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    • 专利摘要:
      MICRO-PUMP OR MICRO-VALVE NORMALLY DISABLED.It is a microvalve for use in a biosensor, a microfluidic device, use of such a device and a microfluidic element. Biosensors are used to detect molecules and / or ions, such as protein, drug, DNA, RNA, hormone, glucose, insulin, enzyme, fungus, bacteria, etc., in a biological sample. The sensor can be used for diagnostic application, but, for example, drugs, whether therapeutic or abusive, can be detected, for example, in blood, urine and saliva.
    公开号:BR112013018065A2
    申请号:R112013018065-0
    申请日:2012-01-20
    公开日:2020-10-27
    发明作者:Roel Penterman；Johannes Van Eemeren；Reinhold Wimberger-Friedl；Henrik Van Amerongen
    申请人:Biocartis Sa；
    IPC主号:
    专利说明:

    [0001] [0001] The invention relates to a micro valve and / or micro pump for use in a biosensor, a microfluidic device, use of such a device and a microfluidic element. The invention especially relates to a microfluidic cartridge for diagnostic use. The microfluidic cartridge can be to be inserted into a parallel pneumatic interface plate of a pneumatic instrument, an interface plate to interface with a microfluidic cartridge and between a pneumatic instrument, a system for fluid performance within a microfluidic cartridge comprising such plate interface and refers to a pneumatic instrument. BACKGROUND OF THE INVENTION
    [0002] [0002] Biosensors are used to detect molecules and / or ions, such as protein, drug, DNA, RNA, hormone, glucose, insulin, enzyme, fungus, bacteria, etc., in a biological sample. The sensor can be used for diagnostic application, but, for example, also drugs, or therapeutic or abuse, can be detected in, for example, blood, urine and saliva.
    [0003] [0003] Such tests are designed to be used in many different definitions, for example, at the point of care for medical applications, or in any desired call for drugs of abuse (DOA), for example, on the side of the road. In all cases, a robust, reliable and sensitive device is required, which must also be inexpensive since it must be discarded after measurement.
    [0004] [0004] Performing such a biochemical test requires a certain degree of fluid manipulation, at least the sampling fluid needs to be introduced into the detection device in order to allow the target molecules to bind to the sensor surface. The term fluid refers to a fluidum, and can refer to a liquid, a gas and a combination thereof. Depending on the type of assay, more or less complicated microfluidic systems are designed. Since a sample is, in itself, contamination, it does not need to come into contact with the instrument and needs to be stored safely inside, for example, a cartridge during and after a measurement.
    [0005] [0005] There is a focus on the development of lab-on-chip type systems or fully integrated chip biochemical microfluidic systems. A problem in these microfluidic systems is the handling of fluids from and to different reaction chambers, so that micro actuators such as pumps and valves are typically needed. Pumping and valve systems can be done in numerous ways, an overview of microvalve concepts is provided in Oh & Ahn and a review of micro pumps by Laser & Santiago (KW. Oh & CH Ahn, “A review of microvalves', J. Micromech. Microeng. 16 (2006) R13 to R39 and DJ Laster & JG Santiago, “A review of micropumps', J. Micromech. Microeng. 14 (2004) R35 to R64).
    [0006] [0006] For cartridges integrated in medical diagnostics or other applications, reliable storage of (bio) chemical reagents is important. For example, wet reagents may not evaporate and / or leak out while being stored. Some should not have or have only limited contact with oxygen or ambient air that carries bacteria and fungi. A valve that is normally closed is preferred. Therefore, a challenge in microfluidic systems based on active fluid handling using micro actuators, that is, individually addressable pumps and valves, refers to the storage of liquids before the use of a device, such as a chip or cartridge. To prevent unwanted fluid from flowing and mixing when the chip / cartridge is not addressed, that is, not in operation, reagent chambers must be sealed. In addition, for long shelf life, this seal must be of high quality, that is, low permeation of volatile components and no leakage over a long period of time and high temperature, while the cartridge is not present in an instrument (analytical ) so that the energized sealing device cannot be actuated. An additional feature is that when used, these seals must open easily with means present in the cartridge and the instrument. For low cost and complexity, it is preferred not to require extra elements, such as mechanical drilling or local heating to break the seal, but the use of the fluid actuation means present for fluid actuation. A known valve or micro pump is shown in Figure 1. A diaphragm is closed mechanically by pressing the bottom of the diaphragm in a pressure chamber using an actuator. In a micro pump, the actuator is moved back and forth. Like a valve, it is normally opened until it is closed by the actuator. A problem with such a valve or micro pump is the alignment of the actuator and the chamber or pressure orifice (indicated with “1”), especially when there are multiple valves.
    [0007] [0007] Several documents recite valves and their use.
    [0008] [0008] US 2010137784 (A1) recites a one-way valve comprising a seat and a membrane that has an inner portion that is located over the seat, in which, in use, the inner membrane portion is selectively deflected from the seat in such a way that a fluid path is created from one side of the membrane to the other in order to open the valve, and in which an outer peripheral portion of the membrane is more rigid than the inner portion, such that the membrane deflection is substantially restricted to the inner portion only. The one-way valve can be used on a pump for an infusion system. This document does not describe a normally closed valve. The membrane is perforated. The valve is dependent on the fluid pressure to actuate the valve. In addition, the two-material membrane used is quite complex.
    [0009] [0009] US 2010171054 (A1) recites an integrated microvalve system comprising at least a first fluid branch and a microvalve that is controlled by a control pressure in a control channel. The microvalve is adapted to control a fluid flow in the first fluid branch. A flow restrictor arrangement is located between a control port and the control channel to provide predetermined on and off response characteristics of the microvalve. Preferably, the flow restrictor arrangement comprises an emptying channel and an inflation channel arranged in parallel. Each channel comprises a check valve and a flow restrictor, which may have a different flow restriction to provide different shut-off and on response characteristics for the microvalve.
    [0010] [0010] This document does not describe a normally closed valve. Inflation and deflation are necessary to operate the valve. The system is not reliable without a power source, for example, the pressure needs to be maintained properly to keep the valve closed.
    [0011] [0011] US 2007275455 (A1l) describes a tube microfluidic device, microfluidic cell culture device and system incorporating the devices are disclosed. The valved microfluidic device includes a substrate, a microchannel through which liquid can be moved from one station to another within the device, and a pneumatic microvalve adapted to be switched between open and closed states to control fluid flow through a microchannel. The microvalve is made up of three flexible membranes, one of which is responsive to pneumatic pressure applied to the valve and the other two of which deform to produce a more sealable channel cross-section. The cell culture device provides a valve system to allow controlled loading of cells into the individual well of the device, and the exchange of cell culture components in the wells.
    [0012] [0012] US 2007237686 (A1) recites membrane valves and locking valve structures for microfluidic devices are provided. A demultiplexer can be used to address lock valve structures. Membrane valves and lock valve structures can be used to form pneumatic logic circuits, which include processors.
    [0013] [0013] US 2010151565 (A1) recites a cartridge for detecting the presence, absence and / or quantity of a target nucleotide sequence in a sample comprising one or more nucleic acid sequences. The cartridge comprises a first component and a second component that are connectable with each other, the first component comprising at least a first fluid opening and a first sealing surface, and the second component comprising at least a second fluid opening and a second sealing surface. By connecting the first and second components, the first and second fluid openings are in fluid communication and the first and second sealing surfaces are movable against each other to seal fluid communication between the first and second fluid openings . The invention is characterized by the fact that the cartridge comprises means of predisposition to predispose the second sealing surface towards the first sealing surface.
