Apparatus and method for dispensing fluid, semi-solid and solid samples

• US 20050136534A1
• Filed: 10/25/2004
• Published: 06/23/2005
• Est. Priority Date: 10/24/2003
• Status: Active Grant

• Current Assignee: Aushon BiosyStems, Inc. (Quanterix Corporation)
• Original Assignee: Aushon BiosyStems, Inc. (Quanterix Corporation)
• Inventors: Honkanen, Peter D., Austin, John
• Granted Patent: US 7,585,463 B2
• Time in Patent Office: Days
• US Class Current: 435/287.200
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00364 Pipettes
• CPC Class Codes: B01J 2219/00387 Applications using probes
• CPC Class Codes: B01J 2219/00533 essentially rectangular
• CPC Class Codes: B01J 2219/00567 Transponder chips
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01L 2200/025 Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/142 Preventing evaporation
• CPC Class Codes: B01L 2300/022 Transponder chips
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2300/0822 Slides
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 3/0244 using pins
• CPC Class Codes: B01L 9/52 Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
• CPC Class Codes: B01L 9/523 for multisample carriers, e.g. used for microtitration plates
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: C40B 70/00 Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• CPC Class Codes: G01N 2035/00158 Elements containing microarrays, i.e. "biochip"
• CPC Class Codes: G01N 2035/1037 Using surface tension, e.g. pins or wires
• CPC Class Codes: G01N 35/1009 Characterised by arrangements for controlling the aspiration or dispense of liquids
• CPC Class Codes: G01N 35/1011 : Control of the position or alignment of the transfer device
• CPC Class Codes: G01N 35/1074 : arranged in a two-dimensional array
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The invention relates generally to the field of automated collection and deposition of fluid, semi-solid, and solid samples of biological or chemical materials. More specifically, the invention relates to the field of microarrayers, which are devices for autonomously depositing minute droplets of biological or chemical fluid samples in ordered arrays onto substrates. The invention also relates to tissue arrayers, which are devices for the collection and deposition of solid and semi-solid tissue samples in ordered arrays. Other aspects of the invention relate to fluidics robots, which are devices for the autonomous collection, dispensing and processing of biological or chemical fluid samples. The invention improves the throughput of microarrayers, tissue arrayers, and fluidics robots by providing methods and apparatuses to precisely and repeatably load supplies into the machines.

Claims

1-49. -49. (canceled)

50. A microarrayer assembly for depositing minute droplets of fluid on a substrate comprising:

a deposit element for depositing minute droplets of fluid onto a surface of a substrate; and

a removable substrate-holder for holding at least one substrate, the substrate-holder comprising an apparatus for precisely and repeatably positioning the substrate-holder on a substrate-holder support.

51. The microarrayer assembly of claim 50 wherein the apparatus for precisely and repeatably positioning the substrate-holder on the substrate-holder support further comprises:

a first element for mating with a first datum disposed on the substrate-holder support, and for restricting movement of the removable substrate-holder along an x-axis and a mutually orthogonal y-axis and defining a first point in a z-axis, the z-axis mutually orthogonal to the x-axis and the y-axis;

a second element for mating with a second datum disposed on the substrate-holder support, and for at least partially locating the removable substrate-holder along at least one of the x-axis and the y-axis while defining a second point in the z-axis; and

a third element for mating with a third datum disposed on the substrate-holder support and defining a third point in the z-axis.

52. The microarrayer assembly of claim 51, wherein the first element forms a conical recess for mating with the first datum.

53. The microarrayer assembly of claim 51 wherein at least two of the elements are adjustable along the z-axis.

54. The microarrayer assembly of claim 50 wherein the substrate-holder support further comprises a datum plane defined by at least three datums:

a first datum for engaging the substrate-holder and for restricting movement of the substrate-holder along an x-axis and a mutually orthogonal y-axis, and defining a first point in a z-axis, the z-axis mutually orthogonal to the x-axis and the y-axis;

a second datum for engaging the substrate-holder and for at least partially locating the substrate-holder along at least one of the x-axis and the y-axis and defining a second point in the z-axis; and

a third datum for engaging the substrate-holder and defining a third point in the z-axis.

55. The microarrayer assembly of claim 54 wherein the first datum comprises at least a portion of a sphere for engaging a conical recess formed in the substrate-holder.

56. The microarrayer assembly of claim 54 wherein the second datum is engageable with a linear recess formed in the substrate-holder.

