EP2308597A2 - Micro-fluidic structure and method for measuring and/or positioning a liquid volume - Google Patents
Micro-fluidic structure and method for measuring and/or positioning a liquid volume Download PDFInfo
- Publication number
- EP2308597A2 EP2308597A2 EP20100186100 EP10186100A EP2308597A2 EP 2308597 A2 EP2308597 A2 EP 2308597A2 EP 20100186100 EP20100186100 EP 20100186100 EP 10186100 A EP10186100 A EP 10186100A EP 2308597 A2 EP2308597 A2 EP 2308597A2
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- EP
- European Patent Office
- Prior art keywords
- liquid
- abmesskanal
- valve
- gas
- abmesskanals
- 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.)
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- 239000007788 liquid Substances 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000012530 fluid Substances 0.000 claims abstract description 52
- 239000012528 membrane Substances 0.000 claims abstract description 18
- 239000000758 substrate Substances 0.000 claims abstract description 10
- 238000000926 separation method Methods 0.000 claims description 15
- 238000005086 pumping Methods 0.000 claims description 13
- 238000005259 measurement Methods 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 2
- 239000013039 cover film Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002313 adhesive film Substances 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229920005597 polymer membrane Polymers 0.000 description 1
- -1 polytetrafluoroethylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Images
Classifications
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- 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
-
- 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
- B01L3/502738—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 integrated valves
-
- 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
- B01L2200/0605—Metering of fluids
-
- 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
- B01L2300/0883—Serpentine channels
-
- 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
- B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
-
- 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
- B01L2400/0622—Valves, specific forms thereof distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/06—Valves, specific forms thereof
- B01L2400/0633—Valves, specific forms thereof with moving parts
- B01L2400/0644—Valves, specific forms thereof with moving parts rotary valves
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2400/00—Moving or stopping fluids
- B01L2400/06—Valves, specific forms thereof
- B01L2400/0694—Valves, specific forms thereof vents used to stop and induce flow, backpressure valves
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T137/00—Fluid handling
- Y10T137/8593—Systems
Definitions
- the invention relates to a Abmesskanal for use in a microfluidic system, a microfluidic structure in a substrate, in particular in a lab-on-chip system, with a plurality of fluid lines including a Abmesskanals and connected to the fluid lines valve for selectively connecting and / or disconnecting the fluid lines.
- the invention further relates to a method for measuring and / or positioning a volume of a liquid in a microfluidic system, in particular in a lab-on-chip system.
- the measuring and positioning or distribution of liquids in a microfluidic chip is known to be done with the help of so-called Abmessschleifen in combination with one or more rotary valves and fluidic light barriers. Since virtually no more than two such Abmessschleifen can be connected via a valve, it requires the dimensioning and positioning of more than two liquids of several separate valve assemblies. The space required increases as a result, as well as the number of valve components and the optical components for the realization of the light barriers. Overall, this increases the cost of the system. Furthermore, through the combination of Abmessschleifen and rotary valves increased dead volumes and fluid losses are accepted.
- the object of the present invention is to reduce the above disadvantages and to provide a cost-effective and efficient method for measuring and / or positioning a volume of a liquid in a microfluidic To provide system or a cost microfluidic structure for this purpose.
- the inventive Abmesskanal for use in a microfluidic system in particular in a lab-on-chip system, has a first end, on which a first liquid-impermeable and gas-permeable wall portion is provided, which provides a gas connection, and a second end to which the Abmesskanal is connectable to at least one fluid line and to which a separation means is arranged, wherein in the Abmesskanal between the wall portion and the separating means a defined volume is included on.
- the Abmesskanal which may for example be formed as a groove in a microfluidic chip and completed with a cover foil is limited by one or more the channel cross-section defining walls.
- wall portion in the sense of this document is meant a limited, contiguous portion of one or more of these walls.
- the channel is further limited by its two ends, which, however, do not require frontal walls, but initially only indicate positions and define the length or the volume of the Abmesskanals. The first end is thus the position of the first wall section along the Abmesskanals, the second end of the separation means.
- the measuring takes place in the Abmesskanal (even without active optical monitoring) alone by filling the Abmesskanals up to the first wall section with a liquid and separating the volume of liquid trapped in the Abmesskanal between the wall portion and the separating means of a pending on the side of its second end in front of the separating means excess liquid residue.
- the Abmesskanal is preferably closed or closed at a first end.
- the following is also spoken of a dead channel.
- This shape has the advantage, in particular in conjunction with the fact that the first liquid-impermeable and gas-permeable wall section is arranged at the closed or closable end of the Abmesskanals, that a small dead space and a very precise positioning of the metered liquid plug is ensured.
- the separation means is advantageously designed as a second liquid-impermeable and gas-permeable wall section which provides a gas connection.
- the separation or measuring takes place in the Abmesskanal (without active optical monitoring) alone by applying a pressure difference between an opening into the Abmesskanal filling opening and the gas connection over the first liquid-impermeable and gas-permeable wall section. Since pressure control for moving and positioning the so-called liquid plugs is necessary anyway in most microfluidic systems, the invention thus requires a smaller amount of equipment for measuring in comparison with measuring devices according to the prior art.
- the separation means is advantageously designed as a valve alternatively.
- the valve is again preferably at the same time separating means for measuring the volume of liquid and control valve for selectively connecting and / or separating the Abmesskanals with a desired fluid line (inlet or outlet). Also in this embodiment, the Abmesskanal comes without additional Fluid control or fluid control components.
- Valve controls of different types are basically known in microfluidics. It will be an example of the writings US 2005/0056321 A1 or DE 102 28 767 A1 directed.
- liquid-impermeable and gas-permeable wall sections are preferably designed in the form of a membrane and / or have a capillary structure passing through the channel wall, which presents an increased resistance to the passage of a liquid. It is crucial in both cases that the liquid through the wall section - if any - only by applying an increased limit differential pressure .DELTA.P G between the internal pressure P i in the Abmesskanal and the external pressure P a in the gas connection, starting from a for filling, emptying, or in general to overcome the normal differential pressure ⁇ P N used to convey the liquid.
- a membrane as a liquid-impermeable and gas-permeable wall section, this preferably consists of a non-wettable material, preferably a polymer membrane and particularly preferably polytetrafluoroethylene.
- a non-wettable material preferably a polymer membrane and particularly preferably polytetrafluoroethylene.
- Such liquid-impermeable and gas-permeable membranes in a microfluidic system are known, for example, from the document US 2005/0266582 A1 known.
- the gas connection is formed according to a preferred embodiment of the invention by an exhaust port beyond the liquid-impermeable and gas-permeable wall portion to the environment.
- This construction is simple, as no pump connection is needed on the side of the gas connection.
- the liquid transport in the metering channel is controlled on the inlet or outlet side, wherein the filling in this embodiment at the inlet requires an overpressure and the emptying at the outlet requires a negative pressure.
- the microfluidic structure according to the invention in a substrate, in particular in a lab-on-chip system has a plurality of fluid conduits for receiving and / or conducting a fluid flow and a valve connected to the fluid conduits for selectively connecting and / or disconnecting the fluid conduits.
- One of the fluid conduits is in the form of a metering channel as described above which is connected on the side of its second end via the valve to at least one other fluid conduit and closed or closable on the side of its first end.
- "On the side of the first and second ends”, respectively, implies that the closure or valve forms the respective end of the metering channel, that is to say functionally associated with it, and that they lie at a distance from the ends outside the fluid channel.
- a closure forming the first end which coincides with the first wall portion, allows filling and emptying with minimal fluid loss through dead spaces.
- the filling, measuring and emptying can be realized in a simple manner.
- the valve for selectively connecting and / or separating the fluid lines forms the separating means. It is also possible for a plurality of valves, and in particular more than two, of the metering channels according to the invention to be connected to one valve.
- the gas connection and / or the at least one other fluid line is preferably connectable to a pump device which is set up to generate a pressure difference between the gas connection and the at least one other fluid line for supplying and / or discharging a fluid into the measurement channel.
- a pump device which is set up to generate a pressure difference between the gas connection and the at least one other fluid line for supplying and / or discharging a fluid into the measurement channel.
- the chip with the microfluidic structure according to the invention can be inserted into a so-called operator device, which provides a fluidic connection to the microfluidic chip via interfaces.
- a pressure measuring device communicating with a fluid line in the microfluidic structure is provided, the signal of which can advantageously be used to control the pumping device according to one of the methods described below.
