may contain different solutions as required by the technique being applied to the biological sample.
  • the sample container (150) may be, for example, a DNA binding matrix.
  • the sample container (150) may be connected with cylinders (1 10) through openings (155) that allow the passage of fluids.
  • the sample container (150) may be moved between the cylinders (1 10) by a horizontal sliding movement, manually or automatically operated, of a bar (160).
  • the bar (160) may be flexible, while the openings (155) are rigid. The flexibility would allow the bar (160) to slide in the housing (105) while providing a waterproof seal at each opening (155).
  • the bar (160) may be rigid, while the openings (155) are flexible.
  • the openings (155) may have O-rings. Other combinations may be used.
  • FIG. 2 illustrates a crossectional view of a bar (205) with a sealing structure (210).
  • the bar (205) may comprise, for example, an inner structure (215), such as an aluminum bar, coated with a sliding layer (220).
  • the sliding layer (220) may be Teflon tape.
  • Devices such as that of FIG. 1 may be used for sample preparation, in other words for preparing a sample for further processing.
  • a device may be used to extract or isolate DNA, proteins or other analytes, from a biological sample.
  • the analyte may be extracted in a remote location, and analyzed at a later time in a laboratory.
  • Portable instruments may also be used, which accept the prepared sample and apply further processing, for example thermal cycling for qPCR.
  • a sample may be extracted and prepared with a device such as that of FIG. 1 , and then inserted in a portable instrument which has a heater that can perform thermal cycling.
  • thermal cycling can be employed for qPCR.
  • the instrument may also have optical read-out capabilities.
  • the instrument may have a contact heater operated with a solenoid, a housing where the sample is inserted, light source and detectors, and any necessary waveguides to direct the light onto the sample. Multiple detectors may be used, for example each detector able to sense a specific wavelength.
  • the instrument may also comprise necessary electronic components for its control and operation.
  • the solenoid may be a bistable solenoid: an electric pulse may activate the solenoid, in turn moving the heater in contact with the sample cartridge. Another pulse may activate the solenoid again, thereby moving the contact heater away from the sample cartridge.
  • the devices for sample preparation may have plungers or similar operational controls which are manually activated. Such plungers or similar controls may be operated automatically by an instrument once the device is inserted into the instrument. The instrument may then have automatic means to push the plungers, for example. In some embodiments, the instrument may have pistons which are automatically controlled to push on the plungers of sample preparation devices.
  • Devices and instruments which combine sample preparation and a technique such as qPCR may be termed as sample-to-answer devices and instruments. Alternatively, the sample preparation step, and the qPCR step may be done separately. In that case, instruments and devices may be specific to sample preparation. Other instruments and devices may be specific to qPCR.
  • devices and instruments may be 'sample preparation' devices and instruments, 'qPCR' devices and instruments, or 'sample-to-answer' devices and instruments, when both 'sample preparation' and 'qPCR' are performed.
  • Other techniques may substitute qPCR, if such techniques can be effectively applied in the reaction chambers as described in the present disclosure.
  • cylinders 1 10 may have additional openings to facilitate their operation.
  • cylinder (125) illustrates a possible level for a liquid (165) introduced in the cylinder (125).
  • openings (170) and (175) may be present.
  • Opening (175) may be a vent hole, through which air can escape when a liquid is introduced.
  • Opening (170) may be a sample injection hole or port, through which a sample can be introduced.
  • a syringe or other device may be used to introduce the sample.
  • a pipette or a capillary may be used.
  • finger pricks with attached capillary and hand-operated bulb exist which let an operator draw blood and push it out of the capillary.
  • Opening (170) and (175) may be self-sealing, or have rubber caps or similar ways of closing.
  • opening (170) may be a self-healing or self-sealing injection port (septa).
  • the injection port (170) may have an integrated, or removable, adapter to allow the insertion of a pipette tip.
  • a capillary may be pre- attached to the injection port, for easier operation.
  • FIG. 3 illustrates some examples of injection ports and their operation.
  • a capillary (305) may be attached to injection port (307).
  • a liquid solution may be present at a level (315) below injection port (310).
  • Plunger (320) may be operated to contact liquid level (325) below injection port (330). In this way, the liquid cannot flow out of the injection port (330) and operation of the device can continue. For example, plunger (335) may be pushed to move the liquid (340) out of the cylinder (345).
  • FIG. 4 illustrates an exemplary sample preparation device with an additional inlet cylinder on the side.
  • cylinder (420) has an additional cylinder (405) on a side.
  • Cylinder (405) may also have a sample injection port (410).
  • a filter (415) may be present.
