EP2847465A1 - Pompe microfluidique - Google Patents

Pompe microfluidique

Info

Publication number
EP2847465A1
EP2847465A1 EP13767323.2A EP13767323A EP2847465A1 EP 2847465 A1 EP2847465 A1 EP 2847465A1 EP 13767323 A EP13767323 A EP 13767323A EP 2847465 A1 EP2847465 A1 EP 2847465A1
Authority
EP
European Patent Office
Prior art keywords
pump
microchannel
groove
less
substrate
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.)
Granted
Application number
EP13767323.2A
Other languages
German (de)
English (en)
Other versions
EP2847465B1 (fr
EP2847465A4 (fr
Inventor
Remus Haupt
Horst BÖßNECK
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.)
Alere San Diego Inc
Original Assignee
Alere San Diego Inc
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 Alere San Diego Inc filed Critical Alere San Diego Inc
Publication of EP2847465A1 publication Critical patent/EP2847465A1/fr
Publication of EP2847465A4 publication Critical patent/EP2847465A4/fr
Application granted granted Critical
Publication of EP2847465B1 publication Critical patent/EP2847465B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B43/00—Machines, pumps, or pumping installations having flexible working members
    • F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
    • F04B43/14—Machines, pumps, or pumping installations having flexible working members having peristaltic action having plate-like flexible members
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B19/00—Machines or pumps having pertinent characteristics not provided for in, or of interest apart from, groups F04B1/00 - F04B17/00
    • F04B19/006—Micropumps
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B43/00—Machines, pumps, or pumping installations having flexible working members
    • F04B43/02—Machines, pumps, or pumping installations having flexible working members having plate-like flexible members, e.g. diaphragms
    • F04B43/04—Pumps having electric drive
    • F04B43/043—Micropumps
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B43/00—Machines, pumps, or pumping installations having flexible working members
    • F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B43/00—Machines, pumps, or pumping installations having flexible working members
    • F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
    • F04B43/1238—Machines, pumps, or pumping installations having flexible working members having peristaltic action using only one roller as the squeezing element, the roller moving on an arc of a circle during squeezing
    • F04B43/1246—Machines, pumps, or pumping installations having flexible working members having peristaltic action using only one roller as the squeezing element, the roller moving on an arc of a circle during squeezing the roller being placed at the outside of the tubular flexible member
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B43/00—Machines, pumps, or pumping installations having flexible working members
    • F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
    • F04B43/1253—Machines, pumps, or pumping installations having flexible working members having peristaltic action by using two or more rollers as squeezing elements, the rollers moving on an arc of a circle during squeezing
    • F04B43/1261—Machines, pumps, or pumping installations having flexible working members having peristaltic action by using two or more rollers as squeezing elements, the rollers moving on an arc of a circle during squeezing the rollers being placed at the outside of the tubular flexible member
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B43/00—Machines, pumps, or pumping installations having flexible working members
    • F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
    • F04B43/1253—Machines, pumps, or pumping installations having flexible working members having peristaltic action by using two or more rollers as squeezing elements, the rollers moving on an arc of a circle during squeezing
    • F04B43/1292—Pumps specially adapted for several tubular flexible members

