Apparatus and method for performing microfluidic manipulations for chemical analysis and synthesis

• US 6,010,607 A
• Filed: 09/16/1998
• Issued: 01/04/2000
• Est. Priority Date: 08/01/1994
• Status: Expired due to Term

• Current Assignee: Lockheed Martin Energy Research Corporation (Martin Marietta Corporation)
• Original Assignee: Lockheed Martin Energy Research Corporation (Martin Marietta Corporation)
• Inventors: Ramsey, J. Michael
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): STARSIAK, JOHN S
• Application Number:
  US09/153,186
• Time in Patent Office: 475 Days
• Field of Search: 204/600, 204/601, 204/602, 204/603, 204/604, 204/605, 204/450, 204/451, 204/452, 204/453, 204/454, 204/455, 435/287.1, 435/287.2, 435/287.3, 435/288.3, 435/288.4, 435/288.5, 435/288.6, 435/288.7
• US Class Current: 204/435
• CPC Class Codes: B01D 15/3842 Micellar chromatography
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 33/3011 using a sheathing stream of a fluid surrounding a central stream of a different fluid, e.g. for reducing the cross-section of the central stream or to produce droplets from the central stream
• CPC Class Codes: B01F 33/3031 using electro-hydrodynamic [EHD] or electro-kinetic [EKI] phenomena to mix or move the fluids
• 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 2219/00826 Quartz
• CPC Class Codes: B01J 2219/00828 Silicon wafers or plates
• CPC Class Codes: B01J 2219/00831 Glass
• CPC Class Codes: B01J 2219/00853 Employing electrode arrangements
• CPC Class Codes: B01J 2219/00889 Mixing micromixers B01F33/30
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• CPC Class Codes: B01J 2219/00912 by electrophoresis
• CPC Class Codes: B01J 2219/00916 by chromatography
• CPC Class Codes: B01J 2219/00952 Sensing operations
• CPC Class Codes: B01J 2219/0097 Optical sensors
• CPC Class Codes: B01J 2219/00995 Mathematical modeling
• CPC Class Codes: B01L 2200/0605 Metering of fluids
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• 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 2400/0415 : electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/0418 : electro-osmotic flow [EOF]
• CPC Class Codes: B01L 2400/0421 : electrophoretic flow
• CPC Class Codes: B01L 3/5027 : by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• 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 3/502753 : characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation separation in general B01D; microapparatus for analysis using electrophoresis G01N27/44791; sample preparation G01N1/28
• CPC Class Codes: B01L 3/502776 : specially adapted for focusing or laminating flows
• 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: B29C 65/4895 : Solvent bonding, i.e. the surfaces of the parts to be joined being treated with solvents, swelling or softening agents, without adhesives
• CPC Class Codes: B29C 66/026 : Chemical pre-treatments B29C66/028 takes precedence
• CPC Class Codes: B29C 66/034 : Thermal after-treatments
• CPC Class Codes: B29C 66/54 : Joining several hollow-preforms, e.g. half-shells, to form hollow articles, e.g. for making balls, containers; Joining several hollow-preforms, e.g. half-cylinders, to form tubular articles
• CPC Class Codes: G01N 2030/027 : Liquid chromatography
• CPC Class Codes: G01N 2030/162 : electromigration
• CPC Class Codes: G01N 2030/285 : electrically driven carrier
• CPC Class Codes: G01N 2030/383 : by using auxiliary fluid
• CPC Class Codes: G01N 2030/8435 : for chemical reaction
• CPC Class Codes: G01N 27/44743 : Introducing samples
• CPC Class Codes: G01N 27/44791 : Microapparatus sample containers with integrated microfluidic structures B01L3/5027
• CPC Class Codes: G01N 30/02 : Column chromatography
• CPC Class Codes: G01N 30/16 : Injection G01N30/24 takes precedence
• CPC Class Codes: G01N 30/6095 : Micromachined or nanomachined, e.g. micro- or nanosize
• CPC Class Codes: Y10S 366/01 : Micromixers: continuous laminar flow with laminar boundary mixing in the linear direction parallel to the fluid propagation with or without conduit geometry influences from the pathway

Abstract

A microchip laboratory system and method provide fluid manipulations for a variety of applications, including sample injection for microchip chemical separations. The microchip is fabricated using standard photolithographic procedures and chemical wet etching, with the substrate and cover plate joined using direct bonding. Capillary electrophoresis and electrochromatography are performed in channels formed in the substrate. Analytes are loaded into a four-way intersection of channels by electrokinetically pumping the analyte through the intersection, followed by switching of the potentials to force an analyte plug into the separation channel.

