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EP3108962B1 - Porte échantillons - Google Patents

Porte échantillons Download PDF

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Publication number
EP3108962B1
EP3108962B1 EP15173174.2A EP15173174A EP3108962B1 EP 3108962 B1 EP3108962 B1 EP 3108962B1 EP 15173174 A EP15173174 A EP 15173174A EP 3108962 B1 EP3108962 B1 EP 3108962B1
Authority
EP
European Patent Office
Prior art keywords
sample
carrier
flow cell
sample carrier
use according
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.)
Active
Application number
EP15173174.2A
Other languages
German (de)
English (en)
Other versions
EP3108962A1 (fr
Inventor
Lutz Weber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thinxxs Microtechnology GmbH
Original Assignee
Thinxxs Microtechnology GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thinxxs Microtechnology GmbH filed Critical Thinxxs Microtechnology GmbH
Priority to EP15173174.2A priority Critical patent/EP3108962B1/fr
Priority to PCT/EP2016/060498 priority patent/WO2016206854A1/fr
Priority to US15/738,421 priority patent/US11045802B2/en
Publication of EP3108962A1 publication Critical patent/EP3108962A1/fr
Application granted granted Critical
Publication of EP3108962B1 publication Critical patent/EP3108962B1/fr
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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
    • 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
    • B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • 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
    • B01L2300/04—Closures and closing means
    • B01L2300/046—Function or devices integrated in the closure
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • 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
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • 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
    • B01L3/502707—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 manufacture of the container or its components

Definitions

  • the invention relates to the use of a microfluidic flow cell with a sample carrier according to claim 1.
  • a sample carrier for holding a biological sample with a capillary that takes up the sample in a metered manner is known.
  • the capillary is connected to a cylinder chamber in which a piston can be moved over an air cushion to expel the sample from the capillary. While the sample is being taken up by the capillary, an opening channel ensures that the cylinder is ventilated. When the piston is moved in the cylinder, this opening channel closes.
  • the WO 00/74853 A1 describes a sample carrier that is combined with a closure element for a container.
  • a biological sample for example, enters the interior of the container, where it is shielded from the outside environment and comes into contact with a diluent liquid.
  • the diluted sample can then be removed from the container and analyzed.
  • From the DE 94 17 612 U1 is a device for taking a liquid sample, especially a blood sample.
  • the blood sample remains in a capillary that is closed off from the outside.
  • the sampling device can be inserted into the analysis device with a transparent cuvette part at the front and the sample liquid can be transferred from the capillary into the cuvette part.
  • the sample in the cuvette part is then x-rayed for analysis.
  • the US 2014/0295441 A1 describes an arrangement of a flow cell 415 and a plurality of sample acceptors 400 that can be connected to the flow cell.
  • the flow cell 415 is part of an analyzer for nucleic acids.
  • the sample acceptors 400 each comprise an acceptor region 445 in the form of a cotton ball and a removable sample collection container 430.
  • the sample acceptors form a functional component of the flow cell in that an extractant is conveyed by positive and/or negative pressure from a reservoir of the flow cell into the acceptor region 445 and the extractant with extracted material is conveyed back into the reservoir.
  • the EP 2 821 138 A1 describes a microfluidic flow cell in which the dry reagents required in the flow cell are introduced by means of plug-in, plug-like carriers.
  • a flow cell and a sample carrier that can be connected to the flow cell are used to measure a volume of a sample to be analyzed by the flow cell and to introduce the sample volume into the flow cell
  • the flow cell has an opening that opens into a cavity in the flow cell, which the sample carrier closes in a fluid-tight manner like a plug and which forms a press fit for a conical carrier element of the sample carrier
  • the conical carrier element has a sample receiving area comprising means for metered receiving of the sample on an end face facing the cavity
  • the sample carrier has an area for handling the sample carrier on a side facing away from the sample receiving area
  • the sample carrier adheres to the sample carrier by capillary forces while measuring a sample volume of between 1 and 100 ⁇ l in the sample receiving area, and the sample carrier with the sample volume adhered to it by the capillary forces is inserted into the opening to introduce the sample into the flow cell.
