Microfluidic rotary flow reactor matrix

• US 7,413,712 B2
• Filed: 04/30/2004
• Issued: 08/19/2008
• Est. Priority Date: 08/11/2003
• Status: Expired due to Fees

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Liu, Jian, Quake, Stephen R., Hansen, Carl L.
• Primary Examiner(s): Griffin; Walter D.
• Assistant Examiner(s): Mui; Christine T
• Application Number:
  US10/837,025
• Publication Number:
  US 20050037471A1
• Time in Patent Office: 1,572 Days
• Field of Search: 436/6, 422/100, 435/6, 435/287.2, 435/7.9
• US Class Current: 422/504
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00828 Silicon wafers or plates
• CPC Class Codes: B01J 2219/00833 Plastic
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/0095 Control aspects
• CPC Class Codes: B01L 2200/10 Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2300/0861 Configuration of multiple channels and/or chambers in a single devices
• CPC Class Codes: B01L 2300/088 Channel loops
• CPC Class Codes: B01L 2300/123 Flexible; Elastomeric
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2400/0481 squeezing of channels or chambers
• CPC Class Codes: B01L 2400/0655 pinch valves
• CPC Class Codes: B01L 3/5025 for parallel transport of multiple samples
• 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 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/50273 characterised by the means or forces applied to move the fluids micropumps F04B19/006, of the membrane type F04B43/043
• CPC Class Codes: B01L 3/502738 characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 7/52 : with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples amplification or hybridisation processes per se C12Q1/68; controlling sequential reactions for synthesis B01J19/0046
• CPC Class Codes: B81B 3/00 : Devices comprising flexible or deformable elements, e.g. comprising elastic tongues or membranes B81B5/00 takes precedence
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• CPC Class Codes: F04B 43/043 : Micropumps
• CPC Class Codes: F04B 43/14 : having plate-like flexible members
• CPC Class Codes: G01N 2035/00158 : Elements containing microarrays, i.e. "biochip"

Abstract

A microfluidic device comprises a matrix of rotary flow reactors. The microfluidic matrix device offers a solution to the “world-to-chip” interface problem by accomplishing two important goals simultaneously: an economy of scale in reagent consumption is achieved, while simultaneously minimizing pipetting steps. N² independent assays can be performed with only 2N+1 pipetting steps, using a single aliquot of enzyme amortized over all reactors. The chip reduces labor relative to conventional fluid handling techniques by using an order of magnitude less pipetting steps, and reduces cost by consuming two to three orders of magnitude less reagents per reaction. A PCR format has immediate applications in medical diagnosis and gene testing. Beyond PCR, the microfluidic matrix chip provides a universal and flexible platform for biological and chemical assays requiring parsimonious use of precious reagents and highly automated processing.

Claims

1. A microfluidic device comprising:

a plurality of flow channels defined within a first layer to form a matrix of rotary flow reactors;

a first set of control lines proximate to and separated from the flow channels by first membranes, the first membranes actuable to introduce fluids into the rotary flow reactors and to isolate the rotary flow reactors, and wherein the first set of control lines are defined in a second layer adjacent to the first layer; and

a second set of control lines proximate to and separated from the flow channels by second membranes, the second membranes actuable to cause peristaltic pumping of the fluids within the isolated rotary flow reactors, and wherein the second set of control lines are defined in a third layer adjacent to the first layer on a side opposite to the second layer.

2. The microfluidic device of claim 1 wherein the second layer overlies the first layer, and the third layer underlies the first layer.

3. The microfluidic device of claim 1 wherein the second layer underlies the first layer, and the third layer overlies the first layer.

4. The micro fluidic device of claim 1 wherein the flow channels are oriented in rows and columns, and the reactors are formed by intersection of a selection from a group consisting of:

a row flow channel and a column flow channel;

alternate successive pairs of a row flow channel or a column flow channel; and

a branch channel connecting the alternate successive pairs of the row or the column flow channels.

5. The microfluidic device of claim 1 wherein the flow channels are oriented in rows and columns, and the reactors are formed by branch flow channels connecting alternate successive pairs of one of row and column flow channels.

