EP3263217B1 - Cellule d'écoulement microfluidique comprenant un espace de stockage recevant un matériau d'échantillon et/ou de réactif - Google Patents

Cellule d'écoulement microfluidique comprenant un espace de stockage recevant un matériau d'échantillon et/ou de réactif Download PDF

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Publication number
EP3263217B1
EP3263217B1 EP16190102.0A EP16190102A EP3263217B1 EP 3263217 B1 EP3263217 B1 EP 3263217B1 EP 16190102 A EP16190102 A EP 16190102A EP 3263217 B1 EP3263217 B1 EP 3263217B1
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Prior art keywords
storage space
flow cell
cell according
section
cross
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EP16190102.0A
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German (de)
English (en)
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EP3263217A1 (fr
Inventor
Lutz Weber
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Thinxxs Microtechnology GmbH
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Thinxxs Microtechnology GmbH
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Priority to CN201780039510.1A priority Critical patent/CN109414697B/zh
Priority to US16/314,539 priority patent/US11045804B2/en
Priority to PCT/EP2017/062609 priority patent/WO2018001648A1/fr
Publication of EP3263217A1 publication Critical patent/EP3263217A1/fr
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502715Containers 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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers 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
    • B01L3/502746Containers 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 for controlling flow resistance, e.g. flow controllers, baffles
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/52Containers specially adapted for storing or dispensing a reagent
    • B01L3/523Containers specially adapted for storing or dispensing a reagent with means for closing or opening
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02Adapting objects or devices to another
    • B01L2200/026Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16Reagents, handling or storing thereof
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/04Closures and closing means
    • B01L2300/041Connecting closures to device or container
    • B01L2300/044Connecting closures to device or container pierceable, e.g. films, membranes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/04Closures and closing means
    • B01L2300/046Function or devices integrated in the closure
    • B01L2300/047Additional chamber, reservoir
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867Multiple inlets and one sample wells, e.g. mixing, dilution
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877Flow chambers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0883Serpentine channels
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/16Surface properties and coatings
    • B01L2300/161Control and use of surface tension forces, e.g. hydrophobic, hydrophilic

