Error detection in chemical array fabrication

• US 6,943,036 B2
• Filed: 04/30/2001
• Issued: 09/13/2005
• Est. Priority Date: 04/30/2001
• Status: Expired due to Fees

• Current Assignee: Agilent Technologies, Inc.
• Original Assignee: Agilent Technologies, Inc.
• Inventors: Bass, Jay K.
• Primary Examiner(s): Warden, Jill
• Assistant Examiner(s): Gordon, Brian R.
• Application Number:
  US09/846,474
• Publication Number:
  US 20020160370A1
• Time in Patent Office: 1,597 Days
• Field of Search: 436/180, 436/174, 436/164, 436/166, 422/100, 422/68.1, 422/82.05, 435/6, 435/7.1, 435/174
• US Class Current: 436/180
• 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) providing a substrate having multiple feature locations and multiple test locations;

(b) depositing a reagent drop set from a single dispenser onto each feature location so as to attach a corresponding moiety for each feature location, wherein said deposition of a reagent drop set is a cycle;

(c) repeating step (b) at each feature location until the addressable array is formed;

wherein for each feature location of said addressable array a multi-dispenser drop group is deposited thereon, wherein said multi-dispenser drop group is formed over two or more cycles of (b) and (c); and

wherein said drops deposited in said two or more cycles are deposited from at least two or more different dispensers;

the method additionally comprising;

(d) depositing individual reagent drops of a previously formed multi-dispenser drop group from said different dispensers at respective, separate test locations on the substrate;

wherein each of said separate test locations does not include a previously deposited drop; and

(e) detecting said individual reagent drops at said respective test locations.

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

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

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

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

6. The method according to claim 2 wherein in step (e) the drops are detected on the separate test locations on the substrate.

7. The method according to claim 1, wherein step (e) additionally comprises capturing an image of drops deposited during step (d).

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

10. The method according to claim 6 additionally comprising evaluating results from the detecting based at least in part on at least one multi-dispenser group for which the results were obtained.

11. The method according to claim 10 wherein results from detecting multiple dispenser groups are obtained and the evaluation is based at least in part on the dispenser groups for which the results were obtained.

12. The method according to claim 2, wherein steps (d) and (e) are performed between two cycles and afterwards adjusting a parameter of the dispensing in step (b) or (c) based at least in part on the results from step (e).

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

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

15. The method according to claim 1 wherein during step (b) or (c) 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 feature location.

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

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

18. The 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 feature locations in step (b) or (c), and wherein the drops deposited in step (d) and detected in step (e) are deposited in a test pattern area of said substrate separate from the array.

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

(a) providing a substrate having multiple feature locations and multiple test locations, where said multiple test locations are present in a test pattern area separate from the multiple feature locations;

(b) depositing a reagent drop set from a single dispenser onto each feature location so as to attach a corresponding moiety for each feature location, wherein said deposition of a reagent drop set is a cycle;

(c) repeating step (b) at each feature location until the addressable array is formed;

wherein for each feature location of said addressable array a multi-dispenser drop group is deposited thereon, wherein said multi-dispenser drop group is formed over two or more cycles of (b) and (c); and

wherein said drops deposited in said two or more cycles are deposited from at least two or more different dispensers;

the method additionally comprising;

(d) depositing individual reagent drops of a previously formed multi-dispenser drop group from said different dispensers at respective, separate test locations on the substrate;

wherein each of said separate test locations does not include a previously deposited drop; and

(e) detecting said individual reagent drops at said respective test locations.

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

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

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

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

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

(a) providing a substrate having multiple feature locations and multiple test locations;

(b) depositing a reagent drop set from a single dispenser onto each feature location so as to attach a monomeric unit of the corresponding polymer for each feature location, wherein said deposition of a reagent drop set is a cycle;

(c) repeating step (b) at each feature location until the addressable array is formed;

wherein for each feature location of said addressable array a multi-dispenser drop group is deposited thereon, wherein said multi-dispenser drop group is formed over two or more cycles of (b) and (c); and

wherein said drops deposited in said two or more cycles are deposited from at least two or more different dispensers;

the method additionally comprising;

(d) depositing individual reagent drops of a previously formed multi-dispenser drop group from said different dispensers at respective, separate test locations on the substrate;

wherein each of said separate test locations does not include a previously deposited drop; and

(e) detecting said individual reagent drops at said respective test locations.

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

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

28. The 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 feature location upon activation by an activator moiety, and at least one other drop comprises the activator moiety, such that the monomeric unit and activator moiety are deposited at separate test locations in step (d).

29. The method according to claim 25 wherein steps (d) and (e) are performed between two cycles.

30. The method according to claim 25 wherein steps (d) and (e) are performed between two cycles, and performed again between another two cycles.

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

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

33. The method according to claim 25, wherein step (e) additionally comprises capturing an image of drops deposited during step (d).

34. The method according to claim 28 wherein step (d) and e are 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 moiety so as to correct the error.

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

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

37. The method according to claim 25 wherein different multi-dispenser drop groups are deposited at respective substrate feature locations in step (b) or (c), and wherein the drops deposited in step (d) and detected in step (e) 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) providing a substrate having multiple feature locations and multiple test locations;

(b) depositing a reagent drop set from a single dispenser onto each feature location so as to attach a monomeric unit of the corresponding polymer for each feature location, wherein said deposition of a reagent drop set is a cycle;

(c) repeating step (b) at each feature location until the addressable array is formed;

wherein for each feature location of said addressable array a multi-dispenser drop group is deposited thereon, wherein said multi-dispenser drop group is formed over two or more cycles of (b) and (c); and

wherein said drops deposited in said two or more cycles are deposited from at least two or more different dispensers;

the method additionally comprising;

(d) depositing individual reagent drops of a previously formed multi-dispenser drop group from said different dispensers at respective, separate test locations on the substrate;

wherein each of said separate test locations does not include a previously deposited drop and wherein the drops are deposited at a separate test pattern area between arrays with the number of test locations of the test pattern area being less than one tenth the number of feature locations in the smallest of the arrays which the test pattern area is between; and

(e) detecting said individual reagent drops at said respective test locations.

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