  • a blood sample may be introduced in cylinder (405), and blood cells may be filtered at filter (415), thereby introducing plasma in cylinder (420).
  • the plasma may then be processed by a sample preparation device or a sample-to-answer device, for example to test for malaria.
  • filters which can be attached to a syringe, they present a few disadvantages: for example, they may have a small surface area and become easily clogged.
  • An advantage of having a filter built-in into the device, such as filter (415) is that it can be fabricated with a large surface area, thereby allowing fast filtering of a biological sample.
  • FIG. 5 shows the upper half of an exemplary device.
  • Circular recesses (505) may be present where O-rings can be inserted to provide a seal when the sample container is moved between cylinders.
  • a plug-in connector (515) may be present where, for example, a custom cylinder may be inserted for specific applications.
  • a capillary may be connected to connector (515) to move the liquid sample to another device or instrument for further processing.
  • a capillary configured to be used for optical detection may be attached to connector (515). In this way, optical detection can be applied to the sample in the capillary, after processing in a sample preparation device or a sample-to-answer device.
  • a bottom view of the device also illustrates circular recesses (510).
  • FIG. 6 illustrates an exemplary side view of a sample preparation device.
  • the cylinders (605) in FIG. 6 are placed in a line, other arrangements may be possible. For example, a circular arrangement.
  • FIG. 7 illustrates an exemplary sample-to-answer device, where a sample preparation device (705), comprising several cylinders, is attached to a reaction cartridge (710).
  • Cartridge (710) may comprise, for example, a qPCR chamber, and it may be permanently attached to device (705), or may be removable.
  • the reaction cartridge (710) comprises three separate compartments or reaction chambers (715), connected by microfluidics channels (720).
  • a prism (725) may be part of the cartridge (710), to guide light onto the reaction chambers (715).
  • the prism may be made of the same material of cartridge (710) and sample preparation device (705), such as acrylic, PVC or other plastic materials.
  • FIG. 8 illustrates a top view of a sample-to-answer device, with a reaction cartridge (804) with three compartments (805).
  • FIG. 9 illustrates an exemplary sample-to-answer device.
  • the reaction cartridge (904) comprises, in this example, one reaction compartment (905).
  • a prism (915) to guide light is part of the reaction chamber (905).
  • Handles (910) are also part of the chamber (905), to facilitate handling.
  • the reaction cartridge (904), prism (915) and handles (910) may all be fabricated from the same material.
  • the cartridges of the present disclosure may have a metallic back plate attached to the acrylic, PVC, or plastic material from which the rest of the cartridge is fabricated.
  • the metallic back plate may be made of aluminum.
  • One purpose of such metallic plate is to increase thermal exchange between the solution inside a reaction chamber and an outside heater or cooler. It is known to the person skilled in the art that in some reactions, for example PCR, thermal cycling may be required. In such cases, it may be advantageous to have a material with increased thermal conductivity relative to plastic.
  • Aluminum is safe to use with PCR and is cheaper than noble metals, therefore it may be a good choice. Other metals may also be used, comprising noble metals.
  • a metallic back plate may be bonded to a reaction cartridge by, for example, the use of adhesives.
  • One method comprises using a robot to reliably apply dots of adhesives at bonding sites of the reaction chamber and/or the metallic back plate. The two sides can then be pressed together with a constant and uniform pressure.
  • the use of automated means of assembly such as through a robot, allows a high degree of repeatability and control.
  • a mask perforated in an appropriate pattern may be used, and adhesive or other bonding agent may be sprayed or squeezed through the perforated mask, thereby printing adhesive dots, or an adhesive continuous line, along a desired pattern.
  • the two sides to be bonded can then be pressed together at an appropriate pressure.
  • Such means of bonding enable an automated fabrication, suitable for lowering the price of each device and increase its deployment in areas where low cost is necessary for their establishment.
  • FIG. 10 illustrates an exemplary sample-to-answer device.
  • a sample preparation set of cylinders is visible (1005), as well as a reaction cartridge (1010).
  • Adapters (1015) may be present on both sides of the device, to allow plugging into an instrument for automatic operation of plungers, sample movement, thermal cycling and optical detection.
  • optical detection can be carried out even in the presence of the remaining liquid sample.
  • electrochemical detection can be used using patterned electrodes on a surface of the chamber, either the metal or polymer (plastic) surface.
  • the surface area can be increased by structuring the surface, for example with nanopillars, fractal shapes and other surface treatments which can increase the interaction area.
  • a plastic surface can be patterned via injection molding or other techniques. Increasing the interaction area can reduce the time for hybridization.