Definitions

  • the invention relates to a microfluidic flow cell having a storage space containing liquid reagent and / or sample material and having an inflow channel for a fluid removing the reagent and / or sample material from the storage space and a drainage channel for the reagent and / or sample material and the fluid communicates, wherein the inflow channel and the outflow channel are connected by a bypass surrounding the storage space.
  • Microfluidic flow cells with these features are each out WO 2015/162060 A1 .
  • Microfluidic flow cells which are used primarily in the life sciences for diagnostics, analysis and synthesis, process increasingly smaller volumes of liquid samples and liquid reagents.
  • the invention has for its object to provide a new microfluidic flow cell of the type mentioned above with particular suitability for receiving and processing small amounts of reagent and / or sample material.
  • the problem solved microfluidic flow cell according to the invention is characterized in that the flow cross-section of the bypass for venting the inflow channel just sufficient to prevent the removal of reagent and / or sample material from the storage space by increasing in the inflow air pressure.
  • this invention solution allows a targeted removal and targeted mixing of stored in a storage space of the flow cell reagent and / or sample material by and with the transporting away fluid.
  • a sample or reagent quantity to be processed is provided in a channel section of a microfluidic network.
  • Typical volumes are in the range of 1 to 100 ⁇ l.
  • processing the sample or reagent amount is meant e.g. mixing with another sample or reagent or e.g. dilution in the ratio of typically 1: 1 to 1: 1000 or controlled onward transport.
  • the transport or processing or dilution liquid is typically at a different location of the sample from the position of the sample of the microfluidic network, e.g. a storage area or liquid blister. That is, between the two quantities of liquid is an empty, usually filled with gas or air channel-shaped inflow area.
  • the bypass branches off in the direction of flow immediately before the storage space from the inflow channel.
  • no air cushion can form between the front of the fluid flowing into the inflow channel and the reagent and / or sample material contained in the storage space, through which the reagent and / or sample material is transported out of the storage space before it reaches the front of the inflowing fluid ,
  • the storage space forms a flush with the inflow channel and the drainage channel section.
  • the cross section of the storage space perpendicular to the flow direction preferably coincides with the cross section of the inflow channel and / or the cross section of the outflow channel.
  • the vertical cross section of the storage space in the flow direction may be smaller or larger than the cross section of the inflow channel and / or the cross section of the outflow channel.
  • the flow cross-section of the bypass may in particular be dimensioned such that a desired proportion of the fluid flowing in through the inflow channel flows over the bypass, the proportion corresponding to a desired mixing ratio of reagent and / or sample material and fluid.
  • the bypass can be produced by deflection of a flexible, adjacent to the storage space cover.
  • the cover sheet may e.g. be pneumatically deflectable by the air pressure in the inflow channel or by a suction pressure generated from the outside by an operator device, alternatively mechanically.
  • the inflow channel, the outflow channel and possibly the storage space are formed by recesses in a substrate and the recesses are closed in a fluid-tight manner by a cover connected to the substrate.
  • the cover is preferably a covering film which is welded or / and glued to a plate surface of the substrate or else a preferably injection-molded covering substrate.
  • samples or reagents can be finally used in the otherwise completely completed flow cell.
  • Impairment in a storage space in the substrate introduced reagents by subsequent welding and / or bonding of the substrate, for example, with a cover omitted.
  • a receiving region of the carrier element for the reagent and / or sample material adjacent to the storage space is expediently formed in an end piece of a plug-like carrier element.
