Devices and methods for using centripetal acceleration to drive fluid movement in a microfluidics system

• US 6,319,469 B1
• Filed: 12/18/1996
• Issued: 11/20/2001
• Est. Priority Date: 12/18/1995
• Status: Expired due to Fees

• Current Assignee: Tecan Trading AG (Tecan Group AG)
• Original Assignee: Silicon Valley Bank (SVB Financial Group)
• Inventors: Mian, Alec, Corey, George D., Kieffer-Higgins, Stephen G.
• Primary Examiner(s): WALLENHORST, MAUREEN
• Application Number:
  US08/768,990
• Time in Patent Office: 1,798 Days
• Field of Search: 422/63, 422/64, 422/67, 422/72, 436/45
• US Class Current: 422/64
• 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 25/31 in conduits or tubes through which the main component flows
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 35/71725 using centrifugal forces
• CPC Class Codes: B01F 35/71805 using valves, gates, orifices or openings
• 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 2219/00833 Plastic
• CPC Class Codes: B01J 2219/00891 Feeding or evacuation
• 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 2200/0621 Control of the sequence of chambers filled or emptied
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2300/0645 Electrodes
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0806 Standardised forms, e.g. compact disc [CD] format
• 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 2300/0887 : Laminated structure
• CPC Class Codes: B01L 2300/1822 : using Peltier elements
• CPC Class Codes: B01L 2300/1827 : using resistive heater
• CPC Class Codes: B01L 2300/1861 : using radiation
• CPC Class Codes: B01L 2400/0406 : capillary forces
• CPC Class Codes: B01L 2400/0409 : centrifugal forces
• CPC Class Codes: B01L 2400/0421 : electrophoretic flow
• CPC Class Codes: B01L 2400/0655 : pinch valves
• CPC Class Codes: B01L 2400/0688 : surface tension valves, capillary stop, capillary break
• CPC Class Codes: B01L 3/0268 : using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
• CPC Class Codes: B01L 3/5025 : for parallel transport of multiple samples
• 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: B29C 59/14 : by plasma treatment plasma tubes per se H01J
• CPC Class Codes: F15C 1/005 : for measurement techniques, e.g. measuring from a distance; for detection devices, e.g. for presence detection; for sorting measured properties (testing); for gyrometers; for analysis; for chromatography fluid information or impulse transducers F15B5/00; postal sorting according to size B07C1/10; dial gauges, spherometers G01B3/22, G01B5/22; gyroscopic apparatus G01C19/00; viscosimeters G01N11/00; speed measurement, flowmeters G01P
• CPC Class Codes: F15C 5/00 : Manufacture of fluid circuit elements; Manufacture of assemblages of such elements integrated circuits
• CPC Class Codes: G01N 2030/326 : pumps
• CPC Class Codes: G01N 2035/00782 : reprogrammmable code
• CPC Class Codes: G01N 21/07 : Centrifugal type cuvettes G01N21/09 takes precedence
• CPC Class Codes: G01N 27/44704 : Details; Accessories
• CPC Class Codes: G01N 30/20 : using a sampling valve
• CPC Class Codes: G01N 30/6095 : Micromachined or nanomachined, e.g. micro- or nanosize
• CPC Class Codes: G01N 35/00069 : whereby the sample substrate is of the bio-disk type, i.e. having the format of an optical disk
• CPC Class Codes: G01N 35/00732 : Identification of carriers, materials or components in automatic analysers
• CPC Class Codes: G01N 35/00871 : Communications between instruments or with remote terminals
• CPC Class Codes: Y10T 436/111666 : Utilizing a centrifuge or compartmented rotor

Abstract

This invention relates to methods and apparatus for performing microanalytic and microsynthetic analysis and procedures. The invention provides a microsystem platform and a micromanipulation device for manipulating the platform that utilizes the centripetal force resulting from rotation of the platform to motivate fluid movement through microchannels. The microsystem platforms of the invention are also optionally provided having system informatics and data acquisition, analysis and storage and retrieval informatics encoded on the surface of the disk opposite to the surface containing the fluidic components. Methods specific for the apparatus of the invention for performing any of a wide variety of microanalytical or microsynthetic processes are provided.

