Sample-holding devices and systems

• US 6,488,892 B1
• Filed: 01/05/2000
• Issued: 12/03/2002
• Est. Priority Date: 04/17/1998
• Status: Expired due to Term

• Current Assignee: Midwest Research Institute, Molecular Devices
• Original Assignee: LJL Biosystems, Inc. (Molecular Devices)
• Inventors: Richardson, Derrick A., Burton, William G., Leytes, Lev J., Leytes, Joseph S., Modlin, Douglas N, Owicki, John C., Petersen, Jon F., El-Hage, Amer
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Handy, Dwayne K
• Application Number:
  US09/478,819
• Time in Patent Office: 1,063 Days
• Field of Search: 422/52, 422/63, 422/82.05, 422/82.08, 422/99, 422/101, 422/102, 422/104, 436/43, 436/164, 436/165, 436/172, 356/244, 356/246
• US Class Current: 422/82.05
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00621 by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00686 Automatic
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01J 2219/00707 separated from the reactor apparatus
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 9/523 for multisample carriers, e.g. used for microtitration plates
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: G01N 21/0303 Optical path conditioning in cuvettes, e.g. windows; adapted optical elements or systems; path modifying or adjustment G01N21/031 - G01N21/15 take precedence
• CPC Class Codes: G01N 35/028 having reaction cells in the form of microtitration plates
• CPC Class Codes: Y10T 436/11 Automated chemical analysis

Abstract

Sample-holding devices and systems for efficiently utilizing relatively small-volume fluid samples.

Claims

1. A system for detecting light transmitted from a sensed volume, the system comprising:

an optical device capable of detecting light substantially exclusively from a sensed volume; and

a sample holder configured to support a sample so that the shape of the sample substantially conforms to a conical portion of the sensed volume;

wherein the optical device is configured to direct light through an opening characterized by a numerical aperture; and

wherein the cone angle of the conical portion of the sensed volume is determined at least in part by the numerical aperture.

2. The system of claim 1, wherein the sample holder has a frusto-conical shape.

3. The system of claim 1, further comprising at least a second sample holder, wherein the sample holders are disposed as wells in a microplate.

4. The system of claim 3, wherein the number of wells in the microplate is selected from the group consisting of 96, 384, and 1536.

5. The system of claim 3, wherein the wells are organized in a density of at least about 1 well per 81 mm².

6. The system of claim 1, wherein the sensed volume has a waist.

7. The system of claim 1, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a conical shape configured to conform to substantially one-half of the hourglass shape.

8. The system of claim 1, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a frusto-conical shape configured to conform to substantially one-half of the hourglass shape.

9. The system of claim 8, wherein the conical portion of the frusto-conical shape is characterized by a cone angle of at least about 8°

.

10. The system of claim 8, wherein the conical portion of the frusto-conical sample holder is characterized by a cone angle of about 25°

.

11. The system of claim 8, the sample holder having a top and a bottom, wherein the diameter of the bottom of the sample holder is about 1.5 millimeters.

12. The system of claim 1, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a cylindrical shape configured to correspond to substantially all of the hourglass shape.

13. The system of claim 1, wherein the optical device includes:

an examination site;

a light source positioned to deliver light to the examination site;

a detector positioned to receive light transmitted from the examination site; and

an optical relay structure capable of transmitting light substantially exclusively from a sensed volume of a sample positioned at the examination site to the detector.

14. The system of claim 1, wherein the optical device includes:

an examination site;

a light source positioned to deliver light to the examination site;

a detector positioned to receive light transmitted from the examination site; and

an optical relay structure capable of delivering light from the light source substantially exclusively to a sensed volume of a sample positioned at the examination site.

15. The system of claim 14, wherein the optical relay structure also is capable of transmitting light to the detector substantially exclusively from a sensed volume of a sample positioned at the examination site.

16. The system of claim 1 further comprising a light source and a detector, wherein the optical device includes a fused-silica fiber optic cable that directs light from the light source toward the sample holder or from the sample holder toward the detector.

17. The system of claim 1, the optical device having an optical axis, wherein the optical device includes a confocal optics element that at least partially defines the extent of the sensed volume along the optical axis.

18. The system of claim 1, wherein the sample holder includes a reference fiducial disposed on the sample holder to provide information that facilitates the luminescence assay.

19. The system of claim 1, wherein the sample holder also is configured to reduce the formation and trapping of bubbles as the sample well is filled with a fluid sample.

20. The microplate of claim 19, wherein the sample well is configured to reduce the formation and trapping of bubbles through the choice of sample well coating.

21. The microplate of claim 19, wherein the sample well is configured to reduce the formation and trapping of bubbles through the geometry of the sample well.

22. The system of claim 1, where the maximum volume capacity of the sample holder is no greater than about 55 μ

L.