- two or more of the above-described Abmesskanäle be arranged one behind the other, wherein the second end of a first Abmesskanals forms the first end of a second Abmesskanals.
- step b) After filling in step b) is filled depending on the available amount of liquid, the entire Abmesskanal or only a part thereof. However, if the metering channel is in any case filled via the separating means, separation c) ensures that only exactly that between the first wall section and the defined, remaining liquid volume remains for further use.
- step c If, as stated above, after the filling in step b), the metering channel is filled beyond the second wall section closer to the valve, it is ensured by the removal in step c ") that only the precisely defined liquid volume remaining between the wall sections in the metering channel remains remains for further use.
- This variant represents the simpler case of a transverse filling, ie running in the direction of the channel.
- the case is simpler insofar as the measuring has already taken place in one step.
- the prerequisite is that the liquid is sucked through the inlet opening by a lower pressure at the gas connections than the pressure prevailing in the rest of the system.
- the valve then serves to connect the metering channel to an outlet channel for emptying.
- the second end of a first measuring channel forms the first end of a second measuring channel
- the steps a) to c) or the step d) repeated.
- the first filling of the Abmesskanals according to step b) takes place up to the first closer to the valve second wall portion which forms the starting point and the first wall portion during the second filling. Accordingly, the first removal takes place the excess liquid according to step d) of the first second wall portion and the second removal from a valve closer to the separation means.
- the term "initially second” or “initially closer” refers to the wall section / separating means closer to the valve in the first filling / removal, and the indication “lying closer again” refers to the wall section / separating means closer to the valve in the second filling / removal.
- supply line first derivative and second derivative is functional to understand and, so to speak, the same physical fluid line may be designated.
- the filling is preferably carried out by continuously pumping the liquid into the metering channel by means of a pumping device.
- Continuous pumping is one of two alternative pumping principles in addition to constant pressure pumping.
- the pressure in the system is preferably monitored by means of a pressure measuring device communicating with the supply line or the metering channel.
- the pressure at which the pumping device is switched off is higher than the system normal pressure P i and less than the limit differential pressure ⁇ P G between an increased internal pressure P ' i in the metering channel and the external pressure P a in the gas port the liquid breaks through the liquid-impermeable and gas-permeable wall section.
- FIG. 1 the Abmesskanal 10 according to the invention is shown in a section through a microfluidic chip 12.
- the microfluidic chip 12 typically has a substrate 14, in which the Abmesskanal 10 and any other fluid lines and / or other functional structures from its top 16 and / or its bottom 17 (this case is not shown here) are incorporated.
- substrates with the fluid lines are produced by injection molding. Alternatively, they can also be milled into the surface of the substrate 14 or embossed in the injection-compression molding process.
- the Abmesskanal 10 and the other, not shown here, fluid lines are closed to the environment by means of a cover film 18 on the top 16 (or bottom).
- the cover sheet 18 is provided with two openings 20 and 22, of which an opening 20 opens flush with an end face 24 of the Abmesskanals 10 in the same. Due to the measuring surface 10 unilaterally limiting end face 24 of the Abmesskanal 10 for the liquid is a dead channel, but not for a gas which, as described below, can flow out of the channel 10 through the openings 20 and 22.
- the liquid of Abmesskanal thus has only one access opening 25 through which it is fluidly connected or connected to the connected fluid lines. Nevertheless, it can be completely filled without dead spaces due to the flush with the opening 20 end surface 24.
- the opening 20 Above the opening 20 is a liquid-impermeable and gas-permeable first wall section and above the opening 22 is a liquid-impermeable and gas-permeable second wall section.
- the first wall portion and the second wall portion are each in the form of a membrane 26 and 28 is formed. Due to their gas permeability, these membranes provide a gas connection 27 or 29 for the metering channel 10.
- For the supply or supply of gas is on the outside of the membranes 26 and 28 each have a gas line 30 and 32 flanged or mounted by the operator device.
- the arrangement of the membranes as well as the gas lines is shown here only schematically simplified.
- the membranes are preferably embedded in a membrane seat formed in the substrate and held, for example, by means of a pressing ring.
- the pressing ring is preferably captively (ultrasonically) welded to the substrate and forms with the substrate a flush surface, which provides a sealing surface for the connection of a gas line.
- This pressure increase can be detected by a suitable pressure measuring device (not shown) which is connected to a fluid line communicating with the metering channel 10. The corresponding signal is then supplied to a pump control, which shuts off the pump, to the increased internal pressure P ' i not so far increase so that the pressure difference between P ' i and P a exceeds the limit differential pressure .DELTA.P G , at which the liquid would escape through the membrane.
- the liquid column is in front of the metering channel 10 beyond the second opening 22.
- the measuring is now carried out in a second step by the second gas port 29 closer to the access opening 25 is acted upon by a higher external pressure P a than the internal pressure P i .
- the resulting pressure difference causes the liquid present in front of the opening 22 in the direction of the access opening 25 to be pushed or sucked out of the channel in the opposite direction, so that only the volume V of liquid V between the two openings determined by the length of the measuring channel 10 remains 20 and 22 remains.
- the second wall section thus forms the separating means.
- This precisely metered volume of liquid can then be discharged from the metering channel 10 for further use by applying the gas port 27, which is further away from the opening 25, to a higher external pressure P a than the internal pressure P i .
- FIG. 2 an exemplary microfluidic structure with a plurality of fluid lines on a microfluidic chip 100 is shown schematically simplified in plan view.
- the plurality of fluid lines are: a supply line 102, a first, Abmesskanal 104, a merge channel or second, separate Abmesskanal 106, a meandering mixing section 108, a third Abmesskanal 110, which actually consists of two directly adjacent Abmesskanälen, and a discharge 112.
- a rotary valve 114 is provided which selectively connects or disconnects the fluid lines.
- the supply line 102 opens in the center of the rotary valve 114 and can via a first valve port 116 are selectively connected to each of the fluid lines 104, 106, 108, 112 directly.
- the first metering channel 104 has at its end remote from the rotary valve 114 a liquid-impermeable and gas-permeable first wall section 118.
- the first wall section 118 is formed by a membrane which fits into a membrane seat 120.
- the merge passage 106 has two liquid-impermeable and gas-permeable first and second wall sections 122 and 124 spaced one behind the other, of which the first wall section 124 is at the opposite end of the rotary valve 114, and thus the second wall section 122 is approximately midway in the merge passage 106 and thus closer are arranged to the rotary valve 114. Between the two wall sections 122 and 124 opens a transverse filling opening 126 in the Georgia Events- or second Abmesskanal 106th
- the mixing channel 108 is folded meander-shaped, so that two immediately consecutively introduced fluids due to the long distance and the multiple direction reversal at the output 128 of the meander arrived mixed.
- the third Abmesskanal 110 connects, which has a total of three liquid-impermeable and gas-permeable wall sections 130, 132 and 134.
- the wall portion 130 is the valve 114 nearest, the wall portion 134 of the valve 114 farmost wall portion.
- the second Abmesskanal 106 between the distal first wall portion 124 and the closer second wall portion 122 through the filling opening 126 (for example by means of a syringe or by dropping a drop on the filling opening) with a liquid A (shown as a black bar) filled by a pressure difference is applied between the liquid flowing through the filling opening 126 on the one hand and the two gas ports on the wall portions 124 and 122 on the other hand.
- the pressure difference causes the filling of the merge passage 106 to stop as soon as the fluid covers both wall sections 122 and 124.
- the filling opening 126 can be closed, for example by means of an adhesive film or a plug.
- the supply line 102 is connected to the first metering channel 104 and the metering channel 104 is subsequently filled with a liquid B (shown as a black bar) by applying a pressure difference between the supply line 102 and the first wall section 118 of the first metering channel.
- a liquid B shown as a black bar
- the gas connection can be switched to ambient pressure via the first wall section 118 and the supply line 102 can be operated with overpressure. If the wall section 118 is reached by the liquid B, a pressure rise can be registered with a pressure measuring device, not shown, which is for example in fluid communication with the supply line 102. A corresponding signal can then be supplied to the pressure source or pumping device or a valve and these automatically cause the fluid flow to be switched off or diverted.
- the rotary valve 114 is adjusted so that the first Abmesskanal 104 is connected to the input of the second Abmesskanals 106. At the same time the supply line 102 of the first Abmesskanal 104 separated.
