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

• US 7,585,463 B2
• Filed: 10/25/2004
• Issued: 09/08/2009
• 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
• Primary Examiner(s): Gordon; Brian R.
• Application Number:
  US10/972,792
• Publication Number:
  US 20050136534A1
• Time in Patent Office: 1,779 Days
• Field of Search: 422/100, 422 63- 67, 422/68.1, 436/180
• US Class Current: 422/63
• 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. 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;

a substrate holder support; and

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

2. The microarrayer assembly of claim 1 wherein the first datum comprises at least a portion of a sphere for engaging a conical recess formed in the substrate-holder.

3. The microarrayer assembly of claim 1 wherein the second datum is engageable with a linear recess formed in the substrate-holder.

4. The microarrayer assembly of claim 1, further comprising:

a removable fluid-reservoir for holding at least one fluid; and

a fluid reservoir holder support, the removable fluid-reservoir comprising an apparatus for repeatably positioning the removable fluid-reservoir on the fluid-reservoir support.

5. The microarrayer assembly of claim 1 further comprising:

a removable fluid-reservoir holder for holding a removable fluid-reservoir; and

a fluid-reservoir holder support, the fluid-reservoir holder comprising an apparatus for precisely and repeatably positioning the removable fluid-reservoir holder on the fluid-reservoir holder support.

6. The microarrayer assembly of claim 4, further comprising:

a fluid-reservoir holder support motion stage for moving the fluid-reservoir holder support; and

a substrate holder support motion stage for moving the substrate holder support, wherein the fluid-reservoir holder support motion stage and the substrate holder support motion stage are adapted for movement in at least one dimension, wherein the fluid-reservoir holder support motion stage moves in unison with the substrate-holder support motion stage.

7. The microarrayer assembly of claim 1 wherein the deposit element comprises a solid pin.

8. The microarrayer assembly of claim 4, further comprising a fluid-reservoir storage and an apparatus for moving the removable fluid-reservoir between the fluid-reservoir storage and the fluid-reservoir support.

9. The microarrayer assembly of claim 8, further comprising a sensor to determine presence of a fluid-reservoir in a bay of the fluid-reservoir storage.

10. The microarrayer assembly of claim 1, further comprising a substrate-holder storage and an apparatus for moving the removable substrate-holder between the substrate-holder storage and the substrate-holder support.

11. The microarrayer assembly of claim 10, further comprising a sensor to determine presence of a substrate-holder in a bay of the substrate-holder storage.

12. The microarrayer assembly of claim 1 further comprising:

a deposit element motion stage for moving the deposit element, wherein the deposit element is constrained to move along a z-axis during a deposition procedure; and

a substrate-holder support motion stage for moving the substrate-holder support, wherein the substrate-holder support is constrained to move in a plane substantially perpendicular to the z-axis during a deposition procedure.

13. The microarrayer assembly of claim 4 further comprising:

a deposit element motion stage for moving the deposit element, wherein the deposit element is constrained to move along a z-axis during a deposition procedure; and

a fluid-reservoir support motion stage for moving the fluid-reservoir support, wherein the fluid-reservoir support is constrained to move in a plane substantially perpendicular to the z-axis during a deposition procedure.

14. The microarrayer assembly of claim 13, further comprising a substrate-holder support motion stage for moving the substrate-holder support, wherein a fluid-reservoir support plane of motion is parallel to and displaced from a substrate-holder support plane of motion during a deposition procedure.

15. The microarrayer assembly of claim 14 wherein the fluid-reservoir support motion stage is moveable independently of but in coordination with the substrate-holder motion stage and the deposit element motion stage.

16. The microarrayer assembly of claim 4 wherein the removable fluid-reservoir is a multi-well plate having 96 wells or a multiple thereof.

17. The microarrayer assembly of claim 1, further comprising a substrate, wherein the substrate comprises a multi-well plate.

18. The microarrayer assembly of claim 1, further comprising:

a first deposit element, wherein the deposit element comprises the first deposit element;

a second deposit element;

a first printhead for holding the first deposit element; and

a second printhead for holding the second deposit element, each printhead for holding at least one deposit element.

19. The microarrayer assembly of claim 1, 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 surfaces proximate the perimeter and extending from the perimeter and defining a reference plane, the reference surfaces adapted to engage a top surface of the substrate when the substrate is disposed in the aperture.

20. The microarrayer assembly of claim 19, further comprising means to bias the substrate against the at least three reference surfaces.

21. The microarrayer assembly of claim 1, further comprising a sensor to measure a distance from the deposit element to a top surface of the substrate.

22. The microarrayer assembly of claim 21, 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.

23. The microarrayer assembly of claim 5, further comprising:

a fluid reservoir;

a barcode reader; and

a barcode reader-readable label secured to at least one of the fluid-reservoir holder and the fluid-reservoir.

24. The microarrayer assembly of claim 10 wherein the apparatus is adapted to:

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

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

25. The microarrayer assembly of claim 10 wherein the removable substrate-holder is adapted for at least one of being removed from and added to the substrate-holder storage during active fluid capture and droplet deposition operations.

