Synthesis of arrays of oligonucleotides and other chain molecules

• US 7,722,824 B2
• Filed: 08/01/2006
• Issued: 05/25/2010
• Est. Priority Date: 08/02/2005
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Golovkina, Viktoriya N., Cerrina, Franco
• Primary Examiner(s): Griffin; Walter D
• Assistant Examiner(s): Ramdhanie; Bobby
• Application Number:
  US11/497,544
• Publication Number:
  US 20070183943A1
• Time in Patent Office: 1,393 Days
• Field of Search: 422/130
• US Class Current: 422/130
• 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 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/00434 Liquid crystal masks
• CPC Class Codes: B01J 2219/00439 using micromirror arrays
• CPC Class Codes: B01J 2219/00441 using lasers
• CPC Class Codes: B01J 2219/0045 using optical fibres
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: G02B 17/0663 off-axis or unobscured systems in which not all of the mirrors share a common axis of rotational symmetry, e.g. at least one of the mirrors is warped, tilted or decentered with respect to the other elements
• CPC Class Codes: G02B 26/0833 the reflecting element being a micromechanical device, e.g. a MEMS mirror, DMD G02B26/0825 takes precedence; micromechanical devices in general B81B

Abstract

Synthesis of arrays of chain molecules, such as oligonucleotides, in large quantities can be carried out utilizing projection onto an active substrate of a magnified image of a light emitting object array having selectable regions of light and dark areas forming a pattern. Projection optics formed entirely of mirrors are used to receive the light emitted from the object array and image the pattern of the array onto the active surface of the substrate. The mirrors in the projection optics include a first, concave mirror, a second, convex mirror, a third, concave mirror, and a fourth, convex mirror, each receiving the beam of light in turn, with the light reflected from the fourth mirror being imaged onto the active surface of the substrate with an image area greater than that of the original light emitting array.

Claims

1. Apparatus for synthesis of arrays of chain molecules comprising:

(a) a substrate with an active surface on which the arrays may be formed;

(b) a light emitting object array configured to emit a pattern of light and dark areas; and

(c) projection optics configured to receive the light emitted from the light emitting object array and to image the pattern of light and dark areas onto the active surface of the substrate, the projection optics comprising a first, concave mirror configured to receive the light from the object array and to reflect that light at an angle off the axis of the light received from the object array, a second, convex mirror configured to receive the light reflected from the first mirror and to reflect the light off the axis of the light received from the first mirror, a third, concave mirror configured to receive the light reflected from the second mirror and to reflect the light off the axis of the light received from the second mirror, and a fourth, convex mirror configured to receive the light from the third mirror and to reflect the light off the axis of the light received from the third mirror and to image the light onto the active surface, the first, second, third and fourth mirrors arranged to form a magnified image of the pattern of light and dark areas at the active surface.

2. The apparatus of claim 1 further including a flow cell enclosing the active surface of the substrate and having ports for applying DNA synthesis reagents into the flow cell which can be flowed over the active surface of the substrate.

3. The apparatus of claim 1 wherein the first, second, third, and fourth mirrors are arranged to provide two times magnification of the image of the pattern of light and dark areas at the active surface.

4. The apparatus of claim 1 wherein the first, second, third, and fourth mirrors are each spherical mirrors.

5. The apparatus of claim 4 wherein the first and second mirrors have the same radius of curvature and the third and fourth mirrors have the same radius of curvature.

6. The apparatus of claim 1 wherein the object array comprises a light source and a micromirror device configured to receive a light beam from the light source and formed of an array of electronically addressable micromirrors, each of which can be selectively tilted between one of at least two separate positions, wherein in one of the positions of each micromirror the light from the source incident upon the micromirror is deflected away from an optical axis and in a second of the at least two positions of the micromirror the light is reflected along the optical axis.

7. The apparatus of claim 6 further including a condenser between the light source and the micromirror device, the condenser configured to receive the light from the source and to provide a collimated beam of light to the micromirror device.

8. The apparatus of claim 7 wherein the condenser includes a light pipe.

9. The apparatus of claim 6 wherein the micromirror device is formed of a two dimensional array of micromirrors.

10. The apparatus of claim 1 wherein the first mirror is configured to forms an image of the pattern of light and dark areas at the second mirror surface.

11. The apparatus of claim 1 wherein the substrate is transparent and the projection optics are arranged to form the magnified image on the active surface of the substrate which is opposite to the surface which initially receives the light from the projection optics.

12. The apparatus of claim 1 wherein the projection optics are symmetric about an axis of symmetry and the image array is located off the axis of symmetry.

13. Apparatus for synthesis of arrays of chain molecules comprising:

(a) a substrate with an active surface on which the arrays may be formed;

(b) a flow cell enclosing the active surface of the substrate and having ports for applying DNA synthesis reagents into the flow cell which can be flowed over the active surface of the substrate;

(c) a light emitting object array comprising a light source and a micromirror device configured to receive a light beam from the light source and formed of an array of electronically addressable micromirrors, each of which can be selectively tilted between one of at least two separate positions, wherein in one of the positions of each micromirror the light from the source incident upon the micromirror is deflected away from an optical axis and in a second of the at least two positions of the micromirror the light is reflected along the optical axis; and

(d) projection optics configured to receive the light emitted from the light emitting object array and to image the pattern of light and dark areas onto the active surface of the substrate, the projection optics comprising a first, concave mirror configured to receive the light from the object array and to reflect that light at an angle off the axis of the light received from the object array, a second, convex mirror configured to receive the light reflected from the first mirror and to reflect the light off the axis of the light received from the first mirror, a third, concave mirror configured to receive the light reflected from the second mirror and to reflect the light off the axis of the light received from the second mirror, and a fourth, convex mirror configured to receive the light from the third mirror and to reflect the light off the axis of the light received from the third mirror and to image the light onto the active surface, the first, second, third and fourth mirrors arranged to form a magnified image of the pattern of light and dark areas at the active surface.

14. The apparatus of claim 13 wherein the first, second, third, and fourth mirrors are arranged to provide two times magnification of the image of the pattern of light and dark areas at the active surface.

15. The apparatus of claim 13 wherein the first, second, third, and fourth mirrors are each spherical mirrors.

16. The apparatus of claim 15 wherein the first and second mirrors have the same radius of curvature and the third and fourth mirrors have the same radius of curvature.

17. The apparatus of claim 13 further including a condenser between the light source and the mircromirror device, the condenser configured to receive the light from the source and to provide a collimated beam of light to the micromirror device.

18. The apparatus of claim 17 wherein the condenser includes a light pipe.

19. The apparatus of claim 13 wherein the first mirror is configured to forms an image of the pattern of light and dark areas at the second mirror surface.

20. The apparatus of claim 13 wherein the micromirror device is formed of a two dimensional array of micromirrors.

21. The apparatus of claim 13 wherein the substrate is transparent and the projection optics are arranged to form the magnified image on the active surface of the substrate which is opposite to the surface which initially receives the light from the projection optics.

22. The apparatus of claim 13 wherein the projection optics are symmetric about an axis of symmetry and the image array is located off the axis of symmetry.