  • a sample to be analyzed is fed directly into the analysis process via the sample carrier using the shortest route.
  • Sample input e.g. the input of a body fluid such as blood, urine and saliva, a food sample or an environmental sample, in particular a water sample, into a flow cell, no longer takes place via an input port that has to be closed after input, but rather sample input into the analysis process is completed with the fluid-tight placement of the sample carrier, which may already have the sample quantity dosed. Sample dosing within the flow cell can be eliminated.
  • the sample placed in the analysis device together with the sample carrier borders on the cavity in the flow cell involved in the analysis and the sample carrier seals the cavity to the outside in a fluid-tight manner.
  • the flow cell is automatically sealed by the sample carrier itself.
  • the cavity can also be filled with a liquid-absorbing material, such as a fleece or a porous membrane.
  • the above-mentioned cavity can, for example, be a transport channel or a chamber, in particular a mixing chamber.
  • the sample placed together with the sample carrier in the analysis device can be detached from the sample receiving area by a fluid flow.
  • the fluid can be either a rinsing liquid or a gas, in particular compressed air.
  • the above-mentioned fluid flow can be generated, for example, by emptying a reagent reservoir integrated into the analysis device or connected to the analysis device in a fluid-tight manner, whereby, for example, a deformation of the storage space of the reagent reservoir occurs by actuation.
  • the sample carrier itself can have devices for transporting the sample to be analyzed away from the sample carrier, e.g. a rinsing channel running through the sample carrier and carrying a rinsing liquid or a rinsing gas.
  • the sample carrier has devices for preprocessing supplied sample material. During the preprocessing, the sample to be analyzed is formed from this.
  • the preprocessing devices preferably comprise means for dosing the sample material, reagents and/or separating agents, in particular for separating blood plasma.
  • the sample carrier has a cone corresponding to a LUER closure.
  • the sample carrier which closes the opening like a plug, can be rotated in the opening under fluid-tight closure.
  • sample carrier is manufactured, preferably in one piece, as a plastic injection-molded part, wherein, if necessary, several receiving areas for a sample are formed on a sample carrier.
  • the receiving area itself has means for the dosed reception of the sample, whereby in addition to geometric limitations of the sample receiving area, surface coatings and/or locally used plastic materials for controlling the wettability of the receiving area are particularly suitable, in particular in such a way that the sample receiving area can be selectively wetted with sample material.
  • the handling area allows manual handling of the sample carrier without touching the sample.
  • the handling area can be a handle which can be broken off from the rest of the sample carrier at a predetermined breaking point after the sample carrier has been placed in the analysis device.
  • the sample carrier can have a closure device that prevents the placed sample carrier from being removed from the analysis device, such as a snap closure or the like.
  • the receiving area of the sample carrier comprises a dry reagent, possibly for a first reaction with the sample.
  • a flow cell comprises a substrate 1 injection-molded from plastic, a laminate film 2 with layers of aluminum and plastic, and a cover film 3 on the side of the substrate 1 facing away from the laminate film 2.
  • Chambers and channels are formed in the substrate 1, e.g. the chamber 4 and the channel 5. Bulges in the laminate film 2 form storage spaces 6.
  • a sample carrier 7 is arranged on a chamber wall 16 forming the chamber 4, which is screwed to a nozzle 12 protruding from the chamber wall 16 and having threaded projections 13.
  • the sample carrier 7 comprises a conical carrier element with a sample receiving area 9 at a free front end.
  • the carrier element 8 protrudes from the bottom of a pot-shaped rotary handle part 10 with an internal thread 11, into which the thread projections 13 engage, and with rib projections 14.
  • the sample receiving area 9 of the sample carrier 7 screwed to the nozzle 12 extends into the chamber 4.
  • Sample material 15 is applied to the sample receiving area 9.
  • the sample receiving area 9 comprises a groove 18 that is open on three sides and in which a sample quantity remains that is held by capillary forces.