    [0014] [0014] US 2010078584 (A1) recites a valve device comprising a substrate and an elastic membrane, the membrane being joined at least around a valve area to the substrate. The substrate comprises a first channel and a second channel, both of which end in the valve area, the first channel having, in the valve area, a first channel end surface and the second channel having, in the valve area, a second channel end surface, wherein the area of the first channel end surface is substantially larger than the area of the second channel end surface.
    [0015] [0015] It is a disadvantage of the present microvalves that they cannot withstand pressures above 1 bar. Likewise, the present microvalves cannot be used at an elevated temperature. SUMMARY OF THE INVENTION
    [0016] [0016] l It is an object of the present invention to provide a microvalve, a micro pump, a microfluidic device, the use of such a device, a microfluidic element or a Total Analysis Biosensor, bioreactor or Microsystem that includes such a microvalve.
    [0017] [0017] The invention relates to a normally closed microvalve for use in a microfluidic device, comprising a valve seat, an outlet opening, an inlet, and one or more flexible pre-compressed or pre-stretched separators, preferably membranes or diaphragms, with one or more flexible pre-compressed or pre-stretched separators arranged so that pre-stretching or pre-compression forces the one or more separators against a valve seat in a normally closed state. As a separator, a diaphragm or non-perforated membrane can be used. This has the advantage that the operation of the microvalve is not dependent on the fluid pressure to actuate the valve and, in addition, leads to a more reliable closed state.
    [0018] [0018] Such a valve can be used as a microfluidic element, in a micro pump, in a microfluidic device, etc. Modalities of the present invention can be applied, for example, in any bio-detection applications where rapid, sensitive and low-cost tests are required. They can also be applied to cartridges for diagnostic and life sciences applications.
    [0019] [0019] Therefore, the present invention provides a valve for use in a chemical sensor, a biosensor, a bioreactor, and includes use in a microfluidic device to detect molecules / ions, as well as a system, such as a Total Analysis Microsystem . Such biosensors, bioreactors and systems generally have a sampling unit, one or more reagent containers, microfluidic channels that interconnect them, and at least one valve according to one embodiment of the present invention.
    [0020] [0020] How such modalities of the present invention can overcome one or more of the above problems and / or disadvantages, without compromising other desired characteristics thereof.
    [0021] [0021] A valve according to the modalities of the present invention can be used in cartridges and can have virtually no leakage, which is a significant improvement over prior art valves. Experiments with the present project showed no failure due to leaking valves (> 100 cartridges were tested).
    [0022] [0022] It is assumed that increased reliability is mainly due to the pre-stretching or pre-compression of the valve membrane, that is, the membrane is predisposed against the valve seat without requiring the need for a power source. Optionally, the diaphragm can be further pressed against the valve seat. Applying pressure against the remote diaphragm side of the valve seat further increases the leak pressure of the valve, for example, the pressures created in the channel.
    [0023] [0023] The cartridge can contain one or more of a sampling unit, a container such as a reagent container, a filter, a pump, a mixing chamber, a reactor chamber. The cartridge can be a disposable cartridge.
    [0024] [0024] For example, the present invention can provide a valve that can be used in an embodiment in an automated enrichment protocol. The protocol can be implanted by a diagnostic device, for example, in the form of a cartridge that includes the valve and is adapted to optionally isolate, identify and / or purify pathogen genetic information, such as DNA or RNA, or a protein pathogen, an antibody or a fraction of an antibody created against the pathogen, a pathogen lipid, a pathogen cell membrane or part of it, a virus or a part of it, etc. from a fluid sample such as a body fluid sample, for example, a complete blood sample of 0.1 to 10 ml or 1 to 5 ml, a urine sample, a saliva sample, a sample of sperm, a sputum sample, a wound exudate sample, a tear sample, a sample of exhaled air, etc. Other samples can be obtained from air or water samples, such as polluted air or water samples. The cartridge can contain, for example, a filter. The filter can filter, for example, intact pathogens or parts of it after selective lysis of cells such as lysis of mammalian, reptile or bird or insect cells. For example, a means for rinsing can be provided and after rinsing, means are provided so that pathogens can be lysed in the filter and genetic information such as DNA or RNA is eluted for further purification and optionally amplification, for example, by PCR . The use of a large volume of fluid samples, such as blood samples, in combination with a filtration approach requires a reliable valve, as provided in the embodiments of the present invention, that can withstand pressures above 1 bar. These high pressures are necessary to obtain sufficient processing times.
    [0025] [0025] The pre-stretched or pre-compressed membrane, in embodiments of the present invention, comes in contact with the valve seat sealably when the valve is in a normally deactivated condition. For example, the sealing contact can seal a reagent chamber from a channel. Attributes of a valve according to the modalities of the present invention can be one or more of: a pre-stretched or pre-compressed flexible diaphragm or membrane and a corresponding valve seat; wherein the valve is normally closed, and therefore it is suitable for storage of reagent;
    [0026] [0026] To open the valve, a force such as a vacuum is applied to the outer side (opposite fluid channel side) of the membrane (pneumatic actuation);
    [0027] [0027] Optionally, the valve is part of a pump and / or other microfluidic element; and
    [0028] [0028] Pre-stretching or pre-compression of the separator can optionally be combined with applying pressure to the separator in the closed state, which provides a highly reliable valve that does not show leakage using pressures of the order of 0.5 at 2 bar.
    [0029] [0029] By increasing the size, for example, height, width or thickness of the valve seat, the membrane can be additionally pre-stretched or pre-compressed, which increases leak resistance in the closed state, which further improves , thus, reliability.
    [0030] [0030] In order to provide this increase in resistance against leakage, the flexible membrane can be adhered, in an example of the invention, to the valve body by a layer of double-sided adhesive tape when in the pre-stretched or pre-stretched state compressed.
    [0031] [0031] An alternative to an independent invention comprises a microvalve comprising a body portion, a membrane and a valve seat, the body portion having an inlet and outlet channel and in which the inlet channels and outlet enter a chamber around the valve seat at an angle to a plane of the membrane between 45 and 135 °, preferably between 75 and 105 °, more preferably between 80 and 100 °, such as 90 °, that is, substantially perpendicular. The valve body can be made of one or more layers of material such as a plastic of which PMMA is an example, and at least part of the inlet and outlet channels are formed by paths through the valve body.
    [0032] [0032] The present invention also includes a system such as a Total Analysis Microsystem that comprises one or more of a valve according to any of the embodiments of the present invention, a microfluidic element according to any of the embodiments of the present invention or a microfluidic device according to any of the embodiments of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
    [0033] [0033] These and other aspects of the invention will be further clarified with reference to the Figures, in which:
    [0034] [0034] Figure 1 is a diagrammatic cross-sectional view of a prior art valve.
    [0035] [0035] Figure 2 is an example of a microfluidic device according to an embodiment of the present invention.
    [0036] [0036] Figure 3 is an example of a microfluidic device according to an embodiment of the present invention comprising a valve according to any of the embodiments of the present invention.
    [0037] [0037] Figure 4 is an example of a microfluidic device according to one embodiment of the present invention comprising a valve according to any of the embodiments of the invention.
    [0038] [0038] Figures 5ab is an example of two standardized layers of a device according to an embodiment of the invention.
