Error detection in chemical array fabrication

• US 20050287586A1
• Filed: 08/11/2005
• Published: 12/29/2005
• Est. Priority Date: 04/30/2001
• Status: Abandoned Application

• Current Assignee: Jay K. Bass
• Original Assignee: Jay K. Bass
• Inventors: Bass, Jay K.
• Application Number:
  US11/202,564
• Publication Number:
  US 20050287586A1
• Time in Patent Office: Days
• US Class Current: 435/6.11
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00378 Piezoelectric or ink jet dispensers
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00529 DNA chips
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00693 Means for quality control
• CPC Class Codes: B01J 2219/00695 Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: C40B 40/06 Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: Y10T 436/25 including sample preparation
• CPC Class Codes: Y10T 436/2575 Volumetric liquid transfer

Abstract

A method, apparatus, and computer program product, for forming an addressable array of chemical moieties on a substrate. The method may include, for each of multiple locations on the substrate, depositing a reagent drop set during a cycle so as to attach a corresponding moiety for that location. This may be repeated as required, until the addressable array is formed. Test location are also formed by depositing drops from dispensers in a manner which can facilitate detection of dispenser errors.

Claims

1. A method of forming an addressable array of chemical moieties on a substrate, comprising:

(a) for each of multiple locations on the substrate, depositing a reagent drop set during a cycle so as to attach a corresponding moiety for that location; and

(b) repeating step (a) if required, until the addressable array is formed;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers;

the method additionally comprising;

(c) depositing and detecting drops at respective separate locations on the substrate from different dispensers which deposit a multi-dispenser drop group.

2. A method according to claim 1 wherein drops of the multi-dispenser drop group in step (c) are not independently detected at the corresponding location in step (b).

3. A method according to claim 1 wherein a multi-dispenser drop group comprises a drop including an attachment moiety which becomes attached at the location at which the group is deposited in step (a) or (b) but which does not become attached at a location in step (c).

4. A method according to claim 1 wherein a multi-dispenser drop group comprises a drop including an attachment moiety which will become attached at the location at which the group is deposited upon activation by an activator, and at least one other drop comprises the activator moiety, such that the attachment moiety and activator are deposited at separate locations in step (c).

5. A method according to claim 1 wherein drops are deposited and detected at respective separate locations on the substrate from all those dispensers which deposit a multi-dispenser drop group.

6. A method according to claim 2 wherein in step (c) the drops are detected on the substrate.

7. A method according to claim 1 additionally comprising capturing an image of drops deposited during step (c).

8. A method according to claim 6 additionally comprising evaluating results from the detecting for an indication of a dispenser error and, when an error is detected, discarding the array or depositing further drops to correct the error.

9. A method according to claim 6 additionally comprising saving results from the detecting in a memory.

10. A method according to claim 6 additionally comprising evaluating results from the detecting based at least in part on a cycle during which the results were obtained.

11. A method according to claim 10 wherein results from detecting during multiple cycles are obtained and the evaluation is based at least in part on the cycles during which the results were obtained.

12. A method according to claim 2 additionally comprising adjusting a parameter of the dispensing in step (a) based at least in part on the results from step (c).

13. A method according to claim 1 wherein in step (c) replicates of a same drop from a same dispenser are deposited at multiple different locations on the substrate, the method additionally comprising evaluating a characteristic of the substrate based on the results of detecting the replicates.

14. A method according to claim 1 additionally comprising evaluating dispenser performance based on relative characteristics of drops of different composition deposited from different dispensers.

15. A method according to claim 1 wherein during step (a) or (b) drops of multi-dispenser drop groups are deposited at respective substrate locations such that one drop of the group contacts a previously deposited drop of the same group at the same location.

16. A method according to claim 2 wherein different multi-dispenser drop groups have at least one drop deposited by a same dispenser and another drop deposited by a different dispenser.

17. A method according to claim 2 wherein the at least some of the drops of a multi-dispenser drop set are of a different composition.

18. A method according to claim 2 wherein at least one of the drops of different multi-dispenser drop groups are deposited from a same dispenser.

19. A method according to claim 1 wherein different multi-dispenser drop groups are deposited at respective substrate locations in step (a) or (b), and wherein the drops deposited and detected in step (c) are deposited in a test pattern area separate from the array.

20. A method of forming an addressable array of chemical moieties on a substrate, comprising:

(a) for each of multiple locations on the substrate, depositing a reagent drop set during a cycle so as to attach a corresponding moiety for that location; and

(b) repeating step (a) if required;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers;

the method additionally comprising;

(c) depositing and detecting drops from different dispensers which deposit a multi-dispenser drop group, onto the substrate at respective separate locations in a test pattern area separate from the array.

