EP4173708A1 - Élément microfluidique, en particulier cellule d'écoulement, avec réactifsec intégré - Google Patents
Élément microfluidique, en particulier cellule d'écoulement, avec réactifsec intégré Download PDFInfo
- Publication number
- EP4173708A1 EP4173708A1 EP21205300.3A EP21205300A EP4173708A1 EP 4173708 A1 EP4173708 A1 EP 4173708A1 EP 21205300 A EP21205300 A EP 21205300A EP 4173708 A1 EP4173708 A1 EP 4173708A1
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- end section
- microfluidic element
- liquid
- pressure
- dry reagent
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Images
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Definitions
- the invention relates to a microfluidic element, in particular a flow cell, for processing a quantity of liquid to be transported in a channel area of the microfluidic element, which quantity comes into contact with a dry reagent integrated into the microfluidic element.
- the invention further relates to a method for producing such a microfluidic element, a combination of such a microfluidic element with operating devices and a method for operating such a microfluidic element.
- microfluidic elements in particular flow cells, are increasingly being used in the life sciences for analysis and/or synthesis.
- flow cells with cavity structures comprising channels and chambers, very small volumes of fluid can be transported and processed, e.g. amounts of liquid less than 10 ⁇ l.
- a particular problem in the production of microfluidic elements is the integration of dry reagents, which must be reconciled with further production steps. Subsequent welding and gluing processes in particular can have a significant impact on dry reagents that have already been introduced.
- the invention is based on the object of creating a new microfluidic element of the type mentioned at the outset, which requires a further reduced production outlay.
- microfluidic element that achieves this object according to the invention is characterized in that the dry reagent is arranged in an end section of the channel area that is open to the outside.
- this inventive solution allows a dry reagent to be introduced into the microfluidic element in a final production step without being adversely affected by production steps such as gluing or welding, with the end section open to the outside for receiving a liquid reagent being accessible by pipetting or immersion and the liquid near the opening drying quickly can.
- the amount of liquid e.g the quantity of liquid has a further outwardly open end section which is in fluid communication with the end section containing the dry reagent.
- the amount of fluid can be transferred by means of pneumatic pressure to the end section containing the dry reagent, where the dry reagent is redissolved, e.g. with diffusion or back and forth movement of the amount of fluid.
- the end section containing the dry reagent and the further end section for the introduction of the quantity of liquid are expediently delimited in each case by a narrowing of the channel cross section.
- the constriction forms a barrier to liquid up to a limiting pressure, but allows air to pass.
- the surfaces of both or one of the end sections that come into contact with liquid are preferably hydrophilized and have a contact angle to water of ⁇ 60°, e.g. by a hydrophilic coating or by a surface treatment such as corona or plasma treatment or by plasma polymerisation, or by wet chemical treatment.
- the end section and the further end section are preferably each designed as a capillary channel and are in particular made hydrophilic.
- the end section and/or the further end section is/are formed in a projection that projects, in particular perpendicularly, from an essentially plate-shaped base body of the microfluidic element.
- An end section with a hydrophilic surface can take up a quantity of liquid introduced by dispensing or pipetting, e.g.
- the attachment or attachments are preferably formed in one piece with a substrate comprised by the base body, so that the attachments can be produced in one operation with the substrate during injection molding of the substrate.
- the end section with the dry reagent can be formed in a separate carrier element, which at least partially forms the attachment and is connected to the microfluidic element by gluing, welding and/or a press fit.
- the end section containing the dry reagent is covered from the outside by a frangible foil or a membrane which is permeable to gas but impermeable to liquid.
- the foil that can be broken off advantageously protects the dry reagent from the effects of moisture when the microfluidic element is stored.
- the advantage of the gas-permeable membrane is that the channel area is delimited, which prevents liquid from escaping unintentionally from the channel area.
- the channel area can, for example, comprise a chamber which forms, for example, a detection and/or reaction area, with the microfluidic element being expediently transparent at least in the area of the chamber for optical measurements.
- operating devices for the microfluidic element designed as a separate structural unit expediently comprise a controllable, pneumatic pressure source for connection to the further end section provided for receiving the quantity of liquid and a passive pressure source comprising a closed compression space for connection to the end section containing the dry reagent. In the closed space of the passive pressure source, trapped air is compressed when the amount of liquid is displaced.