57. The microarrayer assembly of claim 50, further comprising a removable fluid-reservoir for holding at least one fluid, the removable fluid-reservoir comprising an apparatus for repeatably positioning the removable fluid-reservoir on a fluid-reservoir holder support.

58. The microarrayer assembly of claim 57 further comprising a removable fluid-reservoir holder for holding the removable fluid-reservoir, the fluid-reservoir holder comprising an apparatus for precisely and repeatably positioning the removable fluid-reservoir holder on the fluid-reservoir holder support.

59. The microarrayer assembly of claim 57 wherein the fluid-reservoir holder support moves in unison with the substrate-holder support.

60. The microarrayer assembly of claim 58 wherein the apparatus for repeatably positioning the removable fluid-reservoir holder on the fluid-reservoir holder support comprises:

a first element for mating with a first datum disposed on the fluid-reservoir holder support, and for restricting movement of the removable fluid-reservoir holder along an x-axis and a mutually orthogonal y-axis and defining a first point in a z-axis, the z-axis mutually orthogonal to the x-axis and the y-axis;

a second element for mating with a second datum disposed on the fluid-reservoir holder support, and for at least partially locating the removable fluid-reservoir holder along at least one of the x-axis and the y-axis while defining a second point in the z-axis; and

a third element for mating with a third datum disposed on the fluid-reservoir holder support and defining a third point in the z-axis.

61. The microarrayer assembly of claim 60 wherein the first element forms a conical recess for mating with the first datum.

62. The microarrayer assembly of claim 60 wherein at least two of elements are adjustable along the z-axis.

63. The microarrayer assembly of claim 57 wherein the fluid-reservoir holder support comprises:

a first datum for engaging the removable fluid-reservoir and for restricting movement of the removable fluid-reservoir along an x-axis and a mutually orthogonal y-axis, and defining a first point in a z-axis, the z-axis mutually orthogonal to the x-axis and the y-axis;

a second datum for engaging the removable fluid-reservoir and for at least partially locating the removable fluid-reservoir along at least one of the x-axis and the y-axis and defining a second point in the z-axis; and

a third datum for engaging the removable fluid-reservoir and defining a third point in the z-axis.

64. The microarrayer assembly of claim 63 wherein the first datum comprises at least a portion of a sphere for engaging a conical recess disposed on the removable fluid-reservoir.

65. The microarrayer assembly of claim 63 wherein the second datum is engageable with a linear recess disposed on the removable fluid-reservoir.

66. The microarrayer assembly of claim 50 wherein the deposit element comprises a solid pin.

67. The microarrayer assembly of claim 57, further comprising a fluid-reservoir storage and an apparatus for moving a fluid-reservoir between the fluid-reservoir storage and the fluid-reservoir holder support.

68. The microarrayer assembly of claim 67, further comprising a sensor to determine presence of a fluid-reservoir in a bay of the fluid-reservoir storage.

69. The microarrayer assembly of claim 50, further comprising a substrate-holder storage and an apparatus for moving a substrate-holder between the substrate-holder storage and the substrate-holder support.

70. The microarrayer assembly of claim 69, further comprising a sensor to determine presence of a substrate-holder in a bay of the substrate-holder storage.

71. The microarrayer assembly of claim 50 wherein the deposit element is constrained to move along a z-axis and wherein the substrate-holder is constrained to move in a plane substantially perpendicular to the z-axis when disposed beneath the deposit element.

72. The microarrayer assembly of claim 57 wherein the deposit element is constrained to move along a z-axis and wherein the fluid-reservoir is constrained to move in a plane substantially perpendicular to the z-axis when disposed beneath the deposit element.

73. The microarrayer assembly of claim 72 wherein the fluid-reservoir plane of motion is parallel to and displaced from the substrate-holder plane of motion when disposed beneath the deposit element.

74. The microarrayer assembly of claim 73 wherein the fluid-reservoir is moveable independently of but in coordination with the substrate-holder and the deposit element.

75. The microarrayer assembly of claim 57 wherein the removable fluid-reservoir is a multi-well plate having 96 wells or a multiple thereof.

76. The microarrayer assembly of claim 50 wherein the substrate comprises a multi-well plate.

77. The microarrayer assembly of claim 50, further comprising a first printhead and a second printhead, each printhead for holding at least one deposit element, wherein the first printhead and the second printhead are optionally arranged for moving independently of each other in separate parallel axes.

