Patent Grant
8425863
1. Field of the Invention
This invention relates to a micro fluidic device comprising a valve/pump-unit. The micro fluidic device comprising said valve/pump-unit according to the present invention is preferably used in molecular diagnostics.
2. Background Art
The biotechnology sector has directed substantial effort towards developing miniaturized fluid sample transport devices such as microfluidic devices, often termed labs-on-a-chip (LOC) or micro total analyses systems (microTAS), for sample manipulation and analysis. These systems are used for detection and analyses of specific bio-molecules, such as DNA and proteins.
In general micro-system devices contain fluidic, electrical and mechanical functions, comprising pumps, valves, mixers, heaters, and sensors such as optical-, magnetic- and/or electrical sensors. A typical molecular diagnostic assay includes process steps such as cell lyses, washing, amplification by PCR, and/or detection.
Integrated microfluidic devices need to combine a number of functions, like filtering, mixing, fluid actuation, heating, cooling and optical, electrical or magnetic detection, on a single template. Following a modular concept the different functions can be realised on separate functional substrates, like silicon or glass. The functions need to be assembled with a microfluidic channel system, which is typically made of plastic. With small channel geometries this way of integration becomes a very challenging process. The interfaces between the substrates and the channel plate need to be very smooth and accurate, and the channel geometries need to be reproducible, while the functional substrates should have a minimum footprint for cost efficiency. Especially with functions, which need a fluidic as well as an electric interface, the separation of the wet interface is critical. Bonding techniques must be compatible with the biochemical reagents and surface treatments present on the functional substrates.
US-A1 2003/0057391, incorporated by reference, discloses a low power integrated pumping and valving array which provides a revolutionary approach for performing pumping and valving operations in micro fabricated fluidic systems for applications such as medical diagnostic microchips. This approach integrates a lower power, high-pressure source with a polymer, ceramic, or metal plug enclosed within a micro channel, analogous to a micro syringe. When the pressure source is activated, the polymer plug slides within the micro channel, pumping the fluid on the opposite side of the plug without allowing fluid to leak around the plug. The plugs also can serve as micro valves.
However, the pump system of US-A1 2003/0057391 does not provide a sufficient small dead volume and does not provide an optimized fast fluid transport. Further, the plugs must have a positive fitting to avoid sample fluid leakage thus the low power integrated pumping and valving arrays can not be provided at low vertical range of manufacture.
US 2005/0098749 discloses a micro valve and a method of forming a diaphragm stop for a micro valve. The micro valve includes a first layer and a diaphragm member to control the flow of fluid through the micro valve. The method comprises the step of forming a contoured shaped recess extending inward from a surface of the layer by using a laser to remove material in a series of areas, at successively greater depths extending inward from said surface. Preferably, the recess has a dome shape, and may be formed by a direct-write laser operated via a computer aided drawing program running on a computer. For example, CAD artwork files, comprising a set of concentric polygons approximating circles, may be generated to create the dome structure. Modifying the offset step distance of the polygons and equating certain line widths to an equivalent laser tool definition can control the laser ablation depth. Preferably, the laser tool definition is combined with the CAD artwork, which defines a laser path such that the resulting geometry has no sharp edges that could cause the diaphragm of the valve to tear or rupture.
US 2005/0098749 is directed to a micro valve only. Thus, the micro valve unit of US 2005/0098749 does not simultaneously integrate a pump as well as a valve function in the same unit. Further, the diaphragm member is not flexible so that the micro valve unit of US 2005/0098749 does not form and reform a temporally channel through which a fluid flow can be directed. As disclosed in US 2005/0098749 the diaphragm member opens a hole at a specific gas pressure so that the gas can pass through. However, the gas can not be pumped with the diaphragm member.
In the last decade, considerable research efforts have been made to the development pump-systems for microfluidic system devices in order to reducing the analyze samples volumes of liquid.
Despite this effort, there is still a need for a valve/pump-unit with an optimized reduced dead volume.
An object of the present invention is to provide a valve/pump-unit for a micro fluidic device.
The valve/pump-unit according of the present invention provides a fluid valve or pump action on a micro fluidic device with an optimized dead volume reduced to a minimum, preferably about zero.