- the amount of liquid is shifted towards the end section with the dry reagent.
- the pressure of the controllable pressure source By constantly controlling the pressure of the controllable pressure source, the amount of liquid within the channel area can be placed at a pressure-dependent location. In this way, a to-and-fro movement of the amount of liquid is possible, which promotes redissolution and mixing of the dry reagent with the amount of liquid.
- the separate operating device and possibly the microfluidic element expediently have valve devices for pressureless decoupling of the microfluidic element from the operating device, which ensures that the pressure of both pressure sources is at ambient pressure during decoupling.
- the operator devices expediently include one or more sensors for detecting the respective position of the amount of liquid within the channel area, e.g. a pressure sensor.
- the mentioned pneumatic pressure sources expediently have a cap-like connection piece, which can be placed over the attachment containing the end section and rests against the microfluidic element in a gas-tight manner, for example via an O-ring.
- a flow cell in which several end sections containing a dry reagent are formed, in which the channel region branches into several channel parts, each containing an end section with a dry reagent.
- the microfluidic element shown comprises a plate-shaped base body 1, from which projections 2,2' and 3,3' project perpendicularly.
- the base body 1 has a substrate 4 to which the projections 2,2' and 3,3' are integrally connected.
- the substrate 4 is glued or welded to a film 5 on its side facing away from the projections.
- the substrate 1 with the approaches 2.2' and 3.3' is injection molded and consists of a plastic, preferably COC, COP, PMMA, PC, PS, PE, PP or PEEK.
- the film 5 closes recesses formed in the substrate, so that within the base body 1 an in 2 visible cavity structure 6 is formed for two independently operable flow cells.
- FIG 3 shows schematically a cross section through one of the flow cells with the projections 2 and 2'.
- the flow cell comprises a channel area 7, which extends from an opening 8 through the attachment 2, the base body 1 and the attachment 2' to an opening 9.
- the channel area 7 comprises a chamber 10 arranged approximately in the middle of the channel area in relation to the channel length.
- Figure 3b shows a drop of a reagent liquid 13' which can be introduced into the end section 12 of the channel area 7, for example with the aid of a pipette, whereby it fills the end section 12 up to the constriction 14'.
- a reagent liquid 13' which can be introduced into the end section 12 of the channel area 7, for example with the aid of a pipette, whereby it fills the end section 12 up to the constriction 14'.
- an in 4 shown dry reagent 13 from.
- An operator device comprises a controllable pneumatic pressure source with a cap-shaped connecting piece 19 which can be slipped over the end section 11 and pressed against the flow cell in a gas-tight manner via an O-ring 20 .
- the sample quantity 15 is shifted further beyond the chamber 10 by increasing the pressure of the controllable pressure source of the operator device and according to FIG Fig. 4f reaches the end section 12 of the channel region 7, where it comes into contact with the dry reagent 13 and redissolves the dry reagent.
- the liquid sample quantity with the redissolved dry reagent can be Fig. 4f and the inside Fig. 4g be shifted back and forth from the position shown, the transport around the 90° bend in the channel area 7 near the end section 12 ensuring intensive mixing of the liquid 15 with the reagent.
- the liquid sample quantity with the redissolved reagent is in the chamber 10, it being possible for the liquid sample quantity to be examined optically through the substrate 4 and/or the film 5, which is transparent in the example.
- Optical measurements are also already included in the in Figure 4d shown position of the liquid sample is possible. With such double measurements, effects influencing the optical signal, such as transparency or autofluorescence of the materials of the flow cell of substrate and foil arranged in the detection area, can be calculated from the optical signal by subtraction.
- the sample liquid By lowering the pressure of the controllable pressure sources to atmospheric pressure, the sample liquid can be conveyed back from the chamber 10 to its starting position and the flow cell can be decoupled from the operator device without pressure.
- a reagent liquid is introduced into the end section 12 of the channel area 7, e.g. using a pipette, with the constriction 14' preventing the channel area 7 from being wetted beyond the end section 12.
- the inner surface of the end section 12 for example, with axial grooves or in a star shape figure 5 form, whereby the reagent preferably dries in the area of the grooves and not in the center of the end section 12 by capillary action.