Claims

1. A method of controllably moving material in a microfluidic device, comprising:

providing a microfluidic device that includes a body having at least first, second, third and fourth channels disposed therein, the first, second, third and fourth channels communicating at a first intersection, the first channel connecting at least a first material source to the first intersection;

applying a first voltage difference between the first material source and the second channel to move the first material from the first channel, through the intersection and into the second channel;

applying a second voltage difference between the third channel and the first intersection, and a third voltage difference between the fourth channel and the first intersection simultaneously with the applying of the first voltage difference, to direct movement of the first material through the intersection into the second channel.

2. The method of claim 1, wherein the step of applying the first voltage difference comprises applying a first voltage to the first channel, and maintaining a second voltage level different from the first voltage at a reservoir that is fluidly connected to the second channel.

3. The method of claim 1, wherein the step of applying the first voltage difference comprises applying a first voltage to the first channel and grounding a reservoir that is fluidly connected to the second channel.

4. The method of claim 1, wherein the step of applying the first voltage difference comprises applying a first voltage to the first channel and a second voltage lower than the first voltage, to the second channel.

5. The method of claim 1, wherein the step of applying the first voltage difference comprises applying a first voltage to the second channel and a second voltage lower than the first voltage, to the first channel.

6. The method of claim 1, wherein the step of simultaneously applying the second and third voltage differences comprises applying a third voltage to the third channel and a fourth voltage to the fourth channel, each of the third and fourth voltages being less than a voltage applied to the first channel, and greater than a voltage level maintained at a reservoir fluidly connected to the second channel.

7. The method of claim 1, wherein the first channel communicates with the first intersection between the third and fourth channels, and the third channel communicates with the first intersection between the first and second channels, and wherein the second and third voltage differences move at least a second material from the third and fourth channels, respectively, into the second channel.

8. The method of claim 7, further comprising:

removing the second and third voltage differences; and

applying a fourth voltage difference between the third and fourth channels through the first intersection to move the first material in the intersection, into the fourth channel.

9. The method of claim 8, further comprising applying a fifth voltage difference between the first channel and the first intersection, and a sixth voltage difference between the second channel and the intersection to move the first material in the first and second channels away from the intersection concurrently with the step of applying the fourth voltage difference.

10. The method of claim 1, wherein the first channel communicates with the first intersection between the fourth channel and the second channel and the second channel communicates with the first intersection between the first channel and the third channel, and wherein the second and third voltage differences move at least a second material from the fourth channel into the third channel.

11. The method of claim 10, wherein the first, second and third voltage differences move at least a second material from the fourth channel into both the second and third channels.

12. The method of claim 10, further comprising:

removing the third voltage difference; and

applying a fourth voltage difference between the first and third channels through the first intersection, to move the first material in the first channel into the third channel.

13. The method of claim 1, wherein the first material comprises charged species that are moved by electrophoresis.

14. The method of claim 1, wherein the material is moved by electroosmosis.

15. The method of claim 1, wherein the first material is moved by a combination of electrophoresis and electroosmosis.

16. The method of claim 1, wherein the channels of the device provided in the providing step have first and second ends, the second ends being in communication at the first intersection, and wherein the applying steps comprise applying electrical potentials to the first ends of the channels.

17. The method of claim 1, wherein the first material comprises nucleic acids.

18. The method of claim 17, wherein the nucleic acids comprise DNA.

19. The method of claim 18, wherein the DNA comprises restriction enzyme fragments of DNA.

20. The method of claim 1, wherein the first material comprises proteins.

21. The method of claim 20, wherein the first material further comprises a micellar material.

22. The method of claim 21, wherein the micellar material is sodium dodecyl sulfate.

23. The method of claim 1, wherein at least a portion of the first material is fluorescently labeled.

24. The method of claim 23, wherein the fluorescently labeled material is labeled with a fluorescein dye.

25. The method of claim 23, wherein the fluorescently labeled material is labeled with a rhodamine dye.

26. The method of claim 8, wherein the first material comprises a fluorescent label, and further comprising detecting the fluorescently labeled material in the fourth channel.

27. The method of claim 26, wherein the detecting step comprises exciting the fluorescent label, and detecting emitted fluorescence.

28. The method of claim 27, wherein the step of detecting emitted fluorescence comprises imaging a portion of the fourth channel with an array detector.

29. The method of claim 27, wherein the step of detecting emitted fluorescence comprises imaging a portion of the fourth channel with a charge coupled device (CCD).

30. The method of claim 27, wherein the step of detecting emitted fluorescence comprises detecting the emitted fluorescence with a PMT.