21. A method according to claim 20 wherein a multi-dispenser drop group comprises a drop including an attachment moiety which becomes attached at the location at which the group is deposited in step (a) or (b) but which does not become attached at a location in step (c).

22. A method according to claim 20 wherein a multi-dispenser drop group comprises a drop containing an attachment moiety which will become attached at that location upon activation by an activator, and at least one other drop containing the activator moiety, such that the attachment moiety and activator are deposited at separate locations in step (c).

23. A method according to claim 22 wherein in step (c) no activator containing drop is deposited at a same location as an attachment moiety containing drop.

24. A method according to claim 22 wherein different multi-dispenser drop groups are deposited at respective substrate locations in step (a) or (b), and wherein drops from dispensers which deposit different multi-dispenser drop groups are deposited and detected in step (c) in a test pattern area separate from the array.

25. A method of forming an addressable array of polymers on a substrate, comprising:

(a) for each of multiple locations on the substrate, depositing a reagent drop set during a cycle so as to attach a monomeric unit of the corresponding polymer for that location; and

(b) repeating step (a), until the addressable array is formed;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers;

the method additionally comprising;

(c) depositing and detecting drops at respective separate locations on the substrate from different dispensers which deposit a multi-dispenser drop group.

26. A method according to claim 25 wherein a multi-dispenser drop group comprises a drop including an attachment moiety which becomes attached at the location at which the group is deposited in step (a) or (b) but which does not become attached at a location in step (c).

27. A method according to claim 25 wherein the polymers are biopolymers.

28. A method according to claim 27 wherein a multi-dispenser drop group deposited during a cycle comprises a drop including the monomeric unit which will become attached at that location upon activation by an activator, and at least one other drop comprises the activator moiety, such that the monomeric unit and activator are deposited at separate locations in step (c).

29. A method according to claim 25 wherein step (c) is performed between two cycles.

30. A method according to claim 25 wherein step (c) is performed between two cycles, and performed again between another two cycles.

31. A method according to claim 25 wherein drops are deposited and detected at respective separate locations on the substrate from all those dispensers which deposit a multi-dispenser drop group.

32. A method according to claim 25 wherein in step (c) the drops are detected on the substrate.

33. A method according to claim 25 additionally comprising capturing an image of drops deposited during step (c).

34. A method according to claim 28 wherein step (c) is performed between two cycles, the method additionally comprising when an error in a monomeric unit or activator drop dispenser is detected then depositing further drops containing the monomeric unit or activator so as to correct the error.

35. A method according to claim 26 wherein during step (a) or (b) drops of multi-dispenser drop groups are deposited at respective substrate locations such that one drop of the group contacts a previously deposited drop of the same group at the same location.

36. A method according to claim 28 wherein the activator containing drop for multiple locations is deposited from a same dispenser.

37. A method according to claim 25 wherein different multi-dispenser drop groups are deposited at respective substrate locations in step (a) or (b), and wherein the drops deposited and detected in step (c) are deposited in a test pattern area separate from the array.

38. A method of forming multiple addressable arrays of chemical moieties on a substrate, comprising for each array:

(a) for each of multiple locations on the substrate, depositing a reagent drop set during a cycle so as to attach a corresponding moiety for that location; and

(b) repeating step (a) if required, until the addressable array is formed;

wherein multiple dispensers are used to dispense drops to form the array, the method additionally comprising;

(c) depositing and detecting drops from the different dispensers at respective separate locations on the substrate, wherein the drops are deposited at a separate test pattern area between arrays with the number of locations of the test pattern area during any one cycle being less than one tenth the number of locations in the smallest of the arrays which the test pattern area is between.

39. A method according to claim 38 wherein the number of locations of the test pattern area during any one cycle is not greater than ten times the number of the dispensers used to form an array during any one cycle.

40. An apparatus for forming an addressable array on a substrate, comprising:

(a) a deposition system having multiple dispensers each of which can dispense a reagent drop;

(b) a transport system to move at least one of the deposition system or the substrate;

(c) a drop detector;

(d) a processor which controls the deposition system and the transport system such that;

(i) for each of multiple locations on the substrate, a reagent drop set is deposited during a cycle so as to attach a corresponding moiety for that location; and

(ii) step (i) will be repeated if required, until the addressable array is formed;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers and which drops are not independently detected at the corresponding location;

and such that;

(iii) drops from different dispensers which deposit a multi-dispenser drop group will be deposited and detected by the detector at respective separate locations on the substrate.

