Three-dimensional microfluidic devices

• US 8,628,729 B2
• Filed: 03/27/2009
• Issued: 01/14/2014
• Est. Priority Date: 03/27/2008
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Carrilho, Emanuel, Martinez, Andres W., Mirica, Katherine A., Phillips, Scott T., Siegel, Adam C., Wiley, Benjamin, Whitesides, George M.
• Primary Examiner(s): WHITE, DENNIS MICHAEL
• Application Number:
  US12/934,499
• Publication Number:
  US 20110123398A1
• Time in Patent Office: 1,754 Days
• Field of Search: 422/52, 422/82.05, 422/82.06, 422/82.07, 422/82.08, 422/82.09, 422/82.11, 422/407, 422/501, 422/502, 422/503, 422/420, 422/507, 435/164, 435/165, 435/283.1, 435/287.1, 435/287.2, 435/288.7, 435/808, 435/4, 435/5, 435/7.2, 435/7.9, 436/164, 436/165, 436/172, 436/174, 436/518, 436/805, 436/809
• US Class Current: 422/420
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/087 Multiple sequential chambers
• CPC Class Codes: B01L 2300/0874 Three dimensional network
• CPC Class Codes: B01L 2300/0887 Laminated structure
• CPC Class Codes: B01L 2300/126 Paper
• CPC Class Codes: B01L 2300/1855 using phase changes in a medium
• CPC Class Codes: B01L 2300/1877 using chemical reactions
• CPC Class Codes: B01L 2400/0406 capillary forces
• CPC Class Codes: B01L 2400/0633 with moving parts
• CPC Class Codes: B01L 2400/0672 Swellable plugs
• CPC Class Codes: B01L 3/5023 with a sample being transported to, and subsequently stored in an absorbent for analysis
• CPC Class Codes: B01L 3/502707 characterised by the manufacture of the container or its components by shaping or joining plastic parts B29C59/00, B29C65/00; by laminating B32B37/00; manufacture of microstructural devices in general B81C
• CPC Class Codes: B01L 3/502738 characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 7/525 with physical movement of samples between temperature zones
• CPC Class Codes: F16K 2099/008 Multi-layer fabrications
• CPC Class Codes: F16K 99/0001 Microvalves microdevices B81B1/00; manufacture or treatment of devices or systems in or on a substrate B81C1/00; microfluidic structures B01L3/5027; micropumps F04B19/006
• CPC Class Codes: F16K 99/0015 Diaphragm or membrane valves
• CPC Class Codes: F16K 99/0025 Valves using microporous membranes
• CPC Class Codes: Y10T 436/25 : including sample preparation

Abstract

Three-dimensional microfluidic devices including by a plurality of patterned porous, hydrophilic layers and a fluid-impermeable layer disposed between every two adjacent patterned porous, hydrophilic layers are described. Each patterned porous, hydrophilic layer has a fluid-impermeable barrier which substantially permeates the thickness of the porous, hydrophilic layer and defines boundaries of one or more hydrophilic regions within the patterned porous, hydrophilic layer. The fluid-impermeable layer has openings which are aligned with at least part of the hydrophilic region within at least one adjacent patterned porous, hydrophilic layer. Microfluidic assay device, microfluidic mixer, microfluidic flow control device are also described.

Claims

1. A three-dimensional device for assay of a fluid sample, the device comprising at least first and second stacked, porous, hydrophilic layers each of which comprise a pattern of fluid-impermeable barriers that substantially permeate the thickness of the layer to define boundaries within each said layer of one or more porous hydrophilic regions of said hydrophilic layers that wick fluids laterally by capillary action through the porous hydrophilic regions of said hydrophilic layers;

a fluid-impermeable layer disposed between said first and second layers defining one or more openings communicating vertically between hydrophilic regions in separate layers, said opening being in fluidic contact with at least one of said porous hydrophilic regions within each of said first and second layers;

a porous hydrophilic medium disposed in a said opening in fluidic contact with at least one of said hydrophilic regions within each of said first and second layers; and

one or more reagents disposed in fluid communication with a said hydrophilic region and with a detection zone in a hydrophilic region for colorimetrically detecting the presence of an analyte in a said detection zone.

2. The device of claim 1 further comprising at least a third porous, hydrophilic layer separated from an adjacent porous, hydrophilic layer by a fluid-impermeable layer and in fluid communication with a hydrophilic region in one of said first and second layers.

3. The device of claim 1 further comprising a fluid-impermeable layer on the outside of a said porous, hydrophilic layer defining an opening to permit application of a sample to said device.

4. The device of claim 1 further comprising a filter in fluid communication with a said hydrophilic region to remove solid contaminants from a sample or to remove red blood cells from a blood sample.

5. The device of claim 1 comprising plural separate hydrophilic regions and multiple separate detection zones thereby to permit conducting multiple assays simultaneously.

6. The device of claim 1 further comprising a plug filling one or more said openings and in direct contact with at least a portion of one of said hydrophilic regions to provide local temperature control, to provide reagents for assaying a sample, to filter a sample, or to modulate sample flow.

7. The device of claim 1 wherein said one or more openings in fluid communication with one of said layers in the device contains a chemical or biological reagent, an indicator, a binder, a fluid flow-impeding agent, a fluid flow-promoting agent, magnetic particles, a gel which swells when in contact with fluid, a fluid-mixable material which dissolves when in contact with fluid to allow microfluidic communication, a salt which either absorbs heat or gives off heat when in contact with fluid, a low-melting-point hydrophobic material capable of melting and flowing at a pre-selected temperature to flow into and thereby substantially obstruct microfluidic flow within a said hydrophilic region, or a combination thereof.

