Apparatus for microfluidic processing and reading of biochip arrays

• US 20040248318A1
• Filed: 01/29/2004
• Published: 12/09/2004
• Est. Priority Date: 01/30/2003
• Status: Active Grant

• Current Assignee: Bio-Rad Laboratories Incorporated
• Original Assignee: Ciphergen Biosystems Incorporated
• Inventors: Weinberger, Scot R., Hlousek, Louis
• Granted Patent: US 7,046,357 B2
• Time in Patent Office: Days
• US Class Current: 436/173
• CPC Class Codes: B01L 2300/0636 Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0654 Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2400/0415 electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0605 check valves
• CPC Class Codes: B01L 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 9/527 for microfluidic devices, e.g. used for lab-on-a-chip
• CPC Class Codes: G01N 21/553 and using surface plasmons fluorescence excitation G01N21/648; enhanced Raman G01N21/658
• CPC Class Codes: G01N 27/44782 of a plurality of samples
• CPC Class Codes: G01N 30/6095 Micromachined or nanomachined, e.g. micro- or nanosize
• CPC Class Codes: G01N 33/54366 Apparatus specially adapted for solid-phase testing
• CPC Class Codes: G01N 33/54386 Analytical elements
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

A method and a device for detecting an analyte, including a substrate having a chemically selective surface; and a fluidic system disposed on the substrate, the manifold having at least one fluid path in communication with at least a discrete region of the surface, wherein the one fluid path and the discrete region together define a contained sample region on the surface. The fluidic system has a removable portion, wherein the removal of the removable portion of the fluidic system renders the discrete region directly interrogatable by a surface-based analytical tool.

Claims

1. A device, comprising:

(a) a substrate having a chemically selective surface;

(b) a fluidic system disposed on said substrate, said fluidic system comprising;

(i) at least one fluid path in communication with at least a discrete region of said surface, wherein said one fluid path and said discrete region together define a contained sample region on said surface, and

(ii) a removable fluidic system portion;

(c) means for fastening the fluidic system to the substrate;

(d) means for engaging a first detection system, wherein the device is removably insertable into the detection system; and

wherein the first detection system comprises means for interrogating the substrate surface when the fluidic system portion is integrated with the device, and

(e) means for engaging a surface-based analytical tool, wherein the surface-based analytical tool comprises means for interrogating the substrate surface as a result of removal of the fluidic system portion.

2. The device of claim 1 wherein said substrate is adapted for use in a first detection system selected from the group consisting of an optical device, an electrochemical device, an atomic force device, a radio frequency device, a piezoelectric vibrating member, a resonant cantilever device, and combinations thereof.

3. The device of claim 1 wherein said substrate is adapted for use in a surface-based analytical tool selected from the group consisting of a desorption spectrometer and an atomic force device.

4. The device of claim 1 wherein said substrate comprises an optically transparent material.

5. The device of claim 1 wherein said substrate comprises an optically transparent material and said surface comprises a material with a higher refractive index than the substrate.

6. The device of claim 5 wherein said a material with a higher refractive index than the substrate comprises a metal oxide, selected from the group consisting of Ta₂O₅, TiO₂, ZrO₂, HfO₂, SiO₂, Si₃N₄.

7. The device of claim 1 wherein said substrate comprises a grating coupler waveguide that couples through the discrete region.

8. The device of claim 1 wherein said substrate comprises structured electrodes that couple through the discrete region.

9. The device of claim 1 wherein said chemically selective surface comprises a chromatographic capture reagent.

10. The device of claim 1 wherein said chemically selective surface comprises a biospecific capture reagent.

11. The device of claim 1 wherein said chemically selective surface comprises a reactive moiety capable of binding a capture reagent.

12. The device of claim 1 wherein said chemically selective surface comprises a material that supports desorption and ionization of adsorbed species upon laser irradiation.

13. The device of claim 1 wherein said sample region includes a chromatographic stationary phase, said stationary phase configured to perform thin layer, open tubular, capillary, packed, gel or retentate chromatography.

