DEVICE AND METHOD FOR PRESSURE-DRIVEN PLUG TRANSPORT AND REACTION

• US 20050272159A1
• Filed: 05/09/2003
• Published: 12/08/2005
• Est. Priority Date: 05/09/2002
• Status: Active Grant

• Current Assignee: University of Chicago
• Original Assignee: University of Chicago
• Inventors: Tice, Joshua David, Ismagilov, Rustem F., Song, Helen
• Granted Patent: US 7,129,091 B2
• Time in Patent Office: Days
• US Class Current: 436/34
• CPC Class Codes: B01F 2101/23 Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials
• CPC Class Codes: B01F 23/45 using flow mixing
• CPC Class Codes: B01F 25/31 in conduits or tubes through which the main component flows
• CPC Class Codes: B01F 25/433 Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
• CPC Class Codes: B01F 25/4331 Mixers with bended, curved, coiled, wounded mixing tubes or comprising elements for bending the flow
• CPC Class Codes: B01F 33/3021 the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• 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 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/00576 fluorophore
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00599 Solution-phase processes
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B01J 2219/00736 Non-biologic macromolecules, e.g. polymeric compounds
• CPC Class Codes: B01J 2219/0074 Biological products
• CPC Class Codes: B01J 2219/00756 Compositions, e.g. coatings, crystals, formulations
• CPC Class Codes: B01J 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00837 comprising coatings other than catalytically active coatings
• CPC Class Codes: B01J 2219/0086 : Dimensions of the flow channels
• CPC Class Codes: B01J 2219/00867 : Microreactors placed in series, on the same or on different supports
• CPC Class Codes: B01J 2219/00869 : Microreactors placed in parallel, on the same or on different supports
• CPC Class Codes: B01J 2219/00889 : Mixing
• CPC Class Codes: B01J 2219/00891 : Feeding or evacuation
• CPC Class Codes: B01J 2219/00975 : Ultraviolet light
• CPC Class Codes: B01J 2219/00977 : Infrared light
• CPC Class Codes: B01L 2200/0647 : Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2200/0668 : Trapping microscopic beads
• CPC Class Codes: B01L 2200/0673 : Handling of plugs of fluid surrounded by immiscible fluid
• 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 2300/0867 : Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/0883 : Serpentine channels
• CPC Class Codes: B01L 2400/0424 : Dielectrophoretic forces
• CPC Class Codes: B01L 2400/0448 : Marangoni flow; Thermocapillary effect
• CPC Class Codes: B01L 2400/0454 : radiation pressure, optical tweezers
• CPC Class Codes: B01L 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 3/502746 : characterised by the means for controlling flow resistance, e.g. flow controllers, baffles B01L3/502738 takes precedence
• CPC Class Codes: B01L 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B01L 3/502784 : specially adapted for droplet or plug flow, e.g. digital microfluidics automatic analysis using a stream of discrete samples in a tube system G01N35/08
• 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: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C12P 19/34 : Polynucleotides, e.g. nucleic acids, oligoribonucleotides
• CPC Class Codes: C12Q 1/44 : involving esterase
• CPC Class Codes: G01N 15/1404 : Handling flow, e.g. hydrodynamic focusing
• CPC Class Codes: G01N 15/1409 : Handling samples, e.g. injecting samples
• CPC Class Codes: G01N 15/1484 : microstructural devices
• CPC Class Codes: G01N 35/08 : using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
• CPC Class Codes: G01N 35/085 : Flow Injection Analysis
• CPC Class Codes: Y02A 90/10 : Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
• CPC Class Codes: Y10T 436/118339 : with formation of a segmented stream
• CPC Class Codes: Y10T 436/12 : Condition responsive control
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The present invention provides microfabricated substrates and methods of conducting reactions within these substrates. The reactions occur in plugs transported in the flow of a carrier-fluid.