    [0039] [0039] Figure 6a a | are diagrammatic cross-sectional views of an embodiment of the present invention.
    [0040] [0040] Figure 7a, b is a photograph of a cartridge and present table according to the modalities of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
    [0041] [0041] A diaphragm valve or membrane valve, as provided by embodiments of the present invention, comprises a valve body with two or more ports, a diaphragm (or membrane), and a "saddle" or seat through which the diaphragm closes the valve. A diaphragm valve can be controlled by an actuator.
    [0042] [0042] A diaphragm pump or diaphragm pump valve, as provided by the embodiments of the present invention, is a positive displacement pump that uses a combination of the reciprocating action of a diaphragm or membrane and a suitable valve such as a diaphragm valve. non-return retention to pump a fluid.
    [0043] [0043] A liquid is considered as an aggregate of matter that comprises molecules or particles that are able to flow in addition to each other, such as a liquid, a gas, a plasma and combinations thereof.
    [0044] [0044] Body fluid should be interpreted widely and includes liquid or gas obtained from a living or dead creature. It is not limited to humans or mammals, but includes any creature that can carry a pathogen such as both vertebrates and invertebrates, such as birds, mammals, reptiles, rodents, insects, fish, shellfish.
    [0045] [0045] As used in the description and in the claims, the word "separator" refers to an element that separates a fluid component from other components. To achieve this, the separator is preferably unperforated. According to embodiments of the present invention, a separator is a permanent layer without holes that would not allow fluid to pass through the layer from a fluid chamber to another element, for example, out of the microvalve.
    [0046] [0046] According to the present invention, "pre-stretched" means that the separator is in a tensioned state when the valve is ready for operation and in its resting state, that is, in the valve before being actuated. Pre-stretching can be achieved by the valve seat which forces the separator to extend when it is mounted on the valve and / or the separator can be tensioned or extended before bringing it to the position on the valve seat.
    [0047] [0047] According to the present invention, "pre-compressed" means that the separator is in a compressed state when the valve is ready for operation and in its resting state, that is, in the valve before being actuated. Pre-compression can be achieved by the valve seat which forces the separator to compress when it is mounted on the valve and / or the separator can be installed in a compressed state when it is brought into position on the valve seat.
    [0048] [0048] Therefore, for both pre-stretching and pre-compression, the separator has elastic potential in a passive and normally closed state. DETAILED DESCRIPTION OF THE INVENTION
    [0049] [0049] The present invention will be described in relation to particular modalities and with reference to certain drawings, but the invention is not limited to them, but only by the claims. The drawings described are only schematic and are not limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to scale for illustrative purposes. Where an indefinite or defined article is used when referring to a singular noun, for example, "a" or "an", "o", "a", this includes a plural of that noun unless something else is specifically stated .
    [0050] [0050] The term "comprising", used in the claims, should not be interpreted as restricting to the means listed after the same; it does not exclude other elements or steps. Thus, the scope of the expression “device comprising means A and B” should not be limited to devices consisting only of components A and B. This means that, in relation to the present invention, the only relevant components of the device are A and B.
    [0051] [0051] In addition, the terms first, second, third and similar in the description and in the claims are used to distinguish between similar elements and not necessarily to describe a sequential or chronological order. It is to be understood that the terms so used are interchangeable under the appropriate circumstances and that the modalities of the invention described in this document have the ability to operate in sequences other than that described or illustrated in this document.
    [0052] [0052] In addition, the terms top, bottom, over, under and the like in the description and in the claims are used for descriptive purposes and not necessarily to describe relative positions. It is to be understood that the terms so used are interchangeable under the appropriate circumstances and that the modalities of the invention described in this document have the ability to operate in other orientations than those described or illustrated in this document.
    [0053] [0053] The present invention relates to a valve that is normally closed, which is optionally kept closed without an external force applied. To provide additional security, an external force can be applied.
    [0054] [0054] According to a first aspect, the invention relates to a normally closed microvalve for use in a microfluidic device comprising a valve seat, an outlet opening, an inlet, and one or more separators - pre-compressed or flexible pre-stretched, preferably membranes or diaphragms, and the one or more flexible pre-compressed or pre-stretched separators are arranged so that the pre-stretching or pre-compression forces the one or more separators against a seat valve in a normally closed state.
    [0055] [0055] Advantages are among others that, if no pressure is used to keep the valve closed, then the normally closed valve is closed and passive, that is, not energized and, therefore, is not dependent on a battery or other source of power. This is better than those prior art designs that require a positive closing force to be applied, which will mean that they require a power source and are non-passive devices. In addition, microchannels can be provided as paths through the valve body, and such a path design is easy to process using traditional MEMS or macrotechnical techniques such as injection molding.
    [0056] [0056] As a separator, a non-perforated diaphragm or membrane can be used. This has the advantage that the operation of the microvalve is not dependent on the fluid pressure to actuate the valve and, in addition, leads to a more reliable closed state.
    [0057] [0057] The valve can be used on a cartridge, especially a disposable cartridge such as a diagnostic cartridge. Where a detector is used, it can be placed in an integrated manner with the valve, but is preferably located outside the cartridge, which makes design and implantation easier. This means that an expensive and / or sophisticated detection unit can be made in table top size while the cartridge is small and disposable.
    [0058] [0058] The outlet and inlet openings are adapted to allow the passage of fluids, in such quantity as is required by an application.
    [0059] [0059] In one example, the present valve has one or more of a cavity, a channel, a body portion, a seal, such as a seal ring, an adhesive, a flow regulator, such as a flow restrictor , a controller and a frame. In view of functionality, the present valve is provided with a cavity or container or the like for storing fluid or passing fluid through it. One or more cavities may be present. A cavity can also be used as a reaction and / or detection chamber. Typically, various parts of the present device, such as cavities, valves, regulators, etc. they are connected by one or more channels, which allows the passage of a fluid. Typically, channels are microchannels, that is, which have a diameter of 1 to 100 µm. The valve typically has a body portion, such as a solid body, typically formed from a plastic or the like, but without limitation. In order to perform various functions and / or to store fluids, parts of the valve have one or more sealing members. Typically, several layers are connected by an adhesive, such as a double-sided adhesive, or layers can adhere by nature and / or by adding adhesives. For flow purposes, one or more flow regulators can be provided, such as a restrictor. Likewise, a controller to perform the various functions required may be present. The controller can be an integrated microcontroller. The microcontroller can be powered by an integrated power source such as a battery, or it can include a solar or photovoltaic cell or any other energy sequestering device.
    [0060] [0060] In one example, the present valve further comprises a body portion and wherein the valve seat is less than the width of one or more flexible pre-compressed or pre-stretched separators, for example, membranes or diaphragms , and each of the separators has a region that is larger than the valve seat. As such, the separator, for example, membrane or diaphragm, fully covers a valve, can be forced tightly against the valve seat, which prevents leakage, can be pre-compressed or pre-stretched sufficiently, and can even operate by external force, such as pressure, whose pressure can be (relatively) negative.
    [0061] [0061] In one example, the microvalve additionally comprises a means for fluid-proof preservation of the body portion to the region of each of the one or more flexible pre-compressed or pre-stretched separators, for example, membranes or diaphragms, being that the region is larger than the valve seat. In one embodiment, preferably, the fluid-proof preservation means is double-sided adhesive tape. Such fluid-proof preservation provides a longer storage life and allows higher pressures to be used, which thereby increases, for example, functionality.
