Combinatorial synthesis system

• US 20030008411A1
• Filed: 04/03/2002
• Published: 01/09/2003
• Est. Priority Date: 10/03/2000
• Status: Active Grant

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Unger, Marc A., Quake, Stephen R., Van Dam, Michael
• Granted Patent: US 7,097,809 B2
• Time in Patent Office: Days
• US Class Current: 436/174
• 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 2219/00355 peristaltic
• CPC Class Codes: B01J 2219/00398 in multiple arrangements
• CPC Class Codes: B01J 2219/00418 using pressure
• CPC Class Codes: B01J 2219/00427 using masks
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/00527 Sheets
• 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 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00617 by chemical means
• CPC Class Codes: B01J 2219/00621 by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00635 by reactive plasma treatment
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00641 the porous medium being continuous, e.g. porous oxide substrates
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00675 : In-situ synthesis on the substrate
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00729 : Peptide nucleic acids [PNA]
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• 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 50/14 : Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G01N 15/06 : Investigating concentration of particle suspensions by weighing G01N5/00; investigating sedimentation of particle suspensions G01N15/04; investigating individual particles G01N15/10
• CPC Class Codes: Y10T 436/10 : Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/255 : including use of a solid sorbent, semipermeable membrane, or liquid extraction
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The present invention provides a microfluidic device for synthesizing an array of compounds and methods for using the same. In particular, the microfluidic device of the present invention comprises a solid support base, an elastomeric layer attached to the solid support, and a plurality of flow channels located within the interface between the solid support and the elastomeric layer. In addition, the solid support comprises a functional group for forming a bond with a reactive reagent. In some embodiments, the microfluidic device further comprises a second plurality of flow channels that intersect the first plurality of flow channels. A plurality of control channels are also present in the microfluidic devices of the present invention. The control channels can be actuated to regulate flow of fluids within the flow channel(s).

Claims

1. A microfluidic combinatorial chemical synthesis device comprising:

a plurality of microfluidic flow channels defined by an elastomeric layer and a solid support, wherein flow channels are adapted to allow flow of a solution therethrough, and wherein the solid support comprises a reactive functional group within an inner surface of the flow channels for attaching a reactive reagent thereto;

a plurality of control channels; and

a plurality of valves disposed in between said fluid flow channel and said control channel to regulate flow of the solution through said fluid flow channels, wherein each of said valves comprises one of said control channels and a segment of said elastomeric layer that is deflectable into or retractable from said fluid flow channel upon which said valve operates in response to an actuation force applied to said control channel, said elastomeric segment when positioned in said flow channel restricting solution flow therethrough.

2. The microfluidic combinatorial chemical synthesis device of claim 1, wherein the plurality of flow channels comprises a first set of flow channels and a second set of flow channels such that the first set of flow channels intersect the second set of flow channels, thereby forming a plurality of flow channel intersections.

3. The microfluidic combinatorial chemical synthesis device of claim 1, wherein the inner surface of said flow channel comprising said elastomeric layer is coated with a coating material that is substantially inert to the chemical reaction solvent.

4. The microfluidic combinatorial chemical synthesis device of claim 3, wherein said coating material is selected from the group consisting of a fluoropolymer, Vitrinite®

protective coating, silicon dioxide, Cytop, and Teflon AF.

5. The microfluidic combinatorial chemical synthesis device of claim 1, wherein said elastomeric layer is disposed in between a solid support fluid flow channel layer and a control channel layer.

6. The microfluidic combinatorial chemical synthesis device of claim 5, wherein the solid support fluid flow channel layer is comprised of a material selected from the group consisting of glass, polystyrene, polystyrene-divinylbenzene copolymer, silicone rubber, quartz, latex, polyurethane, a derivatizable transition metal, silicon dioxide, silicon nitride, gallium arsenide, and a derivative thereof.

7. The microfluidic combinatorial chemical synthesis device of claim 6, wherein said derivatizable transition metal is gold.

8. The microfluidic combinatorial chemical synthesis device of claim 5, wherein said solid support is a rigid material.

9. The microfluidic combinatorial chemical synthesis device of claim 8, wherein said fluid flow channel is formed from a channel within the rigid material.

10. The microfluidic combinatorial chemical synthesis device of claim 9, wherein said control channel layer is made from a rigid material.

