Method and device for producing biochemical reaction supporting materials

• US 7,737,088 B1
• Filed: 08/27/1999
• Issued: 06/15/2010
• Est. Priority Date: 08/28/1998
• Status: Expired due to Fees

• Current Assignee: Comprehensive Biomarker Center GmbH
• Original Assignee: Febit Holding GmbH (FEBIT)
• Inventors: Müller, Manfred, Lindner, Hans, Stähler, Fritz, Stähler, Peer F., Stähler, Cord F.
• Primary Examiner(s): Low; Christopher
• Assistant Examiner(s): Gross; Christopher M
• Application Number:
  US09/763,607
• Time in Patent Office: 3,945 Days
• Field of Search: 435/6, 435/283.1, 435/299.1, 435/305.1, 435/970, 435/973, 536/25.3, 536/25.31, 530/333, 530/334, 436/518, 436/527, 436/528, 436/89
• US Class Current: 506/30
• 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 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00432 Photolithographic masks
• CPC Class Codes: B01J 2219/00436 Maskless processes
• CPC Class Codes: B01J 2219/00439 using micromirror arrays
• CPC Class Codes: B01J 2219/00441 using lasers
• CPC Class Codes: B01J 2219/00448 using microlens arrays
• CPC Class Codes: B01J 2219/00479 Means for mixing reactants or products in the reaction vessels
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/00511 Walls of reactor vessels
• 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 2219/00603 Making arrays on substantially continuous surfaces
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/00608 DNA chips
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00621 : by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00637 : by coating it with another layer
• CPC Class Codes: B01J 2219/00648 : by the use of solid beads
• 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 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00704 : integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/00711 : Light-directed synthesis
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01L 2300/0654 : Lenses; Optical fibres
• CPC Class Codes: B01L 2300/069 : Absorbents; Gels to retain a fluid
• CPC Class Codes: B01L 2300/0816 : Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0864 : comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/5085 : for multiple samples, e.g. microtitration plates
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C12N 15/10 : Processes for the isolation, preparation or purification of DNA or RNA chemical preparation of DNA or RNA C07H21/00; preparation of non-structural polynucleotides from microorganisms or with enzymes C12P19/34
• CPC Class Codes: C12P 19/34 : Polynucleotides, e.g. nucleic acids, oligoribonucleotides
• 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: G01N 21/253 : for batch operation, i.e. multisample apparatus analytical automats G01N35/00
• CPC Class Codes: G01N 21/6454 : using an integrated detector array
• CPC Class Codes: G01N 33/551 : the carrier being inorganic
• CPC Class Codes: G03F 7/70216 : Mask projection systems
• CPC Class Codes: Y10S 435/97 : Test strip or test slide
• CPC Class Codes: Y10S 435/973 : Simultaneous determination of more than one analyte

Abstract

The present invention relates to arrays of biochemical and/or biofunctional elements such as nucleic acids (oligonucleotides, for example) or other biomolecules on a carrier surface and methods of producing such arrays using photoactivation of predetermined areas for synthesis using an illumination matrix that is computer-controlled to generate an exposure pattern. This exposure pattern can be adjusted and monitored by computer using a light sensor matrix, for example a CCD matrix, to allow precise, controlled illumination of specific regions and therefore attachment of array building blocks to those specific regions. The methods and compositions of the invention permit spatially resolved photochemical synthesis of polymer probes on a carrier.

Claims

1. A method of biochip manufacture, which comprises

(a) providing a programmable illumination matrix and a light sensor detection matrix, wherein said illumination matrix and said detection matrix are arranged facing each other such that the detection matrix is situated in the light path of the illumination matrix and such that the detection matrix can detect light from the illumination matrix;

(b) positioning a transparent biochip carrier, wherein said carrier has a surface that comprises photoactivatable cleavable protective groups located thereon for photochemical synthesis at predetermined areas of said biochip carrier surface, between said illumination matrix and said detection matrix and in the light path of said illumination matrix such that light from the illumination matrix illuminates and is transmitted through said biochip carrier and to said detection matrix;

(c) specifically illuminating said biochip carrier to produce an adjustable two-dimensional light exposure pattern that illuminates selected predetermined areas of said biochip carrier;

(d) monitoring and controlling the quality of said specific two-dimensional light exposure pattern by detecting the location of the illuminated areas of said two-dimensional light exposure pattern on said biochip carrier using the detection matrix and adjusting said two-dimensional light exposure pattern where appropriate, taking into account the information obtained by said monitoring.