Claims

1. A centripetally-motivated fluid micromanipulation apparatus that is a combination of

a microsystem platform, comprising a substrate having a first flat, planar surface and a second flat, planar surface opposite thereto, wherein the first surface comprises a sample input means, a multiplicity of reaction chambers and a multiplicity of microchannels embedded in said first surface, wherein the sample input means, microchannels and reaction chambers are connected and in fluidic contact with one another, wherein each microchannel is connected to a microvalve and is vented to an air displacement channel located over each reaction chamber, whereby fluid flow through the microchannels is controlled by the opening and closing of the microvalves and the venting of air through the air displacement channels,

a micromanipulation device, comprising a base, a rotating means for rotating the platform, a power supply and user interface and operations controlling means, wherein the rotating means is operatively linked to the microsystem platform and in rotational contact therewith

wherein a volume of fluid within the platform is moved from one microchannel to another by centripetal force arising from rotational motion of the platform which causes the air in a microchannel to be displaced through an air displacement channel located over a connecting reaction chamber and a microvalve connected to the microchannel to open so as to transfer fluid to a connecting microchannel.

2. The apparatus of claim 1, wherein the first flat, planar surface and second flat, planar surface of the microsystem platform form a disk.

3. The apparatus of claim 2, wherein the microsystem platform is a disk having a radius of about 1 to 25 cm.

4. The apparatus of claim 1, wherein the first and second flat, planar surfaces of the microsystem platform define a centrally located aperture that is engaged to a spindle on the micromanipulation device, whereby rotational motion of the spindle is translated into rotational motion of the microsystem platform.

5. A centripetally-motivated fluid micromanipulation apparatus according to claim 4 wherein fluid flow from a position on the platform more proximal to the center of the platform to a position more distal to the center of the platform is dependent on an increase in the rotational velocity of the platform.

6. The apparatus of claim 5, wherein the microsystem platform is rotated at a velocity of from about 1 to about 30,000 rpm.

7. The apparatus of claim 1, wherein the microsystem platform is constructed of an material selected from the group consisting of an organic material, an inorganic material, a crystalline material and an amorphous material.

8. The apparatus of claim 7, wherein the microsystem platform is constructed of a material selected from the group consisting of silicon, silica, quartz, a ceramic, a metal and a plastic.

9. The apparatus of claim 1, wherein the microsystem platform has a thickness of about 0.1 to 100 mm, and wherein the cross-sectional dimension of the microchannels between the first and second flat, planar surfaces is less than 500 μ

m and from 1 to 90 percent of the cross-sectional dimension of the platform.

10. The apparatus of claim 1, wherein the microsystem platform is rotated at a rotational velocity of about 1 to about 30,000 rpm.

11. The apparatus of claim 1, wherein the microsystem platform further comprises a multiplicity of sample input means, and reagent reservoirs, connected thereto and embedded therein, wherein a volume of a fluid containing a sample is moved on the platform from the sample input means into and out from the reaction chambers, and a volume of a reagent is moved from the reagent reservoirs into and out from the reaction chambers, by centripetal force arising from rotation of the microsystem platform.

12. The apparatus of claim 1, wherein the microsystem platform comprises a detection chamber embedded within the first planar surface of the platform and connected to a microchannel, and wherein the micromanipulation device comprises a detection means, whereby the detection chamber is assayed by the detecting means to yield an assay output.

13. The apparatus of claim 12, wherein the detecting means on the device is brought into alignment with the detection chamber on the platform by rotational motion of the microsystem platform.

14. The apparatus of claim 13, wherein the detecting means is stationary and samples the detection chamber at a frequency equal to the frequency of rotation of the platform or multiples thereof.

15. The apparatus of claim 14, wherein the detecting means comprises a stroboscopic light source.

16. The apparatus of claim 15, wherein the detecting means is a monochromatic light source.

17. The apparatus of claim 12, wherein the detecting means comprises a light source and a photodetector.

18. The apparatus of claim 17, wherein the light source illuminates the detection chamber wherein light is reflected transversely through the detection chamber and detected by a photodetector.

19. The apparatus of claim 18, wherein the detection chamber on the microsystem platform is optically transparent.

20. The apparatus of claim 12, wherein the detecting means detects absorbance, fluorescence, chemiluminescence, light-scattering or radioactivity.

21. The apparatus of claim 1, further comprising a temperature controlling element in thermal contact with the microplatform.