    [0062] [0062] In an independent example, which can be used with the present invention or with other types of membrane other than those described in this document, a valve is provided with a body portion that has an inlet channel and an outlet channel and a valve seat and a membrane, in which the inlet and outlet channels enter a chamber around the valve seat at an angle relative to a plane of the membrane between 45 and 135º, preferably between 75 and 105º, more preferably between 80 and 100º, such as 90º, that is, substantially perpendicular. Such channels can be provided as paths and, therefore, can be provided by conventional semiconductor or processing by MEMS. As such, a more robust design is provided, which reduces the risk of damage, and improves storage life and reduces leakage.
    [0063] [0063] In one example, the present valve has an opening adapted to allow the application of an external force to at least assist in opening the microvalve. As such, the valve can be actuated and performs several functions. The opening can be adapted for use with a table top detector.
    [0064] [0064] In one example, the opening is adapted to allow fluid pressure to be applied to the side of one or more flexible pre-compressed or pre-stretched separators, for example, membranes or diaphragms, which is remote to the side that makes contact with the valve seat. The fluid pressure is preferably a vacuum. Fluid pressure is typically provided by means, such as pumps, that are present in the table detector which is below the device comprising the present valve, for example, during detection.
    [0065] [0065] In one example, a height of the valve seat is 1.1 to 5 times the first height of the outlet opening, preferably 1.2 to 2.5 times, such as 1.5 to 2 times. By increasing the height of the valve seat, the separator, for example, membrane or diaphragm, is more strongly attached to the seat, which thus improves storage life and prevents leakage. In addition, the valve can be operated at a higher pressure. It has been experimentally verified that the height does not need to be very large in order to achieve a desired effect, the height depending in part on a type of membrane used. If the height increase is small, a negligible effect is observed. It has been experimentally verified that a significant effect is observed by increasing the height by 20% or more.
    [0066] [0066] In one example, the separator, for example, membrane or diaphragm, comprises a material chosen from the group comprising elastomer, such as PDMS, natural and synthetic rubber, saturated and unsaturated rubber, and thermoplastics.
    [0067] [0067] An M elastomer is, for example, a polymer with the property of viscosity (colloquially "elasticity"), which generally has remarkably low Young's modulus and high yield stress compared to others. Young's modulus can be less than 1 MNm-2, such as 0.5 MNm-2. The term, which is derived from elastic polymer, is often used interchangeably with the term rubber, although the latter is preferred when referring to vulcanized. Each of the monomers that bond to form the polymer is usually made of carbon, hydrogen, oxygen and / or silicon. Elastomers are typically amorphous polymers that exist above their glass transition temperature, so that considerable segmental movement is possible. At room temperatures, rubbers are thus relatively soft (E-3MPa) and deformable. Its primary uses are for sealing, adhesives and flexible molded parts.
    [0068] [0068] Examples of elastomers are unsaturated rubbers that can be cured by sulfur vulcanization, such as natural polyisoprene, such as natural cis-1,4-polyisoprene (NR) rubber and trans-1,4-polyisoprene gutta-percha , synthetic polyisoprene (IR for Isoprene Rubber), polybutadiene (BR for Butadiene Rubber), chloroprene rubber (CR), polychloroprene, Neoprene, Baypren etc., butyl rubber (isobutylene and isoprene copolymer, IIR), halogenated butyl (butyl chlorine rubber: CIIR, butyl bromine rubber: BIIR), styrene-butadiene rubber (styrene and butadiene copolymer, SBR), nitrile rubber (butadiene and acrylonitrile copolymer, NBR), also called rubbers Buna N, hydrogenated nitrile rubbers (HNBR) such as Therban and Zetpol, saturated rubbers that cannot be cured by sulfur vulcanization, such as EPM (ethylene propylene rubber, a copolymer of ethylene and propylene) and EPDM rubber (rubber ha of ethylene propylene diene, an ethylene terpolymer, propylene and a diene component), epichlorohydrin rubber (ECO), polyacrylic rubber (ACM, ABR), silicone rubber (SI, Q, VMOQ), fluorosilicone rubber (FVMOQ ), fluoroelastomers (FKM, and FEPM) such as Viton, Tecnoflon, Fluorel, Aflas and Dai-El, perfluoroelastomers (FFKM) such as Tecnoflon PFR, Kalrez, Chemraz, Perlast, polyether block amides (PEBA), chlorosulfonated polyethylene ( CSM), (Hypalon), ethylene vinyl acetate (EVA). Several other types of elastomers are: thermoplastic elastomers (TPE), for example, Elastron,
    [0069] [0069] In one example, the present valve separator, for example, membrane or diaphragm, is pre-stretched to an elongation greater than 1 and up to 10 times the initial size, preferably between 1.05 and 7 times, more preferably between 1.1 and 5 times, such as between 1.25 and 2 times. Depending on the type of separator used, for example, membrane or diaphragm, the separator, for example, membrane or diaphragm, can be pre-stretched to a stretch of 5% plus up to about 700% more. To obtain an improvement, some pre-stretching is required, preferably 5% or more is used. A very large pre-elongation faces thresholds typical of a material, in which a material will break or similar, or creep that results in opening the valve, which is undesirable. Experimentally, the best results are obtained when the separator, for example, membrane or diaphragm, is stretched from 10% to 100%, such as 20% or more.
    [0070] [0070] According to a second aspect, the invention relates to a microfluidic element, such as a microfluidic pump, which comprises a valve according to the modalities of the invention. When operated as a pump, a means for reciprocating movement of the separator, for example, membrane or diaphragm, is provided (for example, sequential vacuum applications) in combination with a one-way valve. As the present valve is especially suitable for use at an elevated temperature and / or to reduce leakage, microfluidic elements aimed at such use are especially contemplated.
    [0071] [0071] According to a third aspect, the invention relates to a microfluidic device comprising no more than four layers, comprising a cover layer, a first patterned layer below the cover layer, an intermediate layer below the first standardized layer, and a standardized layer below the intermediate layer, and one or more valves, preferably one or more valves according to the invention.
    [0072] [0072] According to an example of the present invention, a microfluidic cartridge to be placed on a parallel pneumatic interface plate of a pneumatic instrument is provided. The cartridge comprises a three-dimensional fluid channel in which a fluid is to be transported by pneumatically pumping a pneumatic instrument. In addition, the microfluidic cartridge comprises a flexible separator, for example, membrane or diaphragm, in which the flexible separator covers a plane and in which the flexible separator builds an external surface of the cartridge. In addition, the three-dimensional fluid channel is spatially defined in three dimensions by the inner walls of the cartridge and by the flexible separator, for example, membrane or diaphragm, where the flexible separator, for example, membrane or diaphragm, is in a fundamental state or rest when no pressure or vacuum is applied to the flexible separator, for example, membrane or diaphragm. The flexible separator, for example, membrane or diaphragm, is pneumatically deflectable from the perpendicularity of the ground state to the plane of the flexible separator, for example, membrane or diaphragm, in two directions when the cartridge is placed on the parallel pneumatic interface plate.
    [0073] [0073] In other words, the fluid is not transported along a smooth surface, but is moved along the three-dimensional liquid channel.