  • the user holding the sample carrier 7 on the rotary handle part 10 does not come into contact with the sample quantity when he introduces the sample quantity into the flow cell by screwing the sample carrier 7 to the nozzle 12.
  • the conical carrier element 8 forms a fluid-tight press fit with the conical inner surface of the nozzle 12.
  • a defined amount of sample is measured that remains in the groove 18, which is open on three sides. This is done, for example, by immersing the receiving area 9 in an openly accessible sample drop, which can be located, for example, at the outlet of a syringe, in a container such as a microtiter plate or, especially in the case of blood as sample material, on the skin of a patient, eg according to Fig. 4a on a fingertip 70.
  • the sample material can also be pipetted or dripped on.
  • the geometric shape of the groove 18, whose groove walls form boundaries, is decisive for the measurement of a defined sample quantity.
  • the groove cross-section is approximately 2 ⁇ 2 mm 2 .
  • the reproducible measurement of a sample quantity is also ensured by a coating in the receiving area 9, which is decisive for the wettability of the groove walls.
  • blood or other aqueous samples as fluid sample material fill the groove by capillary action, whereby a certain blood sample quantity is measured due to the hydrophilic wetting properties.
  • the blood sample quantity bound by capillary forces remains in the receiving area 9 and is introduced into the chamber 4 with the aid of the sample carrier 7, as described above. During the course of an analysis to be carried out, the sample is rinsed off the sample carrier.
  • a sample carrier corresponding to sample carrier 7 is in Fig. 5a
  • Fig. 5b shows a receiving area in the form of a pocket-shaped depression 19 in the front surface of the conical carrier element 8.
  • a sample quantity 20 in drop form is reproducibly formed by the depression 19.
  • Fig. 5c concerns how Fig. 5b a receiving area in the form of a round depression.
  • the preferably hydrophilized depression has a microstructure that increases the wetting surface, e.g. columns 21 protruding from the bottom of the depression.
  • the grid size of the column arrangement is between 10 and 500 ⁇ m, preferably between 20 and 200 ⁇ m.
  • the microstructure leads to improved wetting properties and better control of droplet formation and thus further improved reproducibility of the sample quantities.
  • a receiving area emerges which is formed by a serpentine groove channel 22 in the front wall of the conical carrier element, which is open at its ends.
  • the cross-section of this channel in the example shown is 0.2 x 0.2 mm 2 , preferably between 0.1 and 0.5 mm 2 .
  • the smaller cross-sectional dimensions of the optionally hydrophilically modified channel allow better control of the wettability and thus the reproducibility of the measured sample quantity.
  • FIG. 5e The embodiment shown is similar to the example of Fig. 5d except for a cover film 23 arranged on the front surface of the conical carrier element, which forms part of the sample carrier, which in this case is constructed in two parts.
  • the groove channel 22 closed by the cover film 23 is filled capillary via an open end, whereby, in particular by partial or complete hydrophilic modification, a sample quantity can be measured very precisely, in that the capillary filling ends automatically at the other end of the channel.
  • a targeted flushing device is preferably used in the analysis device.
  • Another two-part sample carrier with a through hole 24 as the receiving area has a through hole closing the through hole at one end.
  • permeable membrane 25 The membrane has pores of such a size that they are not permeable to gas but are permeable to liquid.
  • the air permeability of the membrane 25 allows capillary filling of the through hole 24.
  • An embodiment with the same function but without permeable membrane 25 is also conceivable.
  • FIG. 5g A sample receiving area is formed by an absorbent fleece 26 applied to the front side of the conical carrier element.
  • the fleece 26 absorbs sample liquid by capillary action.
  • the sample can be released by squeezing the fleece or flushed out using a rinsing liquid.
  • the sample can also be fed into the analysis process by bringing it into contact with a lateral flow membrane, where it is sucked out of the fleece 26 of the sample carrier by the capillary action of the lateral flow membrane. This process can be supported by a rinsing liquid which is transported through the lateral flow membrane.
  • a two-part sample carrier which comprises a conical carrier element 27 with a through hole 28.