Claims

1. A method of conducting a reaction within at least one plug comprising the steps of:

introducing a carrier-fluid into a device comprising a first channel in fluid communication with a first;

simultaneously introducing at least two streams of plug-fluids into the first inlet so that at least one plug forms in the carrier-fluid after the streams contact the carrier-fluid;

wherein;

a first plug-fluid comprises a first reagent;

a second plug-fluid comprises a second reagent different from the first reagent,

each plug-fluid is immiscible with the carrier-fluid; and

each plug comprises both the first and second plug-fluids so that the reagents may undergo the reaction,

each plug is substantially surrounded by carrier.

2. The method of claim 1, wherein the carrier-fluid comprises an oil.

3. The method of claim 1, wherein the carrier-fluid comprises a fluorinated compound.

4. The method of claim 3, wherein the fluorinated compound is perfluorodecaline or perfluoroperhydrophenanthrene.

5. The method of claim 1, wherein the carrier-fluid comprises at least one surfactant.

6. The method of claim 1, wherein the at least one of the plug-fluids comprises a reagent and solvent.

7. The method of claim 1, wherein at least one of the plug-fluids comprises a solvent and a surfactant.

9. The method of claim 1, further independently adjusting flow rates of the each plug-fluids so that an array of plugs forms where at least two plugs contain different concentration of reagents.

10. The method of claim 1, wherein plugs are formed at a capillary number of ≦

about 0.2.

11. The method of claim 1, wherein the reaction of the plug-fluids forms an insoluble reaction product within at least one plug.

12. The method of claim 1, wherein the reaction of the plug-fluids forms a soluble reaction product within at least one plug.

14. The method of claim 1, wherein the plug-fluids are distinct laminar streams at or before the inlet.

25. The method of claim 1, further comprising a step of merging at least one plug with a second plug downstream of the first inlet.

29. The method of claim 1, further comprising a step of splitting at least one plug into two or more parts by splitting the channel downstream of the first inlet.

30. The method of claim 1, further comprising splitting at least one plug into two or more parts such that a first part of the plug passes into a second channel through an opening, wherein the second channel is downstream of the first inlet.

31. The method of claim 30, wherein the cross-section dimension of the first channel differs from a cross-section dimension of the second channel.

32. The method of claim 30, wherein a cross-section dimension of the first channel is approximately equal to a cross-section dimension of the second channel.

33. The method of claims 30, wherein the pressure within the first channel differs from the pressure in the second channel.

34. The method of claim 30, wherein a constriction exists at or near the junction of the first and second channels.

35. The method of claim 1, further comprising separating at least one plug from the carrier-fluid.

36. The method of claim 1, further comprising detecting the presence of at least one plug downstream of the plug forming region in the first channel first inlet.

37. The method of claim 1, further comprising detecting the product of the reaction.

38. The method of claim 1, further comprising monitoring the reaction.

39. The method of claim 1, further comprising monitoring the kinetics of the reaction.

40. The method of claim 38, wherein monitoring comprises measuring at least one optical property of the plugs.

41. The method of claim 1, wherein refractive indices of the carrier-fluid and the plug-fluids are substantially similar.

42. The method of claim 38, wherein monitoring is conducted at one or more positions along a channel of the device.

43. The method of claim 1, further comprising employing a number of devices in parallel.

44. The method of claim 1, further comprising stopping the introducing of carrier-fluid and plug-fluids for a period of time.

45. The method of claim 1, wherein the reaction is a polymerization reaction.

55. The method of claim 1, wherein the reaction results in an unstable intermediate.

58. The method of claim 1, wherein each plug initially has a cross section that is substantially the same size as the cross section of the channel at the inlet.

59. The method of claim 1, wherein a cross section of the first inlet is about 30 μ

m to about 50 μ

m.