- the valve 114 thus acts simultaneously as a release agent in the context of the invention.
- a pressure difference between the wall portion 118 of the first Abmesskanals 104 and the valve 114 closer wall portion 122 of the second Abmesskanals 106 moves the previously located in the Abmesskanal 104, measured liquid B up to the wall portion 122 in the second Abmesskanal 106 inside.
- a fourth step according to FIG. 6 the rotary valve 114 is further rotated by one step, so that it connects the second metering channel 106 with the meandering mixing channel 108.
- a pressure difference between the rotary valve 114 further lying wall portion 124 of the second Abmesskanals 106 and at least the valve 114 distalmost wall portion 134 of the third Abmesskanals 110 are both liquids A and B initially successively through the meandering mixing channel 108 promoted, mixed therein and then in the third Abmesskanal 110 advanced to its distance from the mixing channel wall portion 134, see.
- FIG. 7
- the mixed liquid AB is then measured by the excess excess liquid located in front of the second wall section 130 closest to the valve 114 by applying a pressure difference between the gas connection over the second wall section 130 and the gas connection above the wall section 124 of the second dimensioning channel 106 remote from the valve derived the second Abmesskanal 106.
- the second Abmesskanal 106 is used in the used state as a waste channel or waste.
- the liquid AB located between the second wall portion 130 closest to the valve 114 and the nearest, middle (first) wall portion 132 is transported for further use inside or outside the microfluidic chip in the direction of the discharge line 112 by a pressure difference is applied between the gas port of the wall portion 132 and the internal pressure of the drain 112.
- FIGS. 2 to 10 The basis of the FIGS. 2 to 10 For example, it is incumbent on the skilled person to generate the respectively necessary for the liquid transport pressure difference either by suction or pressure described sequence and the design of the microfluidic structure. It becomes apparent from the overall view of the present specification that it is not necessary to focus solely on the embodiment described in detail, but rather the underlying and in the patent claims specified method, the Abmesskanal and the microfluidic structure are relevant to the scope of protection.
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Abstract
Description
Die Erfindung betrifft einen Abmesskanal zur Verwendung in einem mikrofluidischen System, eine mikrofluidische Struktur in einem Substrat, insbesondere in einem Lab-on-Chip-System, mit mehreren Fluidleitungen einschließlich eines Abmesskanals und einem mit den Fluidleitungen verbundenen Ventil zum wahlweisen Verbinden und/oder Trennen der Fluidleitungen. Die Erfindung betrifft ferner ein Verfahren zum Abmessen und/oder Positionieren eines Volumens einer Flüssigkeit in einem mikrofluidischen System, insbesondere in einem Lab-on-Chip-System.The invention relates to a Abmesskanal for use in a microfluidic system, a microfluidic structure in a substrate, in particular in a lab-on-chip system, with a plurality of fluid lines including a Abmesskanals and connected to the fluid lines valve for selectively connecting and / or disconnecting the fluid lines. The invention further relates to a method for measuring and / or positioning a volume of a liquid in a microfluidic system, in particular in a lab-on-chip system.
Das Abmessen und Positionieren bzw. Verteilen von Flüssigkeiten in einem Mikrofluidikchip erfolgt bekanntermaßen mit Hilfe von sogenannten Abmessschleifen in Kombination mit einem oder mehreren Drehventilen und fluidischen Lichtschranken. Da praktisch nicht mehr als zwei solcher Abmessschleifen über ein Ventil verbunden werden können, bedarf es zur Abmessung und Positionierung von mehr als zwei Flüssigkeiten mehrerer getrennter Ventilanordnungen. Der Platzbedarf steigt in Folge dessen ebenso wie die Anzahl von Ventilkomponenten und der optischen Komponenten zur Realisierung der Lichtschranken. Insgesamt erhöht dies die Kosten des Systems. Ferner werden durch die Kombination von Abmessschleifen und Drehventilen erhöhte Totvolumina und Flüssigkeitsverluste in Kauf genommen.The measuring and positioning or distribution of liquids in a microfluidic chip is known to be done with the help of so-called Abmessschleifen in combination with one or more rotary valves and fluidic light barriers. Since virtually no more than two such Abmessschleifen can be connected via a valve, it requires the dimensioning and positioning of more than two liquids of several separate valve assemblies. The space required increases as a result, as well as the number of valve components and the optical components for the realization of the light barriers. Overall, this increases the cost of the system. Furthermore, through the combination of Abmessschleifen and rotary valves increased dead volumes and fluid losses are accepted.
Aufgabe der vorliegenden Erfindung ist es, die vorstehenden Nachteile zu reduzieren und ein kostengünstiges und effizientes Verfahren zum Abmessen und/oder Positionieren eines Volumens einer Flüssigkeit in einem mikrofluidischen System bzw. eine kostengünstige mikrofluidische Struktur zu diesem Zweck bereitzustellen.The object of the present invention is to reduce the above disadvantages and to provide a cost-effective and efficient method for measuring and / or positioning a volume of a liquid in a microfluidic To provide system or a cost microfluidic structure for this purpose.
Die Aufgabe wird gelöst durch einen Abmesskanal mit den Merkmalen des Patentanspruches 1, eine mikrofluidische Struktur mit den Merkmalen des Patentanspruches 5 und ein Verfahren mit den Merkmalen der Patentansprüche 8 oder 9. Vorteilhafte Weiterbildungen sind Gegenstand der Unteransprüche.The object is achieved by a Abmesskanal with the features of claim 1, a microfluidic structure with the features of claim 5 and a method having the features of claims 8 or 9. Advantageous further developments are the subject of the dependent claims.
Der erfindungsgemäße Abmesskanal zur Verwendung in einem mikrofluidischen System, insbesondere in einem Lab-On-Chip-System, weist ein erstes Ende, an dem ein erster flüssigkeitsundurchlässiger und gasdurchlässiger Wandabschnitt angeordnet ist, der einen Gasanschluss bereitstellt, und ein zweites Ende, an dem der Abmesskanal mit wenigstens einer Fluidleitung verbindbar ist und an dem ein Abtrennmittel angeordnet ist, wobei in dem Abmesskanal zwischen dem Wandabschnitt und dem Abtrennmittel ein definiertes Volumen eingeschlossen ist, auf.The inventive Abmesskanal for use in a microfluidic system, in particular in a lab-on-chip system, has a first end, on which a first liquid-impermeable and gas-permeable wall portion is provided, which provides a gas connection, and a second end to which the Abmesskanal is connectable to at least one fluid line and to which a separation means is arranged, wherein in the Abmesskanal between the wall portion and the separating means a defined volume is included on.
Der Abmesskanal, der beispielsweise als Nut in einem mikrofluidischen Chip ausgebildet und mit einer Deckelfolie abgeschlossen sein kann, wird durch eine oder mehrere den Kanalquerschnitt definierende Wände begrenzt. Unter "Wandabschnitt" im Sinne dieser Schrift wird ein begrenzter, zusammenhängender Abschnitt einer oder mehrerer dieser Wände verstanden. Der Kanal wird ferner durch seine beiden Enden begrenzt, die jedoch keine stirnseitigen Wände voraussetzen, sondern zunächst lediglich Positionen angeben und die Länge bzw. das Volumen des Abmesskanals definieren. Das erste Ende ist also die Position des ersten Wandabschnittes entlang des Abmesskanals, das zweite Endes die des Abtrennmittels.The Abmesskanal, which may for example be formed as a groove in a microfluidic chip and completed with a cover foil is limited by one or more the channel cross-section defining walls. By "wall portion" in the sense of this document is meant a limited, contiguous portion of one or more of these walls. The channel is further limited by its two ends, which, however, do not require frontal walls, but initially only indicate positions and define the length or the volume of the Abmesskanals. The first end is thus the position of the first wall section along the Abmesskanals, the second end of the separation means.
Das Abmessen erfolgt in dem Abmesskanal (auch ohne aktive optische Überwachung) alleine durch Befüllen des Abmesskanals bis zu dem ersten Wandabschnitt mit einer Flüssigkeit und Abtrennen des in dem Abmesskanal zwischen dem Wandabschnitt und dem Abtrennmittel eingeschlossenen Flüssigkeitsvolumens von einem auf der Seite seines zweiten Endes vor dem Abtrennmittel anstehenden überschüssigen Flüssigkeitsrest.The measuring takes place in the Abmesskanal (even without active optical monitoring) alone by filling the Abmesskanals up to the first wall section with a liquid and separating the volume of liquid trapped in the Abmesskanal between the wall portion and the separating means of a pending on the side of its second end in front of the separating means excess liquid residue.