  • the through hole 28 which can be filled with sample material via capillary, ends at a flushing channel 30 delimited by a film 29.
  • the capillary filling of the through hole 28 automatically ends at the flushing channel 30.
  • the flushing channel 30 leads through a further cone 31.
  • the sample carrier can be connected to a flow cell via the conical carrier element 27 and the cone 31, where a measured sample quantity 32 can be flushed out of the through hole 28 hydraulically or pneumatically.
  • Fig. 7 shows an embodiment that differs from the embodiment of Fig. 6 differs in that instead of a through hole 28 with an approximately constant cross-section, a conically widening through hole 34 is formed. This allows a larger sample quantity 33 to be accommodated in a smaller space. The smaller end opening of the through hole 34 makes the sample quantity accommodated more reproducible.
  • Typical diameters at the narrowest point are between 0.1 and 0.3 mm. At the widest point, the Diameters are between 0.5 and 2 mm, with the length of the through hole 34 typically being 2 to 10 mm.
  • sample volumes can be effectively introduced into a microfluidic flow cell simply by exchanging the sample carrier with the same external dimensions, thus adapting the measured quantities to the requirements of different analyses and/or samples.
  • the sample carrier shown is similar to the sample carrier of Fig. 6 except for a constriction 35 of its through hole 28 at its end facing the flushing channel 30.
  • the constriction 35 of the sample carrier of Fig. 8 forms a capillary stop that limits the capillary filling of the sample receiving area particularly precisely.
  • the reproducibility of the sample dimensions is correspondingly high. Compared to the diameter of the through hole 28, the dimensions of the constriction are typically reduced by 10 to 50%.
  • the thickness of the lip forming the constriction is typically 0.02 to 0.2 mm.
  • Fig. 9 concerns a sample carrier which is opposite to the sample carrier of Fig. 8 is further extended by a cone 36 and has a flushing channel 37 with two inlets 38 and 39.
  • the formation of an air cushion in the direction of flow in front of the rinsing liquid can be advantageously prevented by first filling the rinsing liquid from the inlet 38 to the inlet 39 and thus removing all air from the rinsing channel 37.
  • the inlet for the sample is blocked by a valve (not shown).
  • the valve is opened and a valve (not shown) is closed at the inlet 39.
  • the rinsing liquid flowing through the inlet 38 now transports the sample quantity 40 out of the sample receiving area.
  • the sample carrier of Fig. 9a similar sample carrier has three conical plug-in elements with which it can be plugged onto a flow cell.
  • the middle plug-in element forms a sample receiving area with an expanding receiving space 71 for receiving a blood sample.
  • the receiving space 71 which has hydrophilically coated walls and can be filled by capillary, is delimited at its end facing away from an opening by a plasma separation membrane 72, which limits the amount of blood sample received.
  • the plasma separation membrane 72 borders on a channel 74 which is coated hydrophilically on the inside and covered by a film 73, the ends of which are connected via a constriction 75 or 76 to a flushing channel 77 or 78 leading through an external plug element.
  • the volume of the receiving space 71 is approximately 2 1 ⁇ 2 times as large as the volume of the channel 74.
  • the middle conical element ends in a blind hole so that the receiving space 71 is closed.
  • Plasma from the blood sample received in the receiving space 71 passes through the plasma separation membrane 77 into the channel 74, which fills up via capillary action, with the constrictions 75, 76 each forming a capillary stop so that a precisely measured amount of plasma fills the channel 74.
  • This amount of plasma can be flushed out via the flushing channels 77, 78 using a flushing liquid or a flushing gas and fed to the processing within the flow cell.
  • the one in Fig. 9a The sample carrier shown therefore has the function of sample preprocessing in addition to the sample holding function.
  • Fig. 10 illustrates possibilities for connecting a sample carrier with different functional areas of a flow cell.
  • Fig. 10a the receiving area of a sample carrier with a conical carrier element protrudes into a mixing chamber 41 of a flow cell, wherein it is connected to the chamber wall via a conical press fit.
  • the mixing chamber can be partially or completely filled with rinsing liquid, e.g. from a reagent reservoir, via a channel 42, whereby the sample is released from the sample carrier and diluted.