Definitions

  • the invention relates to micro fluidics technology, and more particularly to a microfiuidic pump for control of fluid flow through microchannels.
  • Microfluidics systems are of significant value for acquiring and analyzing chemical and biological information using very small volumes of liquid. Use of microfiuidic systems can increase the response time of reactions, minimize sample volume, and lower reagent and consumables consumption. When volatile or hazardous materials are used or generated, performing reactions in microfiuidic volumes also enhances safety and reduces disposal quantities.
  • Microfiuidic devices have becoming increasingly important in a wide variety of fields from medical diagnostics and analytical chemistry to genomic and proteomic analysis. They may also be useful in therapeutic contexts, such as low flow rate drug delivery.
  • micropump may be used to mix reagents and transport fluids between a disposable analysis platform component of the system and an analysis instrument (e.g., an analyte reader with display functions). Yet controlling the direction and rate of fluid flow within the confines of a microfiuidic device, or achieving complex fluid flow patterns inside microfiuidic channels is difficult.
  • the present invention provides a microfiuidic pump module.
  • the microfiuidic pump module includes a first plate element and a second plate element, the first plate element being elastomeric and the second plate element being non-elastomeric.
  • the second plate element includes a microchannel formed on a surface of the second plate element, and the first and second plate elements are coupled to form a fluid tight seal along the boundary of the microchannel defining a fluid flow path.
  • the invention provides a microfiuidic device utilizing the microfiuidic pump module described herein.
  • the microfiuidic device includes (a) a rigid substrate having a microchannel formed on a surface thereof; and (b) a flexible layer coupled to and overlying the rigid substrate thereby enclosing the microchannel, wherein the flexible layer comprises a raised element disposed over a portion or all of the microchannel.
  • the device further includes a fluid tight seal formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary.
  • the invention provides a microfiuidic device utilizing the microfiuidic pump module described herein.
  • the microfiuidic device includes (a) a rigid substrate having a microchannel formed on a surface thereof; and (b) a flexible layer coupled to and overlying the rigid substrate thereby enclosing the microchannel, wherein the flexible layer has a flat surface disposed over a portion or all of the microchannel.
  • the device further includes a fluid tight seal formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary.
  • the invention provides a microfiuidic device utilizing the microfiuidic pump module described herein, wherein the pump module comprises at least two independent microchannels arranged in a substantially parallel manner.
  • One or more actuators are provided which act upon the two or more microchannels simultaneously, thereby providing means to pump two fluids separate from one another.
  • the microchannels have identical cross sectional areas, such that the volume of fluid transported per unit distance of the microchannel is substantially the same.
  • the at least two microchannels have different cross sectional areas, in which instance the volume of fluid transported per unit distance of the microchannel is different.
  • the invention provides a micro fluidic device utilizing the microfluidic pump module described herein, wherein the pump module comprises at least two independent microchannels arranged concentrically about a point upon which at least one actuator rotates.
  • the invention provides a method for performing a microfluidic process.
  • the method includes (a) applying a voltage to a microfluidic pump module as described herein.
  • the applied voltage activates a motor which advances an actuator element, such as one or more rollers, which is rotatably engaged with the second substrate, causing deformation of the second substrate into the microchannel formed on the surface of the first substrate.
  • Deformation of the elastomeric second substrate into the microchannel forces fluid within the microchannel along the microchannel resulting in a fluid flow.
  • the first substrate is formed from a material having a Shore D hardness of between about 75 and about 90. Such materials include, but are not limited to, polystyrene, polypropylene,
  • the microchannel or groove formed in the surface of the first substrate is dimensionally stable, by which is meant that when the second substrate is deformed into the groove in the first substrate, the width of the groove is at least about 75%, at least about 90%>, at least about 95%>, at least about 97.5%>, at least about 99%), or essentially the same as in the uncompressed state and height the groove is at least about 75%o, at least about 90%>, at least about 95%>, at least about 97.5%>, at least about 99%>, or essentially the same as in the uncompressed state.
  • the dimensions of the groove are thus considered to be essentially unchanged as a consequence of the deformation of the second substrate into the first substrate,
  • the second substrate is formed from a material having a Shore A hardness of between about 15 and 90.
  • Such materials include, but are not thermoplastic elastomer (TPE), polydimethylsiloxane (PDMS), silicone rubber,
  • fluoroelastomer and the like are considered to be dimensionally unstable, by which is meant that when a compressive force or a stretching force is applied to such polymeric materials the material deforms, either through elongation in one or more directions, or the material compresses in one or more dimensions.
  • the invention provides a method of manufacturing a microfluidic device.