Der Abmesskanal ist bevorzugt an einem ersten Ende geschlossen oder verschließbar. In diesem Fall wird nachfolgend auch von einem Totkanal gesprochen. Diese Gestalt hat insbesondere in Verbindung damit, dass der erste flüssigkeitsundurchlässige und gasdurchlässige Wandabschnitt an dem geschlossenen oder verschließbaren Ende des Abmesskanals angeordnet ist, den Vorteil, dass ein geringer Totraum und eine sehr präzise Positionierung des abgemessenen Flüssigkeitsplugs gewährleistet wird.The Abmesskanal is preferably closed or closed at a first end. In this case, the following is also spoken of a dead channel. This shape has the advantage, in particular in conjunction with the fact that the first liquid-impermeable and gas-permeable wall section is arranged at the closed or closable end of the Abmesskanals, that a small dead space and a very precise positioning of the metered liquid plug is ensured.
Das Abtrennmittel ist vorteilhafter Weise als ein zweiter flüssigkeitsundurchlässiger und gasdurchlässiger Wandabschnitt ausgebildet, der einen Gasanschluss bereitstellt. Das Abtrennen bzw. Abmessen erfolgt in dem Abmesskanal (ohne aktive optische Überwachung) alleine durch Anlegen einer Druckdifferenz zwischen einer in den Abmesskanal mündenden Einfüllöffnung und dem Gasanschluss über dem ersten flüssigkeitsundurchlässigen und gasdurchlässigen Wandabschnitt. Da eine Drucksteuerung zur Bewegung und Positionierung der sogenannten Flüssigkeitsplugs ohnehin bei den meisten mikrofluidischen Systemen notwendig ist, benötigt die Erfindung im Vergleich mit Abmesseinrichtungen nach dem Stand der Technik also einen geringeren apparativen Aufwand zum Abmessen.The separation means is advantageously designed as a second liquid-impermeable and gas-permeable wall section which provides a gas connection. The separation or measuring takes place in the Abmesskanal (without active optical monitoring) alone by applying a pressure difference between an opening into the Abmesskanal filling opening and the gas connection over the first liquid-impermeable and gas-permeable wall section. Since pressure control for moving and positioning the so-called liquid plugs is necessary anyway in most microfluidic systems, the invention thus requires a smaller amount of equipment for measuring in comparison with measuring devices according to the prior art.
Das Abtrennmittel ist vorteilhafter Weise alternativ als ein Ventil ausgebildet. Das Ventil ist wiederum bevorzugt gleichzeitig Abtrennmittel zum Abmessen des Flüssigkeitsvolumens und Steuerventil zum wahlweisen Verbinden und/oder Trennen des Abmesskanals mit einer gewünschten Fluidleitung (Zu- oder Ableitung). Auch in dieser Ausgestaltung kommt der Abmesskanal ohne zusätzliche Fluidsteuerungs- oder Fluidkontrollbauteile aus. Ventilsteuerungen unterschiedlicher Art sind in der Mikrofluidik grundsätzlich bekannt. Es wird beispielhaft auf die Schriften
Einer oder beide flüssigkeitsundurchlässige und gasdurchlässige Wandabschnitte sind vorzugsweise in Form einer Membran ausgebildet und/oder weisen eine die Kanalwand durchsetzende Kapillarstruktur auf, die dem Durchtritt einer Flüssigkeit einen erhöhten Widerstand entgegensetzt. Entscheidend ist in beiden Fällen, dass die Flüssigkeit durch den Wandabschnitt - sofern überhaupt - nur unter Aufbringen eines erhöhten Grenzdifferenzdruckes ΔPG zwischen dem Innendruck Pi in dem Abmesskanal und dem Außendruck Pa im Gasanschluss, ausgehend von einem zum Befüllen, Entleeren, oder allgemein zum Fördern der Flüssigkeit verwendeten Normaldifferenzdruck ΔPN zu überwinden im Stande ist.One or both of the liquid-impermeable and gas-permeable wall sections are preferably designed in the form of a membrane and / or have a capillary structure passing through the channel wall, which presents an increased resistance to the passage of a liquid. It is crucial in both cases that the liquid through the wall section - if any - only by applying an increased limit differential pressure .DELTA.P G between the internal pressure P i in the Abmesskanal and the external pressure P a in the gas connection, starting from a for filling, emptying, or in general to overcome the normal differential pressure ΔP N used to convey the liquid.
Im Falle einer Membran als flüssigkeitsundurchlässiger und gasdurchlässiger Wandabschnitt besteht diese bevorzugt aus einem nicht-benetzbaren Material, vorzugsweise einer Polymermembran und besonders bevorzugt Polytetraflourethylen. Derartige flüssigkeitsundurchlässige und gasdurchlässige Membranen in einem mikrofluidischen System sind beispielsweise aus der Schrift
Der Gasanschluss wird gemäß einer bevorzugten Ausgestaltung der Erfindung durch eine Abluftöffnung jenseits des flüssigkeitsundurchlässigen und gasdurchlässigen Wandabschnittes zur Umgebung gebildet. Diese Konstruktion ist einfach, da kein Pumpenanschluss auf der Seite des Gasanschlusses benötigt wird. Der Flüssigkeitstransport im Abmesskanal wird einlass- bzw. auslassseitig gesteuert, wobei das Befüllen bei dieser Ausgestaltung am Einlass einen Überdruck und das Entleeren am Auslass einen Unterdruck erfordert.The gas connection is formed according to a preferred embodiment of the invention by an exhaust port beyond the liquid-impermeable and gas-permeable wall portion to the environment. This construction is simple, as no pump connection is needed on the side of the gas connection. The liquid transport in the metering channel is controlled on the inlet or outlet side, wherein the filling in this embodiment at the inlet requires an overpressure and the emptying at the outlet requires a negative pressure.
Die erfindungsgemäße mikrofluidische Struktur in einem Substrat, insbesondere in einem Lab-on-Chip-System, weist mehrere Fluidleitungen zum Aufnehmen und/oder Leiten eines Fluidstromes und ein mit den Fluidleitungen verbundenes Ventil zum wahlweisen Verbinden und/oder Trennen der Fluidleitungen auf. Eine der Fluidleitungen ist in Form eines wie vorstehend beschriebenen Abmesskanals ausgebildet, der auf der Seite seines zweiten Endes über das Ventil mit mindestens einer anderen Fluidleitung verbunden und auf der Seite seines ersten Endes geschlossen oder verschließbar ist. "Auf der Seite des ersten bzw. zweiten Endes" schließt ein, dass der Verschluss bzw. das Ventil das jeweilige Ende des Abmesskanals bilden, also funktional dazugehören und dass sie beabstandet von den Enden außerhalb des Fluidkanals liegen. Insbesondere ein das erste Ende bildender Verschluss, der mit dem ersten Wandabschnitt zusammenfällt, erlaubt ein Befüllen und Entleeren mit minimalem Flüssigkeitsverlust durch Toträume.The microfluidic structure according to the invention in a substrate, in particular in a lab-on-chip system, has a plurality of fluid conduits for receiving and / or conducting a fluid flow and a valve connected to the fluid conduits for selectively connecting and / or disconnecting the fluid conduits. One of the fluid conduits is in the form of a metering channel as described above which is connected on the side of its second end via the valve to at least one other fluid conduit and closed or closable on the side of its first end. "On the side of the first and second ends", respectively, implies that the closure or valve forms the respective end of the metering channel, that is to say functionally associated with it, and that they lie at a distance from the ends outside the fluid channel. In particular, a closure forming the first end, which coincides with the first wall portion, allows filling and emptying with minimal fluid loss through dead spaces.
In Verbindung mit einer Ventilanordnung lassen sich das Befüllen, Abmessen und Entleeren auf einfache Weise realisieren. Insbesondere bildet das Ventil zum wahlweisen Verbinden und/oder Trennen der Fluidleitungen das Abtrennmittel. Auch können an ein Ventil mehrere und insbesondere mehr als zwei der erfindungsgemäßen Abmesskanäle anschließen.In conjunction with a valve arrangement, the filling, measuring and emptying can be realized in a simple manner. In particular, the valve for selectively connecting and / or separating the fluid lines forms the separating means. It is also possible for a plurality of valves, and in particular more than two, of the metering channels according to the invention to be connected to one valve.