  • the flow cell is preferably in a vertical position so that the liquid level in the mixing chamber can be checked through a transparent cover film 43 and/or air in the mixing chamber can escape during the mixing process. To redissolve the sample, it is advantageous to agitate the rinsing liquid, i.e. to pump it back and forth.
  • the diluted sample can be transported through channel 42 or another channel connected to the mixing chamber for further analysis or processing within the flow cell.
  • the flow cell and the sample carrier can have structures such as snap closures, undercuts or locking lugs that lock into place when the sample carrier is connected to the flow cell once and prevent removal of the sample carrier after connection to the flow cell.
  • a sample carrier of Fig. 5a The corresponding sample carrier is in accordance with Fig. 10b connected to a chamber 44 which is arranged close to but outside a center of rotation of the flow cell.
  • the fluid transport takes place partially or completely by centrifugation.
  • the sample is also transported almost completely by centrifugal force into a channel 44a connected to the transport chamber 44 for further analysis.
  • An undiluted liquid sample can be transported away in the manner described.
  • a sample receiving area of a sample carrier with a conical carrier element projects into a transport channel 45 of a flow cell.
  • the end of the conical sample carrier reaches up to a cover film 46 of the flow cell.
  • the sample carrier and the flow cells have an alignment element 47 and 48 respectively to ensure that a groove-shaped sample receiving area is aligned with the transport channel 45.
  • the sample can be transported pneumatically or hydraulically from the sample receiving area in the transport channel 45 of the flow cell to further processing devices.
  • a Fig. 10d In the embodiment shown, alignment structures such as a slot 49 or the like are provided, which indicate that a sample carrier with a groove-shaped sample receiving area is aligned transversely to the longitudinal direction of a transport channel. A sample carrier is still rotatable despite the press fit and can be moved from such a position into the Fig. 5d shown position, where according to example of Fig. 10c the sample collection area can be emptied.
  • FIG. 11 A connection of the sample carrier from Fig. 5 with a flow cell.
  • the flushing channel 30 of the sample carrier is connected to a channel 50 of the flow cell, via which compressed air or flushing liquid is supplied according to arrow 51, which presses the sample quantity 32 into another channel 52 of the flow cell.
  • FIG. 12 An example of a connection of the sample carrier of Fig. 9 with a flow cell shows Fig. 12
  • the stored sample quantity is flushed out via channels 53 to 55 of the flow cell, avoiding an air cushion, as can be seen from Fig. 9 described.
  • Plastics generally have hydrophobic surfaces that are difficult to wet with aqueous fluids such as blood. Hydrophilic surfaces are advantageous for the sample receiving area of sample carriers, also with regard to the precise measurement of sample quantities.
  • Fig. 13a shows a sample carrier whose sample receiving area 57 and whose conical sealing area are hydrophilically coated, e.g. with a glassy layer.
  • the contact angle to water is ⁇ 50°.
  • surface treatment is limited to a groove-shaped receiving area 58, which can be hydrophilically modified, for example, by wet-chemical treatment or masked plasma coating.
  • the sample is preferably taken up by dipping the sample carrier into a drop of sample, e.g. blood on a fingertip.
  • the amount of sample taken up is defined by the geometry of the hydrophilically modified sample receiving area. In the adjacent areas with a hydrophobic surface, the sample hardly adheres or does not adhere at all.
  • Fig. 13c corresponds to the previous embodiment, but additionally has a hydrophobic coating 60 outside the sample receiving area 59.
  • the typical contact angle is > 90° in order to further increase the contrast of wettability between the receiving area and the adjacent area and thus to measure sample quantities even more precisely.
  • Fig. 13d shows an embodiment of a sample carrier that consists of two differently wettable plastics.
  • a core part 56 of a conical carrier element has a contact angle ⁇ 70°, e.g. PMMA, while an outer area of the conical carrier element, which consists of e.g. olefin plastic such as PP, has a contact angle > 90°.
  • the geometry of the core part 56 is cylindrical.