    [0074] [0074] In addition, the flexible separator, for example, membrane or diaphragm, can be pneumatically deflectable in the areas that are part of the external surface of the cartridge. In other words, in a first region, the flexible separator, for example, membrane or diaphragm, covers the fluid channel in which the first region is part of the outer surface of the cartridge. According to this exemplary embodiment, the flexible separator, for example, membrane or diaphragm, can additionally extend into a second region under the outer surface of the cartridge, so that the separator, for example, membrane or diaphragm, is not accessible to from outside the cartridge in that second region.
    [0075] [0075] In addition, a "fundamental state of the flexible separator, for example, membrane or diaphragm" describes the situation in which pressure or vacuum is not applied to the flexible separator, for example, membrane or diaphragm. Starting from this situation, the flexible separator, for example, membrane or diaphragm, is deflectable towards the inside of the cartridge and is also deflectable away from the cartridge. This can, for example, be seen in Figure 2 in which an up and down deflection of the flexible separator, for example, membrane or diaphragm, in different positions along the separator leads to a desired liquid transport. In other words, the flexible separator, for example, membrane or diaphragm, is deflectable in two directions namely towards the fluid channel and away from the fluid channel.
    [0076] [0076] The cartridge, which can be, in this and any other modality, for example, a disposable cartridge, allows the pneumatic actuation that is performed through a reversible pneumatic interconnection between the pneumatic instrument and the cartridge, in which the interconnection is formed by the flexible separator, for example, membrane or diaphragm. Pneumatic actuators are integrated into the instrument for a low-cost and reliable cartridge solution. The performance of the fluid that is contained in the fluid channel inside the cartridge is achieved by deflecting the flexible separator, for example, membrane or diaphragm, which can be attached to the main surface of the cartridge. Thus, when the cartridge is attached or inserted into the pneumatic interface plate compartments, they are formed by the flexible separator, for example, membrane or diaphragm, of the cartridge and parts of the pneumatic interface plate. The pressure in these compartments, where pressure can be generated by the separate pneumatic instrument, determines the deflection of the flexible separator, for example, membrane or diaphragm, in which, in turn, the fluid acts through which a movement is caused.
    [0077] [0077] This microfluidic cartridge takes advantage of the high power and long stroke of pneumatic actuation while at the same time keeping the cartridge simple and at low costs and allowing the easy introduction of other physical transport through the interface board, such as heat or acoustic vibration.
    [0078] [0078] In addition, a large number of actuators can be easily integrated into the smooth pneumatic interface plate, as no individual fixation, such as tubing, is required for pneumatic actuation.
    [0079] [0079] In other words, as elements of pneumatic piping and pressure or vacuum generating elements are not present in the microfluidic cartridge and are not present in the corresponding interconnect interface board, a large number of actuators can be easily integrated into the interface board . In other words, a planar microfluidic cartridge is provided that can, in connection with a planar pneumatic interface plate, allow a reliable and convenient pneumatic drive of fluids in the cartridge without the need for piping inside the cartridge. In addition, this can be easily extended to a large number of pneumatic elements, and the integration of thermal, acoustic or other interface cards in the same plane can be simplified.
    [0080] [0080] The term pneumatic elements, in this and all other modalities of the invention, describes positions in which the flexible separator, for example, membrane or diaphragm, is actuated pneumatically, that is, valves and pumps, or more generally areas of interaction . The same is also the flexibility of changing positions and being able to have position in close proximity, which is an advantage of the present invention.
    [0081] [0081] It can be seen as a characteristic of the supplied microfluidic cartridge to perform the actuation of fluids in the cartridge by a pneumatic instrument. The facts that the pneumatic drive makes use of a flexible cartridge separator, for example, membrane or diaphragm, and that the pneumatic chambers below the separator, for example, membrane or diaphragm, are reversibly mounted, are important. This means that the separation plane between the cartridge and the pneumatic instrument crosses the pneumatic chambers.
    [0082] [0082] In other words, when the cartridge is removed, the pneumatic supply channels, pneumatic channels and pneumatic chambers are opened. The chambers below the actuated membrane are formed by the combination of the cartridge and the interface plate on the instrument. When the cartridge is lifted, the pressure can no longer be transferred to the membrane, in contrast to the tubing, which is not used for the actuation of the membrane according to the present invention, and in which the tubing is mechanically fixed.
    [0083] [0083] The microfluidic cartridge can be used in combination with a pneumatic instrument, which contains supply channels for the pneumatic drive and which contains a substantially smooth interface plate towards the microfluidic cartridge containing the fluid channels. The fluid channels are confined by a flexible layer, for example, a separator such as a membrane or diaphragm, which can be actuated once the cartridge is placed in the instrument. By moving the flexible separator, for example, membrane or diaphragm, up and down, a volume is displaced within the cartridge and the separator, for example, membrane or diaphragm, can close channels to provide a valve function within the channel of fluid.
    [0084] [0084] The course of the separator deflection, for example, membrane or diaphragm, is based on the height between the position of the separator, for example, membrane or diaphragm, when it touches the pneumatic interface plate of the pneumatic instrument, as can be seen, for example, in the following Figure 7 and / or the position when it touches the substrate chamber at the top of the separator, for example, membrane or diaphragm, in the cartridge (control attributes).
    [0085] [0085] In other words, the microfluidic cartridge comprises a flexible separator, for example, membrane or diaphragm, which covers a fluid path. In this way, the flexible separator, for example, membrane or diaphragm, covers the total fluid channel system which can contain different fluid paths. It doesn't have to be the complete outer surface everywhere. But likewise, a modality is possible in which the flexible separator, for example, membrane or diaphragm, constructs the entire outer surface of the cartridge. However, the flexible separator, for example, membrane or diaphragm, is always attached to the cartridge. After inserting the cartridge in a pneumatic instrument, the separator, for example, membrane or diaphragm, is deflected locally by tires in the instrument in such a way that the fluid is moved along the fluid path inside the cartridge.
    [0086] [0086] As the cartridge is free of pneumatic or electrical elements, it can be produced in an inexpensive and reliable way.
    [0087] [0087] The flexible separator, for example, membrane or diaphragm, in combination with an interface plate leads to the possibility of attaching the cartridge to the interface plate only by pneumatic forces. Therefore, no other means of fixation, such as screws and the like, may be necessary other than the pneumatic forces generated by the pneumatic instrument. That is why the pneumatic interface board is called a parallel interface. In other words, a deflection of the flexible membrane is created in the closed pneumatic system, which comprises the cartridge and the interface plate and the deflection, in turn, leads to fixation. The suction of the membrane creates the fixation.
    [0088] [0088] Cartridges for table diagnostics must contain all the reagents they need for diagnostics and must be able to be stored for long periods without degradation of the final diagnostic result. The diagnostic result should be obtained, preferably, within a maximum of 20 minutes. This means that the cartridge must be supplied not only with all reagents, but also be designed to perform the microfluidic operations necessary for the diagnosis and storage of reagents in a safe manner for long periods. Preferably, detection is not done on the cartridge itself, as this makes the cartridge more expensive. Instead, it is better to have an accurate, sophisticated and complicated detection device that is located on the desktop diagnostic equipment and access the cartridge through a window. The window can be for optical, infrared, ultraviolet, nuclear radiation, or electrical, pneumatic or magnetic detection techniques.
    [0089] [0089] If the cartridge contains a power source to maintain reagent integrity, it means that the life of the cartridge is reduced and there is a risk that the cartridge will be used after the power supply is depleted, which can result in incorrect diagnosis - a potentially life-threatening situation with associated medical product liability.