  • the method includes coupling a rigid substrate having a microchannel formed on a surface thereof, to a flexible layer overlying the rigid substrate and enclosing the
  • a fluid tight seal is formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary.
  • the rigid substrate and the flexible layer are coupled via a laser welding process. The process includes:
  • the invention provides a method of manufacturing a microfluidic device.
  • the method includes coupling a rigid substrate having a microchannel formed on a surface thereof, to a flexible layer overlying the rigid substrate and enclosing the
  • a fluid tight seal is formed between the rigid substrate and the flexible layers along a periphery of the microchannel forming an enclosed capillary.
  • the rigid substrate and the flexible layer are coupled via a process of over-molding.
  • the process includes: (a) injecting a first polymer composition into an injection mold cavity to form the rigid substrate;
  • Figure 1 is a series of schematics illustrating movement of various components during operation of a microfluidic device in embodiments of the invention.
  • Figure 1 A is a cross-sectional view of a portion of a microfluidic device in embodiments of the invention.
  • Figure IB is a cross-sectional view of a portion of a microfluidic device in embodiments of the invention.
  • Figure 2 is a cross-sectional view of a portion of a microfluidic device in embodiments of the invention.
  • Figure 3 is a perspective view of a portion of a microfluidic device in an embodiment of the invention.
  • Figure 4 is a top view of a portion of a microfluidic device in an embodiment of the invention.
  • Figure 5 is a perspective view of a microfluidic device in an embodiment of the invention.
  • Figure 6 is a series of schematics illustrating a microfluidic device in embodiments of the invention.
  • Figure 6A is a top view of a microfluidic device in an embodiment of the invention.
  • Figure 6B is a top view of a microfluidic device in an embodiment of the invention.
  • Figure 6C is a top view of a microfluidic device in an embodiment of the invention.
  • Figure 7 is a graphical representation depicting data generated with a microfluidic device in an embodiment of the invention.
  • Figure 8 is a graphical representation depicting data generated with a microfluidic device in an embodiment of the invention.
  • Figure 9 is a graphical representation depicting data generated with a microfluidic device in an embodiment of the invention.
  • Figure 10 is a top view of a portion of a microfluidic device in an embodiment of the invention.
  • Figure 11 is a cross-sectional schematic of a drive for use in one embodiment of the invention.
  • Figure 12 is a cross-sectional schematic of a drive for use in one embodiment of the invention.
  • Figure 13 is a top view schematic of a microfluidic device in an embodiment of the invention. DETAILED DESCRIPTION OF THE INVENTION
  • a microfluidic pump and device containing the pump have been developed in order to provide, in embodiments, low cost, high accuracy and low flow rate means for onboard sample handling for disposable assay devices.
  • the rate of fluid flow within the pump is essentially constant even at very low flow rates.
  • the pump comprises a first substrate and a second substrate secured with respect to one another to provide a structure having one or more microchannels which are sealed along the boundaries of the microchannels thereby defining fluid flow paths.
  • microchannel structures (40) are formed in a major surface of a first substrate (20) formed, e.g., of a non- elastomeric or rigid material.
  • the second substrate In the compressed state, the second substrate typically occludes a sufficient portion of the microchannel (40) to displace a substantial portion of fluid from microchannel (40) at the site of compression.
  • the second substrate may occlude a sufficient portion of the microchannel (40) to separate fluid disposed within microchannel (40) on one side of the site of compression from fluid disposed within microchannel (40) on the other side of the site of compression.
  • the second substrate occludes, in the compressed state, at least about 50%, at least about 75%, at least about 90%>, at least about 95%, at least about 97.5%), at least about 99%, or essentially all of the uncompressed cross-sectional area of the groove at the site of compression.
  • the compression may create a fluid-tight seal between the first and second substrates within the groove at the site of compression.
  • fluid e.g., a liquid
  • the fluid-tight seal may be transient, e.g., the second substrate may fully or partially relax upon removal of the compression thereby fully or partially reopening the groove.
  • the groove has a first cross-sectional area in an uncompressed state and a second cross-sectional area in the compressed state.
  • the portion of the elastomer is compressed into the groove without substantially deforming the groove.
  • a ratio of the cross-sectional area at the site of compression in the compressed state to the cross- sectional area at the same site in the uncompressed state may be at least about 0.75, at least about 0.85, at least about 0.925, at least about 0.975, or about 1.
  • the height of the groove e.g.
  • the maximum height of the groove at the site of compression, in the compressed state may be at least about 75%, at least about 85%, at least about 90%>, at least about 95%), or about 100% of the height of the groove at the same site in the uncompressed state.
  • the width of the groove, e.g. , the maximum width of the groove at the site of compression, in the compressed state may be at least about 75%, at least about 85%, at least about 90%>, at least about 95%, or about 100% of the width of the groove at the same site in the uncompressed state.
