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
  • G01N1/38—Diluting, dispersing or mixing samples
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
  • B01F33/30—Micromixers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
  • B01F35/80—Forming a predetermined ratio of the substances to be mixed
  • B01F35/88—Forming a predetermined ratio of the substances to be mixed by feeding the materials batchwise
  • B01F35/882—Forming a predetermined ratio of the substances to be mixed by feeding the materials batchwise using measuring chambers, e.g. volumetric pumps, for feeding the substances
  • B01F35/8823—Forming a predetermined ratio of the substances to be mixed by feeding the materials batchwise using measuring chambers, e.g. volumetric pumps, for feeding the substances using diaphragms or bellows
• • 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
  • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C69/00—Combinations of shaping techniques not provided for in a single one of main groups B29C39/00 - B29C67/00, e.g. associations of moulding and joining techniques; Apparatus therefore
• • 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
• • 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
  • B01L2200/0621—Control of the sequence of chambers filled or emptied
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0809—Geometry, shape and general structure rectangular shaped
  • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
  • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
• • 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
  • B01L2300/0887—Laminated structure
• • 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
  • 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
  • B01L2400/0481—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure squeezing of channels or chambers
• • 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
  • B01L2400/0655—Valves, specific forms thereof with moving parts pinch valves
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
  • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
  • B29C51/00—Shaping by thermoforming, i.e. shaping sheets or sheet like preforms after heating, e.g. shaping sheets in matched moulds or by deep-drawing; Apparatus therefor
  • B29C51/08—Deep drawing or matched-mould forming, i.e. using mechanical means only
  • B29C51/082—Deep drawing or matched-mould forming, i.e. using mechanical means only by shaping between complementary mould parts
• • 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
  • G01N1/38—Diluting, dispersing or mixing samples
  • G01N2001/381—Diluting, dispersing or mixing samples by membrane diffusion; Permeation tubes