Der Gasanschluss und/oder die wenigstens eine andere Fluidleitung ist vorzugsweise an eine Pumpvorrichtung anschließbar, die eingerichtet ist, eine Druckdifferenz zwischen dem Gasanschluss und der wenigstens einen anderen Fluidleitung zum Zu- und/oder Abführen eines Fluids in den Abmesskanal zu erzeugen. Der Chip mit der erfindungsgemäßen mikrofluidischen Struktur kann zum Zweck des Anschließens in ein sogenanntes Betreibergerät eingelegt werden, welches über Schnittstellen eine fluidische Verbindung zum mikrofluidischen Chip zur Verfügung stellt.The gas connection and / or the at least one other fluid line is preferably connectable to a pump device which is set up to generate a pressure difference between the gas connection and the at least one other fluid line for supplying and / or discharging a fluid into the measurement channel. For the purpose of connection, the chip with the microfluidic structure according to the invention can be inserted into a so-called operator device, which provides a fluidic connection to the microfluidic chip via interfaces.
Vorteilhaft ist es ferner, wenn eine mit einer Fluidleitung in der mikrofluidischen Struktur kommunizierende Druckmesseinrichtung vorgesehen ist, deren Signal vorteilhaft zur Steuerung der Pumpvorrichtung gemäß einem der nachfolgend beschriebenen Verfahren eingesetzt werden kann.It is furthermore advantageous if a pressure measuring device communicating with a fluid line in the microfluidic structure is provided, the signal of which can advantageously be used to control the pumping device according to one of the methods described below.
Vorteilhafter Weise können zwei oder mehr der vorstehend beschriebenen Abmesskanäle hintereinander angeordnet werden, wobei des zweite Ende eines ersten Abmesskanals das erste Ende eines zweiten Abmesskanals bildet.Advantageously, two or more of the above-described Abmesskanäle be arranged one behind the other, wherein the second end of a first Abmesskanals forms the first end of a second Abmesskanals.
Das erfindungsgemäße Verfahren zum Abmessen und/oder Positionieren eines Volumens einer Flüssigkeit in einem solchen mikrofluidischen System sieht gemäß einem Aspekt der Erfindung die folgenden Schritte vor:
- a) Verbinden des Abmesskanals über das Ventil mit einer Zuleitung,
- b) Befüllen des Abmesskanals bis zu dem ersten Wandabschnitt mit einer Flüssigkeit aus der Zuleitung, indem eine Druckdifferenz zwischen der Zuleitung und dem Gasanschluss angelegt wird,
- c) Abtrennen des in dem Abmesskanal zwischen dem Wandabschnitt und dem Abtrennmittel eingeschlossenen Flüssigkeitsvolumens von einem auf der Seite seines zweiten Endes vor dem Abtrennmittel anstehenden überschüssigen Flüssigkeitsrest.
- a) connecting the Abmesskanals via the valve with a supply line,
- b) filling the Abmesskanals up to the first wall portion with a liquid from the supply line by a pressure difference between the supply line and the gas port is applied,
- c) separating the liquid volume enclosed in the metering channel between the wall section and the separating means from an excess liquid residue which is present on the side of its second end in front of the separating means.
Die Unterscheidung der Begriffe Zuleitung und Ableitung ist funktional zu verstehen, gleichwohl kann damit dieselbe körperliche Fluidleitung bezeichnet sein.The distinction between the terms supply and discharge is to be understood functionally, nevertheless, the same physical fluid line can be designated.
Nach dem Befüllen in Schritt b) ist je nach verfügbarer Flüssigkeitsmenge der gesamte Abmesskanal oder auch nur ein Teil davon befüllt. Ist der Abmesskanal jedenfalls aber über das Abtrennmittel hinaus befüllt, wird durch das Abtrennen c) sichergestellt, dass nur noch genau das zwischen dem ersten Wandabschnitt und dem Abtrennmittel verbleibende, definierte Flüssigkeitsvolumen zur weiteren Verwendung zurück bleibt.After filling in step b) is filled depending on the available amount of liquid, the entire Abmesskanal or only a part thereof. However, if the metering channel is in any case filled via the separating means, separation c) ensures that only exactly that between the first wall section and the defined, remaining liquid volume remains for further use.
Ist das Abtrennmittel als ein zweiter flüssigkeitsundurchlässiger und gasdurchlässiger Wandabschnitt ausgebildet, der einen Gasanschluss bereitstellt, umfasst Schritt c) vorzugsweise:
- c') Verbinden des Abmesskanals über das Ventil mit einer ersten Ableitung,
- c") Abtransportieren der zwischen dem Ventil und dem zweiten Wandabschnitt befindlichen überschüssigen Flüssigkeit durch die erste Ableitung, indem eine Druckdifferenz zwischen dem Gasanschluss des zweiten Wandabschnittes und der ersten Ableitung angelegt wird.
- c ') connecting the Abmesskanals via the valve with a first derivative,
- c ") removing the excess liquid located between the valve and the second wall portion through the first drain by applying a pressure difference between the gas port of the second wall portion and the first drain.
Ist wie vorstehend vorausgesetzt nach dem Befüllen in Schritt b) der Abmesskanal über den dem Ventil näherliegenden zweiten Wandabschnitt hinaus befüllt, wird durch das Abtransportieren in Schritt c") sichergestellt, dass nur noch das genau das zwischen den Wandabschnitten in dem Abmesskanal verbleibende, definierte Flüssigkeitsvolumen zur weiteren Verwendung zurück bleibt.If, as stated above, after the filling in step b), the metering channel is filled beyond the second wall section closer to the valve, it is ensured by the removal in step c ") that only the precisely defined liquid volume remaining between the wall sections in the metering channel remains remains for further use.
Ist das Abtrennmittel als Ventil zum wahlweisen Verbinden und/oder Trennen der Fluidleitungen ausgebildet, umfasst Schritt c) vorzugsweise:
- c"') Trennen des Abmesskanals von der Zuleitung durch Schließen des Ventils.
- c '') Separating the Abmesskanals from the supply line by closing the valve.
Gemäß einem zweiten Aspekt der Erfindung sieht das Verfahren in einem mikrofluidischen System mit einem auf der Seite seines ersten Endes geschlossenen oder verschließbaren und auf der Seite seines zweiten Endes über ein Ventil mit wenigstens einer Fluidleitung verbindbaren Abmesskanal, der an seinem ersten Ende einen ersten und an seinem zweiten Ende einen zweiten flüssigkeitsundurchlässigen und gasdurchlässigen Wandabschnitt aufweist, welche Wandabschnitte jeweils einen Gasanschluss bereitstellen und zwischen denen in dem Abmesskanal ein definiertes Volumen eingeschlossen ist, folgenden Schritt vor:
- d) Befüllen des Abmesskanals über eine zwischen den Wandabschnitten in den Abmesskanal mündenden Einfüllöffnung mit einer Flüssigkeit, indem eine Druckdifferenz zwischen der Einfüllöffnung einerseits und den beiden Gasanschlüssen andererseits angelegt wird, und anschließendes Verschließen der Einfüllöffnung.
- d) filling the Abmesskanals via an opening between the wall sections in the Abmesskanal filling opening with a liquid by a pressure difference between the filling opening on the one hand and the two gas connections on the other hand is applied, and then closing the filling opening.
Diese Variante stellt den einfacheren Fall einer transversalen, also in Kanalrichtung verlaufende Befüllung dar. Der Fall ist insofern einfacher, als das Abmessen bereits in einem Schritt erfolgt ist. Voraussetzung ist, dass die Flüssigkeit durch einen niedrigeren Druck an den Gasanschlüssen über die Einlassöffnung eingesaugt wird, als der in dem übrigen System vorherrschende Druck. Das Ventil dient einem Anschließenden Verbinden des Abmesskanals mit einem Auslasskanal zum Entleeren.This variant represents the simpler case of a transverse filling, ie running in the direction of the channel. The case is simpler insofar as the measuring has already taken place in one step. The prerequisite is that the liquid is sucked through the inlet opening by a lower pressure at the gas connections than the pressure prevailing in the rest of the system. The valve then serves to connect the metering channel to an outlet channel for emptying.