  • a raised element (30), such as a bump, is present on the elastomer (10), which may be placed over the microchannel region (40), thereby increasing the thickness of elastomeric material which may aid sealing of the elastomer into the channel when compressed against the non-elastic component (20).
  • the elastomer in the uncompressed state, may have a first thickness overlying the groove and a second thickness spaced apart laterally a first distance from the center of the groove.
  • the second thickness is at least about 1 10%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% greater than the first thickness.
  • the second thickness may be at least about 500% or less, about 400% or less, about 300%> or less, or at about 250% or less greater than the first thickness.
  • the first distance may be at least about 1 mm, at least about 2.5 mm, at least about 5 mm, or at least about 1 cm.
  • the first distance may be about 2.5 cm or less, about 2 cm or less, about 1.5 cm or less, or about 1.25 cm or less.
  • the first distance is at about 1.5 times greater, about 1.75 times greater, about 2 times greater, or about 4 times greater than a width, e.g., a maximum width, of the groove.
  • the first distance may be about 25 times greater or less, about 20 times greater or less, about 15 times greater or less, or about 10 times greater or less than a width, e.g., a maximum width, of the groove.
  • a microfluidic pump module (100) is provided utilizing the microfluidic structure described herein.
  • the microfluidic pump module (100) includes a first elastomeric plate element (10) and a second rigid plate element (20).
  • the second plate element (20) includes a microchannel (40) formed on a surface of the second plate element (20), and the first and second plate elements are coupled to form a fluid tight seal along the boundary of the microchannel (40) defining a fluid flow path.
  • the invention provides a microfluidic device (100) utilizing the microfluidic pump module described herein.
  • the microfluidic device (100) includes a rigid substrate (20) having a microchannel (40) formed on a surface thereof and a flexible layer (10) coupled to and overlying the rigid substrate (20) thereby enclosing the microchannel (40).
  • the invention provides a microfluidic device (100), which again with reference to Figures 1A and IB, the reverse orientation is provided.
  • microchannel (40) is formed in flexible layer (10); and rigid substrate (20) is provided with a flat surface profile, such that when flexible layer (10) is coupled to and overlying rigid substrate (20) a microchannel (40) is formed therebetween.
  • the flexible layer (10) comprises a raised element (30) disposed over a portion or all of the microchannel (40).
  • the raised element (30) provides an increased cross-section thickness in the area which coincides with the microchannel (40).
  • the raised element (30) may be one of a number of suitable shapes such as a bump.
  • flexible layer (10) has no raised element (30), in which case microchannel (40) is covered entirely by flexible layer (10) which has a flat upper surface profile, which surface is not in contact with rigid substrate (20).
  • microchannels (40) may be formed on a surface of the rigid substrate (20) by any number of suitable techniques known in the art.
  • microchannels may be formed by deposition of materials through a mask, chemical etching, laser etching, molding of a plastic substrate, and the like.
  • a fluid tight seal is also formed between the rigid substrate (20) and the flexible layer (10) along a periphery of the microchannel (40) forming an enclosed capillary having a defined fluid flow path.
  • Microchannels may be dimensioned to define the volume within the microchannel and resultant flow rate for a given rate at which the elastomer is progressively deformed into the microchannel.
  • the high quality and precision of the so formed microchannel results in a microfluidic pump element that can achieve very slow and consistent flow rates, which may not otherwise be achieved if alternate processes of manufacture were employed.
  • microchannel may be dimensioned such that it has a constant width dimension and a constant depth dimension along all or a portion of its length.
  • a microchannel will have a constant width dimension and a constant depth dimension along a length of the microchannel which engages a deformation element.
  • a microchannel has a width dimension of between 500 to 900 microns and a depth dimension of between 40 to 100 microns.
  • the device may be adapted for a flow rate within the microchannel of between 0.001 ⁇ /s to 5.0 ⁇ /s.
  • FIG. 1 A and IB depict a microchannel (40) in which the bottom surface of the microchannel is arced and defines a concave circular geometry.
  • the microchannel (40) may have a rounded, elliptical or generally U shaped bottom.
  • the microchannel has an arced shaped bottom having a radius of curvature of between 0.7 and 0.9 mm.
  • Figure 2 is a cross-sectional view of a portion of a microfluidic device in one embodiment of the invention in which specific dimensions (shown in mm) are described for various features.
  • microchannels (40) may be modified, for example by varying hydrophobicity.
  • hydrophobicity may be modified by application of hydrophilic materials such as surface active agents, application of hydrophobic materials, construction from materials having the desired hydrophobicity, ionizing surfaces with energetic beams, and/or the like.
  • a device of the present invention may include a plurality of microchannels (40), each having various geometries and disposed on the rigid substrate (20) (or in the alternate on the flexible layer (10)) in a variety of patterns.
  • microchannels (40) may be linear or extend arcuately along the surface of the rigid substrate (20).
  • Figures 3 and 4 illustrate microchannels (40) being disposed as generally circular or spiral geometries.