    [0090] [0090] Even if a power source is used during storage to maintain reagent integrity, it is preferred that the de-energized situation is not yet harmful, that is, that there is a backup mechanism that still maintains reagent integrity, even after the battery is empty.
    [0091] [0091] Battery life can be increased by power hijacking and this should be included as an option for cartridges.
    [0092] [0092] To maintain integrity, the present invention proposes a normally deactivated valve that is prevented from being opened by the pre-stretching or pre-compression of the valve separator, for example, membrane or diaphragm, which forces the separator, for example, membrane or diaphragm, against a valve seat. This provides a normally deactivated and safe, power-free, passive valve that can be used to prevent reagent degradation. In one example, a side pressure can be applied to the separator, for example, membrane or diaphragm, to further increase safety. This may require a power source in the cartridge. In one example, the cartridge is pre-pressurized, in which case no power source is required. In an additional example, the separator, for example, membrane or diaphragm, is compressed.
    [0093] [0093] The above also applies to bioreactors.
    [0094] [0094] In one example, the present device further comprises one or more valves according to the invention. As such, the mentioned benefits are obtained.
    [0095] [0095] In one example, the present device comprises one or more containers that have a volume of 0.1 to 10 ml, preferably 0.5 to 5 ml, such as 2 to 3 ml. The containers can be, for example, reagent containers, refuse containers, reaction chambers, etc. In an example, the present device comprises a microfluidic element according to the invention and / or a sample inlet unit, and / or one or more processing units. A sampling unit can be provided to collect a sample and / or insert a sample into the cartridge. In addition, one or more processing units, such as analytical units, functional units, etc. can be provided for the purpose of obtaining detection or the like. Typically, a sample needs to be processed, for example, a reaction needs to be performed, filtration needs to occur, separation needs to occur, etc. In an additional example, a control unit (electronics) is also present.
    [0097] [0097] In one example, the present device comprises one or more of a filter, a micro-actuator, such as a pump, a seal, an opening, an outlet, an inlet, and an inclination means. This is comparable to the present valve.
    [0098] [0098] In one example, the present device is one or more of a biosensor, a cartridge, such as a diagnostic cartridge.
    [0099] [0099] In an example of the present device, it is in the form of a disposable cartridge, optionally in a package, the packaging of which may be under vacuum or pressure, and / or optionally comprising an additional seal to maintain pressure. Preferably, the device is disposable, to be used once, typically in combination with a table. Additional means to maintain pressure / vacuum can be provided in order to improve the shelf life.
    [00100] [00100] In one example, the present device has a detection window to allow a detector to be placed adjacent to the microfluidic device and to detect the presence, absence and / or quantity of one or more molecules and / or ions, such such as a protein, drug, DNA, RNA, nucleic acid, nucleic acid sequence, cell membrane or cell membrane fragment, cell organelle, antibody, hormone, glucose, insulin, enzyme, fungus, bacteria, such as pathogenic bacteria, viruses, for cell culture, and magnetic particle. Preferably, detection occurs in a blood sample, such as from a human. Likewise, another human body fluid can be tested.
    [00101] [00101] According to a fourth aspect, the invention relates to a use for detecting, for example, presence, absence and quantity, and / or isolating, and / or purifying one or more molecules and / or ions, such as protein, drug, genetic information such as DNA, RNA, a nucleic acid, a nucleic acid sequence, or a protein such as a hormone, insulin, an enzyme, or other molecules such as glucose, or creatures such as a fungus, a bacteria, such as a pathogenic bacterium, virus, for cell culture, in an array or in an assay.
    [00102] [00102] According to a fifth aspect, the invention relates to a system comprising one or more of a valve for the invention, a microfluidic element according to the invention and a microfluidic device according to the invention.
    [00103] [00103] The present invention will be further explained with reference to the Figures and the description will mainly include exemplary pre-stretched membranes, but the scope of the invention is not limited by this, but only by the claims.
    [00104] [00104] Figure 1 is a diagrammatic cross-sectional view of a prior art valve. The valve has a body with channels in it and a valve chamber. A membrane forms part of the valve, and is shown in the middle part where it seals the valve chamber. An actuator (see arrow) - applies pressure to bend the membrane and force it against a valve seat. The area indicated with a dashed circle and number (1) refers to a weak point in the project, where the project is subject to leakage, specifically in the indicated area. From left to right, a (closed) channel is visible.
    [00105] [00105] In this design, a maximum pressure that can be applied to the valves is mainly determined by the leak between the valve body and the membrane. It was found that this is mainly caused by the position of the input and output channels, depending on the project. When the channels are positioned just above the membrane layer, the cartridge can easily be pushed away locally, and the resulting leak increases pressure in the surrounding areas that are kept under vacuum to keep the cartridge attached to a table top detector. Figure 2 is an example of a microfluidic device according to an embodiment of the present invention. In it, a top layer (cover) (210) is shown, such as a single-sided tape. Below the top layer, a patterned layer (220) is present, such as a laser or molded patterned layer. The standardized layer provides the valve body and can be made of a material such as PMMA that can be shaped and / or machined or mechanically, electrically or chemically. Below, the standard double-sided adhesive tape may be present (not shown). Under it, a second standardized layer (230) is present. Standardized layers provide most of the functionality of the device that includes a valve seat. Below the second standardized layer, a sealing member (240), such as a diaphragm or flexible membrane, is present. The flexible membrane can be made of materials as indicated above. The membrane is also part of the valve, shown in the middle. The membrane is not perforated or porous, that is, it functions as a separator. The membrane has a region that is larger than the valve seat. The membrane is preferably pre-compressed so that a positive force pushes the membrane against a valve seat in its normal, passive condition. This can be achieved by forming the membrane with a convex or dome portion facing the valve seat, as shown in Figure
    [00106] [00106] The example shows that the present device has a solid base. As a consequence, the vacuum is applied more easily, without leakage, and, in addition, the membrane can be attached more easily and more firmly. The present microfluidic device is optionally adapted to rest on, a cooperation with, a table device (290), in which the table device provides additional functionality, such as pressure / vacuum, diagnostics, etc.
    [00107] [00107] As the outlet and the inlet are placed substantially perpendicular and in a different position compared, for example, to the previous technique of Figure 1, the influence of outside forces, such as vacuum, is diminished or even absent, and much better leak prevention is achieved.
    [00108] [00108] The table device 209 in Figure 2 can comprise one or more pumping means that actuate the present device pneumatically.
    [00109] [00109] In one embodiment, the present invention provides a cartridge that has one less layer, compared to prior art cartridges. A membrane layer, such as a rubber layer, becomes a bottom layer of the new cartridge design. The membrane is not perforated or porous, that is, it functions as a separator, so that it seals the valve from the outside. Cartridges with four layers, of which two are standardized (rubber - tape layer - PMMA layer - cover layer), are thus supplied. An additional advantage is that an interface between the cartridge and the table detection device can now be made from a material that can be easily cleaned, such as a metal. A metal (on the desktop device) and rubber (on the cartridge) connection will provide a seal. As such a robust interface is provided, it can be used repeatedly. Experiments showed no "aging" effect (for example, from a rubber layer). An additional advantage is that pressures that can be safely applied (without leakage) to the valves are significantly higher (from -1 to 3 bar), where pressures can be easily increased additionally to 5 bar, or even more. Increased pressures allow for additional functionality, improved processing times, etc.