14. The device of claim 1 wherein the fluid path comprises an inlet port configured to accept fluid from a fluid delivery system.

15. The device of claim 1 wherein the fluidic system comprises a first solid portion and a gasket, wherein the gasket is in contact with the substrate.

16. The device of claim 1 wherein said at least one fluid path is in communication with a plurality of discrete portions of said surface.

17. The device of claim 1 wherein said fluid path comprises at least one diaphragm valve.

18. The device of claim 1 wherein said fluidic system comprises a plurality of fluid paths in fluid communication with said same sample region.

19. The device of claim 1 wherein said fluidic system comprises the means for fastening to the substrate.

20. The device of claim 1 wherein the fluidics system comprises an electrophoretic separation column.

21. The device of claim 1 wherein the entire fluidic system is removable from the device.

22. The device of claim 1 wherein said means for fastening comprises a holder that receives the fluidics system and receives the substrate between the fluidics system and the holder.

23. The device of claim 1 wherein said means for fastening comprises a holder that receives the fluidics system and receives the substrate between the fluidics system and the holder and further comprises a pin that holds the fluidics system to the holder.

24. The device of claim 1 wherein said means for fastening comprises a first frame that receives the fluidics system and a second frame comprising a surface complementarily shaped with respect to the first frame to securely hold the fluidics system inside the first frame.

25. The device of claim 1 wherein said removable fluidics portion is peelably removable from the device.

26. The device of claim 1 wherein said removable fluidics portion is removably fastened to device by mechanical means, adhesive means or frangible attachment to the fluidics system.

27. The device of claim 13 wherein said stationary phase is the chemically selective surface of the region.

28. The device of claim 13 comprising a plurality of stationary phases arranged serially within the device, so as to perform multi-stage chromatography.

29. A method for detecting an analyte, comprising:

providing a substrate having a chemically selective surface, and wherein said substrate is attached with a fluidic system;

delivering a sample comprising an analyte using said fluidic system to at least one sample region on said substrate;

monitoring physicochemical changes of said surface in response to said analyte;

removing a portion of said fluidic system to render a portion of said surface directly interrogatable by a surface based analytical technique; and

detecting physicochemical changes of the surface region.

30. The method of claim 29 further comprising interrogating said surface after said removing using LDI-MS.

31. The method of claim 29 wherein said providing comprises

providing a chemically selective surface comprising a reactive moiety and delivering to said sample region a capture reagent that is bound by said reactive moiety.

32. The method of claim 29 wherein said providing comprises

providing a selective surface comprising a moiety and delivering to said sample region a capture reagent that is bound by said moiety by physi-sorption.

33. The method of claim 29 further comprising delivering a conditioning fluid to said surface after said delivering said sample.

34. The method of claim 29 further comprising delivering a reagent to selectively functionalize said surface after said delivering said sample.

35. The method of claim 29 further comprising delivering said sample to a plurality of discrete locations on said surface.

36. The method of claim 29 wherein said sample is one of a plurality of samples and said sample region is one of a plurality of different sample regions and said delivering comprises delivering each of said plurality of samples to said different sample regions.

37. The method of claim 29 further comprising delivering a matrix solution to said sample region before said removing.

38. The method of claim 29 wherein said monitoring is selected from the group consisting of optical monitoring, electrochemical monitoring, atomic force monitoring, a radio frequency monitoring, a piezoelectric vibrating member monitoring, a resonate cantilever device monitoring, and combinations thereof.

39. The method of claim 38 wherein said optical-based monitoring is configured to monitor changes in properties of polarization of light caused by interaction of light with said surface.

40. The method of claim 38 wherein said properties are selected from a group consisting of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, birefringence, refractive index and combinations thereof.

41. The method of claim 38 wherein said optical monitoring comprises using an optical-based device that is configured to detect changes in the refractive index at the surface.

42. The method of claim 38 wherein said optical monitoring comprises using an optical-based device that comprises a grating coupler waveguide device.

43. The method of claim 42 wherein said grating coupler waveguide device is interrogated by varying the wavelength of incident radiation at a fixed angle and determining the wavelength of maximum coupling.