  • Figure 3 is a perspective view of a device in which microchannels (40) are disposed as spirals, a smaller volume microchannel disposed within a microchannel having a larger volume.
  • Figure 4 is a top view of a device in which the microchannel (40) is disposed in a spiral manner having ports (100) and (110) which may be in fluid communication with one or more additional microchannels or structures.
  • the circular or spiral portion of the microchannel has a length of between 20 to 100 mm.
  • a spiral or generally circular shaped microchannel allows for fluid to be advanced through the microchannel of the pump module or device by a deformation element (50) that is radially coupled to the device.
  • Figure 5 is an illustration depicting a pump module and device of the present invention in which multiple deformation elements (50) are radially coupled and configured to engage a microchannel having a circular or spiral geometry.
  • the deformation elements (50) are provided in a housing (80) configured to radially traverse one or more microchannels provided on the microfluidic laminate structure (110) when the structure is placed in contact with the deformation elements (50) (spiral microchannel is disposed on the opposite side of laminate structure (1 10) shown).
  • the rotational direction of the deformation elements (50) with relation to the micro fluidic laminate structure (1 10) dictates the direction of flow within the microchannel.
  • fluid flow through the pump may be bidirectional.
  • Housing (80) may be rotated by applying a voltage to a motor controlling movement thereof.
  • the invention further provides a method for performing a microfluidic process which includes applying a voltage to a device as described herein.
  • the applied voltage activates a motor which advances at least one deformation element (50), such as one or more rollers, which are rotatably engaged with the elastomeric first plate element (10), causing deformation of a raised element (30) on the flexible layer (10) into the microchannel (40) formed on the surface of the rigid substrate (20).
  • a wide range of pulses per second may be applied to the electrical motor thereby effectuating a wide range of flow rates within microchannels
  • the fluid flow is essentially constant, with little or no shear force being imposed on the fluid, even at very low flow rates.
  • These characteristics of the pump enhance the accuracy of analyses performed with it (e.g., analyte integrity is preserved by minimizing exposure of sample components to shear and degradation), while low flow rates provide sufficient time for chemical reactions to occur.
  • a low, constant pumped flow rate can also be very useful in drug delivery, to ensure dosing accuracy.
  • between 100 and 10,000 pulses per second may be applied resulting in a flow rate of between 0.001 ⁇ /s to 5.0 ⁇ /s through microchannels.
  • the design of the present invention allows forces within microchannels of the present invention to remain fairly constant over a wide range of applied pulses.
  • Figures 7-9 are graphs plotting forces generated within
  • microchannels as a function of the number of pulses per second. As depicted in the graphs of
  • FIGs 7-9 forces generated within the microchannels are relatively constant over a wide ano p nf rm1 « p ;s per second indicating substantially constant flow with minimal shear.
  • Figures 6A-6C illustrate various configurations in different embodiments of the invention in which at least one spiral or circular microchannel is provided. Circular or spiral microchannels (40) may be disposed such that they are in fluid communication with one or more additional microchannels (140) through ports (100) and (110). Additional
  • microchannels (140) may be provided with various reagents, immobilized therein or otherwise provided such that a biological assay may be performed on a fluid sample.
  • a fluid tight seal is formed between the rigid substrate (20) and the flexible layer (10) along a periphery of the microchannel (40) forming an enclosed capillary having a defined fluid flow path.
  • Figure 10 illustrates a portion of a device having a generally spiral microchannel in which a fluid tight seal (140) is shown along the periphery of the microchannel (40).
  • a variety of methods may be utilized to couple rigid substrate (20) to the elastomer that forms flexible layer (10).
  • the parts may be joined together using UV curable adhesive or other adhesive that permits for movement of the two parts relative one another prior to curing of the adhesive/creation of bond.
  • Suitable adhesives include a UV curable adhesive, a heat cured adhesive, a pressure sensitive adhesive, an oxygen sensitive adhesive, and a double-sided tape adhesive.
  • the parts may be coupled utilizing a welding process.
  • a welding process including an ultrasonic welding process, a thermal welding process, and a torsional welding process.
  • the parts may be joined using a process of two-shot molding or overmolding, in which case first one polymer and then the other is injected into a mold tool.
  • a process of two-shot molding or overmolding in which case first one polymer and then the other is injected into a mold tool.
  • elastomeric and non-elastomeric polymers can be joined in this way to achieve fluid tight seals between the parts.
  • a process of laser welding includes: (a) exposing one of the first or second plate elements to ultra violet laser energy around the periphery of the microchannel so as to carbonize the surface of the first or second plate element;
  • the benefits of such approaches mean that (i) the parts may be manipulated (slid against one another) during manufacture to achieve desired alignments, (ii) intricate forms can be achieved in the non-elastomer - linear or arcuate channels (or combinations thereof) with a plurality of channel geometries, (iii) connections with the device may be made via the non-elastomeric material, which is dimensionally stable.