  • the bypass may suitably run between the end piece and the inner wall of the above-mentioned opening.
  • the microfluidic flow cell shown in detail comprises a plate-shaped substrate 1 and a cover foil 2 welded or bonded to the substrate 1.
  • the cover foil 2 closes cavity structures of the flow cell which are fluid-tightly formed in the substrate 1 and open towards the foil side.
  • Fig. 1 Visible are a storage space 3, an inflow channel 4 and an outflow channel 5.
  • the inflow channel 4 connects with the outflow channel 5 a bypass 6 branching off from the inflow channel 4 in the flow direction immediately before the storage space 3.
  • the storage space 3 has the same cross-section as the inflow and outflow channels in the flow direction, so that the storage space 3 only forms a section of a through-going channel.
  • the walls of the storage space 3 are at least partially hydrophilized, so that there liquid reagent 7 can be held in place and introduced in the course of manufacturing the flow cell in the flow cell.
  • the volume of the liquid reagent material 7 is preferably in the range of 1 to 100 ⁇ l, in particular in the range of 2 to 50 ⁇ l.
  • the storage area 3 can be separated from the inflow and outflow channel by means of local welding of the substrate with the cover film 2 acting as a predetermined breaking point (not shown).
  • the storage area 3 could additionally be connected to closable filling or venting channels for filling the reagent material 7 into the storage area (not shown).
  • another fluid introduced from the outside into the flow cell or fluid originating from a further storage region of the flow cell can flow via the inflow channel 4, flushing out the reagent material 7 from the storage space 3 and mixing it with the further fluid via the outflow channel 5 Reagent material 7 for further processing within the flow cell supplies.
  • the further fluid 8 may be e.g. a sample liquid to be assayed by the flow cell or another liquid reagent, e.g. a washing or dilution buffer, act.
  • a sample liquid to be assayed by the flow cell
  • another liquid reagent e.g. a washing or dilution buffer
  • mixtures of a sample liquid and a liquid reagent are also possible.
  • the flow cell itself or an operator device has a pressure source for the fluid transport through the inflow channel 4, the storage space 3 and the outflow channel 5 (not shown).
  • a pressure source could e.g. be formed by a blister memory for a washing and dilution buffer.
  • an area of the flow cell which can be elastically or plastically deformed from the outside by an operator device or manually by a user or an air pump which can be connected via an air or pneumatic connection of the flow cell to an operating device as a pressure source would be possible.
  • the fluid flowing in for the purpose of flushing out the reagent material 7 from the storage space 3 displaces the air contained in the inflow channel 4 in front of it. Without the bypass 6, an undesirable air cushion impeding the mixing of the reagent material and the fluid would arise between the reagent material 7 and the oncoming fluid.
  • the flow resistance of the bypass 6 for the Air is so low that the air pressure upstream of the storage space 3 in the direction of flow can not rise so high that the air can push out the reagent material 7 from the storage space 3 against the retention capacity of the storage space.
  • the front of the fluid 8 thereby reaches the reagent 7 and rinsing out the reagent 7 from the storage space 3 while mixing with the reagent 7.
  • the flow resistance of the bypass 6 for the fluid 8 is in the example of Fig. 1 on the other hand, so great that no appreciable portion of the oncoming fluid 8 flows past the bypass 6 past the storage space 3. It goes without saying that, when the flow resistance of the bypass 6 for the fluid 8 is reduced by enlarging the bypass cross section, the proportion of the fluid 8 flowing through the bypass increases. With a view to a faster mixing of reagent material 7 and fluid 8, a desired proportion of the fluid flowing through the bypass 6 can be set by selecting the flow source cross section.
  • FIGS. 2 to 7 show exemplary embodiments, which use a carrier element 9 for forming a storage space 3 for liquid reagent and / or sample material 7, which can be inserted into an opening 10 in the flow cell or its substrate 1 and can be connected in a fluid-tight manner to the flow cell.