44. The method of claim 42 wherein said grating coupler waveguide device is interrogated by varying the angle of the incident light of a fixed wavelength and determining the angle of maximum coupling.

45. The method of claim 42 wherein said grating coupler waveguide device is interrogated by illuminating said grating coupler device with light comprising a range of wavelengths and determining the wavelength of maximum coupling by measuring the wavelength of the coupled light.

46. The method of claim 42 wherein said grating coupler waveguide device is interrogated by illuminating said grating coupler device with light of a fixed wavelength over a range of angles and determining the angle of the coupled light.

47. The method of claim 42 wherein said grating coupler waveguide device is interrogated by a combination of

varying the wavelength of incident radiation at a fixed angle and determining the wavelength of maximum coupling,

varying the angle of the incident light of a fixed wavelength and determining the angle of maximum coupling,

illuminating said grating coupler device with light comprising a range of wavelengths and determining the wavelength of maximum coupling by measuring the wavelength of the coupled light, and

illuminating said grating coupler device with light of a fixed wavelength over a range of angles and determining the angle of the coupled light.

48. The method of claim 29 further comprising providing a substrate wherein the substrate comprises means for rendering the substrate compatible with a device for monitoring physiocochemical changes of said surface.

49. The method of claim 48 wherein said monitoring comprises an optical monitoring and the means comprise an optically transmissive path communicating with said surface, said path selected from a window, a lens, a prism, a surface planar waveguide or a fiber optic.

50. The method of claim 48 wherein said monitoring comprises an optical monitoring and the means is selected from a polarizer, a lens, a mirror, a diffraction grating, a wave plate, an attenuator, an interferometer and combinations thereof.

51. The method of claim 48 wherein said monitoring comprises an electrochemical monitoring and the means comprise electrodes in electrical communication with said surface.

52. The method of claim 48 wherein said monitoring comprises using an atomic force microscope (AFM) and the means comprise an AFM probe or port for accepting an AFM probe in physical communication with said surface.

53. The method of claim 48 wherein said monitoring comprises using a radio frequency device and the means comprise a radiofrequency waveguide in radio frequency communication with said surface.

54. The method of claim 29 wherein said sample region comprises:

a thin-layer chromatographic surface and said delivering comprises

flowing said sample across said chromatographic surface, and

chromatographically separating said analyte in said sample region.

55. The method of claim 54 wherein the chromatographically separating is selected from a group consisting of Reverse Phase, ion exchange, mixed mode, normal phase, immobilized metal affinity capture, affinity capture, and combinations thereof.

56. The method of claim 54 wherein said chromatographically separating comprises:

monitoring said chromatographic surface at a plurality of locations; and

detecting analytes bound to said capture reagent at said plurality of locations.

57. The method of claim 29 further comprising prior electrophoresis of the sample, said electrophoresis including capillary denaturing, nascent, free zone, isoelectric focusing, isotachophoresis, gel electrophoresis, or combinations thereof.

58. A method of detecting an analyte, comprising:

providing a device comprising a substrate having a chromatographic surface;

flowing a sample comprising analytes across said surface, whereby analytes are chromatographically separated across, and bound to, said surface; and

detecting the analytes bound to said surface by laser desorption/ionization mass spectrometry.

59. A device for detecting an analyte, comprising:

a substrate having a chromatographic surface;

means for flowing a sample comprising analytes across said surface;

means for chromatographically separating the analytes across said surface, to form analytes that are chromatographically separated across, and bound to, said surface; and

means for detecting the analytes bound to said surface by laser desorption/ionization mass spectrometry.

60. A method of detecting an analyte, comprising:

providing a device comprising a substrate and a fluidic manifold disposed on the substrate, said device having an electrophoresis medium on the substrate surface;

electrophoresing a sample comprising analytes through the medium, whereby analytes are electrophoretically separated through the medium;

detecting in real-time the electroporesis of the sample by a surface scanner; and

;

further detecting the separated analytes by laser desorption/ionization mass spectrometry.