Bevorzugt werden in einem mikrofluidischen System mit wenigstens zwei hintereinander angeordnete Abmesskanälen, wobei des zweite Ende eines ersten Abmesskanals das erste Ende eines zweiten Abmesskanals bildet, nach Schritt c) gemäß dem ersten Aspekt des erfindungsgemäßen Verfahrens bzw. nach Schritt d) gemäß dem zweiten Aspekt des erfindungsgemäßen Verfahrens die Schritte a) bis c) oder der Schritt d) wiederholt. Das erste Befüllen des Abmesskanals gemäß Schritt b) erfolgt bis zu dem dem Ventil zunächst näher liegenden zweiten Wandabschnitt der den Ausgangspunkt und ersten Wandabschnitt beim zweiten Befüllen bildet. Entsprechend erfolgt das erste Abtransportieren der überschüssigen Flüssigkeit gemäß Schritt d) von dem zunächst zweiten Wandabschnitt an und das zweite Abtransportieren ab einem dem Ventil nochmals näher liegenden Abtrennmittel. Die Angabe "zunächst zweiten" oder "zunächst näherliegend" bezieht sich auf den im ersten Befüllen/Abtransportieren dem Ventil näherliegenden Wandabschnitt/Abtrennmittel und die Angabe "nochmals näherliegend" bezieht sich auf den im zweiten Befüllen/Abtransportieren dem Ventil näherliegenden Wandabschnitt/Abtrennmittel. Durch das zweimalige Befüllen eines solchen Abmesskanals mit wenigstens drei flüssigkeitsundurchlässigen und gasdurchlässigen Wandabschnitten werden zwei Flüssigkeiten unmittelbar hintereinander in einem einzigen Abmesskanal abgemessen und können durch Druckbeaufschlagung des gewünschten Gasanschlusses wahlweise sequentiell oder zusammen aus dem Abmesskanal abgeführt werden. In letzterem Fall können Sie anschließend beispielsweise einer Mischstrecke zugeführt werden, um eine Mischung in einem präzisen Verhältnis der Ausgangssubstanzen zu erzeugen.Preferably, in a microfluidic system with at least two measuring channels arranged one behind the other, the second end of a first measuring channel forms the first end of a second measuring channel, after step c) according to the first aspect of the method according to the invention or after step d) according to the second aspect of FIG process according to the invention, the steps a) to c) or the step d) repeated. The first filling of the Abmesskanals according to step b) takes place up to the first closer to the valve second wall portion which forms the starting point and the first wall portion during the second filling. Accordingly, the first removal takes place the excess liquid according to step d) of the first second wall portion and the second removal from a valve closer to the separation means. The term "initially second" or "initially closer" refers to the wall section / separating means closer to the valve in the first filling / removal, and the indication "lying closer again" refers to the wall section / separating means closer to the valve in the second filling / removal. By filling twice such a Abmesskanals with at least three liquid-impermeable and gas-permeable wall sections two liquids are measured immediately after each other in a single Abmesskanal and can be removed by pressurizing the desired gas port either sequentially or together from the Abmesskanal. In the latter case, they can then be fed to a mixing section, for example, in order to produce a mixture in a precise ratio of the starting substances.
Vorteilhaft ist es wenn nach Schritt c) bzw. nach Schritt d) jeweils die folgenden Schritte ausgeführt werden:
- e) Verbinden des Abmesskanals über das Ventil mit einer zweiten Ableitung,
- f) Abtransportieren der zwischen dem dem Ventil näher liegenden Wandabschnitt und dem dem Ventil ferner liegenden Wandabschnitt eingeschlossenen Flüssigkeit durch die zweite Ableitung, indem eine Druckdifferenz zwischen dem Gasanschluss des dem Ventil ferner liegenden Wandabschnittes und der zweiten Ableitung angelegt wird.
- e) connecting the Abmesskanals via the valve with a second derivative,
- f) removing the fluid trapped between the valve-proximal wall portion and the valve-distal wall portion through the second drain by applying a pressure differential between the gas port of the valve-distal wall portion and the second drain.
Auch hier gilt, dass die Unterscheidung der Begriffe Zuleitung, erste Ableitung und zweite Ableitung funktional zu verstehen ist und gleichsam damit dieselbe körperliche Fluidleitung bezeichnet sein kann.Again, it is true that the distinction of the terms supply line, first derivative and second derivative is functional to understand and, so to speak, the same physical fluid line may be designated.
Bevorzugt erfolgt das Befüllen durch kontinuierliches Pumpen der Flüssigkeit in den Abmesskanal mittels einer Pumpeinrichtung. Das kontinuierliche Pumpen stellt neben dem Pumpen mit gleichbleibendem Druck eines von zwei alternativen Förderprinzipien dar.The filling is preferably carried out by continuously pumping the liquid into the metering channel by means of a pumping device. Continuous pumping is one of two alternative pumping principles in addition to constant pressure pumping.
Beim kontinuierlichen Pumpen wird vorzugsweise mittels einer mit der Zuleitung oder dem Abmesskanal kommunizierenden Druckmesseinrichtung der Druck in dem System überwacht.In continuous pumping, the pressure in the system is preferably monitored by means of a pressure measuring device communicating with the supply line or the metering channel.
Dies wird dann vorteilhafter Weise dazu genutzt, die Pumpeinrichtung abzustellen, wenn ein signifikanter Druckanstieg in der Zuleitung oder dem Abmesskanal festgestellt wird. Ein solcher Druckanstieg wird immer dann festzustellen sein, wenn die Flüssigkeit beim Einfüllen einen Wandabschnitt erreicht, an dessen Gasanschluss ein geringerer Außendruck Pa anliegt als der Innendruck Pi im übrigen System im Normalfall (Systemnormaldruck).This is then advantageously used to stop the pumping device when a significant increase in pressure in the supply line or the Abmesskanal is detected. Such an increase in pressure will always be noted when the liquid reaches a wall portion during filling, at the gas connection a lower external pressure P a is applied as the internal pressure P i in the rest of the system in the normal case (system normal pressure).
Insbesondere vorteilhaft ist es dann, wenn der Druck, bei dem die Pumpeinrichtung abgestellt wird, höher als der Systemnormaldruck Pi und geringer als der Grenzdifferenzdruck ΔPG zwischen einem erhöhten Innendruck P'i in dem Abmesskanal und dem Außendruck Pa im Gasanschluss ist, bei dem die Flüssigkeit durch den flüssigkeitsundurchlässige und gasdurchlässige Wandabschnitt durchbricht.It is particularly advantageous if the pressure at which the pumping device is switched off is higher than the system normal pressure P i and less than the limit differential pressure ΔP G between an increased internal pressure P ' i in the metering channel and the external pressure P a in the gas port the liquid breaks through the liquid-impermeable and gas-permeable wall section.
Weitere Aufgaben, Merkmale und Vorteile der Erfindung werden nachfolgend anhand von Ausführungsbeispielen mit Hilfe der Zeichnungen näher erläutert. Es zeigen:
- Figur 1
- eine Schnittdarstellung des prinzipiellen Aufbaus des erfin- dungsgemäßen Abmesskanals;
- Figur 2
- eine mikrofluidische Struktur in einem Lab-on-Chip-System mit mehreren erfindungsgemäßen Abmesskanälen;
- Figur 3
- die mikrofluidische Struktur gemäß
Figur 2 nach einem ersten Schritt einer Sequenz von fluidischen Steuerungen; - Figur 4
- die mikrofluidische Struktur gemäß
Figur 2 nach einem zweiten Schritt einer Sequenz von fluidischen Steuerungen; - Figur 5
- die mikrofluidische Struktur gemäß
Figur 2 nach einem dritten Schritt einer Sequenz von fluidischen Steuerungen; - Figur 6
- die mikrofluidische Struktur gemäß
Figur 2 nach einem vierten Schritt einer Sequenz von fluidischen Steuerungen; - Figur 7
- die mikrofluidische Struktur gemäß
Figur 2 nach einem fünften Schritt einer Sequenz von fluidischen Steuerungen; - Figur 8
- die mikrofluidische Struktur gemäß
Figur 2 nach einem sechsten Schritt einer Sequenz von fluidischen Steuerungen; - Figur 9
- die mikrofluidische Struktur gemäß
Figur 2 nach einem siebten Schritt einer Sequenz von fluidischen Steuerungen und Figur 10- die mikrofluidische Struktur gemäß
Figur 2 nach einem achten Schritt einer Sequenz von fluidischen Steuerungen.
