Microfluidic Device with a Filter
A microfluidic device with a filter includes a substrate; a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate; and a filter disposed across the flowpath.
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The present invention relates to chemical or biochemical analysis devices, particularly, a microfluidic device with a filter.
BACKGROUND OF THE INVENTIONMicrofluidics refers to a set of technologies involving the flow of fluids through channels having at least one linear interior dimension, such as depth or radius, of less than 1 mm. It is possible to create microscopic equivalents of bench-top laboratory equipment such as beakers, pipettes, incubators, electrophoresis chambers, and analytical instruments within the channels of a microfluidic device. Since it is also possible to combine the functions of several pieces of equipment on a single microfluidic device, a single microfluidic device can perform a complete analysis that would ordinarily require the use of several pieces of laboratory equipment. A microfluidic device designed to carry out a complete chemical or biochemical analysis is commonly referred to as a micro-Total Analysis System (μ-TAS) or a “lab-on-a chip.”
A lab-on-a-chip type microfluidic device, which can simply be referred to as a “chip,” is typically used as a replaceable component, like a cartridge or cassette, within an instrument. The chip and the instrument form a complete microfluidic system. The instrument can be designed to interface with microfluidic devices designed to perform different assays, giving the system broad functionality. For example, the commercially available Agilent 2100 Bioanalyzer system can be configured to interface with four different types of assays, namely, DNA (deoxyribonucleic acid), RNA (ribonucleic acid), protein and cell assays, by simply placing the appropriate type of chip into the instrument.
In a typical microfluidic system, all of the microfluidic channels are in the interior of the chip. The instrument can interface with the chip by performing a variety of different functions: supplying the driving forces that propel fluid through the channels in the chip, monitoring and controlling conditions (e.g., temperature) within the chip, collecting signals emanating from the chip, introducing fluids into and extracting fluids out of the chip, and possibly many others. The instruments are typically computer controlled so that they can be programmed to interface with different types of chips and to interface with a particular chip in such a way as to carry out a desired analysis.
Microfluidic devices designed to carry out complex analyses will often have complicated networks of intersecting channels with some of the channels being open to the outside of the microfluidic devices through one or more wells. Performing the desired assay on such chips will often involve separately controlling the flows through certain channels and selectively directing flows from certain channels through channel intersections. Fluid flow through complex interconnected channel networks can be accomplished by either building microscopic pumps and valves into the chip or applying a combination of driving forces to the channels. The use of multiple electrical or pressure driving forces to control flow in a chip eliminates the need to fabricate valves and pumps on the chip itself, thus simplifying chip design and lowering chip cost.
Lab-on-a-chip type microfluidic devices offer a variety of inherent advantages over conventional laboratory processes such as reduced consumption of sample and reagents, ease of automation, large surface-to-volume ratios, and relatively fast reaction times. Thus, microfluidic devices have the potential to perform diagnostic assays more quickly, reproducibly, and at a lower cost than conventional devices. The advantages of applying microfluidic technology to diagnostic applications were recognized early on in development of microfluidics. For example, microfluidic systems exist in which the steps of sample preparation, PCR (polymerase chain reaction) amplification, and analyte detection are carried out on a single chip.
Many chemical and biochemical analyses require use of beads or other loose material in the process stream. One example is the use of beads to extract a component of interest from a raw biological sample. A core of the bead is coated with a ligand that specifically binds to the component of interest, which can then be removed from the bead. The beads provide an increased surface area with which components in a fluid flowing through the beads can interact. Small beads can be packed more closely than large beads, providing more surface area per unit volume. Beads can be used in the wells of microfluidic devices but must be large enough to avoid being swept into the channels. This limits the packing density that can be achieved and the amount of reaction that can take place in a given volume of the chip. In addition, beads entering the channels can enter the process in undesirable places and can clog flow channels.
It would be desirable to have a microfluidic device with a filter that would overcome the above disadvantages.
SUMMARY OF THE INVENTIONOne aspect of the invention provides a microfluidic device including a substrate; a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate; and a filter disposed across the flowpath.
Another aspect of the invention provides a method of treatment of process fluid with loose process material including providing a microfluidic device comprising a substrate, a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate, and a filter disposed across the flowpath, the filter having openings sized to strain the loose process material from the process fluid; depositing the loose process material in the flowpath upstream of the filter; mixing the loose process material with the process fluid; and draining the process fluid from the loose process material through the filter.
Yet another aspect of the present invention provides a microfluidic device for use with loose process material including a substrate; a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate; and means for filtering the loose process material from the flowpath.