  • a carrier element 9 for forming a storage space 3 for liquid reagent and / or sample material 7, which can be inserted into an opening 10 in the flow cell or its substrate 1 and can be connected in a fluid-tight manner to the flow cell.
  • With the memory space 3 are in the same manner as in the embodiment of Fig. 1 Channels connected.
  • the plug-like manner with a cylindrical end piece 11, a cone portion 12 and a collar 13 formed carrier element 9 has an open towards the end receiving groove for liquid reagent and / or sample material.
  • the opening 10 in the substrate 1 of the flow cell is approximately matched in shape to the carrier element 9.
  • the groove is hydrophilized so that the liquid reagent and / or sample material on the support member in the groove is held particularly tight.
  • the carrier element 9 with the end face of the cylindrical end piece 11 extends, if necessary, as far as the covering film 2, so that the carrier element 9 forms the storage space 3 together with the covering film 2.
  • the cross section of the storage space coincides with the cross section of an inflow channel which leads into the storage space (into the Fig. 2 to 7 not visible) and drainage channels match. Of the channels is in Fig. 2a the drainage channel 5 in cross section visible.
  • the storage space 3 is aligned with the channels. To secure the orientation of the storage space 3 to the Channels could be formed on the support member 9 and the substrate 1 per a stop.
  • a bypass 6 consisting of two flow channels is formed.
  • the storage space is closed to the outside fluid-tight.
  • the carrier element 9 could be welded to the substrate 1 in a fluid-tight manner and / or adhesively bonded.
  • Fig. 2 Compared to the embodiment of Fig. 1 have the embodiments of Fig. 2 to 7 the advantage that the reagent and / or sample material is not affected by final welding or / and bonding of the substrate 1 with the cover 2.
  • the embodiment of Fig. 3 differs from the embodiment of Fig. 2 in that the difference between the diameter of the end piece 11 and the end piece 11 receiving portion of the opening 10 is even greater than in the embodiment of Fig. 2 and thus the flow cross section of the formed bypass 6 is greater than the flow cross section of the bypass 6 of the embodiment of Fig. 2 is.
  • the bypass according to Fig. 3 Accordingly, a greater proportion of a fluid flowing through the inflow channel to flow through the bypass and, as already mentioned above, the mixing ratio of reagent and / or sample liquid with the oncoming fluid can be adjusted appropriately.
  • FIGS. 5 and 6 relate to embodiments in which a cover 2 in the region of a storage space 3 is deflected to form a bypass 6. According to Fig. 5 the deflection of the cover 2 is effected by the pressure of the air to be redirected.
  • Fig. 6 serves a negative pressure generating operator device 15 for deflecting the cover 2 by suction.
  • a cylindrical end piece 11 of a carrier element 9 does not have a groove open towards the end face of the end piece, but has a passageway.
  • the passage forms a storage space 3 whose cross section is smaller than the cross section of the channels opening into the storage space, of which in Fig. 7a the drainage channel 5 is visible in cross section.
  • the in Fig. 7a in its position indicated by dashed lines memory space 3 is aligned approximately at the center of the cross section of the opening channels.
  • Fluid flowing in via the bypass with a relatively large flow cross section through the inflow channel encloses the reagent and / or sample material in the outflow channel 5 in the flow, resulting in a type of centering of the reagent and / or sample material in the fluid flushing out the storage space 3.
  • This allows e.g. a sample with particles, e.g. the cells of a blood sample, centered in the drainage channel, to remove them e.g. individually to analyze according to the principle of a cytometer.
  • the substrate 1 and the carrier element 9 of the flow cells described above are preferably made of plastics such as PMMA, PC, COC, COP, PPE, PE and are produced by injection molding.
  • the materials of substrate 1 and carrier element 9 match.