23. A system for detecting light transmitted from a sensed volume, the system comprising:

an optical device capable of detecting light substantially exclusively from a sensed volume; and

a sample holder configured to support a sample so that the shape of the sample substantially conforms to a conical portion of the sensed volume;

wherein the optical device has an optical axis; and

wherein the optical device includes a confocal optics element that at least partially defines the extent of the sensed volume along the optical axis.

24. The system of claim 23, wherein the sample holder has a frusto-conical shape.

25. The system of claim 23, further comprising at least a second sample holder, wherein the sample holders are disposed as wells in a microplate.

26. The system of claim 25, wherein the number of wells in the microplate is selected from the group consisting of 96, 384, and 1536.

27. The system of claim 25, wherein the wells are organized in a density of at least about 1 well per 81 mm².

28. The system of claim 23, wherein the sensed volume has a waist.

29. The system of claim 23, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a conical shape configured to conform to substantially one-half of the hourglass shape.

30. The system of claim 23, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a frusto-conical shape configured to conform to substantially one-half of the hourglass shape.

31. The system of claim 30, wherein the conical portion of the frusto-conical shape is characterized by a cone angle of at least about 8°

.

32. The system of claim 30, wherein the conical portion of the frusto-conical sample holder is characterized by a cone angle of about 25°

.

33. The system of claim 30, the sample holder having a top and a bottom, wherein the diameter of the bottom of the sample holder is about 1.5 millimeters.

34. The system of claim 23, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a cylindrical shape configured to correspond to substantially all of the hourglass shape.

35. The system of claim 23, wherein the optical device includes:

an examination site;

a light source positioned to deliver light to the examination site;

a detector positioned to receive light transmitted from the examination site; and

an optical relay structure capable of transmitting light substantially exclusively from a sensed volume of a sample positioned at the examination site to the detector.

36. The system of claim 23, wherein the optical device includes:

an examination site;

a light source positioned to deliver light to the examination site;

a detector positioned to receive light transmitted from the examination site; and

an optical relay structure capable of delivering light from the light source substantially exclusively to a sensed volume of a sample positioned at the examination site.

37. The system of claim 36, wherein the optical relay structure also is capable of transmitting light to the detector substantially exclusively from a sensed volume of a sample positioned at the examination site.

38. The system of claim 36, further comprising a light source and a detector, wherein the optical device includes a fused-silica fiber optic cable that directs light from the light source toward the sample holder or from the sample holder toward the detector.

39. The system of claim 23, wherein the sample holder includes a reference fiducial disposed on the sample holder to provide information that facilitates the luminescence assay.

40. The system of claim 23, wherein the sample holder also is configured to reduce the formation and trapping of bubbles as the sample well is filled with a fluid sample.

41. The microplate of claim 40, wherein the sample well is configured to reduce the formation and trapping of bubbles through the choice of sample well coating.

42. The microplate of claim 40, wherein the sample well is configured to reduce the formation and trapping of bubbles through the geometry of the sample well.

43. The system of claim 23, where the maximum volume capacity of the sample holder is no greater than about 55 μ

L.

44. A system for detecting light transmitted from a sensed volume, the system comprising:

an optical device capable of detecting light substantially exclusively from a sensed volume; and

a sample holder configured to support a sample so that the shape of the sample substantially conforms to a conical portion of the sensed volume, wherein the sample holder also is configured through the choice of sample well coating to reduce the formation and trapping of bubbles as the sample well is filled with a fluid sample.

45. The system of claim 44, wherein the sample holder has a frusto-conical shape.

46. The system of claim 44, further comprising at least a second sample holder, wherein the sample holders are disposed as wells in a microplate.

47. The system of claim 46, wherein the number of wells in the microplate is selected from the group consisting of 96, 384, and 1536.

48. The system of claim 46, wherein the wells are organized in a density of at least about 1 well per 81 mm².

49. The system of claim 44, wherein the sensed volume has a waist.

50. The system of claim 44, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a conical shape configured to conform to substantially one-half of the hourglass shape.

51. The system of claim 44, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a frusto-conical shape configured to conform to substantially one-half of the hourglass shape.

52. The system of claim 51, wherein the conical portion of the frusto-conical shape is characterized by a cone angle of at least about 8°

.

53. The system of claim 51, wherein the conical portion of the frusto-conical sample holder is characterized by a cone angle of about 25°

.

54. The system of claim 51, the sample holder having a top and a bottom, wherein the diameter of the bottom of the sample holder is about 1.5 millimeters.

55. The system of claim 44, wherein the sensed volume has an hourglass shape, and wherein the sample holder has a cylindrical shape configured to correspond to substantially all of the hourglass shape.

56. The system of claim 44, wherein the optical device includes:

an examination site;

a light source positioned to deliver light to the examination site;

a detector positioned to receive light transmitted from the examination site; and

an optical relay structure capable of transmitting light substantially exclusively from a sensed volume of a sample positioned at the examination site to the detector.

57. The system of claim 44, wherein the optical device includes:

an examination site;

a light source positioned to deliver light to the examination site;

a detector positioned to receive light transmitted from the examination site; and

an optical relay structure capable of delivering light from the light source substantially exclusively to a sensed volume of a sample positioned at the examination site.