- FIG. 1 shows a modification of the operator's equipment which provides a flow connection between fittings 19 and 21 with a valve 23.
- FIG. 6 shows a modification of the operator's equipment which provides a flow connection between fittings 19 and 21 with a valve 23.
- the amount of sample within the decoupled flow cell advantageously remains in place within the chamber 10, so that the flow cell does not have to remain in the operator device to maintain and carry out incubation processes between optical measurements, which is particularly advantageous for long incubation times.
- the operator device can have two valves 24 and 25 which connect the respective pressure sources to the ambient atmosphere ( 7 ), so that also in this case the amount of sample positioned in the chamber 10 remains in the chamber 10 if the valves 24 and 25 take place simultaneously with the same pressure drop in the connection spaces.
- the valves 24,25 can be formed in different ways, for example as pneumatic valves. However, the valves can also be mechanically switched valves as part of the flow cell, membranes or septa of the flow cell that can be pierced by cannulas of the operator device being considered.
- the controllable pressure source of the operator device can have a mechanical pump in connection with a pneumatic interface. A pump can also be designed as part of the flow cell, for example as a mechanical blister pump volume or according to the peristaltic principle.
- a closed volume formed by the flow cell itself or a separate chamber that can be connected to the flow cell and does not form part of an operator facility could also be considered as a passive pressure source.
- This foil 26, made of plastic or aluminum, can be attached by gluing or welding after the reagent liquid has been introduced or after drying, in order to protect the reagent from environmental influences, in particular atmospheric humidity.
- the foil 26 can serve to use the opening 9 during the intended use of the flow cell in order to form a passive pressure source with the aid of the foil.
- Figure 8b shows a porous membrane 27 covering the opening 9, which allows air but (up to a certain pressure) no liquid to pass through.
- Typical pore sizes are in the range of 0.1 - 10 ⁇ m.
- the flow cell can be used as intended using the membrane 27 . Accidental escaping of sample liquid through the opening 9 is advantageously avoided.
- Figure 8c shows an embodiment with a separate carrier 28 for a dry reagent.
- the injection-moulded plastic support with a hydrophilized through-opening coated with dry reagent can be connected to the flow cell by gluing, welding or press-fitting, with the through-opening forming an end section 12 of a channel region 7 .
- the sample liquid can flow over the area of the dry reagent beyond its end without exiting from the channel area, which promotes the mixing of the sample liquid with the reagent.
- the application of the dry substance to the easy-to-handle carrier 28 is easier than applying it directly to an attachment on the base body of the flow cell.
- Figure 8d shows a separate carrier 28', which is plate-shaped with a number of through-holes for receiving a number of identical or different dry reagents is provided. At least two through holes forming the end portions may have different diameters.
- a channel area 7 has a single input section 11 for receiving liquid to be processed and a plurality of end sections 12 with a dry reagent, with parts of the channel area 7 each having at least one chamber, e.g analysis.
- a defined amount of sample liquid is divided into eight fractions and a dry reagent is fed to eight end sections 12, it being possible for the dry reagents to differ from end section to end section.
- the fractions are mixed and processed or analyzed separately.
- the design of the end sections 12 and the input section 11 can be implemented as in the previous exemplary embodiment and can be hydrophilized, for example, in the manner described above.
- chambers 10 forming analysis/detection areas have identical volumes.
- the flow cell of 9 can be used like the flow cells described above. Eight connecting lines and valves are required to place sample liquid after analysis in the chambers when disconnected from an operator facility.
- FIG. 10 shows a schematic representation of a manifold as part of a with the flow cell of 9 connectable operator device with two welded plates, between which are formed pneumatic channels connecting pressure sources.
- the plate facing the flow cell has a fitting corresponding to the aforesaid fitting 19 and eight fittings corresponding to the aforesaid fitting 21, which are connected by means of a gasket or O-rings hermetically sealed with the flow cell. Once connected, the flow cell and manifold form a closed pneumatic circuit.
- the plate facing away from the flow cell has an active pressure source 30 including a pressure sensor, a pneumatic valve 31 for connecting the active pressure source to the environment and eight pneumatic valves 32 which connect the active pressure source 30 to the eight passive pressure sources via pneumatic connecting channels 33 arranged between the plates or separate from each other.