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

Claims (12)

  1. Cellule d'écoulement microfluidique présentant un espace de stockage (3) recevant un matériau de réactif et/ou d'échantillon liquide (7), qui est relié à un canal d'alimentation (4) pour un fluide (8) transportant le matériau de réactif et/ou d'échantillon (7) hors de l'espace de stockage (3) et à un canal d'évacuation (5) pour le matériau de réactif et/ou d'échantillon (7) et le fluide (8), le canal d'alimentation (4) et le canal d'évacuation (8) étant reliés par une dérivation (6) contournant l'espace de stockage (3), caractérisée en ce que la section transversale d'écoulement de la dérivation (6) pour la désaération du canal d'alimentation (4) suffit précisément pour empêcher un transport de matériau de réactif et/ou d'échantillon (7) hors de l'espace de stockage (3) par une pression d'air croissante dans le canal d'alimentation (4).
  2. Cellule d'écoulement selon la revendication 1, caractérisée en ce que l'espace de stockage (3) forme une section de canal alignée avec le canal d'alimentation (4) et le canal d'évacuation (5).
  3. Cellule d'écoulement selon la revendication 1 ou 2, caractérisée en ce que la section transversale, perpendiculaire à la direction d'écoulement, de l'espace de stockage (3) correspond à la section transversale du canal d'alimentation (4) et/ou à la section transversale du canal d'évacuation (5).
  4. Cellule d'écoulement selon l'une quelconque des revendications 1 à 3, caractérisée en ce que la section transversale, perpendiculaire à la direction d'écoulement, de l'espace de stockage (3) est plus petite ou plus grande que la section transversale du canal d'alimentation (4) et/ou que la section transversale du canal d'évacuation (5).
  5. Cellule d'écoulement selon l'une quelconque des revendications 1 à 4, caractérisée en ce que la section transversale, perpendiculaire à la direction d'écoulement, de l'espace de stockage (3) est constante dans la direction d'écoulement.
  6. Cellule d'écoulement selon l'une quelconque des revendications 1 à 5, caractérisée en ce que la dérivation (6) peut être réalisée par déviation d'une feuille de recouvrement (2) souple adjacente à l'espace de stockage (3).
  7. Cellule d'écoulement selon la revendication 6, caractérisée en ce que la feuille de recouvrement (2) peut être déviée par la pression d'air dans le canal d'alimentation (4) ou par une pression d'aspiration générée depuis l'extérieur par un dispositif d'exploitation (15).
  8. Cellule d'écoulement selon l'une quelconque des revendications 1 à 7, caractérisée en ce que le canal d'alimentation (4), le canal d'évacuation (5) et le cas échéant l'espace de stockage (3) sont formés par des évidements dans un substrat (1) et les évidements sont fermés de manière étanche aux fluides par un recouvrement (2) relié au substrat (1).
  9. Cellule d'écoulement selon la revendication 8, caractérisée en ce que le recouvrement est une feuille de recouvrement (2) soudée et/ou collée sur une surface plate du substrat (1).
  10. Cellule d'écoulement selon l'une quelconque des revendications 1 à 9, caractérisée en ce qu'un élément support (9), recevant le matériau de réactif et/ou d'échantillon liquide (7), est adjacent à l'espace de stockage (3) et peut être placé dans une ouverture (10) dans le substrat (1), tout en fermant l'espace de stockage (3) de manière étanche aux fluides, et peut être relié au substrat (1) de manière étanche aux fluides.
  11. Cellule d'écoulement selon la revendication 10, caractérisée en ce qu'une zone de réception (14), adjacente à l'espace de stockage (3), de l'élément support (9) pour le matériau de réactif et/ou d'échantillon (7) est formée dans une partie d'extrémité (11) d'un élément support (9) de type bouchon.
  12. Cellule d'écoulement selon la revendication 11, caractérisée en ce que la dérivation (6) s'étend entre la partie d'extrémité (11) et la paroi interne de l'ouverture (10).
EP16190102.0A 2016-06-30 2016-09-22 Cellule d'écoulement microfluidique comprenant un espace de stockage recevant un matériau d'échantillon et/ou de réactif Active EP3263217B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201780039510.1A CN109414697B (zh) 2016-06-30 2017-05-24 带有容纳液态试剂材料和/或试样材料的存储腔的微流体流动池
US16/314,539 US11045804B2 (en) 2016-06-30 2017-05-24 Microfluidic flow cell having a storage space that holds liquid reagent material and/or sample material
PCT/EP2017/062609 WO2018001648A1 (fr) 2016-06-30 2017-05-24 Micro-cuve à circulation dotée d'une chambre de stockage destinée à contenir un réactif liquide et/ou une substance à analyser liquide

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP16177162.1A EP3263215B1 (fr) 2016-06-30 2016-06-30 Dispositif comprenant un cellule comprenant un dispositif de stockage de reactif

Publications (2)

Publication Number Publication Date
EP3263217A1 EP3263217A1 (fr) 2018-01-03
EP3263217B1 true EP3263217B1 (fr) 2019-11-06

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EP16177162.1A Active EP3263215B1 (fr) 2016-06-30 2016-06-30 Dispositif comprenant un cellule comprenant un dispositif de stockage de reactif
EP16190102.0A Active EP3263217B1 (fr) 2016-06-30 2016-09-22 Cellule d'écoulement microfluidique comprenant un espace de stockage recevant un matériau d'échantillon et/ou de réactif

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US (2) US11426725B2 (fr)
EP (2) EP3263215B1 (fr)
CN (2) CN109414697B (fr)
WO (2) WO2018001648A1 (fr)

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WO2018001647A1 (fr) 2018-01-04
EP3263217A1 (fr) 2018-01-03
EP3263215A1 (fr) 2018-01-03
US20190262830A1 (en) 2019-08-29
CN109328110A (zh) 2019-02-12
CN109414697A (zh) 2019-03-01
US20190321822A1 (en) 2019-10-24
WO2018001648A1 (fr) 2018-01-04
EP3263215B1 (fr) 2021-04-28
CN109414697B (zh) 2021-04-30
US11045804B2 (en) 2021-06-29
CN109328110B (zh) 2021-08-06
US11426725B2 (en) 2022-08-30

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