2. The method of claim 1, wherein said illumination is electromagnetic radiation selected from the group consisting of infrared, visible, ultraviolet and X-ray radiation.

3. The method of claim 1, wherein said illumination is radiation selected from the group consisting of pulsating radiation, coherent radiation, monochromatic radiation, parallel radiation and radiation which can be focused in different planes.

4. The method of claim 1, wherein said selected predetermined areas are illuminated in parallel.

5. The method of claim 1, wherein said illumination matrix is a reflection matrix having a controllably deformable mirror arrangement.

6. The method of claim 5, wherein said reflection matrix is selected from the group consisting of a light modulator with viscoelastic control layers and a light modulator with micromechanical mirror arrays.

7. The method of claim 1, wherein said illumination matrix is selected from the group consisting of a laser array and a diode array.

8. The method of claim 1, wherein said biochip carrier is an optically transparent carrier.

9. The method of claim 1, wherein said biochip carrier has a surface selected from the group consisting of glass and plastics.

10. The method of claim 1, wherein said selected predetermined areas each are from 1 μ

m² to 1 cm².

11. The method of claim 1, wherein said selected predetermined areas each are surrounded by nonactivated areas.

12. The method of claim 1, wherein said illumination takes place at a rate of from 1/10000 to 1000 light patterns per second.

13. The method of claim 1, wherein said biochip carrier is precalibrated using the illumination matrix and light sensor detection matrix.

14. The method of claim 1,

(a) wherein said biochip carrier has a surface which comprises the photoactivatable cleavable protective groups located at predetermined areas of said biochip carrier surface and wherein said programmable illumination matrix is a UV light source array comprising a plurality of individually controllable light sources;

and

(b) wherein said specific two-dimensional light exposure pattern activates said photoactivatable cleavable protective groups at said selected predetermined area areas of said biochip carrier surface.

15. The method of claim 14, which further comprises binding materials selected from the group consisting of (1) biologically functional materials, (2) chemically functional materials, (3) building blocks for said biologically functional materials and (4) building blocks for said chemically functional materials to said activated groups on said selected predetermined areas of said biochip carrier surface.

16. The method of claim 15, wherein said biologically or chemically functional materials or building blocks thereof are selected from the group consisting of nucleic acids, nucleotides, oligonucleotides, nucleic acid analogs, PNA, peptides, proteins, amino acids, saccharides, cells, cell organelles, cell membrane preparations, viral particles, cell aggregates, allergens, pathogens, pharmacological active substances and diagnostic reagents.

17. The method of claim 15, which further comprises synthesizing said biologically or chemically functional materials on said biochip carrier in two or more stages from monomeric or oligomeric building blocks.

18. The method of claim 15, wherein said biologically or chemically functional materials are a library comprising a multiplicity of different biologically or chemically functional materials.

19. The method of claim 14, wherein said activating photoactivatable cleavable protective groups comprises cleaving a protective group at said selected predetermined areas of said biochip carrier surface.

20. The method of claim 15, which further comprises removing materials bound on the carrier.

21. The method of claim 20, wherein said removed materials are used as building blocks for further synthesis of polymers.

22. The method of claim 1, wherein said light sensor detection matrix is a CCD matrix.

23. The method of claim 1, wherein said biochip carrier has a surface selected from the group consisting of silicon, germanium arsenide and gallium arsenide.

24. The method of claim 9, wherein said glass is quartz glass.

25. The method of claim 10, wherein said selected predetermined areas each are from 100 μ

m² to 1 mm².

26. The method of claim 12, wherein said illumination takes place at a rate of from 1/10 to 100 light patterns per second.

27. A method of claim 14 wherein said UV light source array is selected from the group consisting of a diode array, a UV laser array, and both a diode array and a UV laser array.