60. The method of claim 1, wherein the volume of at least one plug is about 1 femtoliter to about 250 nL.

8. (canceled)

13. (canceled)

15-17. -17. (canceled)

19-24. -24. (canceled)

26-28. -28. (canceled)

46-54. -54. (canceled)

56-57. -57. (canceled)

61. A method of conducting a reaction within at least one plug comprising the steps of:

introducing a carrier-fluid into a device comprising a first channel in fluid communication with a first inlet;

simultaneously introducing at least two streams of plug-fluids into the first inlet so that at least one plug forms in the carrier fluid at a junction of the first inlet and the first channel;

wherein;

a first plug-fluid comprises a first reagent;

a second plug-fluid comprises a second reagent different from the first reagent;

each plug-fluid is immiscible with the carrier-fluid; and

each plug comprises both the first and second plug-fluids so that the reagents may undergo the reaction;

each plug is substantially surrounded by carrier.

62. A method of conducting a reaction within at least one plug comprising the steps of:

introducing a carrier-fluid into a device comprising a first channel in fluid communication with a first inlet and a second inlet;

introducing a stream of a first plug-fluid into the first inlet and simultaneously introducing a stream of a second plug-fluid into the second inlet so that at least one plug forms in the carrier-fluid after the first and second plug-fluids contact the carrier fluid;

wherein;

a first plug-fluid comprises a first reagent;

a second plug-fluid comprises a second reagent different from the first reagent;

each plug-fluid is immiscible with the carrier-fluid;

each plug comprises both the first and second plug-fluids so that the reagents can react; and

each plug is substantially surrounded by carrier.

63. The method of claim 62, wherein the carrier-fluid comprises an oil.

64. The method of claim 62, wherein the carrier-fluid comprises at least one surfactant.

65. The method of claim 62, further comprising independently adjusting flow rates of each plug-fluids so that an array of plugs forms where at least two plugs contain different concentration of reagents.

66. The method of claim 62, wherein plugs are formed at a capillary number of ≦

about 0.2.

67. The method of claim 62, wherein the reaction of the plug-fluids forms an insoluble reaction product within at least one plug.

68. The method of claim 62, wherein the reaction of the plug-fluids forms a soluble reaction product within at least one plug.

69. The method of claim 62, wherein the plug-fluids are distinct laminar streams at or before the inlet.

70. The method of claim 62, wherein the channels comprise one or more turns, or bends.

71. The method of claim 62, further comprising a step of merging at least one plug with a second plug downstream of the first inlet.

72. The method of claim 62, further comprising a step of splitting at least one plug into two or more parts by splitting the channel downstream of the first inlet.

73. The method of claim 62, further comprising splitting at least one plug into two or more parts such that a first part of the plug passes into a second channel through an opening, wherein the second channel is downstream of the first inlet.

74. The method of claim 62, further comprising separating at least one plug from the carrier-fluid.

75. The method of claim 62, further comprising detecting the presence of at least one plug downstream of the first inlet.

76. The method of claim 62, further comprising detecting the product of the reaction.

77. The method of claim 62, further comprising monitoring the reaction.

78. The method of claim 62, further comprising employing a number of devices in parallel.

79. The method of claim 62, further comprising stopping the fluid flow for a period of time.

80. The method of claim 62, wherein a cross section of at least one of the first and second inlets is about 30 μ

m to about 50 μ

m.

81. The method of claim 62, wherein the volume of at least one plug is about 1 femtoliter to about 250 nL.

82. A method of conducting a reaction within at least one plug comprising the steps of:

introducing a carrier-fluid into a device comprising a first channel in fluid communication with a first inlet and a second inlet;

introducing a stream of a first plug-fluid into the first inlet and simultaneously introducing a stream of a second plug-fluid into the second inlet so that at least one plug forms in the carrier fluid at a junction area of the first and second inlets and the first channel;

wherein;

a first plug-fluid comprises a first reagent;

a second plug-fluid comprises a second reagent different from the first reagent;

each plug-fluid is immiscible with the carrier-fluid;

each plug comprises both the first and second plug-fluids so that the reagents can react; and

each plug is substantially surrounded by carrier.

83. The method of claim 82, wherein each plug initially has a cross section that is substantially the same size as the cross section of the channel at the junction area.