11. The microfluidic combinatorial chemical synthesis device of claim 10, wherein said elastomeric layer is removeably disposed in between two rigid materials, such that said elastomeric layer forms a part of said fluid flow channels and said control channels.

12. The microfluidic combinatorial chemical synthesis device of claim 1, wherein at least a portion of said plurality of control channels are aligned in between said fluid flow channels.

13. The microfluidic combinatorial chemical synthesis device of claim 12, wherein at least a portion of said control channels is aligned on top of said fluid flow channels.

14. The microfluidic combinatorial chemical synthesis device of claim 13, wherein said control channels aligned on top of said fluid flow channels comprise a varying cross-sections within each control channels, such that when said control channel is actuated only the valves comprising a wide cross-section control channel restricts solution flow.

16. The method of claim 15, wherein said step of introducing a reactive reagent in said step (a) or (b) or both comprises introducing different reactive reagents to different flow channels.

17. The method of claim 16, wherein a homogeneous reagent is added to each of the flow channels.

18. The method of claim 15 further comprising cleaving the library of solid-support bound compounds from the solid support.

19. The method of claim 15, wherein said means for rendering the elastomeric layer of the inner surface of the flow channels substantially inert to a chemical reaction solvent comprises a coating material that is substantially inert to the chemical reaction solvent.

20. The method of claim 19, wherein the coating material is selected from the group consisting of a fluoropolymer, Vitrinite®

protective coating, silicon dioxide, Cytop and Teflon AF.

21. The method of claim 15, wherein said means for rendering the elastomeric layer of the inner surface of the flow channels substantially inert to a chemical reaction solvent comprises providing a laminar flow of a sheath fluid in between the chemical reaction mixture and the elastomeric layer portion of the inner surface, wherein the sheath fluid is compatible with the chemical reaction solvent and the elastomeric layer.

22. The method of claim 15, wherein the microfluidic device comprises an elastic layer and a solid support, and wherein the fluid flow channel is located on the interface of the elastic layer and the solid support.

23. The method of claim 22, wherein prior to said step (b) of introducing another reagent, said method further comprises:

(A) removing the elastic layer from the solid support; and

(B) reattaching the elastic layer to the solid support at a different angle, such that the newly formed flow channels intersect the flow channels of the microfluidic device of said step (a).

24. The method of claim 15, wherein the plurality of flow channels comprises a first set of flow channels and a second set of flow channels such that the first set of flow channels intersect the second set of flow channels, thus resulting in a plurality of flow channel intersections.

25. The method of claim 24, wherein the reactive reagent in said step (a) is introduced into the first set of flow channels and the reactive reagent in said step (b) is introduced into the second set of flow channels.

26. The method of claim 15, wherein said step of introducing the reactive reagent comprises actuating the control channels to regulate flow of the solution through the fluid flow channels.

27. The method of claim 15, wherein the microfluidic device comprises a thin layer of an elastomeric layer disposed in between two solid support bases.

28. The method of claim 27, wherein the fluid flow channels and the control channels are separated by the elastomeric layer.

29. The method of claim 28, wherein the fluid flow channels and the control channels are located on the interface of the elastomeric layer and the solid support.

15. A method for synthesizing a library of compound on a microfluidic device comprising (i) a plurality of fluid flow channels defined by an elastomeric layer and a solid support, where in the flow channels are adapted to allow the flow of a solution therethrough, and wherein the solid support comprises a reactive functional group with the inner surface of the flow channels for attaching a reactive reagent thereto;

(ii) a means for rendering the elastomeric layer of the inner surface of the flow channels substantially inert to a chemical reaction solvent;

(iii) a plurality of control channels; and

(iv) a plurality of valves disposed in between the fluid flow channel and the control channel to regulate flow of the solution through the fluid flow channels, wherein each of the valves comprises one of the control channels and a segment of the elastomeric layer that is deflectable into or retractable from the fluid flow channel upon which the valve operates in response to an actuation force applied to the control channel, the elastomeric segment when positioned in the flow channel restricting solution flow therethrough, said method comprising;

(a) producing a solid-support bound compound by introducing a first reactive reagent into the fluid flow channels under conditions sufficient to covalently attach at least a portion of the first reactive reagent to the reactive functional group of the inner surface of the fluid flow channel;

(b) modifying the solid support-bound compound by introducing another reactive reagent into the fluid flow channels under conditions sufficient to react the solid-support bound compound with the reactive reagent; and

(c) optionally repeating said step (b).