- FIG. 1
- a sectional view of the basic structure of the inventive Abmesskanals;
- FIG. 2
- a microfluidic structure in a lab-on-chip system with several Abmesskanälen invention;
- FIG. 3
- the microfluidic structure according to
FIG. 2 after a first step of a sequence of fluidic controls; - FIG. 4
- the microfluidic structure according to
FIG. 2 after a second step of a sequence of fluidic controls; - FIG. 5
- the microfluidic structure according to
FIG. 2 after a third step of a sequence of fluidic controls; - FIG. 6
- the microfluidic structure according to
FIG. 2 after a fourth step of a sequence of fluidic controls; - FIG. 7
- the microfluidic structure according to
FIG. 2 after a fifth step of a sequence of fluidic controls; - FIG. 8
- the microfluidic structure according to
FIG. 2 after a sixth step of a sequence of fluidic controls; - FIG. 9
- the microfluidic structure according to
FIG. 2 after a seventh step of a sequence of fluidic controls and - FIG. 10
- the microfluidic structure according to
FIG. 2 after an eighth step of a sequence of fluidic controls.
In
Im vorliegenden Fall ist die Deckelfolie 18 mit zwei Öffnungen 20 und 22 versehen, von denen eine Öffnung 20 bündig an einer Endfläche 24 des Abmesskanals 10 in denselben mündet. Aufgrund der den Abmesskanal 10 einseitig begrenzenden Endfläche 24 ist der Abmesskanal 10 für die Flüssigkeit ein Totkanal, nicht jedoch für ein Gas, das, wie nachfolgend beschreiben, durch die Öffnungen 20 und 22 aus dem Kanal 10 ausströmen kann. Für die Flüssigkeit hat der Abmesskanal also nur eine Zugangsöffnung 25, über die er mit angeschlossenen Fluidleitungen fluidisch verbindbar oder verbunden ist. Dennoch kann er aufgrund der mit der Öffnung 20 bündigen Endfläche 24 ohne Toträume vollständig befüllt werden.In the present case, the
Oberhalb der Öffnung 20 befindet sich ein flüssigkeitsundurchlässiger und gasdurchlässiger erster Wandabschnitt und oberhalb der Öffnung 22 ein flüssigkeitsundurchlässiger und gasdurchlässiger zweiter Wandabschnitt. Der erste Wandabschnitt und der zweite Wandabschnitt sind jeweils in Form einer Membran 26 bzw. 28 ausgebildet ist. Diese Membranen stellen aufgrund ihrer Gasdurchlässigkeit einen Gasanschluss 27 bzw. 29 für den Abmesskanal 10 bereit. Zur Ab- bzw. Zuleitung von Gas ist auf der Außenseite der Membranen 26 und 28 jeweils eine Gasleitung 30 bzw. 32 angeflanscht bzw. vom Betreibergerät aufgesetzt. Die Anordnung der Membranen wie auch die der Gasleitungen ist hier nur schematisch vereinfacht dargestellt. Tatsächlich werden die Membranen bevorzugt in einen in das Substrat eingeformten Membransitz eingelassen und beispielsweise mittels eines Andrückrings gehalten. Der Andrückring ist vorzugsweise mit dem Substrat unverlierbar (ultraschall-)verschweißt und bildet mit dem Substrat eine bündige Oberfläche, die ein Dichtfläche für den Anschluss einer Gasleitung bereitstellt.Above the
Zwischen den Wandabschnitten 26 und 28 schließt der Abmesskanal 10 ein definiertes Volumen V ein.Between the
Im Folgenden wird die Funktion des Abmesskanals anhand des Ausführungsbeispiels in
Davon ausgehend, dass der zugeführte Flüssigkeitsplug 34 ein größeres Volumen einnimmt, als das durch den Abmesskanal 10 bestimmte Volumen V, steht die Flüssigkeitssäule über die zweite Öffnung 22 hinaus vor dem Abmesskanal 10 an. Das Abmessen erfolgt nun in einem zweiten Schritt, indem der der Zugangsöffnung 25 näher liegende zweite Gasanschluss 29 mit einem höheren Außendruck Pa als der Innendruck Pi beaufschlagt wird. Die so entstehende Druckdifferenz bewirkt, dass die vor der Öffnung 22 in Richtung der Zugangsöffnung 25 anstehende Flüssigkeit in umgekehrter Richtung aus dem Kanal herausgedrückt oder gesogen wird, so dass nur noch das durch die Länge des Abmesskanals 10 bestimmte Volumen V an Flüssigkeit zwischen den beiden Öffnungen 20 und 22 verbleibt. Der zweite Wandabschnitt bildet also das Abtrennmittel. Dieses genau abgemessene Flüssigkeitsvolumen kann anschließend durch Beaufschlagung des der Öffnung 25 ferner liegenden Gasanschlusses 27 mit einem höheren Außendruck Pa als der Innendruck Pi aus dem Abmesskanal 10 zur weiteren Verwendung abgeleitet werden.Assuming that the supplied
In
Der erste Abmesskanal 104 weist an seinem dem Drehventil 114 fernen Ende einen flüssigkeitsundurchlässigen und gasdurchlässigen ersten Wandabschnitt 118 auf. Der erste Wandabschnitt 118 wird durch eine Membran gebildet, die in einem Membransitz 120 Platz findet.The
Der Zusammenführungskanal 106 weist zwei hintereinander beabstandet angeordnete flüssigkeitsundurchlässige und gasdurchlässige erste und zweite Wandabschnitte 122 und 124 auf, von denen der erste Wandabschnitt 124 an dem Drehventil 114 gegenüberliegenden Ende und somit fernerliegend und der zweite Wandabschnitt 122 in etwa mittig in dem Zusammenführungskanal 106 und somit näherliegend zu dem Drehventil 114 angeordnet sind. Zwischen den beiden Wandabschnitten 122 und 124 mündet eine transversale Einfüllöffnung 126 in den Zusammenführungs- bzw. zweiten Abmesskanal 106.The
Der Mischkanal 108 ist mäanderförmig gefaltet, so dass zwei unmittelbar aufeinander folgend eingeleitete Fluide aufgrund der langen Strecke und der mehrfachen Richtungsumkehr am Ausgang 128 des Mäanders vermischt angelangen.The mixing
Unmittelbar an den Ausgang 128 schließt sich der dritte Abmesskanal 110 an, welcher insgesamt drei flüssigkeitsundurchlässige und gasdurchlässige Wandabschnitte 130, 132 und 134 aufweist. Der Wandabschnitt 130 ist der dem Ventil 114 nächstliegende, der Wandabschnitt 134 der dem Ventil 114 fernstliegende Wandabschnitt.Immediately to the
Im Folgenden wird ein beispielhafter Ablauf von Fluidsteuerung durch die mikrofluidische Struktur aus
In einem ersten Schritt gemäß
In einem zweiten Schritt gemäß
In einem dritten Schritt der Sequenz gemäß
In einem vierten Schritt gemäß
Die gemischte Flüssigkeit AB wird sodann abgemessen, indem der überschüssige, vor dem dem Ventil 114 nächstliegenden zweiten Wandabschnitt 130 befindliche Flüssigkeitsüberschuss durch Anlegen einer Druckdifferenz zwischen dem Gasanschluss über dem zweiten Wandabschnitt 130 und dem Gasanschluss über dem dem Ventil fernliegenden Wandabschnitt 124 des zweiten Abmesskanals 106 in den zweiten Abmesskanal 106 abgeleitet. Der zweite Abmesskanal 106 dient im gebrauchten Zustand als Abfallkanal oder Waste.The mixed liquid AB is then measured by the excess excess liquid located in front of the
In einem nächsten Schritt gemäß
Zuletzt wird auf demselben Weg der zuvor zwischen dem mittleren (und jetzt zweiten) Wandabschnitt 132 und dem dem Ventil 114 fernstliegenden (jetzt ersten) Wandabschnitt 134 befindliche und genau abgemessene Flüssigkeitsplug auf demselben Weg in die Ableitung 112 transportiert, indem nunmehr eine Druckdifferenz zwischen dem Gasanschluss über den fernstliegenden Wandabschnitt 134 und den Innendruck in der Ableitung 112 angelegt wird.Finally, in the same way, the liquid plug previously located between the middle (and now the second)
Die anhand der
- 1010
- AbmesskanalAbmesskanal
- 1212
- mikrofluidischer Chipmicrofluidic chip
- 1414
- Substratsubstratum
- 1616
- Oberseitetop
- 1717
- Unterseitebottom
- 1818
- Deckelfoliecover film
- 2020
- Öffnungenopenings
- 2222
- Öffnungenopenings
- 2424
- Endflächeend face
- 2525
- Zugangsöffnungaccess opening
- 2626
- Membranmembrane
- 2727
- Gasanschlussgas connection
- 2828
- Membranmembrane
- 2929
- Gasanschlussgas connection
- 3030
- Gasleitunggas pipe
- 3232
- Gasleitunggas pipe
- 3434
- Flüssigkeitsplugliquid plug
- 100100
- Mikrofluidikchipmicrofluidic
- 102102
- Zuleitungsupply
- 104104
- erster Abmesskanalfirst measuring channel
- 106106
- zweiter Abmesskanal, Zusammenführungskanalsecond measuring channel, merge channel
- 108108
- Mischstrecke, MischkanalMixing section, mixing channel
- 110110
- dritter Abmesskanalthird measuring channel
- 112112
- Ableitungderivation
- 114114
- Drehventilrotary valve
- 116116
- Ventilkanalvalve channel
- 118118
- Wandabschnittwall section
- 120120
- Membransitzdiaphragm seat
- 122122
- Wandabschnittwall section
- 124124
- Wandabschnittwall section
- 126126
- Einfüllöffnungfill opening
- 128128
- Ausgang des MäandersExit of the meander
- 130130
- Wandabschnittwall section
- 132132
- Wandabschnittwall section
- 134134
- Wandabschnittwall section
- Pi P i
- Innendruck, SystemnormaldruckInternal pressure, system normal pressure
- P'i P'i
- erhöhter Innendruckincreased internal pressure
- Pa P a
- Außendruckexternal pressure
- ΔPN ΔP N
- NormaldifferenzdruckNormal differential pressure
- ΔPG ΔP G
- GrenzdifferenzdruckCross differential pressure
Claims (15)
dadurch gekennzeichnet, dass der Abmesskanal (10, 104, 106, 110) an seinem ersten Ende geschlossen oder verschließbar ist.Abmesskanal (10, 104, 106, 110) according to claim 1,
characterized in that the Abmesskanal (10, 104, 106, 110) is closed or closable at its first end.