- the passive pressure sources are formed from the sum of the volumes of the pneumatic channel areas between the closed valves 32 and the connection pieces 21, the volume formed between the extensions 21 of the manifold and the extensions 2 'of the flow cell and the channel volume 7 of the flow cell between the introduced sample liquid and the End section 12.
- the amount of liquid introduced is increased by pressurization by means of the active pressure source 30 with the valves 31 and 32 closed, as in 4 shown shifted in the direction of the end sections 12 and divided into eight substantially equal fractions due to the eight substantially equal passive pressure sources.
- the separate active and passive pressure sources are at the same pressure level.
- all pressure sources are connected to each other by opening the eight valves 32 simultaneously without substantially changing the pressure level acting on the liquid in the detection chamber upstream and downstream.
- a preferably slow opening of the valve 31 lowers the pressure level to the ambient pressure in order to be able to separate the manifold from the flow cell without pressure, with the eight liquid fractions remaining in the eight detection areas after the separation.
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- Health & Medical Sciences (AREA)
- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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EP21205300.3A EP4173708A1 (fr) | 2021-10-28 | 2021-10-28 | Élément microfluidique, en particulier cellule d'écoulement, avec réactifsec intégré |
PCT/EP2022/078034 WO2023072560A1 (fr) | 2021-10-28 | 2022-10-10 | Élément microfluidique, en particulier cuve à circulation, comprenant un réactif sec intégré |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP21205300.3A EP4173708A1 (fr) | 2021-10-28 | 2021-10-28 | Élément microfluidique, en particulier cellule d'écoulement, avec réactifsec intégré |
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EP4173708A1 true EP4173708A1 (fr) | 2023-05-03 |
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EP21205300.3A Pending EP4173708A1 (fr) | 2021-10-28 | 2021-10-28 | Élément microfluidique, en particulier cellule d'écoulement, avec réactifsec intégré |
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Country | Link |
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EP (1) | EP4173708A1 (fr) |
WO (1) | WO2023072560A1 (fr) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102008021364A1 (de) * | 2008-04-29 | 2009-06-25 | Siemens Aktiengesellschaft | Verfahren zum Einbringen von Trockenreagenzien in eine Analyseeinheit und Kit |
WO2010139295A1 (fr) * | 2009-06-05 | 2010-12-09 | Thinxxs Microtechnology Ag | Dispositif pour transporter un fluide dans un canal d'élément microfluidique |
US20110041922A1 (en) * | 2008-03-12 | 2011-02-24 | Fluimedix Aps | Controlled liquid handling |
EP2496351A2 (fr) * | 2009-11-02 | 2012-09-12 | The Secretary Of State For Environment Food&Rural Affairs | Dispositif et appareil |
EP2821138A1 (fr) | 2013-07-05 | 2015-01-07 | Thinxxs Microtechnology Ag | Cellule d'écoulement avec substance de séchage intégrée |
-
2021
- 2021-10-28 EP EP21205300.3A patent/EP4173708A1/fr active Pending
-
2022
- 2022-10-10 WO PCT/EP2022/078034 patent/WO2023072560A1/fr unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110041922A1 (en) * | 2008-03-12 | 2011-02-24 | Fluimedix Aps | Controlled liquid handling |
DE102008021364A1 (de) * | 2008-04-29 | 2009-06-25 | Siemens Aktiengesellschaft | Verfahren zum Einbringen von Trockenreagenzien in eine Analyseeinheit und Kit |
WO2010139295A1 (fr) * | 2009-06-05 | 2010-12-09 | Thinxxs Microtechnology Ag | Dispositif pour transporter un fluide dans un canal d'élément microfluidique |
EP2496351A2 (fr) * | 2009-11-02 | 2012-09-12 | The Secretary Of State For Environment Food&Rural Affairs | Dispositif et appareil |
EP2821138A1 (fr) | 2013-07-05 | 2015-01-07 | Thinxxs Microtechnology Ag | Cellule d'écoulement avec substance de séchage intégrée |
Also Published As
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WO2023072560A1 (fr) | 2023-05-04 |
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