26. The microarrayer assembly of claim 4, wherein the fluid-reservoir comprises 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.

27. The microarrayer assembly of claim 5 comprising a means for locally storing and updating information on at least one of 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 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.

28. The microarrayer assembly of claim 1, wherein the means for precisely and repeatably positioning the removable substrate-holder on the substrate-holder support system exhibits a position accuracy within ±

0.002″

in a z-axis and within ±

0.01″

in x and y axes.

29. The microarrayer assembly of claim 1, wherein the means for precisely and repeatably positioning the removable substrate-holder on the substrate-holder support system exhibits a position accuracy within ±

0.001″

in a z-axis and within ±

0.005″

in x and y axes.

30. The microarrayer assembly of claim 1, wherein the means for precisely and repeatably positioning the removable substrate-holder on the substrate-holder support system exhibits a position accuracy within ±

0.002″

in a z-axis and within ±

0.01″

in x and y axes.

31. The microarrayer assembly of claim 1, further comprising:

a substrate positioned on the removable substrate-holder;

a barcode reader; and

a barcode reader-readable label secured to at least one of the removable substrate-holder and the substrate.

32. The microarrayer assembly of claim 1, further comprising:

a substrate positioned on the removable substrate-holder, wherein the substrate comprises 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.

33. The microarrayer assembly of claim 1 comprising a means for locally storing and updating information on at least one of the substrate and the substrate-holder, the means comprising at least one of:

a dynamically programmable radio-frequency identification (RFID) transponder mounted on at least one of the substrate and the substrate-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 and the substrate-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.

34. The microarrayer assembly of claim 1 wherein the substrate-holder support further comprises means for restraining the substrate-holder against the substrate holder support.

35. The microarrayer assembly of claim 34 wherein the means for restraining is selected from the group consisting of a magnet, an electromagnet, an electrostatic device, a vacuum device, and a mechanical device.

36. The microarrayer assembly of claim 1, further comprising a second deposit element and an apparatus for moving the deposit element and the second deposit element cooperatively.

37. The microarrayer assembly of claim 36, wherein the deposit element comprises a first printhead and the second deposit element comprises a second printhead.

38. The microarrayer assembly of claim 37, wherein the first printhead moves independently from the second printhead.

39. 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;

a substrate holder support comprising a first datum, a second datum, and a third datum; 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 the substrate-holder support, wherein the apparatus for precisely and repeatably positioning the substrate-holder on the substrate-holder support comprises;

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

40. The microarrayer assembly of claim 39, wherein the first element forms a conical recess for mating with the first datum.

41. The microarrayer assembly of claim 39 wherein at least two of the first element, the second element, and the third element are adjustable along the z-axis.

42. 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;

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;

a fluid reservoir holder support comprising a first datum, a second datum, and a third datum; and

a removable fluid-reservoir holder for holding a 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, wherein the apparatus for repeatably positioning the removable fluid-reservoir holder on the fluid-reservoir holder support comprises;

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

43. The microarrayer assembly of claim 42 wherein the first element forms a conical recess for mating with the first datum.

44. The microarrayer assembly of claim 42 wherein at least two of the first element, the second element, and the third element are adjustable along the z-axis.

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

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

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;

a fluid reservoir support; and

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 the fluid-reservoir support, wherein the fluid-reservoir 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.

46. The microarrayer assembly of claim 45 wherein the first datum comprises at least a portion of a sphere for engaging a conical recess disposed on the removable fluid-reservoir.

47. The microarrayer assembly of claim 45 wherein the second datum is engageable with a linear recess disposed on the removable fluid-reservoir.

48. 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;

a substrate holder support; 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 the substrate-holder support, 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.

49. 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;

a substrate-holder; and

a support for holding the substrate-holder, the support comprising a means for precisely and repeatably positioning the substrate-holder on the support, wherein the means for precisely and repeatably positioning the substrate holder on the support comprises;

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.

50. The microarrayer assembly of claim 49, further comprising a substrate positioned on the substrate-holder and a substrate conveyor for moving the substrate-holder from a first deposition engine to a second deposition engine.

51. The microarrayer assembly of claim 49, further comprising a fluid reservoir positioned on the fluid reservoir-holder and a fluid reservoir conveyor for moving the fluid reservoir-holder from a first deposition engine to a second deposition engine.

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

providing a deposit element;

providing a substrate;

providing a substrate-holder;

providing a substrate holder support;

loading the substrate on the substrate holder;

loading the substrate-holder onto the substrate-holder support, the substrate-holder comprising a means for precisely and repeatably positioning the substrate-holder on the substrate-holder support, wherein the means for precisely and repeatably positioning the substrate holder on the support comprises;

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;

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

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

53. 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;

a substrate-holder support; and

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

54. 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;

a removable substrate-holder for holding at least one substrate; and

a substrate conveyor for moving the removable substrate-holder from a first deposition engine to a second deposition engine, the substrate-holder comprising a means for precisely and repeatably positioning the substrate-holder on the substrate conveyor, wherein the means for precisely and repeatably positioning the substrate holder on the substrate conveyor comprises;

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 v-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 further comprising a fluid reservoir-holder and a fluid reservoir conveyor for moving the fluid reservoir-holder from a first deposition engine to a second deposition engine.