dadurch gekennzeichnet, dass das Abtrennmittel als ein zweiter flüssigkeitsundurchlässiger und gasdurchlässiger Wandabschnitt (28, 122, 130, 132) ausgebildet ist, der einen Gasanschluss (29) bereitstellt.Abmesskanal (10, 108, 110) according to any one of claims 1 or 2,
characterized in that the separation means is formed as a second liquid impermeable and gas permeable wall portion (28, 122, 130, 132) providing a gas port (29).
dadurch gekennzeichnet, dass der flüssigkeitsundurchlässige und gasdurchlässige Wandabschnitt (26, 28, 118, 122, 124, 130, 132, 134) in Form einer Membran ausgebildet ist.Abmesskanal (10, 104, 106, 110) according to any one of the preceding claims,
characterized in that the liquid-impermeable and gas-permeable wall portion (26, 28, 118, 122, 124, 130, 132, 134) is formed in the form of a membrane.
dadurch gekennzeichnet, dass wenigstens eine Fluidleitung in Form eines Abmesskanals (10, 104, 106, 110) nach einem der Ansprüche 1 bis 8 ausgebildet ist, der auf der Seite seines zweiten Endes über das Ventil (114) mit wenigstens einer anderen Fluidleitung verbunden und auf der Seite seines ersten Endes geschlossen oder verschließbar ist.Microfluidic structure in a substrate, in particular in a lab-on-chip system, with a plurality of fluid conduits for receiving and / or passing a fluid stream and one connected to the fluid conduits Valve (114) for selectively connecting and / or disconnecting the fluid lines,
characterized in that at least one fluid conduit in the form of a Abmesskanals (10, 104, 106, 110) is formed according to one of claims 1 to 8, which connected on the side of its second end via the valve (114) with at least one other fluid conduit and closed or lockable on the side of its first end.
dadurch gekennzeichnet, dass das Ventil (114) zum wahlweisen Verbinden und/oder Trennen der Fluidleitungen das Abtrennmittel bildet.Microfluidic structure according to claim 5,
characterized in that the valve (114) for selectively connecting and / or disconnecting the fluid lines forms the separation means.
gekennzeichnet durch eine mit einer Fluidleitung in der mikrofluidischen Struktur kommunizierende Druckmesseinrichtung.Microfluidic structure according to one of claims 5 or 6,
characterized by a communicating with a fluid line in the microfluidic structure pressure measuring device.
dadurch gekennzeichnet, dass das Abtrennmittel als ein zweiter flüssigkeitsundurchlässiger und gasdurchlässiger Wandabschnitt (28, 122, 130, 132) ausgebildet ist, der einen Gasanschluss (29) bereitstellt, wobei Schritt c) umfasst:
characterized in that the separation means is formed as a second liquid impermeable and gas permeable wall portion (28, 122, 130, 132) providing a gas port (29), wherein step c) comprises:
dadurch gekennzeichnet, dass Ventil (114) zum wahlweisen Verbinden und/oder Trennen der Fluidleitungen das Abtrennmittel bildet, wobei Schritt c) umfasst:
characterized in that valve (114) for selectively connecting and / or disconnecting the fluid conduits forms the separation means, wherein step c) comprises:
dadurch gekennzeichnet, dass nach Schritt c) bzw. nach Schritt d) die folgenden Schritte ausgeführt werden:
characterized in that after step c) or after step d), the following steps are carried out:
dadurch gekennzeichnet, dass das Befüllen durch kontinuierliches Pumpen der Flüssigkeit in den Abmesskanal (10, 104, 106, 110) mittels einer Pumpeinrichtung erfolgt.Method according to one of claims 8 to 12,
characterized in that the filling takes place by continuous pumping of the liquid in the Abmesskanal (10, 104, 106, 110) by means of a pumping device.
dadurch gekennzeichnet, dass mittels einer mit der Zuleitung oder dem Abmesskanal (10, 104, 106, 110) kommunizierenden Druckmesseinrichtung der Druck in dem System überwacht wird.Method according to claim 13,
characterized in that by means of a communicating with the supply line or the Abmesskanal (10, 104, 106, 110) pressure measuring device, the pressure in the system is monitored.
dadurch gekennzeichnet, dass die Pumpeinrichtung abgestellt wird, wenn ein signifikanter Druckanstieg in der Zuleitung oder dem Abmesskanal (10, 104, 106, 110) festgestellt wird.Method according to claim 14,
characterized in that the pumping device is turned off when a significant increase in pressure in the supply line or the Abmesskanal (10, 104, 106, 110) is detected.
Applications Claiming Priority (1)
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DE200910045404 DE102009045404B4 (en) | 2009-10-06 | 2009-10-06 | Discharge channel and microfluidic structure and method for measuring and / or positioning a volume of a liquid |
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EP2308597A2 true EP2308597A2 (en) | 2011-04-13 |
EP2308597A3 EP2308597A3 (en) | 2014-07-09 |
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US (1) | US8443835B2 (en) |
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Cited By (2)
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WO2022058267A1 (en) * | 2020-09-18 | 2022-03-24 | Robert Bosch Gmbh | Microfluidic device |
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CN104039453B (en) * | 2011-10-24 | 2015-12-09 | 彭兴跃 | A kind of microfluidic circuit chip |
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DE102014105437A1 (en) | 2014-04-16 | 2015-10-22 | Amodia Bioservice Gmbh | Microfluidic module and cassette for immunological and molecular diagnostics in an automated analyzer |
US20210008550A1 (en) * | 2019-07-09 | 2021-01-14 | Kryptos Biotechnologies, Inc. | Microfluidic reaction vessel array with patterned films |
CN111617812B (en) * | 2019-10-17 | 2021-12-03 | 北京京东方健康科技有限公司 | Microfluidic substrate, fluid driving method thereof and microfluidic device |
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Also Published As
Publication number | Publication date |
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EP2308597A3 (en) | 2014-07-09 |
DE102009045404B4 (en) | 2012-04-19 |
EP2308597B1 (en) | 2016-12-07 |
US20110079094A1 (en) | 2011-04-07 |
DE102009045404A1 (en) | 2011-04-07 |
US8443835B2 (en) | 2013-05-21 |
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