  • the fluid can also be made to flow multiple times through the reaction chamber to increase the chance that the relevant molecules will attach to the binding sites. Flowing the fluid sample through the reaction chamber multiple times can reduce the total reaction time.
  • the capillary as a function of its size, thus allowing detection.
  • a negative voltage can be applied to the metal base of the cartridge to repel the amplified DNA, which will then flow through an attached capillary.
  • the cartridge can thus integrate easily with capillary electrophoresis detection without the need to fabricate additional electrodes.
  • the reagents can be immobilized on a surface of the cartridge.
  • the metal surface or a part of it can aid in electrical detection due to its high metallic conductivity.
  • electrodes may be patterned on the surface to employ cyclic voltammetry.
  • the cartridges can be used to detect multiple DNA targets as required in forensics and human identification.
  • the above technique using voltage to attract DNA, can also be used to enhance hybridization and reaction speed for various techniques which use patterning on the metal surface. Changing the voltage on the surface can also help in mixing (e.g. pulling and pushing DNA) and capture/de- capture operations.
  • FIG. 1 1 illustrates a side entry port, similar to that depicted in FIG. 4.
  • a screw or mixer or screw pump element is visible (1 105), whose purpose is to push the liquid forward.
  • Element (1 105) may also facilitate the mixing of a sample introduced through the port (1 1 15), with the liquid already present in the device (1 120).
  • Element (1 1 15) may be configured to move through cylinder (1 120) when a liquid is introduced, up to an extended position (1 1 10).
  • a similar technique is used in the field of injection molding.
  • FIG. 12 illustrates an exemplary cartridge with a reaction chamber.
  • Such cartridge may be fabricated with a polymer, such as PVC, or other plastic materials, and may comprise a metal backplate.
  • the cartridge of FIG. 12 comprises an inlet port (1205) and an outlet port (1210) or vent.
  • the cartridge comprises a metal backplate (1220), bonded to the polymer side through an adhesive (1225).
  • the cartridge may also comprise handles (1230).
  • the cartridge may also comprise a prism (1235) to focus and distribute light onto the reaction chamber (1215) when an optical detection technique is carried out.
  • Inlet port (1205) may also be attached directly to a sample preparation device.
  • FIG. 10 displays an exemplary cartridge (1010) attached to a sample preparation device (1015) thereby forming a sample-to- answer device.
  • FIG. 13 illustrates several views of an exemplary cartridge.
  • a metal back plate (1330) is bonded to the polymeric part (1335) of the cartridge.
  • the prism (1335) can be spaced away from the back plate (1330) in order to decrease the total surface bonding area between the metal element (1330) and the rest of the cartridge. By having a reduced surface area, less stress is potentially applied to the cartridge, for example during a change of temperature due to different expansion coefficients.
  • a cartridge may comprise more than one prism, in order to accept optical inputs from multiple light sources.
  • the metal back plate (1330) may be coated with various substances such as glass, parylene, polyimide, silicone etc. via spray coating, thermal evaporation, sputtering, physical vapor deposition and many other processes.
  • silicone coatings can be applied to needle syringes as well. The purpose of such coatings is to increase biocompatibility of the metal surfaces, as some metals are toxic to the enzymes used as reagents in several techniques such as qPCR.
  • reflective aluminum for example manufactured by Anomet
  • Such reflective aluminum can be coated via vacuum processes and has low cost and good optical properties.
  • the polymer part of a cartridge can be molded into light-guiding structures such as lenses, concentrators etc. If the cartridge is made of COC (cyclic olefin copolymer) or COP (cyclic olefin polymer) then the optical properties of these materials can be used advantageously as required by optical techniques.
  • COC cyclic olefin copolymer
  • COP cyclic olefin polymer
  • FIG. 14 illustrates a bottom view of an exemplary cartridge with an exemplary shaded area (1405) which illustrates as a bonding area between a polymer cartridge and a metal back plate.
  • FIG. 15 illustrates an exemplary cartridge with several reaction chambers, both in perspective view (1505) and top view (1510).
  • the cartridge may comprise, for example, three reaction chambers (1515) connected by microfluidics channels (1520), and an optical prism (1525).
  • Prism (1525) may be configured to distribute, guide and/or focus light over all of the three chambers (1515) simultaneously, for optical detection applications.
  • By carefully controlling the amount of fluid introduced in a cartridge it is possible to only fill the three chambers (1515) while leaving the connecting channels (1520) empty, or filled with air. In this way, the three chambers (1515) remain separated and their content will not mix. A different reaction can therefore be applied in each of the three chambers (1515), if desired.
  • Such separation with air can be achieved in different embodiments of the cartridges of the disclosure, by using a similar principle of operation, as can be understood by the person skilled in the art.