As noted previously, embodiments of the present invention are directed to a microfluidic device with a filter. Microfluidic devices as defined herein are devices with channels having at least one interior dimension, such as depth or radius, of less than one millimeter.
The wells 106 can be used to introduce fluid into or extract fluid out of the channels 114 of the microfluidic device 100, or to allow driving forces such as electricity or pressure to be applied to the channels 114 to control flow throughout the network of channels 114.
A variety of plate materials may be employed to fabricate a microfluidic device such as microfluidic device 100 in
Microfluidic devices can also be fabricated from polymeric materials such as polymethylmethacrylate (PMMA), polycarbonate, polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polydimethylsiloxane (PDMS), polysulfone, polystyrene, polymethylpentene, polypropylene, polyethylene, polyvinylidine fluoride, ABS (acrylonitrile-butadiene-styrene copolymer), cyclic-olefin polymer (COP), and cyclic-olefin copolymer (COC). Such polymeric plate materials are compatible with a number of the microfabrication techniques described above. Since microfluidic devices fabricated from polymeric plates can be manufactured using low-cost, high-volume processes such as injection molding, polymer microfluidic devices could potentially be less expensive to manufacture than devices made using semiconductor fabrication technology. Nevertheless, there are some difficulties associated with the use of polymeric materials for microfluidic devices. For example, the surfaces of some polymers interact with biological materials, and some polymer materials are not completely transparent to the wavelengths of light used to excite or detect the fluorescent labels commonly used to monitor biochemical systems. Although microfluidic devices may be fabricated from a variety of materials, there can be tradeoffs associated with each material choice.
Materials normally associated with the semiconductor industry are often used as microfluidic plates because microfabrication techniques for those materials are well established. Examples of such materials are glass, quartz, and silicon. In the case of semiconductive materials such as silicon, it will often be desirable to provide an insulating coating or layer, e.g., silicon oxide, over the plate material, particularly in those applications where electric fields are to be applied to the device or its contents. For example, the microfluidic devices employed in the Agilent Bioanalyzer 2100 system are fabricated from glass or quartz because of the ease of microfabricating those materials and because those materials are generally inert in relation to many biological compounds.
Wells on microfluidic devices can be configured in a number of different ways. The well is a fluid-containing reservoir that is connected to one or more of the channels within the interior of the microfluidic device. During operation, the wells serve as either a source of fluid to be introduced into the channel network or as a receptacle for fluid exiting the fluid network. Wells are typically accessible from the exterior of the chip. The volume of those wells 106 can be determined by the thickness of the top plate layer 102 and by the diameter of the circular opening forming the well 106. Exemplary glass plates range in thickness from about 0.5-2 mm. When the holes forming the wells 106 have a diameter ranging from about 0.5-3 mm, and the volume of the wells formed by the well openings would range from 0.1-15 μl. Higher volume wells can be formed by attaching a cover layer to the microfluidic device so that apertures in the cover layer are aligned with the wells 106.
Loose process material, such as process beads, a material capture mat, silica beads, silica coated polymer beads, diatomaceous earth, or the like, can be placed in the wells 106 and/or the channels 114 to process materials included in process fluids that flow through the microfluidic device 100. The loose process material can be used to prepare a sample, such as nucleic acid (DNA and/or RNA) or proteins, and bind a component of interest in the process fluids to the loose process material. The loose process material can have exemplary dimensions from about 0.05 μm to 500 μm.
A cross-sectional view across the line A-A in
The microfluidic devices can be any number of microfluidic devices, not just the device shown in
The material from which the microfluidic device is made can be any material suitable for a desired application, as long as the material does not contaminate or otherwise interfere with the reagents, samples, or reactions involved in practicing the invention. The details of the well structure, such as its cross-sectional shape, whether it is formed entirely within one plate, in multiple plates, or in a plate and a cover layer, can be selected for the particular application, as long as the well interfaces with a microfluidic channel network, and as long as the well is large enough to accommodate enough process fluid and loose process material to procure the desired amount of the component of interest. For example, when the well is formed from the combination of a well in a microfluidic device and an aperture in a cover layer, the aperture and well do not have to be the same shape, size, or depth, as long as the combination of the aperture and well define a volume capable of being used as a fluid reservoir.
The filter 410 can be made of material as desired for a particular application. When the filter 410 is a membrane, the filter 410 can be made of nylon, cellulose, cellulose ester, polyvinylidene difluoride (PVDF), polyethersulfone (PES), polytetrafluoroethylene (PTFE), polyester, polypropylene, polyethylene, or the like. The filter 410 can also be coated with hydrophobic or hydrophilic material.