    [00110] [00110] An additional advantage of modalities of the present invention is that innovative cartridge designs and / or innovative applications of the same are easy to develop and manufacture, as a generic and standardized platform is provided, which allows for a multiplicity of designs and applications. Therefore, the present project refers to versatile cartridge technology, which allows the integration of several complex protocols, flexible design, and rapid prototyping. The inventors have shown that new designs designs can be carried out and tested within 1 week. In other words, the present invention relates to a generic instrument, being a low-cost bench prototype instrument that accepts cartridges to practice different protocols, and that provides various functions, such as mixing, pumping, filtration and heating , if required and / or desired.
    [00111] [00111] The present project provides an improvement of the cartridge that improves the robustness of the technology and reduces the number of components in the cartridge.
    [00112] [00112] Figure 3 is an example of a microfluidic device according to a preferred embodiment of the present invention which comprises a valve according to an embodiment of the present invention. Similar to Figure 2, a top layer (310), a first patterned layer (320), a second patterned layer (330), a membrane (340) and the table are shown. The standardized layers provide the valve body and can be made of a material such as PMMA, which can be shaped and / or machined or mechanically, electrically or chemically. Below, the first standardized double-sided adhesive tape may be present (not shown). The first and second standardized layers form the valve body. Standardized layers provide most of the functionality of the device, which includes a valve seat. The valve seat (350) is additionally indicated, being that it is typically formed from the same material as the second standardized layer. Below the second standardized layer, a sealing member (340), such as a diaphragm or flexible membrane, is present. To achieve this, the membrane is not perforated or porous, that is, it functions as a separator. In this embodiment, the diaphragm is pre-stretched so that the diaphragm is forced against the valve seat in a resting position so that the valve is normally closed. Through cooperation between the valve seat and a fixing means for the membrane, the latter can remain in a pre-stretched state. As the membrane is pre-stretched, it will seal a space, possibly containing a fluid. As such, a storage device is created. The flexible membrane can be made of materials as indicated above. The membrane has a region that is larger than the valve seat. In order to improve the seal between the valve body and the membrane, the membrane can be adhered to the second standardized layer. The membrane is preferably pre-stretched so that a positive force pushes the membrane against a valve seat in its normal and passive condition. The dotted arrow indicates a pressure / vacuum that is optionally applied to open the valve or a pressure that is optionally applied to provide additional pressure on the membrane and improve the seal. The solid arrows indicate a direction of fluid flow through the valve when opened. The horizontal dotted line indicates a separation line between the present device and a table detection device.
    [00113] [00113] The example shows that the present device has a solid base. As a consequence, the vacuum is applied more easily, without leakage, and, in addition, the membrane can be attached more easily and more evenly. The present microfluidic device is optionally adapted to rest on, in cooperation with, a table device (390), in which the table device provides additional functionality, such as pressure / vacuum, diagnostics, etc. The table device (390) in Figure 3 can comprise one or more pumping means that actuate the present device pneumatically.
    [00114] [00114] As the outlet and the inlet are placed substantially perpendicular and in a different position compared, for example, to the previous technique of Figure 1, the influence of outside forces, such as vacuum, is diminished or even absent, and much better leak prevention is achieved. Additionally, as in this example, the outlet and inlet of the valve are substantially perpendicular to the main plane of the valve, with the main plane being perpendicular to the Figure, the valve is more robust and leakage is prevented. The present valve, which comprises a fluid, can be stored for more than 6 months, with no leakage being observed. This is a big improvement.
    [00115] [00115] Figure 4 is an example of a microfluidic device according to the invention comprising a valve according to the invention. Similar to Figure 3, a top layer (410), a first patterned layer (420), a second patterned layer (430), a membrane (440) and table device (490) are shown. A valve seat (450) is additionally indicated, being that it is typically formed from the same material as the second standardized layer. The valve seat is further increased in size, that is, in thickness or height, by an additional layer 451. This increases the pre-elongation of the membrane (440). As such, an even better seal is achieved. To achieve this, the membrane is not perforated or porous, that is, it functions as a separator. The additional layer can be provided by a layer of tape that can be applied to the second patterned layer and then, itself, patterned during manufacturing by laser site patterning. The tape may have a protective PET layer on top of it. In order to improve the seal between the valve body and the membrane, the membrane can be adhered to the second standardized layer. Other details are as described for the device in Figure 3.
    [00116] [00116] Figures 5a, b, c is an example of two standardized layers of a device according to the invention. In this document, several details can be observed, such as channels (521), paths (523), sampling unit (524, 534), reagent chambers (522,532), filter (537), exit / entry openings (532 ), refuse chamber (536), and valves (538). The two layers are placed together in such a way that channels and containers in one layer communicate with each other. Typically, layers are patterned by molding and / or by a laser. Additional molecules to be analyzed (590), such as DNA, are indicated
    [00117] [00117] Figure 6 shows a non-limiting schematic drawing of a valve according to the modalities of the present invention. The essence of these examples is a valve that contains a valve seat and a flexible membrane that is pre-stretched around the valve seat, for example, to seal a reagent chamber from a channel. To achieve this, the membrane is not perforated or porous, that is, it functions as a separator. The main attributes are that the valve comprises a valve seat and a flexible membrane, where the valve is normally closed and, therefore, suitable for reagent storage. In order to open the valve, a mechanical force such as AC driven vacuum can be applied to the outer side (namely the opposite side of the fluid channel) of the membrane (for example, a pneumatic actuation). This arrangement can be combined with applying pressure, optionally, to the flexible membrane in the closed state to make a highly reliable valve that does not show leakage using pressures of the order of 0.5 to 2 bar. Experiments (> 100 cartridges tested) did not fail due to leaking valves.
    [00118] [00118] Figures 6a to d are diagrammatic cross-sectional views of valves according to the modalities of the present invention. On the left (Figure 6a), a cross section of the valve in the closed (top) and open (bottom) state (Figure 6c) is shown. To open the valve, a mechanical force, such as a vacuum, is applied to an opening below the membrane (640). To achieve this, the membrane is not perforated or porous, that is, it functions as a separator. The downward movement of the diaphragm is limited by the upper surface of an opening in the 690 table sensing device. This prevents the diaphragm from being over-extended when the valve is opened. Overextension could cause plastic deformation or creep, which reduces the loss of strength when the membrane is released. On the right (Figure 6b, d), cross sections perpendicular to the channel are shown.
    [00119] [00119] Such cartridges can be constructed by laminating standardized layers, such as laser-standardized PMMA layers (620), together to form the valve body, attachment layers such as double-sided tape layers ((650), Nitto 5015P) and a membrane such as a rubber layer ((640), latex). The valve seat can be constructed by laser standardization of the location of a tape layer such as a PET protective layer present in a tape layer (651). This additional part (651) of the valve seat can be constructed when forming the second standardized layer (650). When during the construction of the device, the protective layer is removed, the PET remains locally behind on top of the valve seats.
    [00120] [00120] Figures 6e to h (top left to right bottom) is a diagrammatic cross-sectional view of valves according to additional embodiments of the present invention. On the left (Figure 6 €), a cross section of the valve in the closed (top) and open (bottom) state (Figure 6g) is shown. In this example, the channels run in parallel with the plane of the membrane. On the right (Figure 6f, h), cross sections of the valve in the closed (top) and open (bottom) state are shown, in which, in addition, the inlet and outlet channels are formed perpendicular or at an angle to the valve membrane. These channels that run parallel to the membrane plane can be formed by corresponding surfaces by machining or engraving the first and second layers, as described above. These channels that travel at an angle or perpendicular to the membrane plane can be formed as paths through the valve body, for example, by laser standardization, engraving or other forms of machining. In the examples shown, both inlet and outlet channels enter a valve chamber formed between the membrane and the valve seat.