  • FIG. 16 illustrates an exemplary cartridge with a capillary, in cross sectional view.
  • the cartridge comprises a polymer part (1605) and a metal back plate (1610).
  • the outlet is linked to a capillary (1615).
  • the capillary's function has been described above in the present disclosure, and comprises, for example, flowing the liquid sample from a cartridge to another container, or even performing detection techniques through the capillary, such as capillary electrophoresis.
  • a positive voltage may be applied at the capillary (1620), and a negative voltage may be applied to the metal plate (1610).
  • DNA may be attracted by the voltage difference, flowing in the capillary (1615) with different speed depending on the size of the DNA.
  • different DNA parts may be spaced along the capillary (1615) through the voltage difference.
  • the presence or absence of the target analyte at the reagent sites (1715) can be detected, through the evanescent field (1725) of light rays (1720).
  • a voltage may also be applied at plate (1710), for example to attract the target analyte inside the reaction chamber through an inlet port.
  • FIG. 18 illustrates the exemplary cartridge of FIG. 17, with fluid (1805) present in the reaction chamber.
  • FIG. 19 illustrates another embodiment of detection based on total internal reflection, with reagent sites (1905) and evanescent waves (1910), where the reagent sites (1905) are placed on the bottom of a cartridge, on the metal plate (1920) side.
  • the metal plate (1920) may be coated with a transparent coating (1915) acting as a waveguide to allow the total internal reflection of light (1925).
  • FIG. 20 illustrates an exemplary cartridge with a fitted metal plate connection.
  • a cartridge comprises a polymer side (2005) and a metal plate (2010), where the polymer side (2005) is fabricated so as to have a snap-on shape which fits the metal plate (2010). In such a way, less adhesive or even no adhesive may be necessary to bond the polymer side (2005) with the metal side (2010).
  • FIG. 21 illustrates an exemplary method of fabrication for a curing an adhesive while protecting reagents applied to a surface inside a reaction chamber.
  • a cartridge comprising a polymer side (2102) and a metal plate (2103) has a layer of coated reagents (2120) inside the reaction chamber (2104).
  • light rays (2125) need to be directed at the adhesive (21 15).
  • a mask (2105) supported by a transparent plate (21 10) may be used to block certain rays while allowing other rays to cure the adhesive (21 15).
  • FIG. 22 illustrates an exemplary reaction chamber with inlet and outlet or vent ports.
  • a reaction cartridge may comprise a reaction chamber (2205) connected through microfluidics channels (2210) to an inlet port (2215) and an outlet port or vent port (2220).
  • Such ports (2215, 2220) may be placed on the same side of a cartridge for ease of access.
  • FIG. 23 illustrates a circular embodiment of a cartridge with several reaction chambers or reservoirs.
  • a circular structure or cartridge (2305) may comprise several chambers or reservoirs able to contain liquid samples, for example four chambers (2310).
  • Light rays (2315), originating from a light source, may be directed at one of the chambers (2310).
  • the circular cartridge (2305) may be configured so as to allow internal reflection of light rays (2320) so that a single light source can illuminate all the chambers (2310).
  • the circular structure (2305) may rotate in order to illuminate one at a time each of the chambers (2310).
  • an inlet port (2325) connects to the chambers (2310) through channels (2330).
  • FIG. 24 illustrates an exemplary circular sample-to-answer device.
  • An arrangement of cylinders (2405) or other similar container structures can be arranged in a circular manner. This arrangement may have the advantage of having a compact shape.
  • the structures (2405) may have different shape or size, depending on the specific application.
  • an elution structure (2410) may have a smaller volume as often the elution requires a smaller volume of liquid as it will be understood by the person skilled in the art.
  • a cartridge (2415) is also present, for example for PCR techniques.
  • the different components of the device of FIG. 24 can be similar as to those previously described in the present disclosure, with a difference being the circular arrangement visible in FIG. 24.
  • FIG. 25 illustrates a side view of the device of FIG. 24.
  • the device of FIG. 25 comprises a top set of cylinders (2505), a bottom set of cylinders (2515), and a central disk (2510) connecting the top (2505) and bottom (2515) set of cylinders.
  • FIG. 26 illustrates a top view of the device of FIG. 24.
  • a set of cylinders (2605) is visible, as well as a cartridge (2610), the cartridge (2610) comprising a reaction chamber (2615) and a prism (2620).
  • FIG. 27 illustrates a bottom perspective view of the device of FIG. 24.
  • a set of cylinders (2705) is visible, as well as a cartridge (2710).
  • a cartridge (2710).
  • different thin films can be used as heaters.