This object is attained with a micro fluidic device comprising at least one valve/pump-unit, wherein the micro fluid device comprises:
a substrate, wherein on the lower surface of said substrate at least two micro channels are arranged to direct a fluid sample flow on the substrate, whereby said two micro channels are not end-to-end connected and spaced apart by a valve/pump-unit area of said substrate;
at least one flexible membrane, wherein the flexible membrane is arranged on the lower surface of said substrate;
an actuating element with an upper surface adjacent arranged to the flexible membrane;
at least one cover element arranged on the lower surface of the flexible membrane, wherein the cover element comprises at least one through going cut-out for receiving an actuating element, so that movement of said actuating element causes a pump and/or valve/pump-unit action of the adjacent arranged flexible membrane area to cause or stop a directed fluid flow on said substrate;
so that a fluid flow between said two not end-to-end connected micro channels is directed among the valve area of the lower surface of the substrate and the upper surface of the flexible membrane through a temporally formable channel formed by the flexible membrane covering the valve area, whereby a movement of the actuating element towards to the lower surface of the substrate causes a valve action and a movement opposite to the lower surface of the substrate releases space in a chamber into which the flexible membrane can engage to form the temporally channel and the upper surface of the actuating element covers at least partly the membrane surface at the valve area.
The valve/pump-unit according to the present invention simultaneously integrates a pump as well as a valve function in the same unit.
It can be preferred that the micro fluidic device comprises at least two valve/pump-units so that a fluid can for example be pumped bidirectional.
The micro fluidic device according to the present invention can be used to direct a fluid flow on a substrate to a desired area through a micro channel systems of permanent channels and temporally formed channels, whereby the fluid can be subjected to a relative low over pressure of for example 50 mbar to 1 bar, preferably 100 mbar to 300 mbar.
According to a preferred embodiment of the invention, the substrate comprises a plurality of micro channels and the sample fluid is directed from one micro channel to a plurality of micro channels via the valve area. Current techniques available allow running many reactions in parallel in different reaction chambers. The invention allows directing the sample fluid simultaneously to multiple reaction chambers via multiple micro channels by operating the valve/pump.
According to a further preferred embodiment of the invention, the valve area includes a fluid chamber, whereby the fluid chamber is arranged to store sample fluid. The sample fluid stored in the fluid chamber is dispensed to different reaction chambers via the micro channels. All the reaction chambers can be filled with the sample fluid at once by operating the valve/pump unit.
According to a further embodiment of the invention, the valve/pump is attached to a flexible foil, wherein the flexible foil is capable of aligning the valve/pump unit to the lower surface of the substrate when the actuating element is moved towards the lower surface of the substrate. This movement of the actuating element causes a fluid flow from the fluid chamber to the multiple not end-to-end connected micro channels. The flexible foil allows guiding of the valve/pump unit without restraining the alignment of the valve/pump unit to the substrate. In other words, the valve/pump unit can be actuated by one actuating element that pushes the valve/pump unit to the substrate closing the temporally formed channel. The flexible foil can be poly-propylene.
According to a still further embodiment of the invention, the micro channels are aligned radially and start from a bottom of the lower surface of the substrate from centre passing the valve area and crossing to a top of the lower surface of the substrate. This unique fluid channel design allows relatively simple sealing of the plurality of the micro channels with the flexible membrane that forms the lower surface of the fluid chamber. The flexible membrane closes all the micro channels with a movement of the actuating element towards to the lower surface of the substrate.
According to yet another embodiment of the invention, the flexible membrane is arranged to form a lower surface of the fluid chamber. The fluid flow is directed among the valve area of the lower surface of the substrate and the upper surface of the flexible membrane through a temporally formable channel formed by the flexible membrane covering the valve area, whereby a movement of the actuating element towards to the lower surface of the substrate causes a valve action and a movement opposite to the lower surface of the substrate releases space in a chamber into which the flexible membrane can engage to form the temporally channel and the upper surface of the actuating element covers at least partly the membrane surface at the valve area.
As used herein, the term “detection means” or “detecting element” refers to any means, structure or configuration, which allows one to interrogate a fluid sample within the sample-processing compartment using analytical detection techniques well known in the art. Thus, a detection means may include one or more apertures, elongated apertures or grooves which communicate with the sample processing compartment and may allow an external detection apparatus or device to be interfaced with the sample processing compartment to detect a fluid sample, also referred as analyte, passing through the fluid sample transport device.
The term “fluid sample” is used to refer to any compound or composition, which can be pumped through the temporally formed channel system. The “fluid sample” is preferably a liquid.
The term “channel” or “channel system” as used in the present invention means a conduit through which a fluid flow can be directed, for example to a desired cavity, recess and/or area located on the substrate.