58. The system of claim 57, wherein the optical relay structure also is capable of transmitting light to the detector substantially exclusively from a sensed volume of a sample positioned at the examination site.

59. The system of claim 44 further comprising a light source and a detector, wherein the optical device includes a fused-silica fiber optic cable that directs light from the light source toward the sample holder or from the sample holder toward the detector.

60. The system of claim 44, wherein the sample holder includes a reference fiducial disposed on the sample holder to provide information that facilitates the luminescence assay.

61. The microplate of claim 44, wherein the sample well is configured to reduce the formation and trapping of bubbles through the geometry of the sample well.

62. The system of claim 44, where the maximum volume capacity of the sample holder is no greater than about 55 μ

L.

63. A system for detecting light transmitted from a sample, the system comprising:

an optical device configured to detect light originating substantially exclusively within a maximum cone; and

a sample holder for supporting the sample that includes a conical portion having a shape that substantially conforms to the shape of at least a portion of the maximum cone, wherein the cone angle of the conical portion is within 10°

of the cone angle of the maximum cone.

64. The system of claim 63, the maximum cone having a cone angle θ

, wherein θ

is given by the formula θ

=2arcsin(NA/n), where “

NA”

is the numerical aperture of the optical device, and “

n”

is the index of refraction of the medium adjacent the optical device.

65. The system of claim 64, wherein the numerical aperture lies in a range from about 0.07 to about 0.5.

66. The system of claim 65, wherein the index of refraction lies in a range from about 1.0 to about 1.25.

67. The system of claim 63, the maximum cone having a cone angle θ

, the optical device having an objective lens and a focal plane, wherein θ

is the angle subtended at the focal plane by the objective lens.

68. The system of claim 63, the maximum cone having a cone angle θ

, the optical device having an optical axis, wherein θ

is twice the angle made by a marginal ray relative to the optical axis.

69. The system of claim 63, the conical portion having a cone axis, wherein the sample holder also includes a planar portion having an orientation substantially perpendicular to the cone axis.

70. The system of claim 69, the planar portion characterized by a planar portion diameter, the optical device having a confocal aperture characterized by an aperture diameter, wherein the planar portion diameter is approximately equal to the aperture diameter.

71. The system of claim 63, wherein the maximum cone is characterized by a cone angle equal to or greater than about 8°

.

72. A system for detecting light transmitted from a sample, the system comprising:

an optical device configured to detect light originating substantially exclusively within a maximum cone; and

a sample holder for supporting the sample that includes a conical portion having a shape that substantially conforms to the shape of at least a portion of the maximum cone;

wherein the maximum cone has a cone angle θ

; and

wherein θ

is given by the formula θ

=2arcsin(NA/n), where “

NA”

is the numerical aperture of the optical device, and “

n”

is the index of refraction of the medium adjacent the optical device.

73. The system of claim 72, wherein the numerical aperture lies in a range from about 0.07 to about 0.5.

74. The system of claim 73, wherein the index of refraction lies in a range from about 1.0 to about 1.25.

75. The system of claim 72, the maximum cone having a cone angle θ

, the optical device having an objective lens and a focal plane, wherein θ

is the angle subtended at the focal plane by the objective lens.

76. The system of claim 72, the maximum cone having a cone angle θ

, the optical device having an optical axis, wherein θ

is twice the angle made by a marginal ray relative to the optical axis.

77. The system of claim 72, the conical portion having a cone axis, wherein the sample holder also includes a planar portion having an orientation substantially perpendicular to the cone axis.

78. The system of claim 77, the planar portion characterized by a planar portion diameter, the optical device having a confocal aperture characterized by an aperture diameter, wherein the planar portion diameter is approximately equal to the aperture diameter.

79. The system of claim 72, wherein the maximum cone is characterized by a cone angle equal to or greater than about 8°

.

80. A system for detecting light transmitted from a sample, the system comprising:

an optical device configured to detect light originating substantially exclusively within a maximum cone, where the optical device has a confocal aperture characterized by an aperture diameter; and

a sample holder for supporting the sample that includes a conical portion and a planar portion, where the conical portion has a cone axis, and the planar portion is characterized by a planar portion diameter;

wherein the conical portion has a shape that substantially conforms to the shape of at least a portion of the maximum cone;

wherein the planar portion has an orientation substantially perpendicular to the cone axis; and

wherein the planar portion diameter is approximately equal to the aperture diameter.

81. The system of claim 80, the maximum cone having a cone angle θ

, the optical device having an objective lens and a focal plane, wherein θ

is the angle subtended at the focal plane by the objective lens.

82. The system of claim 80, the maximum cone having a cone angle θ

, the optical device having an optical axis, wherein θ

is twice the angle made by a marginal ray relative to the optical axis.

83. The system of claim 80, wherein the maximum cone is characterized by a cone angle equal to or greater than about 8°

.