  • laminates like DuPont Pyralux APR embedded resistor laminate
  • they can be bonded to a metallic surface using thin dry film adhesives, for example as those used in the printed circuit board industry as understood by the person skilled in the art.
  • a temperature sensor can also be deposited, for example on a kapton laminate.
  • the temperature sensor can be made, for example, with deposited platinum, copper, nickel or other metals.
  • the heater can be a part of metal plate, without comprising any polymer, in order to have increased total thermal conductivity.
  • the base of a heater is metallic (for example, aluminum or copper) then one side of the metal can be anodized, to render it electrically insulating. Si0 2 or other insulating coatings can also be applied.
  • a nichrome heater could be deposited as a heating element, while copper tracks can be deposited as contacts.
  • current can be passed through a metallic element to increase its temperature, in order to act as a heater.
  • FIG. 30 illustrates an exemplary connecting disk of a circular device.
  • Such connecting disk may correspond, for example, to element (2510) in FIG. 25.
  • the connecting disk structure (3005) is configured so as to slide horizontally, or move relative to the rest of a device.
  • a set of apertures (3010) are visible which correspond to apertures in the containing structures of the device, for example cylinders (2910) of FIG. 29.
  • apertures (2925) can be connected by a connecting channel in the connecting disk, such as channel (3015) in FIG. 30.
  • FIG. 30 the center (3025) of a device is shown to exemplify a movement of disk (3005).
  • disk (3035) which corresponds to disk (3005) before the movement, is moved in the direction indicated by arrow (3030).
  • Disk (3035) is then now translated horizontally relative to the apertures in the containing structures which are located, for example, in a circular pattern (3040).
  • Channel (3045), corresponding to channel (3015) before movement of disk (3005) is now connecting two adjacent apertures (3050).
  • Disk (3005) may be moved by a variety of means, for example by a handle on a side of the disk, or by a rod attached to the bottom of the disk.
  • a rod (3105) may be attached to the center of a disk (31 10).
  • a slot (31 15) for a sample holder (such as a DNA membrane) is visible.
  • the structure is shown in perspective view (3120) as well as side view (3125).
  • a zoomed in view of slot (31 15) is illustrated.
  • Slot (31 15) is configured to hold a sample holder in a stable position, while allowing movement of fluid in and out of the sample holder as desired.
  • Rod (3105) may be rotated or moved in the horizontal plane of the connecting disk (31 10).
  • Slot (31 15) may have a countersink shape to facilitate holding of the sample container, such as the DNA membrane.
  • nucleic acid sample preparation is a highly labor intensive and time consuming process requiring multiple steps to collect DNA and/or RNA from biological materials such as whole blood, blood serum, buffy coat, urine, feces, semen, saliva, sputum, nasopharyngeal aspirate, spinal fluid, and tissue from biopsies.
  • Nucleic acid isolated from said biological materials can also comprise the endogenous nucleic acid from the organism from which the sample is derived and any foreign (viral, fungal, bacterial or parasitic) nucleic acid.
  • nucleic acid is essential to a wide variety of biotech, research, forensic, and clinical applications. These procedures can consume considerable time, labor and costly materials. In order to ensure easy and inexpensive point-of-care diagnostics, it would be advantageous if little or no sample preprocessing at the bench were required.
  • the devices of the present disclosure can simplify sample preparation by combining all of the complex protocols of DNA and/or RNA extraction into just a few steps.
  • the steps for isolating nucleic acid from biological materials comprise (1) take in the biological sample via the sample input port; (2) mix sample with lysis buffer and lyse the nuclei acid-containing cells, tissue, etc.; (3) bind nucleic acid to porous nucleic acid binding membrane; (4) remove contaminants with wash buffer; (5) air dry; and (6) elute nucleic acid in buffer or water. Concentration and purification of nucleic acid can makes each sample ready for downstream molecular diagnostic testing with yields comparable to industry- standard methods.
  • the bar or disk can be fitted with nucleic acid binding membranes from various types of commercially available DNA/R A extraction kits, thus allowing the fluidic cartridge to extract from a wide range of source comprising: Human genomic DNA from blood, saliva, or semen; DNA and RNA from bacteria such as Staphylococcus aureus and Streptococcus pyrogenes; DNA and RNA from blood-borne microbes such as B. anthracis; Microbial DNA in culture, urine and more for such microbes as B. anthracis, Adenovirus, and E. coli; Viral RNA in culture, urine and more for Herpes Virus I, and Chlamydia trachomatis; Influenza A and B from nasal aspirate and respiratory swab samples in viral transport media.