22. The apparatus of claim 1 further comprising a thermal detecting unit in thermal contact with the microplatform.

23. The apparatus of claim 1, wherein the microsystem platform comprises a filtering means linked to a microchannel.

24. The apparatus of claim 1, wherein the microsystem platform comprises a mixing element connected to a reaction chamber or a microchannel.

25. The apparatus of claim 24, wherein the mixing element comprises a static mixer comprising a textured surface of a reaction chamber or microchannel.

26. The apparatus of claim 1, wherein the microsystem platform further comprises a multiplicity of reagent reservoirs, wherein the microvalves are operatively linked to the reagent reservoirs.

27. The apparatus of claim 26, wherein the microsystem platform comprises a capillary microvalve connected to a reaction chamber or microchannel.

28. The apparatus of claim 1, wherein the rotating means of the device is an electric motor.

29. The apparatus of claim 1, wherein the device comprises a rotational motion controlling means for controlling the rotational acceleration and velocity of the microsystem platform.

30. The apparatus of claim 1, wherein the device includes a user interface comprising a monitor and an alphanumeric keypad.

31. The apparatus of claim 1, wherein the device comprises an alternating current or direct current power supply.

32. The apparatus of claim 1, wherein the microsystem platform includes an electrical connector in contact with an electric connector connected to the micromanipulation device.

33. The apparatus of claim 1, wherein the device comprises a microprocessor and a memory connected thereto.

34. The apparatus of claim 1, wherein the device comprises a reading or writing means.

35. The apparatus of claim 34, wherein the reading means is a compact disk laser reading means.

36. The apparatus of claim 34, wherein the writing means is a compact disk writing means.

37. The apparatus of claim 1, wherein the second flat, planar surface of the microsystem platform is encoded with machine language instructions.

38. The apparatus of claim 37, wherein the machine language instructions control operation of the platform, data acquisition or analysis from the platform, data storage and retrieval, communication to other devices, or direct apparatus performance diagnostics.

39. The apparatus of claim 1, wherein the micromanipulation device includes a read-only memory or permanent storage memory that is encoded with machine language instructions.

40. The apparatus of claim 39, wherein the machine language instructions control operation of the platform, data acquisition or analysis from the platform, data storage and retrieval, communication to other devices, or direct apparatus performance diagnostics.

41. The apparatus of claim 1 further comprising first and second microsystem platforms in contact with one another across one planar surface of each microsystem platform.

42. The apparatus of claim 1, wherein fluid on the microsystem platform is moved within the microchannels of the platform with a fluid velocity of from about 0.1 cm/sec to about 1000 cm/sec.

43. An apparatus according to claim 1 for measuring the amount of an analyte in a biological sample, wherein the microsystem platform comprises

a multiplicity of sample inlet ports, arranged concentrically around the center of the platform, wherein each of the sample inlet ports is operatively linked to

a multiplicity of microchannels arrayed radially away from the center of the platform, said microchannels being operatively linked to

a multiplicity of reagent reservoirs containing a reagent specific for the analyte to be measured, wherein release of the reagent from each of the reservoirs is controlled by a microvalve, and wherein the multiplicity of microchannels is also operatively linked to

a multiplicity of analyte detection chambers arranged peripherally around the outer edge of the microplatform,

wherein movement of the biological sample from a sample inlet port and through a microchannel, and movement of the reagent from a reagent reservoir and through a microchannel, is motivated by centripetal force generated by rotational motion of the microsystem platform.

44. The apparatus of claim 43 wherein the biological sample is blood, urine, cerebrospinal fluid, plasma, saliva, semen, or amniotic fluid.

45. The apparatus of claim 43 wherein the analyte detection chambers are optically-transparent.

46. The apparatus of claim 43 further comprising electrical wiring between each of the microvalves and an electrical controller unit, wherein valve opening and closing is controlled by electrical signals from the controller unit.

47. The apparatus of claim 43 wherein the microchannels are arrayed linearly from the center of the platform to the periphery.

48. The apparatus of claim 43 wherein the microchannels are arrayed concentrically from the center of the platform to the periphery.

49. The apparatus of claim 43 wherein the micromanipulation device comprises a detecting means.

50. The apparatus of claim 49 wherein the detecting means is stationary and samples an output from the analyte detection chambers at a frequency equal to the frequency of rotation of the platform or multiples thereof.