The filter 410 can also made from the materials above impregnated with silica beads. In this case, loose material is not needed as the silica in the membrane acts as capture material.
Another configuration is to have a separate filter basket placed into a regular chip well. The filter basket is maintained in the chip well mechanically. The filter basket can contain any of the filter materials described above.
The features of the microfluidic device 400, such as the wells, channels, filters, and filter receivers, can be made in a single step or a series of steps as desired. The microfluidic device 400 can be formed as a single substrate, or a well plate and a channel plate can be manufactured separately, and then combined to form the microfluidic device 400. The features can be made by removing material from the single substrate or plate, such as removal by photolithography or embossing, or by forming with the single substrate or plate, such as forming by injection molding. Those skilled in the art will appreciate that the fabrication method can be selected to suit the particular materials to be used.
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The microfluidic device can optionally include a material capture mat affixed to the filter. The material capture mat can process components of interest included in process fluids that flow through the microfluidic device 400. The loose process material can be used to prepare a sample, such as nucleic acid (DNA and/or RNA) or proteins, and bind a component of interest in the process fluids to the material capture mat. The material capture mat can be made of a silica based material or the like.
Providing a microfluidic device with a filter in a flowpath 1202 includes providing a microfluidic device having a well plate, a channel plate, a flowpath including a well formed in the well plate in fluid communication with a channel formed in the channel plate, and a filter disposed across the flowpath, the filter having openings sized to strain the loose process material from the process fluid, such as described in
Depositing loose process material in the flowpath 1204 includes depositing the loose process material in the flowpath upstream of the filter. Examples of loose process materials include process beads, a material capture mat, silica beads, silica coated polymer beads, silica coated magnetic beads, diatomaceous earth, or the like. In one embodiment, the process fluid including the component of interest is mixed with the loose process material before the loose process material is deposited into the flowpath. The mixing can be performed before the loose process material is loaded onto the microfluidic device or can be performed on the microfluidic device.
Draining the process fluid through the filter 1208 includes draining the process fluid from the loose process material through the filter. When more than one wash is desired for a particular application, the method 1200 can continue by re-mixing the loose process material with the process fluid and re-draining the process fluid from the loose process material. After the desired number of washes, a release reagent can be mixed with the loose process material to release the component of interest from the loose process material and the eluent including the component of interest collected in an eluent collection well on the microfluidic device.
The well can have a top and a bottom, with the filter disposed at the bottom. In one embodiment, the mixing the loose process material with process fluid 1206 includes dispensing the process fluid into the well from the top and the draining the process fluid from the loose process material through the filter 1208 includes draining the process fluid through the bottom. This is a unidirectional wash, since the process fluid enters the well in one direction and exits in the same direction. In another embodiment, the mixing the loose process material with process fluid 1206 includes dispensing the process fluid into the well from the bottom and the draining the process fluid from the loose process material through the filter 1208 includes draining the process fluid through the bottom. This is a bi-directional wash, since the process fluid enters the well in one direction, reverses, and exits in another direction.
Other approaches can also be used to accomplish a unidirectional wash. In one embodiment, a spigot is molded in the well above the filter and connected to a wash-in channel providing process fluid. The spigot delivers the process fluid from the top. The filter is drained through a wash-out channel below the filter. A wash well can also be provided below the filter to evacuate the well. In another embodiment, a large well in the well plate is in fluid connection with two chimney wells in the channel plate. A filter is disposed between the large well and each of the chimney wells. The process fluid fills the large well from one of the chimney wells and drains the large well from the other of the chimney wells. Those skilled in the art will appreciate that the same approach can be used in other layers. For example, the large well could be formed as a large aperture in the cover layer and the multiple wells (the chimney wells in the previous example) can be formed in the well layer.
The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments, therefore, are to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims
1. A microfluidic device, comprising:
- a substrate;
- a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate; and
- a filter disposed across the flowpath.
2. The microfluidic device of claim 1 wherein the filter is formed into the substrate.
3. The microfluidic device of claim 1 further comprising a filter receiver formed across the flowpath between the well and the channel, wherein the filter is retained in the filter receiver.
4. The microfluidic device of claim 3 wherein the filter is glued in the filter receiver.
5. The microfluidic device of claim 3 wherein the filter is held mechanically in the filter receiver.
6. The microfluidic device of claim 1 further comprising a basket having a bottom and being fitted into the well, wherein the filter is attached to the bottom.