  • DNA/R A extraction kits thus allowing the fluidic cartridge to extract from a wide range of source comprising: Human genomic DNA from blood, saliva, or semen; DNA and RNA from bacteria such as Staphylococcus aureus and
  • the sample preparation cartridge's flexible protocol can work with chaotropic salt chemistry and can be designed to handle a range of sample volumes, for example in the range 50 J.LL - 10 mL). Additionally, in order to work directly with human whole blood samples, whole blood filters can be incorporate into the device.
  • the bar can move to the next set of ports to perform an air drying step.
  • air can be aspirated through the nucleic acid binding membrane and dry the membrane.
  • a heating element can also be incorporated to help dry the membrane faster and evaporate off any residual wash buffer.
  • FIG. 32 illustrates an exploded view of an exemplary circular sample-to-answer device, comprising a top set of containers (3205), a connecting disk (3210), a bottom set of containers (3215) and a reaction cartridge (3220).
  • FIG. 34 illustrates different possible features of container structures.
  • a container (3405) may be used for the sample, lysate or mixture.
  • Containers (3410) and (3415) may be for different washes.
  • Container (3420) may be for elution.
  • the bottom containers may have air-permeable membranes (3425), elastic pistons (3430) or flexible reservoirs (3435).
  • reservoirs (3435) may be flexible and may be squeezed by hand, similarly to a rubber balloon.
  • the air-permeable membranes (3425) may be useful for drying as the membranes (3425) can allow air through, but not fluids or DNA.
  • hot air can be directed onto the air-permeable membranes (3425) in order to dry the content of a container.
  • the elastic pistons (3430) may comprise a spring attached to a seal. As fluid is inserted in a container, the spring is pushed back, and when pressure is not applied against it anymore, the spring will push back against the fluid in the container, thereby enabling its movement thanks to the elastic energy stored in the spring of the elastic piston (3430).
  • Container structures of the devices of the present disclosure may be used, for example, for homogenization, lysis, filtration, mixing, ultrasonic lysis, debubbling, or protein filtering. The containers may also be empty.
  • the sliding bars or connecting disks as described in the present disclosure may house elements which can perform different functions other than holding a sample.
  • FIG. 35 illustrates different possible elements of a sliding bar.
  • Different sample holders may be used (3505), for example different membranes.
  • Filters, mixers or homogenizers (3507) may also be used, or even empty channels (3510) to connect different containers of a device and allow the movement of fluids between the container structures.
  • a first container (3605) maybe used, for example, to insert a fluid in a second container (3610).
  • ethanol may be used to enhance binding.
  • the second container (3610) may also be filled with ethanol or other fluid.
  • FIG. 37 illustrates an embodiment of a sample insertion container for the sample- preparation or sample-to-answer devices of the present disclosure.
  • a side container may house a grinder element (3710).
  • This grinder element (3710) may be used to grind solid samples, or liquid samples which container solid particles or semi-solid parts.
  • the grinder element (3710) may be operated, for example, by rotating a handle (3715).
  • the side container (3705) comprises a sample insertion port (3720) and may comprise a filtering element (3725), for example an element with a sharp teethed structure which can aid in grinding or mixing a sample.
  • FIG. 38 illustrates an exemplary operation of a sample preparation device.
  • a lysate, sample or mixture may be moved from one container (3805) to the opposite one (3810), with the fluid flowing through a DNA membrane (3815).
  • Another functional element (3820) may be present, for example a filter, mixer, or lysing element, configured to work with a lysing technique, such as electric, magnetic, mechanical, or ultrasonic lysing.
  • a sample may be moved from a container (3825) to the opposite one (3830) through an empty channel opening (3840), while the DNA membrane (3835) has been rotated to a different position.
  • Other containers (3845) may contain, for example, a washing solution, as understood by the person skilled in the art.
  • FIG. 39 illustrates an elution process, where the fluid, after previous processing in the sample preparation device, undergoes elution and is moved from one container (3905) to the opposite one (3910).
  • FIG. 41 illustrates an exemplary sample-to-answer device configured for capillary electrophoresis.
  • a capillary (4105) attached to a capillary electrophoresis instrument (41 10) enables the separation of biological species through a voltage difference, as it is known to the person skilled in the art.
  • a hybridization chamber (41 15) is also visible.
  • a container (4120) can be configured to be used as a pump to move a fluid to a capillary electrophoresis buffer or a wash buffer for hybridization.
  • FIG. 43 illustrates an exemplary sealing arrangement in details.
  • Container structures (4305) are partially visible.
  • a sealing element (4310), such as a rubber ring, is shown as detached for clarity.
  • Slots (4315) correspond to the sealing element shape for better sealing.