  • the material combination is selected so that the two materials (e.g. PP and PMMA, PP and POM) are not firmly connected during two-component injection molding, but rather are movably connected.
  • Such "assembly injection molding” in which the inner core remains movable, allows a sample receiving area to be formed that can be emptied by moving the inner core.
  • a groove-shaped sample receiving area is formed which is closed on one side with a film 61 but is open at the ends.
  • the inner walls of this channel-shaped receiving area can be hydrophilically coated, for example, by wet chemical or plasma treatment.
  • a sample receiving area is partially or completely coated and functionalized with a dry reagent 62.
  • a sample can be conditioned directly after being received by the sample carrier before the sample carrier is connected to a flow cell or other processing device.
  • an anticoagulation reagent can be applied which, for example, prevents a quantity of blood from clotting on the sample carrier, whereby materials such as heparin or citrate can be considered for this.
  • the dry reagent can also be a lysis buffer for lysing cells, e.g. a blood sample.
  • Fig. 14a again a sample carrier with a handling area surrounding the conical carrier element in a pot-shaped manner
  • the embodiment of Fig. 14b a sample carrier with a conical handle 64 and a receiving area 63.
  • a conical handle part 65 can be broken off at a predetermined breaking point 66 after connection of the sample carrier, e.g. with a flow cell.
  • Fig. 14d shows a sample carrier with a recess 67 into which a handling pin 68 can be inserted which can be removed after the sample carrier has been connected, e.g. to a flow cell.
  • a conically widening sample receiving chamber 79 is formed in a first plastic injection-molded part 81, which is delimited by a plasma separation membrane 80, which initially stops the capillary filling of the sample receiving chamber 79 with a blood sample.
  • a second conical injection-molded part 82 glued or welded to the first injection-molded part 81, has a passage 83 that can be filled by capillary. Both the sample receiving chamber 79 and the passage 83 have a hydrophilic coating on the inside.
  • the sample carrier can be connected to a flow cell via the conical injection-molded part 82.
  • plasma After filling a blood sample into the receiving chamber 79, plasma passes through the plasma separation membrane 80 into the passage 83, the open end of which forms a capillary stop that doses the plasma sample.
  • the first injection-molded part 81 can serve as a handle element, with a cover cap being used to prevent possible contamination of the environment by blood remaining in the receiving space 79.
  • the blood plasma to be analyzed by the flow cell can be sucked out of the passage with the aid of a fleece or a membrane adjacent to the opening of the passage 83.
  • Fig. 16 shows a sample carrier made in one piece as a plastic injection molded part, which has a passage 86 with a constriction 85. Up to the constriction 85, the passage 86 forms a sample receiving capillary 84. The passage 86 runs through a conical element and a handle part connected in one piece to the conical element. An annular shoulder 87 is formed between the handle part and the conical element. When a sample is received in the sample receiving capillary 84, the remaining passage 86 forms a vent channel. When the sample carrier is connected to a flow cell, the passage 86 can also form a flushing channel for flushing the sample into the flow cell.
  • Fig. 17 shows the sample carrier of Fig. 16 in conjunction with a pen-like handling device 88, which can be attached with one end to the ring shoulder 87 and with a conical inner wall 93 to a conical end of the sample carrier and can be used to attach the sample carrier to a flow cell.
  • the handling device has a core element 89 which can be moved in the axial direction in the manner of a ballpoint pen refill, via the movement of which according to Fig. 17c the handling device 88 can be detached from the sample carrier attached to the flow cell.
  • the core element 89 can also have a clamping projection 92 for engaging in the passage 86 of the sample carrier.
  • the clamping is provided in such a way that ventilation of the sample channel is not disturbed.
  • Fig. 18b the outer part of the handling device 88 is pushed forward relative to the core element 89 under pressure against the annular shoulder 87.
  • Fig. 19 indicates that the sample carrier could also have a sample receiving area 90 in the form of a groove or recess, as described above in connection with, for example, the sample carrier 7 of Fig. 4
  • the core element 89 of the handling device 88 could then clamp into a longitudinal channel 91 of the sample carrier.