7. The microfluidic device of claim 1 wherein the filter is a plurality of posts formed into the substrate across the channel.
8. The microfluidic device of claim 1 wherein the filter is a plurality of in-line bars formed into the substrate across the channel.
9. The microfluidic device of claim 8 wherein the plurality of in-line bars are streamlined.
10. The microfluidic device of claim 1 wherein the filter is a plurality of cross-channel dams formed into the substrate.
11. The microfluidic device of claim 10 wherein the plurality of cross-channel dams are of increasing height.
12. The microfluidic device of claim 1 wherein the channel has a channel periphery and further comprising a filter receiver formed into the substrate at the channel periphery, the filter being a screen slidably disposed in the filter receiver.
13. The microfluidic device of claim 1 further comprising a material capture mat, the material capture mat being affixed to the filter.
14. The microfluidic device of claim 1 wherein the filter has openings in the range of about 0.05 μm to 500 μm.
15. The microfluidic device of claim 1 wherein the substrate comprises a well plate and a channel plate, the well being formed in the well plate and the channel being formed in the channel plate.
16. The microfluidic device of claim 15 wherein the filter is formed into the well plate.
17. The microfluidic device of claim 15 further comprising a filter receiver formed across the flowpath between the well plate and the channel plate, wherein the filter is retained in the filter receiver.
18. The microfluidic device of claim 15 wherein the filter is a structure formed into the channel plate across the channel, the structure being selected from the group consisting of a plurality of posts, a plurality of in-line bars, and a plurality of cross-channel dams.
19. The microfluidic device of claim 15 wherein the channel has a channel periphery and further comprising a filter receiver formed into the channel plate at the channel periphery, the filter being a screen slidably disposed in the filter receiver.
20. A method of treatment of process fluid with loose process material, the method comprising:
- providing a microfluidic device comprising a substrate, a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate, and a filter disposed across the flowpath, the filter having openings sized to strain the loose process material from the process fluid;
- depositing the loose process material in the flowpath upstream of the filter;
- mixing the loose process material with the process fluid; and
- draining the process fluid from the loose process material through the filter.
21. The method of claim 20 wherein the substrate comprises a well plate and a channel plate, the well being formed in the well plate and the channel being formed in the channel plate.
22. The method of claim 20 further comprising re-mixing the loose process material with the process fluid and re-draining the process fluid from the loose process material.
23. The method of claim 20 wherein the filter is disposed in the well.
24. The method of claim 20 wherein the well has a top and a bottom, and the filter is disposed at the bottom, and the mixing further comprises dispensing the process fluid into the well from the top and the draining further comprises draining the process fluid through the bottom.
25. The method of claim 20 wherein the well has a top and a bottom, and the filter is disposed at the bottom, and the mixing further comprises dispensing the process fluid into the well from the bottom and the draining further comprises draining the process fluid through the bottom.
26. The method of claim 20 wherein the filter is disposed in the channel.
27. The method of claim 20 wherein the loose process material is selected from the group consisting of process beads, a material capture mat, silica beads, silica coated polymer beads, silica coated magnetic beads, and diatomaceous earth.
28. The method of claim 20 wherein the openings are in the range of about 0.05 μm to 500 μm.
29. A microfluidic device for use with loose process material comprising:
- a substrate;
- a flowpath including a well formed in the substrate in fluid communication with a channel formed in the substrate; and
- means for filtering the loose process material from the flowpath.
30. The microfluidic device of claim 29 wherein the substrate comprises a well plate and a channel plate, the well being formed in the well plate and the channel being formed in the channel plate.
31. The microfluidic device of claim 30 further comprising means for receiving the filtering means formed across the flowpath between the well plate and the channel plate.
32. The microfluidic device of claim 30 wherein the channel has a channel periphery and further comprising means for receiving the filtering means formed into the channel plate at the channel periphery.
33. The microfluidic device of claim 29 wherein the filtering means comprises means for filtering the loose process material having a size of about 0.05 μm to 500 μm.
Type: Application
Filed: May 7, 2007
Publication Date: Nov 13, 2008
Applicant: Caliper Life Sciences, Inc. (Mountain View, CA)
Inventors: Stephane Mouradian (Menlo Park, CA), Josh Molho (Oakland, CA), Ming Wu (Redwood City, CA), Hayley Wu (Sunnyvale, CA), Javier A. Farinas (Los Altos, CA)
Application Number: 11/745,411
International Classification: B01D 37/00 (20060101); B01L 11/00 (20060101);