  • additional microchannels and structures may be provided to allow the device to perform a number of different types of biological assays or reactions.
  • additional fluid or reagent reservoirs may be provided, one or more of which act as a reaction chamber for example. Additional structure and depicted in the following example which is intended to illustrate but not limit the invention.
  • planar circular or spiral peristaltic pump of the present invention for use in low cost diagnostic products consisting of an instrument and consumable, where the consumable requires sealing due to a potential high risk of contamination.
  • the method to perform pumping sample fluids to deposited chemicals followed by mixing of sample fluid with deposited chemicals in a low cost manner involves using only one actuator, for example a DC or stepper motor (1) incorporated into the instrument.
  • the peristaltic pump consists of a planar circular or spiral annular microchannel (2) as a feature of a substrate (3) of the consumable (4) and the deforming membrane of the pump is provided by an elastomeric layer (5) which is deformed by the pump rollers (6).
  • Concentric to the annular pump channels is the mixing chamber (7) which contains a magnetic or magnetized puck (8).
  • Concentric to the pump rollers of the instrument is a structure comprising a mixing head (9) which is magnetic or magnetized and is magnetically coupled to the puck.
  • the pump and mixing chamber are fluidically connected, thus fluid can be pumped from the pump microchannels into the mixing chamber as the motor rotates in a predetermined direction.
  • the instrument component of the pump comprises a suitable mechanism to provide pumping and mixing functionality when the motor is rotated in a certain direction, but only mixing functionality when the motor is rotated in the opposite direction, for example a ratchet system implemented by a pawl (10) and a compression spring (11) whereby the mixing head rotates with the pump rollers in one rotational direction of the motor and whereby the pump rollers disengage from the motor when the motor rotates in the other direction, thus providing rotation of the mixing head only.
  • the compression spring may also provide the necessary contact force on the pump channels to facilitate effective pumping.
  • FIG. 10 Another embodiment provides an annular mixing chamber internal or external to the pump channels.
  • This embodiment could feasibly be produced at a lower cost than the first embodiment and is described with reference to Figure 12.
  • the spiral or circular pump channel (1) as a feature in a substrate (2) is overlaid with an elastomeric membrane (3) and deformed by pump rollers (4) in a similar manner to that described in Figure 11.
  • the mixing chamber is an annular channel (4) as a concentric feature to the pump channel but located on the reverse face of the pump channel substrate.
  • bearing balls (5) Located within this annular channel is one or many bearing balls (5) which are magnetically coupled to a magnetic or magnetized element on the rotor (6) such that as the rotor rotates the bearing balls also rotate in the annular channel, thus providing mixing of chemicals initially deposited inside the annular channel.
  • the drive mechanism to achieve mixing and pumping in one rotational direction of the motor and just mixing in the other rotational direction of the motor is envisaged to be similar to that described with reference to Figure 11.
  • this peristaltic pump can be designed to accommodate multiple fluidic channels on different radii if desired.
  • the sample that is transported is first required to be mixed with stored deposited chemicals (6) located within the mixing chamber (7), followed by a dilution step using a dilution fluid.
  • the dilution fluid it is preferable to store the dilution fluid away from the stored chemicals so the stored chemicals do not become affected by the dilution fluid.
  • the motor rotates in a certain direction the pump rollers engage with the pumping membrane to transport both sample fluid and dilution fluid into the consumable, as the mixing chamber fills with sample fluid, the dilution fluid fills a secondary chamber (8) which is sized according to the amount of dilution fluid required and the geometry of the dilution fluid pumping channels and the mixing chamber volume.
  • an equivalent mechanism as described above could be implemented which rotates the motor in the opposite direction to only provide mixing.
  • the motor rotates to engage the pump rollers which transport the sample and dilution fluid to a location inside the consumable which combines the two fluids (9).
  • passive mixing features may be included at the fluid combining region.
  • the motor continues to rotate to pump the two fluids, the diluted sample can be transported to another location on the consumable, for example a location to carry out detection of an analyte (11).
  • Hi p rtinn A n additional feature of the pump design is the ability for the consumable part of the pump to include multiple pump channels such that multiple fluids may be transported using the same motor drive mechanism.
  • a wide range of pulses per second may be applied to the electrical motor thereby effectuating a wide range of flow rates within microchannels, including very low flow rates.
  • the fluid flow is essentially constant, with little or no shear force being imposed on the fluid, even at very low flow rates.
  • These characteristics of the pump enhance the accuracy of analyses performed with it (e.g., analyte integrity is preserved by minimizing exposure of sample components to shear and degradation), while low flow rates provide sufficient time for chemical reactions to occur.
  • a low, constant pumped flow rate can also be very useful in drug delivery, to ensure dosing accuracy.