Definitions

• test kits marketed based on this method still require a lot of handling (pipetting, mixing) and require a significant technique which inevitably favors the risks inherent in human error. Collecting the data and calculating to get a result is also a limiting factor for users looking for specific performance.
• the subject of the invention is a system for diluting a sample of biological material comprising a fluid circuit, characterized in that said fluid circuit of the dilution system comprises at least: a first container configured to contain a sample of biological material containing a biological material to be diluted, the sample being a fluid, a second container configured to contain a first dilution fluid, the first container and the second container being fluidly connected by at least one fluid path, at least a first metering member for a determined volume of fluid comprising a first wall and a second wall, the first metering member comprising a metering zone configured to pass at least from an initial state in which the first wall and the second wall are in contact with each other in an operating state in which the first wall and the second wall are spaced apart from each other so re to delimit a determined dosing volume, the dosing zone reaching the operating state by conveying the sample and / or a dilution fluid in the dosing zone, the first dosing member being arranged on
• the first metering member allows precise and rapid isolation of a fluid to be diluted / or diluted, and this, in a reproducible manner, the walls of the metering member deviate from one another only. when the fluid to be dosed is fed into the dosing unit.
• the metering zone of the metering member remains in a stable position (operating state) and guarantees a reproducible volume without excess pressure on the upstream container.
• the absence of air in the dosing zone in the initial state and therefore in the operating state also implies the absence of bubbles in the downstream dilution system, which is very advantageous.
• the fluidic circuit is produced by laser welding or thermal welding or ultrasonic welding, of the films making up the device in the form of a flexible bag.
• the metering zone is delimited by a weld of the walls of the metering member at its periphery. Welding allows circumscribe the fluid within the dosing zone and obtain a reproducible volume.
• the dilution system comprises at least a first mixing chamber configured to contain a first fluid mixture formed by the mixture of a part of the sample and at least a part of the first fluid. dilution, the first mixing chamber being fluidly connected to the first container and to the second container.
• the dilution system comprises a second metering member arranged upstream of the second mixing chamber, and preferably between the second mixing chamber and the third container.
• the second metering member is identical to the first metering member in its operation.
• the second metering member comprises at least one fluid outlet opening directly into the second mixing chamber.
• each fluid outlet from the second metering member is in the initial state of the metering zone of the second metering member, hermetically closed by a fragile valve, said fragile valve being configured to be open, preferably irreversibly, by the pressure of the fluid contained towards the second mixing chamber.
• the first metering member has, for example, a volume of IOmI by which IOmI of sample is taken from the first container, which is poured into the first mixing chamber. Then, 90mI of first dilution fluid is taken from the second container which is poured into the first mixing chamber containing the 10mI of sample.
• the reaction chamber comprises a plurality of wells configured to accommodate at least one reagent.
• the device is configured to cooperate with a first plurality of mechanical valves positioned upstream of the fragile valves of the first metering member.
• Each mechanical valve of the first plurality is placed at a fluid inlet or outlet of the first metering member and is configured to allow / disallow fluid to enter the first metering member or to allow / disallow fluid to exit the first. dosing unit.
• a first mechanical valve positioned at a fluid inlet of the first metering member is coupled to a mechanical valve positioned at the fluid outlet of the first metering member.
• the device is configured to cooperate with a second plurality of mechanical valves positioned upstream of the fragile valves of the second metering member.
• Each mechanical valve of the second plurality is placed at a fluid inlet or outlet of the second metering member and is configured to allow / prohibit a fluid from entering the second metering member or to allow / prohibit a fluid from exiting the second metering member.
• second metering device the fragile valves of the dilution system are arranged transversely to a fluidic channel so as to allow or prohibit the circulation of a fluid in said channel.
• a characteristic “pop” noise occurs, which is linked to the separation of the walls of the metering member and to the deformation of the concavity of one of them in the other direction.
• the term “dilution fluid” is understood to mean a fluid, preferably a liquid, which allows a dilution of a substance by its addition to said substance.
• biological material is understood to mean any material containing biological information.
• the term “weld” is understood to mean a definitive welding of the films making it possible to limit the circulation of the fluid and to circumscribe it in the fluid circuit thus created.
• the “welding” can be carried out by laser, heat welding or any other process making it possible to obtain an equivalent result.
• FIG. 3A is a diagram illustrating a third configuration of the dilution system according to the invention.
• FIG. 27 illustrates the fluidic link between the sample container and the reaction chamber of the device according to the invention
• the dilution system comprises a second metering member 17.
• the dilution system 1 comprises a third container 13 configured to contain a second dilution fluid Fd2.