6. The microfluidic device of claim 1 wherein the first set of control lines exhibit a first width and a second width greater than the first width, a first membrane portion defined by the first width and actuable by a greater applied pressure to isolate the reactor, and a second membrane portion defined by the second width and actuable by a lesser applied pressure to permit circulation of fluid within the reactor.

7. The microfluidic device of claim 1 wherein the first set of control lines contain water and the second set of control lines contain air.

8. The microfluidic device of claim 1 wherein the second set of control lines are organized in groups sharing different common inlets and outlets.

9. The microfluidic device of claim 1 wherein the second set of control lines share common inlets and outlets.

10. The microfluidic device of claim 1 further comprising:

a holding chamber in fluidic communication with a reactor; and

a recovery flow channel in fluidic communication with the holding chamber and configured to receive contents of the reactor.

11. The microfluidic device of claim 10 wherein:

the flow channels are oriented in rows and columns;

the reactor is formed by a branch flow channel connecting an alternate successive pair of one of row and column flow channels;

the holding chamber is in fluidic communication with the reactor along the other of the row and column flow channels; and

the recovery flow channel is parallel to the other of the row and column flow channels.

12. A method of conducting a chemical reaction, the method comprising:

providing a microfluidic device comprising;

a plurality of flow channels defined within a first layer to intersect and form a matrix of rotary flow reactors;

a first set of control lines proximate to and separated from the flow channels by first membranes, wherein the first set of control lines are defined in a second layer adjacent to the first layer;

a second set of control lines proximate to and separated from the flow channels by second membranes, wherein the second set of control lines are defined in a third layer adjacent to the first layer on a side opposite to the second layer;

introducing first and second chemicals to the rotary flow reactors;

applying pressure to the first set of control lines to actuate the first membranes to isolate the rotary flow reactors; and

applying pressure to the second set of control lines to actuate the second membranes to cause peristaltic pumping of the fluids within the isolated rotary flow reactors.

13. The method of claim 12 wherein the flow channels are oriented in rows and columns, and the reactors are formed by branch flow channels connecting alternate successive pairs of one of rows and columns, the method comprising:

flowing the first chemical to the reactor through a row flow channel; and

flowing the second chemical to the reactor through a column flow channel.

14. The method of claim 13 wherein the alternate successive pairs of one of the rows and columns have separate inlets, the method further comprising flowing a third chemical to the reactor through the one of the alternate row and column flow channels.

15. The method of claim 14 wherein flowing the first chemical comprises flowing a primer, flowing the second chemical comprises flowing a nucleic acid sample, and flowing the third chemical comprises flowing an enzyme.

16. The method of claim 15 further comprising heating the microfluidic device to amplify the nucleic acid sample.

17. The method of claim 14 wherein flowing the first chemical comprises flowing a nucleic acid sample, flowing the second chemical comprises flowing a primer, and flowing the third chemical comprises flowing an enzyme.

18. The method of claim 17 further comprising heating the microfluidic device to amplify the nucleic acid sample.

19. The method of claim 14 wherein flowing the first chemical comprises flowing a forward primer, flowing the second chemical comprises flowing a reverse primer, and flowing the third chemical comprises flowing a mixture of an enzyme and a nucleic acid sample.

20. The method of claim 19 further comprising heating the microfluidic device to amplify the nucleic acid sample.

21. The method of claim 12 wherein:

applying pressure to the first set of control lines comprises applying pressure to a water-filled control line; and

applying pressure to the second set of control lines comprises applying pressure to an air-filled control line.

22. The method of claim 12 wherein applying pressure to the second set of control lines comprises applying pressure to a plurality of inputs.

23. The method of claim 12 further comprising recovering a contents of the rotary flow reactors after the peristaltic pumping.

24. The method of claim 23 wherein recovering the contents comprises:

flowing the contents from the reactor into an adjacent holding chamber; and

flowing the contents from the holding chamber along a recovery flow channel to an outlet.

25. The method of claim 24 wherein the contents are flowed to the outlet orthogonal to a direction of flow of the contents to the holding chamber.