51. The apparatus of claim 49 wherein the detecting means comprises a stroboscopic light source.

52. The apparatus of claim 49 wherein the detecting means is a monochromatic light source.

53. The apparatus of claim 49 wherein the detecting means detects fluorescence, chemiluminescence, light-scattering or radioactivity.

54. An apparatus according to claim 1 for detecting gas or particles in an environmental sample, wherein the microsystem platform comprises

a multiplicity of sample inlet ports, arranged concentrically around the center of the platform, wherein the sample inlet ports comprise an air intake vent and connecting funnel channel, wherein each of the sample inlet ports is operatively linked to

a multiplicity of microchannels arrayed radially away from the center of the platform, said microchannels being operatively linked to

a multiplicity of reagent reservoirs containing a reagent specific for the gas or particles to be detected, wherein release of the reagent from each of the reservoirs is controlled by a microvalve, wherein the microvalves are in electrical contact with a controller unit, and wherein the multiplicity of microchannels is also operatively linked to

a multiplicity of gas or particle detectors arranged peripherally around the outer edge of the microplatform,

wherein movement of the environmental sample from a sample inlet port and through a microchannel, and movement of the reagent from a reagent reservoir and through a microchannel, is motivated by centripetal force generated by rotational motion of the microsystem platform.

55. The apparatus of claim 54, wherein the environmental sample comprises air, water, soil, or disrupted biological matter.

56. The apparatus of claim 64, wherein the detectors each comprise a gas sensor chip.

57. The apparatus of claim 64, wherein the detectors each comprise an optically-transparent particle collection chamber.

58. The apparatus of claim 67, wherein the detectors each also comprise a coherent light source.

59. The apparatus of claim 58, wherein the particles are detected by light scattering.

60. The apparatus of claim 64, wherein the detectors each comprise a particle collection chamber operatively connected by a microchannel to a reagent reservoir comprising a reagent for chemically testing the particles.

61. An apparatus according to claim 1, wherein the microsystem platform is comprised of a stacked layer of thin film disks, each disk comprising microchannels, sample inlet ports, reactant reservoirs, reaction chambers and sample outlet ports, wherein each of the stacked film disks is self-contained and provides a platform of the apparatus.

62. An apparatus of claim 1 for determining a hematocrit value from a blood sample, wherein the microsystem platform is comprised of a radial array of microchannels having a diameter of about 100 μ

m wherein the microchannels are treated with heparin to prevent coagulation, and wherein the microchannels are open at one end proximal to the center of the platform, the apparatus also comprising a coherent light source and a recording means operatively connected to the micromanipulation device, and wherein movement of the blood sample through a microchannel is motivated by centripetal force generated by rotational motion of the microsystem platform.

63. An apparatus of claim 62, wherein the coherent light source is mounted on a movable track arrayed radially from the center of rotation of the platform.

64. An apparatus of claim 62 further comprising a Clarke electrode operatively connected to each of the microchannels of the microsystem platform, wherein each electrode is in contact with a blood sample within a microchannel.

65. An apparatus of claim 62 further comprising a Severing electrode operatively connected to each of the microchannels of the microsystem platform, wherein each electrode is in contact with a blood sample within a microchannel.

66. An apparatus of claim 1, wherein the microsystem platform further comprises a multiplicity of sample input means, reactant reservoirs, and microvalves operatively connected thereto and embedded therein, wherein the microsystem platform is comprised of a stacked array of layers wherein a first layer comprises the sample input means, reactant reservoirs, reaction chambers and microchannels, a second layer comprises the microvalves, a third layer comprises electrical connections from the microvalves to an electrical controller unit, and a fourth layer comprises a sealing layer, wherein the layers are stacked on top of the substrate of the microsystem platform and fused thereto.

67. An apparatus according to claim 1 further comprising a reagent reservoir connected to at least one of the multiplicity of the microchannels in the platform and in fluidic contact therewith.

68. The apparatus of claim 67, wherein the microsystem platform has a thickness of about 0.1 to 100 nm, and wherein the cross-sectional dimension of a reaction chamber or the reagent reservoir between the first and second flat, planar surfaces is from 1 to 75 percent of said thickness of the platform.