  • Fig. 20 shows a dosing element with a conical plug attachment 94, via which it can be connected to a Fig. 21
  • the plug attachment 94 has a groove channel 95 in an end wall at the free end and is connected to a rotary handle 96 comprising two wings with a stop 97 and 98 on each of the wings.
  • the in Fig. 21 The flow cell shown has a conical plug-in opening 99 for receiving the plug attachment 94.
  • a sample can be introduced into the flow cell via an input port 100, for example using a pipette or syringe.
  • the input port 100 is connected to an overflow port 102 via a channel 101 and the plug-in opening 99.
  • the flow cell consists of a plate 103 and a film 104 which is glued or welded to the plate and covers the channel 101.
  • the flow cell also has flushing connections 105 and 106, which are connected to one another via a channel 107. Stops 108 and 109 are formed on the plate 103 on the side facing away from the channels 101, 107.
  • the dosing element is inserted with the plug attachment 94 first into the plug opening 99 of the flow cell, whereby the groove channel 95 is covered by the film 104.
  • the dosing element is located in the Fig. 22a shown rotational position, in which the wings of the rotary handle 96 rest against the stops 108 and 109. In this position, according to Fig. 22b the groove channel 95 of the conical plug attachment 94 the channel 101 between the input port 100 and the overflow port 102. A sample material filled into the input port 100 can overflow into the overflow port 102.
  • the dosing element is rotated by 90°, whereby it is Fig. 22c with its stops 97 and 98 against the input port 100 and overflow port 102 respectively ( Fig. 22c ). In this position, the openings of the ports are sealed by the wings of the rotary handle 96. The rotation measures a sample quantity that corresponds to the internal volume of the grooved channel 95. In this position, the grooved channel 95 supplements the channel 107 between the flushing connections 105,106.
  • the dosage amount of a sample contained in the groove channel 95 can therefore be flushed out of the flow cell via the flushing connections 105 and 106 and fed for further processing.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (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)
  • Investigating Or Analysing Biological Materials (AREA)

Claims (10)

  1. Utilisation d'une cellule à écoulement et d'un porte-échantillon (7) pouvant être relié à la cellule à écoulement, pour mesurer un volume d'un échantillon à analyser par la cellule à écoulement et pour introduire le volume d'échantillon dans la cellule à écoulement,
    dans laquelle la cellule à écoulement présente une ouverture qui débouche dans une cavité dans la cellule à écoulement et que le porte-échantillon (7) obture de manière étanche aux fluides à la manière d'un bouchon et qui forme un ajustement serré pour un élément porteur conique (8) du porte-échantillon (7),
    l'élément porteur conique (8) présente, sur une face frontale tournée vers la cavité, une zone de réception d'échantillon (9) comprenant des moyens de réception dosée de l'échantillon, et
    le porte-échantillon (7) présente, sur une face détournée la zone de réception d'échantillon (9), une zone pour la manipulation du porte-échantillon (7),
    et dans laquelle l'échantillon, mesurant un volume d'échantillon compris entre 1 et 100 µl, adhère au porte-échantillon (7) par des forces capillaires dans la zone de réception d'échantillon (9), et le porte-échantillon (7) avec le volume d'échantillon qui y adhère par les forces capillaires est inséré dans l'ouverture (12) pour introduire l'échantillon dans la cellule à écoulement.
  2. Utilisation selon la revendication 1,
    caractérisée en ce que
    l'échantillon à analyser, placé conjointement avec le porte-échantillon (7) dans la cellule à écoulement, est adjacent à la cavité (4, 41, 44, 45, 46, 52, 54) dans la cellule à écoulement, se présentant sous la forme d'un canal de transport (45, 46, 52), d'une chambre (4, 41, 44), en particulier d'une chambre de mélange (41), ou/et d'une membrane absorbant l'échantillon.