8. The device of claim 1 wherein at least one of said first and second layers is infused with a chemical or biological reagent, an indicator, a binder, a fluid flow-impeding agent, a fluid flow-promoting agent, magnetic particles, a gel which swells when in contact with fluid, a fluid-mixable material which dissolves when in contact with fluid to allow microfluidic communication, a salt which either absorbs heat or gives off heat when in contact with fluid, a low-melting-point hydrophobic material capable of melting and flowing at a pre-selected temperature to flow into and thereby substantially obstruct microfluidic flow within a said hydrophilic region, or a combination thereof.

9. The device of claim 1 comprising different reagents stored in different said layers in fluid communication with said hydrophilic regions.

10. The device of claim 1 defining in one or more hydrophilic regions a reservoir for depositing a fluid sample;

a distributing region for receiving said sample from said reservoir and distributing said sample; and

an array of spaced apart regions for receiving said sample from said distributing region.

11. The device of claim 10 comprising an assaying reagent in fluid communication with multiple said spaced apart regions for assaying said sample.

12. The device of claim 1 wherein the boundaries of a said hydrophilic regions define fluidic paths which cross laterally in different layers without mixing.

13. The device of claim 1 wherein the boundaries of at least one of said hydrophilic regions in a layer define first and second fluidic flow channels which merge into a combination zone, a second layer comprises a said hydrophilic region comprising a mixing channel, and said fluid-impermeable layer defines an opening permitting fluid communication between said combination zone and said mixing channel.

14. The device of claim 13 wherein said combination zone is capable of being moved vertically into said opening from a first position spaced apart from and not in fluidic contact with said mixing channel into a second position in fluidic contact with said mixing channel.

16. The device of claim 1 wherein an opening is bounded by spaced apart flow channels of hydrophilic regions in separate layers, at least a portion of one of said flow channel being capable of movement from a said spaced apart position into a second position in contact with the other said flow channel, wherein, in said spaced apart position, said one flow channel is not in fluidic communication with said other flow channel, and in said second, contact position, said one flow channel is in fluidic communication with said other flow channel through an opening.

17. The device of claim 1 wherein said porous, hydrophilic layers comprises sheets of paper, nitrocellulose, cellulose acetate, cloth, or porous polymer film.

18. The device of claim 1 wherein said pattern of fluid-impermeable barriers is produced by screening, stamping, printing or photolithography and comprises photoresist, poly(methylmethacrylate), an acrylate polymer, polystyrene, polyethylene, polyvinylchloride, or a photo-polymerizable monomer that forms a hydrophobic polymer.

15. The device of 1 wherein a said reagent comprises a protein assay reagent, a glucose assay reagent, a sodium acetoacetate assay reagent, a sodium nitrite assay reagent, or a combination thereof.

19. A three-dimensional device for assay of a fluid sample, the device comprising at least first and second stacked, porous, hydrophilic layers each of which comprise a pattern of fluid-impermeable barriers that substantially permeate the thickness of the layer to define boundaries within each said layer of one or more hydrophilic regions of said hydrophilic layers that wick fluids laterally by capillary action through porous flow channels;

a fluid-impermeable layer disposed between said first and second layers defining one or more openings;

an opening being bounded by spaced apart flow channels of hydrophilic regions in separate layers, at least a portion of one of said flow channel being capable of movement from a said spaced apart position into a second position in contact with the other said flow channel, wherein, in said spaced apart position, said one flow channel is not in fluidic communication with said other flow channel, and in said second, contact position, said one flow channel is in fluidic communication with said other flow channel through an opening; and

one or more reagents disposed in fluid communication with a said hydrophilic region and with a detection zone in a hydrophilic region for detecting the presence of an analyte in a said detection zone.

20. The device of claim 19 further comprising a porous hydrophilic medium disposed in a said opening in fluidic contact with at least one of said hydrophilic regions within each of said first and second layers.

21. A three-dimensional device for assay of a fluid sample, the device comprising at least first and second stacked, porous, hydrophilic layers each of which comprise a pattern of fluid-impermeable barriers that substantially permeate the thickness of the layer to define boundaries within each said layer of one or more hydrophilic regions of said hydrophilic layers that wick fluids laterally by capillary action through the porous hydrophilic regions of said hydrophilic layers;

a fluid-impermeable layer disposed between said first and second layers defining one or more openings communicating vertically between hydrophilic regions in separate layers; and

disposed in a said opening in fluid communication with a said layer, a chemical or biological reagent, an indicator, a binder, a fluid flow-impeding agent, a fluid flow-promoting agent, magnetic particles, a gel which swells when in contact with fluid, a fluid-mixable material which dissolves when in contact with fluid to allow microfluidic communication, a salt which either absorbs heat or gives off heat when in contact with fluid, a low-melting-point hydrophobic material capable of melting and flowing at a pre-selected temperature to flow into and thereby obstruct microfluidic flow within a said hydrophilic region, or a combination thereof.

22. The device of claim 21 further comprising a porous hydrophilic medium disposed in a said opening in fluidic contact with at least one of said hydrophilic regions within each of said first and second layers.