  • FIG. 44 illustrates some details of an embodiment of a sample-to-answer device.
  • An elution container (4405) which may be part of a sample-to-answer device as described above in the present disclosure, can be tied, in this embodiment, to an additional container (4410), so that they are both operated simultaneously.
  • the two containers (4405, 4410) may be operated by a single plunger (4415). If the volumes of the two containers (4405, 4410) is accurately measured, then it is possible to determine and configure a desired ratio between the fluids contained in both containers (4405, 4410). For example, in certain reactions it is necessary to arrange a precise ratio of solutions to be mixed in order for the reaction to be optimized. By determining the ratio of the volumes of containers (4405, 4410), their solutions can be mixed in a desired ratio.
  • Elution container (4405) may move its liquid through a sample holder, such as a DNA membrane (4420). Subsequently, the fluids of containers (4405, 4410) can be mixed in a mixer (4425).
  • Mixer (4425) may be fabricated in different ways. For example, it may consist of two microfluidics channels. It is known in the art that the flow of liquids in microfluidics channels is often laminar. Therefore, two liquids may flow parallel to each other, in contact but actually without any mixing taking place.
  • Mixer (4425) may be configured, for example, to allow some turbulence in the flow in order for the liquids from containers (4405, 4410) to mix.
  • the reagents comprise a Master Mix comprising enzymes, fluorescent dyes, oligonucleotides etc.
  • a PCR Master Mix is a premixed, ready-to-use solution comprising, for example, Taq DNA polymerase, MgCl 2 and reaction buffers at optimal concentrations for the efficient amplification of DNA templates.
  • the reaction cartridge has a metal back plate, as described previously in the present disclosure.
  • a metal back plate is illustrated (4710).
  • FIG. 49 illustrates a perspective view of an exemplary optical analysis instrument, such as a qPCR instrument. Elements in FIG. 49 retain the same significance as those similarly numbered in FIG. 48.
  • FIG. 52 illustrates one embodiment of a cartridge housing (5205), configured to accept and hold a cartridge (5210), in order to insert the cartridge and housing in an instrument, such as the optical analysis instrument of FIG. 50.
  • FIG. 54 illustrates an exemplary sample preparation instrument (5400).
  • the sample preparation instrument (5400) can accept linear sample preparation devices, such as device (5405), however in other embodiments a sample preparation instrument may accept circular sample preparation devices. Other shapes may also be used.
  • the motorized structure of FIG. 55 comprises a motor (5505) for circular movement of a supporting structure (5510).
  • a linear actuator (5515) can be attached to the supporting structure (5510), so that motor (5505) can rotate and align the linear actuator (5515) with the desired container (5520).
  • the linear actuator (5515) can then be activated to operate a plunger (5525) or similar structure used to move fluid in the container (5520).
  • a similar motorized structure as that of FIG. 55 can be used for a sample preparation device.
  • a heater (5530) is also illustrated on the external surface of container (5520).
  • FIG. 57 illustrates some components of a sample-to-answer instrument.
  • the instrument in FIG. 57 may comprise a motor (5705) and linear actuator (5710) to operate the plungers (5715) of a sample-to-answer device (5720).
  • a sample-to-answer device as described in the present disclosure, comprises a reaction chamber (5725).
  • the sample-to-answer instrument may comprise a solenoid (5730) which can operate a moving plate (5735), similarly to the optical analysis instrument as illustrated in FIG. 49.
  • the sample-to-answer instrument may comprise an optical element (5740).
  • Element (5740) may comprise, for example, an integrated LED light source, a lens and an optical excitation filter.
  • a waveguide (5745) may guide electromagnetic rays onto the prism of reaction chamber (5725).
  • FIG. 58 illustrates some details of the sample-to-answer instrument of FIG. 57.
  • an instrument can comprise a reaction chamber (5805), an optical element (5810) and a waveguide (5815).
  • FIG. 59 illustrates an alternative view of the instrument of FIG. 57.
  • an instrument can comprise a reaction chamber (5905), an optical element (5910) and a waveguide (5915).
  • FIG. 60 illustrates a top view of the instrument of FIG. 57.
  • an instrument can comprise a reaction chamber (6005), an optical element (6010) and a waveguide (6015).
  • an optical structure may comprise an LED light source (6105), as well as a lens and excitation filter element (61 10).
  • elements (6105) and (61 10) may be molded in a single piece.
  • the optical elements of, for example, FIG. 57, together with the motorized parts of, for example, FIG. 57, may be encased in a box with the necessary electronic control elements and interface elements (such as a touchscreen), for a sample-to- answer instrument.
  • Such additional components are illustrated, for example, in FIGS. 49 and 54 for other instruments.