• the second metering member 17 is arranged on the fluid path connecting the first mixing chamber 14 and the third container 13 and in particular, the second metering member 17 is arranged between the first mixing chamber 14 and the third container 13 .
• the second mixing chamber 15 comprises a fluid inlet through which the first fluid mixture Fml and the second dilution fluid Fd2 enter and at least one fluid outlet through which a second fluid mixture Fm2 (not shown) comes out.
• the first metering member 16 and the second metering member 17 are fluidly connected to each other in a direct manner.
• the first metering member 16 which is the only metering member of the dilution system 1, comprises a first fluid inlet connected to the first container 11, a second fluid inlet connected to the second containing 12, a third fluid inlet connected to the third container 13, a fourth fluid inlet connected to the first mixing chamber 14 which also acts as the first fluid outlet, and a second fluid outlet connected to the second mixing chamber 15.
• the dilution system 1 When the device 100 is used for the first time, the dilution system 1 has not yet been used and the metering zones of the first metering member 16 and of the second metering member 17 are in the initial state and all the valves are fragile. are hermetically sealed, as illustrated in FIG. 4.
• the first plurality of valves V1 to V3, the second plurality of mechanical valves V4 to V6 and the third plurality of mechanical valves V7 to V9 are closed and positioned, as shown in figure 8.
• the mechanical valve V3 is opened so that the first dosed dilution fluid Fdl pours into the first mixing chamber 14 already containing the dosed sample Fe, the mixture obtained forming the first mixture of Fml fluid as illustrated in FIG. 18.
• the steps of reinitializing the first metering member 16 and metering the first dilution fluid Fdl being carried out as many times as necessary depending on the required dilution rate.
• the mechanical valves V5 and V6 are open even though the second metering member 17 still contains the first mixture of fluid Fml, the mechanical valve V4 being closed.
• a back-and-forth movement is then carried out between the second dilution fluid Fd2 contained in the third container 13, the second metering member 17 and the second mixing chamber 15 so as to mix the second dilution fluid Fd2 with the first mixture of Fml fluid dosed in order to obtain a second mixture of Fm2 fluid.
• the mechanical valve V6 positioned at the fluid outlet 17c from the second metering member 17 is open so that the first fluid mixture Fml is poured into the second mixing chamber 15, the mechanical valves V4 and V5 being closed, as illustrated in FIG. 21.
• the mechanical valve V5 positioned at the second fluid inlet 17b of the second metering member 17 is opened.
• the mechanical valve V6 being open and the mechanical valve V4 being closed, and the reciprocating operation is carried out as illustrated in FIG. 22 and explained according to the first operating mode above.
• the mechanical valves V5 and V6 are closed, as illustrated in FIG. 23.
• the first mixing chamber 14 comprises a second fluid outlet connected directly to the reaction chamber 103 via a channel 22.
• a valve V8 isolates the channel 22 when the latter is not in use.
• a part of the first fluid mixture Fml, which is conveyed via the fluidic channel 22, as illustrated in FIG. 28, is also collected in one or more rows 104 of dedicated wells. These collections can be performed during the dilution process or after the dilution process.
• the method of manufacturing the device 100 according to the invention will now be described with reference to FIGS. 30 to 35.
• the manufacturing method described is valid regardless of the configuration of the dilution system integrated in the device according to the invention.
• the deformation of the pocket 100 is carried out by sinking by an external deformation element 203 which is a protruding lug with respect to the surface of the cavity 202a of the second mold part 202.
• the shape of the protruding lug 203 is adapted to the shape of the metering member 16, 17 that is to be created, for example the protruding lug is in the form of a ball, at least one hemispherical portion of which protrudes from the second mold part 202 as illustrated in particular in Figures 30 to 32.
• each metering member 16, 17 is produced by external deformation by an external deformation element 203 dedicated as this can be seen in FIG. 32.
• an external deformation element 203 dedicated as this can be seen in FIG. 32.
• two projecting lugs 203 are positioned, preferably in the shape of a ball. These lugs are arranged so that, when the bag is inserted into the mold, each one finds itself facing a deformation zone D to create one metering member each.
• the first mold part 201 comprises counterforms in its mold cavity 201a in order to accompany the deformation of the deformation zone D.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Analytical Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Biochemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pathology (AREA)
• Immunology (AREA)
• General Physics & Mathematics (AREA)
• Physics & Mathematics (AREA)
• Mechanical Engineering (AREA)
• Dispersion Chemistry (AREA)
• Clinical Laboratory Science (AREA)
• Engineering & Computer Science (AREA)
• Hematology (AREA)
• Sampling And Sample Adjustment (AREA)
• Automatic Analysis And Handling Materials Therefor (AREA)
• Accessories For Mixers (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=69468806

Family Applications (1)

Country Status (7)

Families Citing this family (1)

Family Cites Families (13)

• 2019
  • 2019-10-29 FR FR1912110A patent/FR3102558B1/fr active Active
• 2020
  • 2020-10-27 EP EP20817445.8A patent/EP4052013A1/de active Pending
  • 2020-10-27 US US17/769,461 patent/US20240125680A1/en active Pending
  • 2020-10-27 WO PCT/FR2020/000254 patent/WO2021084167A1/fr not_active Ceased
  • 2020-10-27 JP JP2022524187A patent/JP7695238B2/ja active Active
  • 2020-10-27 KR KR1020227017707A patent/KR20220085828A/ko active Pending
  • 2020-10-27 CN CN202080075896.3A patent/CN114729860A/zh active Pending

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