56. The microarrayer assembly of claim 54, wherein at least one of the deposition engines further comprises an ink-jet deposition device.

57. The microarrayer assembly of claim 54, wherein at least one of the deposition engines further comprises a solid pin deposition device.

58. The microarrayer assembly of claim 54, wherein at least one of the deposition engines further comprises a quill pin deposition device.

59. 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;

a fluid-reservoir holder support; and

a fluid-reservoir holder comprising a means for precisely and repeatably positioning the fluid-reservoir holder on the fluid-reservoir holder support, wherein the means for precisely and repeatedly positioning the fluid-reservoir holder on the fluid-reservoir holder support comprises;

a first raised edge disposed on the fluid-reservoir holder support;

a first spring clip disposed on the fluid-reservoir holder support for biasing the fluid-reservoir holder against the first raised edge and for restricting the movement of the fluid-reservoir holder along an x-axis;

a second raised edge disposed on the fluid-reservoir holder support and perpendicular to the first raised edge; and

a second spring clip disposed on the fluid-reservoir holder support for biasing the fluid-reservoir holder against the second raised edge and for restricting the movement of the fluid-reservoir holder along a y-axis orthogonal to the x-axis.

60. The microarrayer assembly of claim 59, wherein the means for precisely and repeatably positioning the fluid-reservoir holder on the fluid-reservoir holder support comprises:

a datum for engaging the fluid-reservoir holder and for restricting movement of the fluid reservoir holder relative to the fluid-reservoir holder support.

61. The microarrayer assembly of claim 60, wherein the means for precisely and repeatably positioning further comprises a magnet to bias the fluid-reservoir holder relative to the fluid-reservoir holder support.

62. 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;

a substrate holder support; and

a removable substrate-holder for holding at least one substrate, the substrate-holder comprising a means for precisely and repeatably positioning the substrate-holder on the substrate-holder support, wherein the means for precisely and repeatedly positioning the substrate-holder on the substrate-holder support 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 a first axis while defining a first point on the z-axis, wherein the first axis defines at least one of an x-axis and a y-axis;

a second element for mating with a second datum disposed on the substrate-holder support, and for restricting movement of the removable substrate-holder along the first axis while defining a second point on the z-axis; and

a third element for mating with a third datum disposed on the substrate-holder support, and for restricting movement of the removable substrate-holder along the second axis while defining a third point on the z-axis, wherein the second axis is orthogonal to the first axis.

63. The microarrayer assembly of claim 62, wherein the means for precisely and repeatedly positioning the substrate-holder on the substrate-holder support further comprises a fourth element for mating with a fourth datum disposed on the substrate-holder support, and for restricting movement of the removable substrate-holder along the second axis while defining a fourth point on the z-axis.

64. The microarrayer assembly of claim 62, wherein each of the first element, the second element, the third element, and the fourth element comprises a linear groove disposed on the substrate-holder.

65. 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;

a substrate holder support; and

a removable substrate-holder for holding at least one substrate, the substrate-holder comprising a means for precisely and repeatably positioning the substrate-holder on the substrate-holder support, wherein the means for precisely and repeatedly positioning the substrate-holder on the substrate-holder support comprises;

a first groove disposed on the substrate-holder, the first groove comprising an axis;

a first datum disposed on the substrate-holder support, wherein the first datum is adapted for mating with the first groove and for restricting movement of the substrate-holder along an x-axis;

a surface disposed on the substrate-holder support, wherein the surface is orthogonal to the axis of the first groove and the surface restricts movement of the substrate-holder along a y-axis orthogonal to the x-axis; and

a biasing means to urge the substrate-holder against the surface.

66. The microarrayer assembly of claim 65, wherein the biasing means comprises a spring.

67. 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;

a substrate holder support; and

a removable substrate-holder for holding at least one substrate, the substrate-holder comprising a means for precisely and repeatably positioning the substrate-holder on the substrate-holder support, wherein the means for precisely and repeatedly positioning the substrate-holder on the substrate-holder support comprises;

a flat bottom surface disposed on the substrate-holder;

a flat upper surface disposed on the substrate-holder support for engaging the planar bottom surface of the substrate-holder and for defining a position on a z-axis;

a first surface disposed on the substrate-holder support and orthogonal to the planar upper surface, wherein the first surface restricts movement of the substrate-holder along an x-axis orthogonal to the z-axis; and

a second surface disposed on the substrate-holder and orthogonal to both the planar upper surface and the first surface, wherein the second surface restricts movement of the substrate-holder along a y-axis mutually orthogonal to the x-axis and the z-axis.

68. The microarrayer assembly of claim 67, wherein the means for precisely and repeatedly positioning the substrate-holder on the substrate-holder support further comprises a biasing means to urge the substrate-holder against the first surface and the second surface.