  • a sample preparation instrument comprises the motors and actuators; the sample-to-answer instrument comprises motors, actuators and optical elements; the optical analysis instrument comprises the optical elements.
  • the electronic components of the instruments of the present disclosure may comprise, for example, a microcontroller, such as an ARM, LPC1768, memory, a solenoid interface, such as A4950, heater drivers (such as MOSFETs), USB, Ethernet, Bluetooth, Wireless or other communication interfaces, motion control sensors to operate plates in contact with a reaction cartridge or to operate motors and actuators for the plungers, for example ST L6470, a resistance temperature detector (RTD) interface, such as MAX31866, an interface such as MAX31865, a photodiode interface, such as DDC1 14, and LED drivers such as CAT4109 or CAT4101.
  • the instruments may be controlled, for example through a smartphone, tablet or other portable computing devices and computers.
  • a portable device for sample preparation or sample-to-answer may be fabricated in the shape of a pen. Such device may be highly integrated with different manual or automatic components.
  • FIG. 62 illustrates an exemplary pen-shaped device, in an exploded schematic view.
  • the device of FIG. 62 may comprise a series of buttons (6205), for example arranged in a circular pattern on the top of a supporting structure shaped like a pen (6210).
  • the buttons (6205) may manually operate plungers (6215) in containers (6220).
  • the buttons (6205) may activate miniaturized motors or actuators (6225) which can in turn operate on the plungers (6215) automatically.
  • the containers (6220) may be connected to a disk (6230), which may host a sample holder such as a DNA membrane (6235).
  • the disk (6230) may also comprise functional elements, such as miniaturized filters or mixers (6240). Additional containers may be housed under the disk (6230), for example waste containers (6245).
  • Such containers may receive the waste or intermediary products through openings in the disk (6230).
  • One or more reaction chambers (6250) may be also contained in the pen-shaped device (6210).
  • the device may also comprise a needle (6255), which may be connected to a reservoir (6260). Through the needle (6255), samples may be collected, for example blood samples.
  • the needle (6255) may be retractable, or may be fixed in the place at the tip of the pen-shaped device (6210). In some embodiments, different needles may be present, and they can in turn be extended through a bottom opening structure (6265) either manually or through miniaturized motors.
  • the sample collected through the needle (6255) may be transferred to containers at the top of the device, such as the container (6220), for the necessary processing.
  • the elution container may comprise a needle injector, to facilitate the transfer of the fluid into an external reaction chamber.
  • the elution container may be configured with a capillary to extract a fluid.
  • a capillary may be attached to the reaction chamber to remove the target analyte from the chamber.
  • the capillary may be configured to perform capillary electrophoresis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne des procédés et des dispositifs de préparation et d'analyse d'échantillons biologiques. Un dispositif peut comporter un agencement linéaire ou circulaire de récipients, avec une structure de raccordement telle qu'une barre ou un disque. Des canaux fluidiques ménagés entre des récipients permettent d'exécuter différentes techniques de préparation d'échantillons, telles que la lyse, le lavage et l'élution. Différents éléments fonctionnels, tels que des meules ou des mélangeurs, peuvent être fixés aux récipients. Le dispositif peut comprendre une cartouche de réaction munie d'une chambre de réaction pour exécuter des techniques telles qu'une réaction en chaîne par polymérase.
PCT/US2013/068171 2012-11-05 2013-11-01 Dispositifs et procédés d'échantillonnage biologique pour réponse et d'analyse Ceased WO2014071258A1 (fr)

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US9518291B2 (en) 2011-12-23 2016-12-13 California Institute Of Technology Devices and methods for biological sample-to-answer and analysis
WO2016207721A1 (fr) * 2015-06-25 2016-12-29 University Of Limerick Dispositif mécanique de production de bibliothèque combinatoire
US9561505B2 (en) 2011-12-23 2017-02-07 California Institute Of Technology Sample preparation devices and systems

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US9518291B2 (en) 2011-12-23 2016-12-13 California Institute Of Technology Devices and methods for biological sample-to-answer and analysis
US9561505B2 (en) 2011-12-23 2017-02-07 California Institute Of Technology Sample preparation devices and systems
US9284520B2 (en) 2012-11-05 2016-03-15 California Institute Of Technology Instruments for biological sample preparation devices
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WO2016207721A1 (fr) * 2015-06-25 2016-12-29 University Of Limerick Dispositif mécanique de production de bibliothèque combinatoire
EP3587629A1 (fr) * 2015-06-25 2020-01-01 Hooke Bio Limited Procédé pour la génération de bibliothèques combinatoires

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