61. A detection system comprising:

(a) a device comprising;

(1) a substrate having a chemically selective surface;

(2) a fluidic system disposed on said substrate, said fluidic system comprising;

(i) at least one fluid path in communication with at least a discrete region of said surface, wherein said one fluid path and said discrete region together define a contained sample region on said surface, and

(ii) a removable fluidic system portion;

(3) means for fastening the fluidic system to the substrate;

(4) means for engaging a first detection system, wherein the device is removably insertable into the detection system; and

wherein the first detection system comprises means for interrogating the substrate surface when the fluidic system portion is integrated with the device, and

(5) means for engaging a surface-based analytical tool, wherein the surface-based analytical tool comprises means for interrogating the substrate surface as a result of removal of the fluidic system portion;

(b) means for interrogating the substrate surface when the fluidic system portion is coupled with the device.

62. The detection system of claim 61 wherein said means for interrogating comprises an optical device and the means for engaging comprise an optically transmissive path communicating with said surface, said path selected from a window, a lens, a prism, a surface planar waveguide or a fiber optic.

63. The detection system of claim 62 wherein said optical device is configured to monitor changes in properties of the polarization of light caused by interaction of light with said surface.

64. The detection system of claim 62 wherein said optical device is configured to monitor properties of said surface selected from a group consisting of fluorescence, luminescence, chemiluminescence, absorbance, reflectance, transmittance, birefringence, refractive index and combinations thereof.

65. The detection system of claim 62 wherein said optical device is configured to detect changes in the refractive index at said surface.

66. The detection system of claim 62 wherein said substrate comprises a grating coupler waveguide.

67. The detection system of claim 65 wherein said waveguide is interrogated by varying the wavelength of incident radiation at a fixed angle and determining the wavelength of maximum coupling.

68. The detection system of claim 65 wherein said waveguide is interrogated by varying the angle of the incident light of a fixed wavelength and determining the angle of maximum coupling.

69. The detection system of claim 65 wherein said waveguide is interrogated by illuminating said grating coupler device with light comprising a range of wavelengths and determining the wavelength of maximum coupling by measuring the wavelength of the coupled light.

70. The detection system of claim 65 wherein said waveguide is interrogated by illuminating said grating coupler device with light of a fixed wavelength over a range of angles and determining the angle of the coupled light.

71. The detection system of claim 65 wherein said waveguide is interrogated by a combination of

varying the wavelength of incident radiation at a fixed angle and determining the wavelength of maximum coupling,

varying the angle of the incident light of a fixed wavelength and determining the angle of maximum coupling,

illuminating said grating coupler device with light comprising a range of wavelengths and determining the wavelength of maximum coupling by measuring the wavelength of the coupled light, and

illuminating said grating coupler device with light of a fixed wavelength over a range of angles and determining the angle of the coupled light.

72. The detection system of claim 61 wherein said means for interrogating comprises an optical device and the means for engaging a first detection system is selected from a polarizer, a lens, a mirror, a diffraction grating, a diffractive element, a wave plate, an attenuator, an interferometer and combinations thereof.

73. The detection system of claim 61 wherein said means for interrogating comprises an electrochemical device and the means for engaging a first detection system comprise electrodes in electrical communication with said surface.

74. The device of claim 61 wherein said means for interrogating comprises a radio frequency device and the means for engaging a first detection system comprise a radiofrequency waveguide in radio frequency communication with said surface.

75. A device, comprising:

(a) a substrate;

(b) a fluidic system disposed on said substrate, said fluidic system comprising;

(i) at least one fluid path in communication with at least a discrete region of the surface of said substrate, wherein said one fluid path and said discrete region together define a contained sample region on said surface, and

(ii) a removable fluidic system portion;

(iii) a remaining portion of the fluidic system that remains after removal of the removable portion, said remaining portion comprising at least one electrostatic and/or pneumatic element;

(c) means for engaging a surface-based analytical tool, wherein the surface-based analytical tool comprises means for interrogating the substrate surface as a result of removal of the fluidic system portion.