Landscapes

  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Micromachines (AREA)

Abstract

L'invention concerne une pompe microfluidique pour gérer un écoulement de fluide dans des dispositifs d'essai jetables La pompe fournit des écoulements constants même à des débits très faibles. L'invention concerne également des dispositifs utilisant la pompe microfluidique, ainsi que des procédés pour la fabrication et la mise en oeuvre d'un processus microfluidique.
EP13767323.2A 2012-03-26 2013-03-15 Pompe microfluidique Active EP2847465B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261615786P 2012-03-26 2012-03-26
PCT/US2013/032020 WO2013148312A1 (fr) 2012-03-26 2013-03-15 Pompe microfluidique

Publications (3)

Publication Number Publication Date
EP2847465A1 true EP2847465A1 (fr) 2015-03-18
EP2847465A4 EP2847465A4 (fr) 2016-04-06
EP2847465B1 EP2847465B1 (fr) 2020-04-15

Family

ID=49261071

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13767323.2A Active EP2847465B1 (fr) 2012-03-26 2013-03-15 Pompe microfluidique

Country Status (5)

Country Link
US (1) US20150050172A1 (fr)
EP (1) EP2847465B1 (fr)
CN (1) CN104204523A (fr)
HK (1) HK1208256A1 (fr)
WO (1) WO2013148312A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3061286C (fr) 2016-04-26 2020-11-17 Remus Brix Anders HAUPT Pompe a couche peristaltique fluidique
US11904311B2 (en) 2016-04-26 2024-02-20 Remus Brix A. HAUPT Fluidic peristaltic layer pump with integrated valves
EP3589409A4 (fr) 2017-02-28 2021-03-31 Abbott Diagnostics Scarborough, Inc. Dispositifs microfluidiques et procédés associés
WO2019078894A1 (fr) 2017-10-20 2019-04-25 Hewlett-Packard Development Company, L.P. Dispositif microfluidique
EP3483441B1 (fr) * 2017-11-13 2020-05-13 Sumitomo Rubber Industries, Ltd. Pompe péristaltique à tuyau
CN114126696B (zh) * 2019-08-27 2024-03-26 深圳迈瑞生物医疗电子股份有限公司 用于医疗设备的流体输送管道的制造方法
EP4090464A1 (fr) 2020-01-17 2022-11-23 F. Hoffmann-La Roche AG Dispositif microfluidique et procédé de synthèse automatisée par division de groupe
CN115003415A (zh) 2020-01-22 2022-09-02 豪夫迈·罗氏有限公司 用于下一代测序库制备的微流控珠粒捕获装置和方法
US20240058753A1 (en) 2020-10-15 2024-02-22 Roche Sequencing Solutions, Inc. Electrophoretic devices and methods for next-generation sequencing library preparation