The term “valve area” as used in the present invention means the surface area on the substrate located between at least two non end-to-end connected micro channels along which a fluid sample flow is possible through a temporally formed membrane channel only.
A channel or channel system can be connected with at least one cavity, recess and/or area located on the substrate where the fluid can be for example processed, collected, controlled and/or detected.
A temporally channel is formed by expanding or stretching the flexible membrane, so that the flexible membrane forms for a example a curve like tunnel on the substrate through that a fluid sample can flow.
The term “temporally” means with respect to the channel, that the channel is not permanent formed. This means that a temporally formed membrane channel can be reformed to a non-channel design, such as a planar or flat membrane design contacting the substrate.
The term “flexible” as used in the present invention with respect to the membrane means that the membrane is stretchable and elastic.
The terms “through going hole” and “through going cut” with respect to the cover element means that the through hole as well as the through cut extend from the upper surface of the cover element to the lower surface of the cover element (from one side to the other side).
The valve/pump-unit according to the present invention can be used on Lab-on-chip (LOC) or Micro Total Analyses Systems (micro TAS) in for example molecular diagnostics applications.
It can be seen from
Another advantage is, that the actuating element needs not to be sealed liquid tight, since the fluid is sealed by the membrane already, so that the fluid flow is caused between the substrate comprising micro channels and the membrane surface arranged adjacent to the substrate.
A further advantage is that the valve/pump unit situated in the cover element does not contact the fluid sample. Thus, the cover element comprising the valve/pump unit is not contaminated with a fluid, e.g. fluid analyte sample, so that all parts can be reused except the substrate covered with the membrane.
Further benefits and advantages of the invention will become apparent from a consideration of the following detailed description, given with reference to the accompanying drawings, which specify and show preferred embodiments of the invention.
Before the invention is described in detail, it is to be understood that this invention is not limited to the particular component parts of the devices described or process steps of the methods described as such devices and methods may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include singular and/or plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a fluid” may include mixtures, reference to “a device” includes two or more such devices, reference to “a unit” includes two or more such units, reference to “a temporally formed channel” may include more than at least one of such temporally formed channels, and the like.
The substrate material can be selected from the group comprising glass, ceramic, silicon, metal and/or polymer.
According to the present invention, the substrate surface can be at least partly covered with a polymeric layer. The micro channel structure can be formed in said polymer layer by general known techniques. For example, micro channels can be formed by use of laser ablation techniques. A laser ablation process can be used, because it avoids problems encountered with micro lithographic isotropic etching techniques which may undercut masking during etching, giving rise to asymmetrical structures having curved side walls and flat bottoms. The use of laser-ablation processes to form microstructures in substrates such as polymers increases simplicity of fabrication, thus lowers manufacturing costs. However, injection molding may also be used as a suitable fabrication method.
On top of the substrate a flexible membrane is arranged. The size of the flexible membrane may be selected so that the flexible membrane completely or partly covers the upper surface of the substrate. It can be preferred also that the flexible membrane wrappers the substrate. It is most preferred that the flexible membrane covers the fluid sample transport device at least on all areas where a pump or valve action is desired and/or a temporally channel 12 needs to be formed for directing the fluid sample to a cavity or area, where the fluid sample is detected, controlled and/or processed. It can be further preferred that the flexible membrane covers the processing, controlling and/or detecting areas as well. However, it is most preferred that the flexible membrane completely covers or wrappers the upper surface of the substrate.
The membrane as used according to the present invention is liquid tight, so that the fluid does not penetrate the membrane during operation. It may be preferred that the membrane is flexible and/or elastic in order to form and reform a temporally micro channel.
Suitable membrane materials are polymers, preferably natural or synthetic rubbers. Since metal foils or metal membranes are not elastic, metal foils or metal membranes can be excluded as a membrane material. Also preferred membrane materials are thermoplastics, elastomers, thermoplastic elastomers and silicones as well as mixtures thereof.
A preferred temporally formed channel can have a U-like profile through which a fluid flow can temporally be directed.
The depth of the temporally formed channels can be of 10 μm to 5000 μm, preferably 20 μm to 500 μm and more preferably 30 μm to 200 μm.
To obtain a good pump and/or valve effect of the membrane it may be preferred that the membrane has a thickness of 1 μm to 1000 μm, preferably 20 μm to 200 μm and more preferably 50 μm to 100 μm. If the membrane is too thin there is a danger of deterioration of the membrane, which may result in leakage of the fluid sample. However, if the membrane is too thick, there is a danger of malfunction of the pump and/or valve effect of said membrane with respect to fluid transportation. Most preferred is a rubber membrane having a thickness between 50 micron and 200 micron.