  3. Utilisation selon la revendication 1 ou 2,
    caractérisée en ce que
    l'échantillon placé conjointement avec le porte-échantillon (7) dans la cellule à écoulement peut être détaché de la zone de réception (9) par un écoulement de fluide, l'écoulement de fluide pouvant être généré par exemple par vidange d'un réservoir de réactifs intégré dans le dispositif d'analyse ou relié au dispositif d'analyse de manière étanche au fluide.
  4. Utilisation selon l'une des revendications 1 à 3,
    caractérisée en ce que
    le porte-échantillon présente des dispositifs pour le prétraitement du matériau échantillon, amené au porte-échantillon, de l'échantillon à analyser, les dispositifs de prétraitement comprenant de préférence des moyens de dosage, des agents réactifs (62) ou/et des moyens de séparation (72 ; 80), en particulier pour la séparation du plasma sanguin.
  5. Utilisation selon l'une des revendications 1 à 4,
    caractérisée en ce que
    le porte-échantillon comporte des dispositifs d'évacuation de l'échantillon à analyser du porte-échantillon, en particulier un canal de rinçage (77, 78 ; 86).
  6. Utilisation selon l'une des revendications 1 à 5,
    caractérisée en ce que
    les moyens de réception dosée de l'échantillon comprennent des délimitations spatiales de la zone de réception d'échantillon (9).
  7. Utilisation selon l'une des revendications 1 à 6,
    caractérisée en ce que
    les moyens de réception dosée de l'échantillon comprennent au moins un revêtement de surface pour contrôler la mouillabilité de la zone de réception (9) ou des matériaux plastiques mouillables différemment et adjacents à la zone de réception d'échantillon (9).
  8. Utilisation selon l'une des revendications 1 à 7,
    caractérisée en ce que
    le porte-échantillon obturant l'ouverture à la manière d'un bouchon peut tourner dans l'ouverture en obturant l'ouverture de manière étanche aux fluides.
  9. Utilisation selon l'une des revendications 1 à 8,
    caractérisée en ce que
    il est prévu un dispositif d'obturation empêchant le retrait du porte-échantillon (7) relié à la cellule à écoulement.
  10. Utilisation selon l'une des revendications 1 à 9,
    caractérisée en ce que
    la zone de réception comprend un réactif sec (62) pour une première réaction avec l'échantillon, destinée au prétraitement du matériau échantillon.
EP15173174.2A 2015-06-22 2015-06-22 Porte échantillons Active EP3108962B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP15173174.2A EP3108962B1 (fr) 2015-06-22 2015-06-22 Porte échantillons
PCT/EP2016/060498 WO2016206854A1 (fr) 2015-06-22 2016-05-11 Porte-échantillon
US15/738,421 US11045802B2 (en) 2015-06-22 2016-05-11 Sample carrier

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP15173174.2A EP3108962B1 (fr) 2015-06-22 2015-06-22 Porte échantillons

Publications (2)

Publication Number Publication Date
EP3108962A1 EP3108962A1 (fr) 2016-12-28
EP3108962B1 true EP3108962B1 (fr) 2024-10-16

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US (1) US11045802B2 (fr)
EP (1) EP3108962B1 (fr)
WO (1) WO2016206854A1 (fr)

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EP3342485B1 (fr) * 2017-01-02 2020-07-08 Thinxxs Microtechnology Ag Supports d'éléments de réactifs
US12042793B2 (en) 2018-01-18 2024-07-23 Qiagen Gmbh Dry chemistry container
US11940458B2 (en) * 2018-11-30 2024-03-26 Sekisui Chemical Co., Ltd. Measurement tool for collecting bodily samples with improved measurement precision
US20220161262A1 (en) * 2019-04-08 2022-05-26 Withings System and apparatus for injecting droplets in a microfluidic system
EP3747542A1 (fr) 2019-06-07 2020-12-09 Thinxxs Microtechnology Ag Système de transfert pour échantillons, en particulier échantillons à analyser

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Also Published As

Publication number Publication date
WO2016206854A1 (fr) 2016-12-29
EP3108962A1 (fr) 2016-12-28
US11045802B2 (en) 2021-06-29
US20180185841A1 (en) 2018-07-05

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