41. An apparatus according to claim 40 wherein different multi-dispenser drop groups are deposited at respective substrate locations in step (i) or (ii), and wherein the drops deposited and detected in step (iii) are deposited in a test pattern area separate from the array.

42. An apparatus according to claim 40 wherein drops are deposited and detected at respective separate locations on the substrate from all those dispensers which deposit a multi-dispenser drop group.

43. A method according to claim 40 wherein the detector detects drops on the substrate.

44. A method according to claim 40 wherein the detector captures an image of deposited drops.

45. A method according to claim 40 wherein at least one of the drops of different multi-dispenser drop groups are deposited from a same dispenser.

46. An apparatus for forming an addressable array on a substrate, comprising:

(a) a deposition system having multiple dispensers each of which can dispense a reagent drop;

(b) a transport system to move at least one of the deposition system or the substrate;

(c) a drop detector;

(d) a processor which controls the deposition system and the transport system such that;

(i) for each of multiple locations on the substrate, a reagent drop set is deposited during a cycle so as to attach a corresponding moiety for that location; and

(ii) step (i) will be repeated if required, until the addressable array is formed;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers and which drops are not independently detected at the corresponding location;

and such that;

(iii) drops from different dispensers which deposit a multi-dispenser drop group will be deposited and detected by the detector at respective separate locations on the substrate in a test pattern area separate from the array.

47. An apparatus according to claim 46 wherein different multi-dispenser drop groups are deposited at respective substrate locations in step (i) or (ii), and wherein drops from dispensers which deposit different multi-dispenser drop groups are deposited and detected in step (iii) in a test pattern area separate from the array.

48. An apparatus for forming an addressable array on a substrate, comprising:

(a) a deposition system having multiple dispensers each of which can dispense a reagent drop;

(b) a transport system to move at least one of the deposition system or the substrate;

(c) a drop detector;

(d) a processor which controls the deposition system and the transport system such that;

(i) for each of multiple locations on the substrate, a reagent drop set is deposited during a cycle so as to attach a corresponding moiety for that location; and

(ii) repeating step (i) until the addressable array is formed;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers;

and such that;

(iii) drops from different dispensers which deposit a multi-dispenser drop group will be deposited and detected by the detector at respective separate locations on the substrate.

49. An apparatus according to claim 48 wherein the multi-dispenser drop group is deposited during a cycle.

50. A apparatus according to claim 49 wherein step (i) is performed between two cycles.

51. A apparatus according to claim 49 wherein step (i) is performed between two cycles, and performed again between another two cycles.

52. A apparatus according to claim 49 wherein drops are deposited and detected at respective separate locations on the substrate from all those dispensers which deposit a multi-dispenser drop group.

53. A apparatus according to claim 49 wherein during step (i) or (ii) drops of multi-dispenser drop groups are deposited at respective substrate locations such that one drop of the group contacts a previously deposited drop of the same group at the same location.

54. A computer program product, comprising:

a computer readable storage medium having a computer program stored thereon which, when loaded into a computer communicating with an apparatus for forming an addressable array on a substrate, performs the steps of;

(a) for each of multiple locations on the substrate, depositing a reagent drop set during a cycle so as to attach a corresponding moiety for that location; and

(b) repeating step (a) if required, until the addressable array is formed;

wherein, for each of multiple locations, a multi-dispenser drop group is deposited over one or more cycles for a corresponding location which group includes drops which are deposited from different dispensers and which drops are not independently detected at the corresponding location;

the steps additionally including;

(c) depositing and detecting drops at respective separate locations on the substrate from different dispensers which deposit a multi-dispenser drop group.

55. A computer program product according to claim 54, wherein different multi-dispenser drop groups are deposited at respective substrate locations in step (a) or (b), and wherein the drops deposited and detected in step (c) are deposited in a test pattern area separate from the array.

56. A computer program product according to claim 55 wherein step (c) is performed between two cycles.

57. A computer program product according to claim 55 wherein a multi-dispenser drop group comprises a drop including an attachment moiety which will become attached at that location upon activation by an activator, and at least one other drop comprises the activator moiety, such that the attachment moiety and activator are deposited at separate locations in step (c).

58. A computer program product according to claim 57 wherein in step (c) no activator containing drop is deposited at a same location as an attachment moiety containing drop.