In order to achieve an improved pump and valve action it can be preferred that the flexible membrane posses an e-modulus of 0.5 Mpa to 250 Mpa, preferably of 1 Mpa to 100 Mpa and more preferred of 5 Mpa to 10 Mpa.
Further, it may be preferred that the flexible membrane has an elastic deformation of at least 105% and preferably of at least 110%. This material feature may have an advantage with respect to facilitate the formation of a temporally channel.
The cover element can be a cartridge that can be removable mounted to the membrane-covered substrate. Preferably, the cover element is a cartridge or an integral part of an apparatus for chemical, diagnostic, medical and/or biological analysis.
The cover element comprises at least one through going cut-out for receiving an actuating element. The through going cut-out is designed such that it allows an up- and down-movement of the actuating element. Further, the through going cut-out comprises a chamber that is released at a movement of the actuating element opposite to the lower surface of the membrane into which the flexible membrane can engage to form a temporal channel.
According to a preferred embodiment of the present invention, the upper part of the through going cut-out of the cover element has the form of a chamber to receive the bottom part and the lower part of the through going cut-out of the cover element has a smaller cylindrical form to receive the shaft part of the actuating element.
The actuating element can be made of plastic, metal, glass and/or ceramic material. Preferably, the actuating element is a plunger.
According to a preferred embodiment, the actuating element has a shaft and a bottom part 20 having a larger diameter than the shaft.
According to a further preferred embodiment of the present invention, the upper surface of the bottom part is covered with an elastic material layer.
The upper surface of the actuating element can be mounted to the membrane. However, it is not necessary that the actuating element is mounted to the membrane. In this case, a temporally membrane channel can be formed for example, if fluid is subjected to an external pressure.
According to a preferred embodiment of the actuating element, the upper surface of the actuating element completely covers the valve area.
However, it is more preferred that the upper surface of the actuating element overlaps the end parts of two micro channels, which are connected via a temporally formable channel formed by the flexible membrane on the substrate to admit a through going fluid flow. This embodiment of an actuating element reduces the dead volume of the valve/pump unit to about zero, since due to the overlap of the upper surface of the actuating element all fluid can be returned from the valve area into the micro channel system of the substrate.
The upper surface of the actuating element can comprise a collar and/or bar. The collar and/or bar can have a sealing function, so that fluid cannot creep between the valve area and the flexible membrane, when the valve is in a closed state. To increase the sealing function of the collar and/or bar it can be preferred that the collar and/or bar partly engages into the contacting micro channels.
Further, the collar and/or bar may have a pump action. For example, if the diameter of the collar is smaller as the diameter of the valve area, movement of the actuating element up and down causes a suction or press action. Thus, the actuating element can be a thin flexible material with a collar and/or bar. Such an actuating element can be actuated for example by finger pressure.
The micro fluidic device according to the present invention can comprise at least one processing, controlling and/or detecting element. The micro fluidic device according to the present invention can be used for:
chemical, diagnostic, medical and/or biological analysis, comprising assays of biological fluids such as egg yolk, blood, serum and/or plasma;
environmental analysis, comprising analysis of water, dissolved soil extracts and dissolved plant extracts;
reaction solutions, dispersions and/or formulation analysis, comprising analysis in chemical production, in particular dye solutions or reaction solutions; and/or
quality safeguarding analysis.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06126466 | Dec 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB2007/055045 | 12/12/2007 | WO | 00 | 6/16/2009 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2008/075253 | 6/26/2008 | WO | A |
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|---|---|---|---|
| 5145152 | Komuro et al. | Sep 1992 | A |
| 5863502 | Southgate et al. | Jan 1999 | A |
| 6736370 | Crockett et al. | May 2004 | B1 |
| 20030057391 | Krulevitch et al. | Mar 2003 | A1 |
| 20040209354 | Mathies et al. | Oct 2004 | A1 |
| 20040261850 | Maula et al. | Dec 2004 | A1 |
| 20050098749 | Claydon et al. | May 2005 | A1 |
| 20050238506 | Mescher et al. | Oct 2005 | A1 |
| Number | Date | Country |
|---|---|---|
| 19534137 | Mar 1997 | DE |
| 9509987 | Apr 1995 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20100104474 A1 | Apr 2010 | US |