78. The microarrayer assembly of claim 50, wherein the removable substrate-holder comprises:

a top surface and a bottom surface spaced from the top surface;

an aperture extending at least partially between the top surface and the bottom surface, an intersection of the aperture and the top surface defining a perimeter; and

at least three reference points proximate the perimeter and defining a reference plane, the reference points for engaging a top surface of the substrate when the substrate is disposed in the aperture.

79. The microarrayer assembly of claim 78, further comprising means to bias the substrate against the at least three reference points.

80. The microarrayer assembly of claim 50 wherein the removable substrate-holder further comprises a removable substrate-mounting fixture, the substrate-mounting fixture including a locking element for securing the substrate-mounting fixture into the removable substrate-holder, the substrate-mounting fixture for holding at least one substrate.

81. The microarrayer assembly of claim 50, further comprising a sensor to measure a distance from the deposit element to a top surface of the substrate.

82. The microarrayer assembly of claim 81, further comprising a motion control system to dynamically adjust a motion of the deposit element in response to the sensor measurement to deposit the minute droplet of fluid onto the substrate without the deposit element contacting the substrate.

83. The microarrayer assembly of claim 58, further comprising a barcode reader for optically sensing labels secured to at least one of the substrate-holder, the substrate, the fluid-reservoir holder, and the fluid-reservoir.

84. The microarrayer assembly of claim 69 wherein the substrate-holders are moved from the substrate-holder storage to the substrate-holder support by the apparatus by:

moving the substrate-holder in a vertical direction within the substrate-holder storage to dispose the substrate-holder on the substrate holder support; and

moving the substrate-holder support in a horizontal direction to retract the substrate-holder support from the substrate-holder storage.

85. The microarrayer assembly of claim 69 wherein the removable substrate-holders are adapted for at least one of being removed from and added to the substrate-holder storage during active fluid capture and droplet deposition operations.

86. The microarrayer assembly of claim 58, wherein at least one of the substrate-holder and the fluid-reservoir holder further comprise a tracking device, the tracking device comprising at least one of:

a barcode;

a radio-frequency identification (RFID) transponder programmed with a unique code readable by an RFID interrogator by non-contact means; and

a semi-conductor memory device programmed with a unique code that is readable by at least one of an electric sensor and an external sensor that is in communication with the semi-conductor memory device through at least one of optical, infra-red, and radio-frequency communication.

87. The microarrayer assembly of claim 58 comprising a means for locally storing and updating information on at least one of the substrate, the substrate-holder, the fluid reservoir, and the fluid-reservoir holder, the means comprising at least one of:

a dynamically programmable radio-frequency identification (RFID) transponder mounted on at least one of the substrate, the substrate-holder, the fluid reservoir, and the fluid-reservoir holder, the transponder readable by an RFID interrogator by non-contact means; and

a dynamically programmable semi-conductor memory device mounted on at least one of the substrate, the substrate-holder, the fluid reservoir, and the fluid-reservoir holder, the semi-conductor memory device readable by at least one of electrical contact and an external sensor that is in communication with the semi-conductor memory device through at least one of optical, infra-red, and radio-frequency communication.

88. The microarrayer assembly of claim 50, wherein overall substrate-holder and substrate-holder support system position accuracy is within +0.002″

in a z-axis and within ±

0.01″

in x and y axes.

89. The microarrayer assembly of claim 50, wherein overall substrate-holder and substrate-holder support system position accuracy is within ±

0.001″

in a z-axis and within ±

±

0.005″

in x and y axes.

90. The microarrayer assembly of claim 50, wherein overall substrate-holder and substrate-holder support system position accuracy is within ±

0.0002″

in a z-axis and within ±

0.001″

in x and y axes.

91. A microarrayer assembly for depositing minute droplets of fluid on a substrate comprising:

a plurality of deposition engines operating cooperatively, each deposition engine comprising;

a deposit element for depositing minute droplets of fluid onto a surface of a substrate; and

a support for holding at least one of a substrate-holder and a fluid reservoir, the support comprising an apparatus for precisely and repeatably positioning at least one of the substrate-holder and the fluid reservoir on the support.

92-93. -93. (canceled)

94. A method for depositing minute droplets of fluid on a substrate comprising:

loading a substrate-holder onto a substrate-holder support, the substrate-holder for holding at least one substrate and comprising an apparatus for precisely and repeatably positioning the substrate-holder on the substrate-holder support;

providing fluid to a deposit element, the deposit element moveable relative to the substrate-holder; and

transferring a droplet of fluid from the deposit element to the substrate.

95-119. -119. (canceled)