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2317526A1 (fr) * 1975-07-08 1977-02-04 Rhone Poulenc Ind Pompe peristaltique
US4673657A (en) * 1983-08-26 1987-06-16 The Regents Of The University Of California Multiple assay card and system
MXPA01012959A (es) * 1999-06-28 2002-07-30 California Inst Of Techn Sistemas elastomericos, microfabricados, de valvulas y bombas.
US20050072147A1 (en) * 2000-08-31 2005-04-07 Hower Robert W Micro-fluidic actuator
US20030153872A9 (en) * 2000-09-22 2003-08-14 Tanner Howard M. C. Apparatus and method for micro-volume infusion
KR100421359B1 (ko) * 2001-07-24 2004-03-06 엘지전자 주식회사 탄성 재질의 기판 내에서 유체를 이송하는 방법 및 이를위한 장치
KR100451154B1 (ko) * 2001-07-24 2004-10-02 엘지전자 주식회사 기판 내에서 유체를 조작하는 방법 및 이를 위한 장치
US7056475B2 (en) * 2002-01-30 2006-06-06 Agilent Technologies, Inc. Fluidically isolated pumping and metered fluid delivery system and methods
JPWO2004068519A1 (ja) * 2003-01-30 2006-05-25 サンアロー株式会社 透光性材料製のキートップへのマーキング方法、これによりマーキングしたキートップ、キーユニット、及びキーユニットの製造方法
ATE432420T1 (de) * 2003-03-10 2009-06-15 Univ Michigan Intergrierte mikrofluidische kontrollvorrichtung mit programmierbaren taktilen stellgliedern
FR2897858B1 (fr) * 2006-02-27 2008-06-20 Commissariat Energie Atomique Procede de fabrication d'un reseau de capillaires d'une puce
US8079836B2 (en) * 2006-03-01 2011-12-20 Novartis Ag Method of operating a peristaltic pump
CN101354030B (zh) * 2008-02-20 2010-09-15 重庆大学 具有主动控制能力的微流体泵
US8414182B2 (en) * 2008-03-28 2013-04-09 State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University Micromixers for nanomaterial production
US20110200802A1 (en) * 2010-02-16 2011-08-18 Shenping Li Laser Welding of Polymeric Materials

Also Published As

Publication number Publication date
US20150050172A1 (en) 2015-02-19
HK1208256A1 (en) 2016-02-26
EP2847465B1 (fr) 2020-04-15
EP2847465A4 (fr) 2016-04-06
WO2013148312A1 (fr) 2013-10-03
CN104204523A (zh) 2014-12-10

Similar Documents

Publication Publication Date Title
EP2847465B1 (fr) Pompe microfluidique
Park et al. Towards practical sample preparation in point-of-care testing: user-friendly microfluidic devices
AU2020201653B2 (en) Fluidic peristaltic layer pump
TWI666398B (zh) 流體控制裝置
US20100104474A1 (en) Micro fluidic device
Rogers et al. Microfluidic valves made from polymerized polyethylene glycol diacrylate
WO2008101196A1 (fr) Dispositifs fluidiques
KR100618320B1 (ko) 유체이동장치 및 이를 구비한 일회용칩
JP2003130765A (ja) 基板内における流体処理方法及びその装置
Mohammadzadeh et al. Rapid and inexpensive method for fabrication of multi-material multi-layer microfluidic devices
US20120138833A1 (en) Multi-Function Eccentrically Actuated Microvalves and Micropumps
JP4819945B2 (ja) チャンバを含む流路部位を有する基板、およびそれを用いて液体を移送する方法
US20070207063A1 (en) Device for controlling fluid sequence
CN111468197B (zh) 一种用于离心式微流体***的水压驱动的弹性膜片微阀及其制备方法
Schuenemann et al. Packaging of disposable chips for bioanalytical applications [microfluidics]
JP2006029485A (ja) マイクロバルブ及び該バルブを有するマイクロ流体デバイス
US11904311B2 (en) Fluidic peristaltic layer pump with integrated valves
Neumann et al. Fluidic Platforms and Components of Lab-on-a-Chip devices
Xie et al. Development of a disposable bio-microfluidic package with reagents self-contained reservoirs and micro-valves for a DNA lab-on-a-chip (LOC) application
Xie et al. Optimization of a microfluidic cartridge for Lab-on-a-chip (LOC) application and bio-testing for DNA/RNA extraction
Xie et al. Development of an integrated bio-microfluidic package with micro-valves and reservoirs for a DNA lab on a chip (LOC) application
Tan et al. A reliable method for bonding polydimethylsiloxane
Tan Development of a lab on a chip for nerve agent detection

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20141023

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1208256

Country of ref document: HK

RA4 Supplementary search report drawn up and despatched (corrected)

Effective date: 20160304

RIC1 Information provided on ipc code assigned before grant

Ipc: F04B 43/12 20060101AFI20160229BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20181210

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20190514

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

INTC Intention to grant announced (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20191028

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602013067951

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1257610

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200515

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20200415

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200817

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200715

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200815

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200716

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1257610

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200415

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200715

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602013067951

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

26N No opposition filed

Effective date: 20210118

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602013067951

Country of ref document: DE

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1208256

Country of ref document: HK

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20210315

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20210331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210315

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210331

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210331

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210315

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210315

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210331

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211001

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20130315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20200415