    [00121] [00121] In Figure 6i a | (top left to right bottom), two other valve modes are shown. On the left (Figure 6i, k), a cross section of the valve with one of the inlet / outlet channels located on the valve seat in the closed (top) and open (bottom) state is shown. On the right (Figure 6j, 1), both the inlet and outlet channels are located on the valve seat, which is similar as above. These channels running parallel to the membrane plane are formed between the top layer of the valve body (650) and the cover layer (610). In these examples, the valve comprises a pre-stretched membrane (640), a fluidic part (650) with channels and valve seat, adhesive to connect the membrane and a top layer (610) to seal the channels.
    [00122] [00122] Figures 7a, b are a photograph of a present cartridge and present table detection device, in which the cartridge is placed on the table detection device, indicated by an arrow, and held in place by a vacuum that can be used for both to keep the cartridge in place and open the valve (s).
    权利要求:
    Claims (16)
    [1]
    1. Microvalve normally closed for use in a microfluidic device, characterized by the fact that it comprises a valve seat, an outlet opening, an inlet, and one or more flexible pre-compressed or pre-stretched separators, preferably membranes, being that the one or more flexible pre-compressed or pre-stretched separators are arranged so that pre-compression or pre-stretched forces the one or more separators against a valve seat in a normally closed state.
    [2]
    2. Normally closed microvalve according to claim 1, characterized by the fact that said separators are membranes, and in which said membranes are non-perforated membranes.
    [3]
    3. Normally closed microvalve according to claim 1 or 2, characterized by the fact that it has one or more of a cavity, a channel, a body portion, a seal, such as a seal ring, an adhesive, a flow regulator, such as a flow restrictor, a controller and a frame.
    [4]
    4. Normally closed microvalve according to any one of claims 1 to 3, characterized in that it additionally comprises a body portion, and in which the valve seat is less than the width of one or more pre-separators compressed or pre-stretched flexible, and each of the separators has a region that is larger than the valve seat.
    [5]
    5. Normally closed microvalve according to claim 4, characterized by the fact that the microvalve additionally comprises a means for fluid-proof preservation of the body portion for the region of each of the one or more pre-compressed separators or flexible pre-stretched, which is larger than the valve seat, where, preferably, the medium for fluid-proof preservation is double-sided adhesive tape.
    [6]
    6. Normally closed microvalve according to claim 4 or 5, characterized by the fact that the body portion has an inlet and an outlet channel and in which the inlet and outlet channels enter a chamber around the valve seat at an angle to a plane of the membrane between 45 and 135 °, preferably between 75 and 105 °, more preferably between 80 and 100 ”, such as 90”, that is, substantially perpendicular.
    [7]
    7. Normally closed microvalve according to any one of the claims | to 6, characterized by the fact that an opening adapted to allow the application of an external force to at least assist in opening the microvalve.
    [8]
    8. Normally closed microvalve according to claim 7, characterized by the fact that the opening is adapted to allow fluid pressure to be applied next to one or more flexible pre-compressed or pre-stretched separators that is remote from from the side that makes contact with the valve seat, preferably, where the fluid pressure is a vacuum.
    [9]
    Normally closed microvalve according to any one of claims 1 to 8, characterized in that the height of the valve seat is 1.1 to 5 times the first height of the outlet opening, preferably 1.2 to 2.5 times, such as 1.5 to 2 times.
    [10]
    10. Microvalve normally closed according to any one of the claims | to 9, characterized by the fact that the separator comprises a material chosen from the group comprising elastomer, such as PDMS, natural and synthetic rubber, saturated and unsaturated rubber, and thermoplastics, or in which the separator is pre-stretched to a elongation greater than 1 and up to 10 times the initial size, preferably between 1.05 and 7 times, more preferably between 1.1 and 5 times, such as between 1.25 and 2 times.
    [11]
    11. Microfluidic element, such as a microfluidic pump, characterized in that it comprises a valve as defined in any of claims 1 to 9, preferably for use at elevated temperature and / or to reduce leakage.
    [12]
    12. Device = microfluidic, characterized by the fact that it comprises no more than four layers, comprising a cover layer, a first patterned layer below the cover layer, an intermediate layer below the first patterned layer and a second patterned layer below the layer intermediate, and one or more valves, preferably one or more valves as defined in any one of claims 1 to 10.
    [13]
    183. Microfluidic device according to claim 12, characterized in that it comprises a sample inlet unit, and / or one or more processing units, or one or more containers, such as reagent containers or one or more among a filter, a micro actuator, such as a pump, a seal, an opening, an outlet, an inlet and a means of inclination.
    [14]
    Microfluidic device according to either of claims 12 or 13, characterized in that the device is one or more of a biosensor, a cartridge, such as a diagnostic cartridge, optionally in the form of a disposable cartridge, optionally in a package, package which may be under vacuum or pressure, and / or which optionally comprises an additional seal to maintain pressure.
    [15]
    Microfluidic device according to any one of claims 12 to 14, characterized in that the device has a detection window to allow a detector to be placed adjacent to the microfluidic device and to perform a presence, absence and / or quantity of one or more molecules and / or ions, such as protein, drug, DNA, RNA, nucleic acid, nucleic acid sequence, cell membrane or cell membrane fragment, cell organelle, antibody, hormone, glucose, insulin, enzyme , fungus, bacteria, such as pathogenic bacteria, viruses, for cell culture and magnetic particle.
    [16]
    16. Use of a microfluidic device, as defined in any of claims 12 to 15, characterized by the fact that it is to detect, for example, presence, absence and quantity, and / or isolate and / or purify one or more molecules and / or ions, such as protein, drug, DNA, RNA, nucleic acid, nucleic acid sequence, hormone, glucose, insulin, enzyme, fungus,
    bacteria, such as pathogenic bacteria, viruses, for cell culture, in an arrangement and in an assay.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112013018065A2|2020-10-27|micro pump or microvalve normally deactivated
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    CN107824233B|2020-06-30|Low elasticity membranes for microfluidic applications
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    同族专利:
    公开号 | 公开日
    RU2588905C2|2016-07-10|
    US20130299015A1|2013-11-14|
    EP2665956A1|2013-11-27|
    WO2012098214A1|2012-07-26|
    EP2665956B1|2018-08-15|
    JP5967552B2|2016-08-10|
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    CA2824331A1|2012-07-26|
    CA2824331C|2018-11-06|
    US9291284B2|2016-03-22|
    CN103282706A|2013-09-04|
    RU2013134957A|2015-02-27|
    CN103282706B|2016-01-20|
    KR20140023889A|2014-02-27|
    AU2012208527B2|2016-11-17|
    JP2014510878A|2014-05-01|
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    法律状态:
    2020-11-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-11-10| B25A| Requested transfer of rights approved|Owner name: BIOCARTIS NV (BE) |
    2020-11-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-02-09| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 9A ANUIDADE. |
    2021-03-09| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    EP11151705.8|2011-01-21|
    EP20110151705|EP2479466A1|2011-01-21|2011-01-21|Micro-Pump or normally-off micro-valve|
    PCT/EP2012/050835|WO2012098214A1|2011-01-21|2012-01-20|Micro-pump or normally-off micro-valve|
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