31. The method of claim 27, wherein the fluorescent label is excited using a laser.

32. The method of claim 27, wherein the fluorescent label is excited using a laser diode.

33. The method of claim 27, wherein the fluorescent label is excited using a LED.

34. A method of controllably moving material through a microfluidic device, comprising:

providing a body having at least first, second, third and fourth channels disposed therein, each channel having a first and second end, the first ends of the first, second, third and fourth channels being in communication at a first intersection, the second ends of the first, second, third and fourth channels respectively communicating with first, second, third and fourth reservoirs;

applying a first voltage difference between the first end of the first channel and the first end of the second channel to move the first material from the first channel, through the intersection and into the second channel;

applying a second voltage difference between the first end of the third channel and the first intersection, and a third voltage difference between the first end of the fourth channel and the first intersection simultaneously with the applying of the first voltage difference, to control movement of the first material through the intersection into the second channel.

35. A method of controllably moving material through a microfluidic channel network, comprising:

electrokinetically moving a first material from a first channel through an intersection of the first channel with second, third and fourth channels, into the second channel; and

electrokinetically transporting material from at least one of the third and fourth channels into the intersection, simultaneously with the electrokinetic moving of the first material from the first channel, to control movement of the first material within the intersection.

36. A method of controllably moving material, comprising:

providing a microchip that includes a substrate having at least first, second, third and fourth channels disposed therein, the first, second, third and fourth channels communicating at a first intersection;

transporting a first material from the first channel, through the intersection and into the second channel;

concurrently transporting at least a second material from at least one of the third and fourth channels into the intersection, to direct movement of the first material through the intersection into the second channel.

37. The method of claim 36, wherein the first channel communicates with the first intersection between the third and fourth channels, and the third channel communicates with the first intersection between the first and second channels, and wherein the at least second material is concurrently transported from the third and fourth channels into the second channel.

38. The method of claim 36, wherein the first channel communicates with the first intersection between the fourth channel and the second channel and the second channel communicates with the first intersection between the first channel and the third channel, and wherein the at least second material is concurrently transported from the fourth channel into the third channel.

39. The method of claim 37, further comprising transporting the first material in the intersection, into the fourth channel subsequent to the transport of the first material from the first channel into the intersection.

40. The method of claim 38, wherein the step of transporting the first material into the third channel is carried out for a selected period of time, a volume of the first material transported into the fourth channel being a function of the selected period of time.

41. The method of claim 38, further comprising transporting the first material in the intersection into the fourth channel subsequent to the transport of the first material from the first channel into the intersection.

42. The method of claim 41, further comprising transporting the first material in the first and second channels away from the intersection concurrently with the transport of the first material in the intersection into the fourth channel.

43. The method of claim 38, further comprising transporting the first material in the intersection into the third channel subsequent to the step of transporting the second material from the fourth channel into the third channel.

44. The method of claim 36, wherein the first material comprises charged species that are transported by electrophoresis.

45. The method of claim 36, wherein the first material is transported by electroosmosis.

46. The method of claim 36, wherein the first material is transported by a combination of electrophoresis and electroosmosis.

47. The method of claim 36, wherein the first material comprises nucleic acids.

48. The method of claim 47, wherein the nucleic acids comprise DNA.

49. The method of claim 48, wherein the DNA comprises restriction enzyme fragments of DNA.

50. The method of claim 36, wherein the first material comprises proteins.

51. The method of claim 50, wherein the first material further comprises a micellar material.

52. The method of claim 51, wherein the micellar material is sodium dodecyl sulfate.

53. The method of claim 36, wherein at least a portion of the first material is fluorescently labeled.

54. The method of claim 53, wherein the fluorescently labeled material is labeled with a fluorescein dye.

55. The method of claim 54, wherein the fluorescently labeled material is labeled with a rhordamine dye.

56. The method of claim 40, wherein the first material comprises a fluorescently labeled material, and further comprising detecting the fluorescently labeled material in the fourth channel.

57. The method of claim 56, wherein the detecting step comprises exciting the fluorescently labeled material, and detecting emitted fluorescence.

58. The method of claim 57, wherein the step of detecting emitted fluorescence comprises imaging a portion of the fourth channel with an array detector.

59. The method of claim 57, wherein the step of detecting emitted fluorescence comprises imaging a portion of the fourth channel with a charge coupled device (CCD).

60. The method of claim 57, wherein the step of detecting emitted fluorescence comprises detecting the emitted fluorescence with a PMT.

61. The method of claim 57, wherein the fluorescently labeled material is excited using a laser.

62. The method of claim 57, wherein the fluorescently labeled material is excited using a laser diode.

63. The method of claim 57, wherein the fluorescently labeled material is excited using a LED.