Molecular biological diagnostic systems including electrodes

• US 5,632,957 A
• Filed: 09/09/1994
• Issued: 05/27/1997
• Est. Priority Date: 11/01/1993
• Status: Expired due to Term

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen
• Inventors: Tu, Eugene, Heller, Michael J., Butler, William F.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US08/304,657
• Time in Patent Office: 991 Days
• Field of Search: 422/50, 422/52, 422/55, 422/56, 422/61, 422/62, 422/63, 422/67, 422/68.1, 422/69, 422/81, 422/82.01-82.05, 435/6, 435/7.1, 435/173.1, 435/287, 435/288, 435/289, 435/291, 435/810, 436/501, 536/22.1, 536/23.1, 536/24.1, 935/77, 935/78, 935/88
• US Class Current: 506/39
• 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 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• 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 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00614 Delimitation of the attachment areas
• 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 2219/00637 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 2219/00644 the porous medium being present in discrete locations, e.g. gel pads
• CPC Class Codes: B01J 2219/00653 the compounds being bound to electrodes embedded in or on the solid supports
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00686 Automatic
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00713 : Electrochemical synthesis
• CPC Class Codes: B01J 2219/0072 : Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00731 : Saccharides
• CPC Class Codes: B01J 2219/00783 : Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00828 : Silicon wafers or plates
• CPC Class Codes: B01J 2219/00853 : Employing electrode arrangements
• CPC Class Codes: B01L 2200/025 : Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/143 : Quality control, feedback systems
• CPC Class Codes: B01L 2300/0636 : Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0645 : Electrodes
• CPC Class Codes: B01L 2300/0816 : Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0838 : Capillaries
• CPC Class Codes: B01L 2300/0877 : Flow chambers
• CPC Class Codes: B01L 2400/0421 : electrophoretic flow
• CPC Class Codes: B01L 3/502707 : characterised by the manufacture of the container or its components by shaping or joining plastic parts B29C59/00, B29C65/00; by laminating B32B37/00; manufacture of microstructural devices in general B81C
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• CPC Class Codes: B01L 3/5085 : for multiple samples, e.g. microtitration plates
• CPC Class Codes: B82Y 10/00 : Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07B 2200/11 : Compounds covalently bound to a solid support
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07K 1/04 : on carriers C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 1/045 : using devices to improve synthesis, e.g. reactors, special vessels
• CPC Class Codes: C07K 1/047 : Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C12Q 1/6813 : Hybridisation assays
• CPC Class Codes: C12Q 1/6816 : characterised by the detection means C12Q1/6804 takes precedence
• CPC Class Codes: C12Q 1/6825 : Nucleic acid detection involving sensors
• CPC Class Codes: C12Q 1/6837 : using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C12Q 2565/515 : characterised by the interaction between or sequential use of two or more arrays
• CPC Class Codes: C12Q 2565/607 : being a sensor, e.g. electrode
• 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 40/12 : Libraries containing saccharides or polysaccharides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G11C 13/0014 : comprising cells based on organic memory material
• CPC Class Codes: G11C 13/0019 : comprising bio-molecules
• CPC Class Codes: G11C 13/04 : using optical elements ; using other beam accessed elements, e.g. electron or ion beam
• CPC Class Codes: G11C 19/00 : Digital stores in which the information is moved stepwise, e.g. shift registers
• CPC Class Codes: H01L 25/50 : Multistep manufacturing processes of assemblies consisting of devices, each device being of a type provided for in group H01L27/00 or H01L29/00 H01L21/50 takes precedence
• CPC Class Codes: H01L 2924/00 : Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
• CPC Class Codes: H01L 2924/0002 : Not covered by any one of groups H01L24/00, H01L24/00 and H01L2224/00
• CPC Class Codes: H01L 2924/09701 : Low temperature co-fired ceramic [LTCC]

Abstract

A system for performing molecular biological diagnosis, analysis and multi-step and multiplex reactions utilizes a self-addressable, self-assembling microelectronic system for actively carrying out controlled reactions in microscopic formats. These reactions include most molecular biological procedures, such as nucleic acid hybridization, antibody/antigen reaction, and clinical diagnostics. Multi-step combinatorial biopolymer synthesis may be performed. A controller interfaces with a user via input/output devices, preferably including a graphical display. Independent electronic control is achieved for the individual microlocations. In the preferred embodiment, the controller interfaces with a power supply and interface, the interface providing selective connection to the microlocations, polarity reversal, and optionally selective potential or current levels to individual electrodes. A system for performing sample preparation, hybridization and detection and data analysis integrates multiple steps within a combined system. Charged materials are transported preferably via free field electrophoresis. DNA complexity reduction is achieved preferably by binding of DNA to a support, followed by cleaving unbound materials, such as by restriction enzymes, followed by transport of the cleaved DNA fragments. Active, programmable matrix devices are formed in a variety of formats, including a square matrix pattern with fanned out electrical connections, an array having electrical connections and optionally optical connections from beneath the specific microlocations. A highly automated DNA diagnostic system results.

Claims

1. An electronic device adapted for performing molecular biological processes comprising:

a support having a first generally planar surface,

a plurality of microlocations, the microlocations including an electrode disposed on the first surface of the support and a permeation layer disposed above the electrode,

individual electrical connections to the electrodes, and

an optical access to the electrodes.

2. The electronic device of claim 1 wherein the individual electrical connections to the electrodes comprise leads disposed on the first surface of the support.

3. The electronic device of claim 1 wherein the individual electrical connections to the electrodes are electrical pathways extending from the contacting portion of the electrodes into the support.

4. The electronic device of claim 1 wherein the support includes an insulator.

5. The electronic device of claim 4 wherein the insulator is an oxide.

6. The electronic device of claim 1 wherein the support includes a semiconductive material.

7. The electronic device of claim 6 wherein the support including the semiconductor further includes an oxide layer disposed thereon.

8. The electronic device of claim 6 wherein control electronics are included within the semiconductive material and connected via the individual electrical connections to the electrodes.

9. The electronic device of claim 1 wherein the optical access is formed through the support so as to access the contacting portion of the electrodes.

10. The electronic device of claim 1 or 9 wherein the optical access includes a fiber optic.

11. The electronic device of claim 1 or 9 wherein the optical access includes a light pipe.

12. The electronic device of claim 1 wherein the access comprises an opening.

13. The electronic device of claim 1 further including an attachment layer disposed above the permeation layer.

14. The electronic device of claim 1 further including a containment vessel disposed above the support.

15. The electronic device of claim 1 further including an electronic sample preparation unit operatively disposed to provide an output to the plurality of microlocations.

16. The electronic system of claim 15 wherein the electronic sample preparation unit includes an electronic cell sorter matrix.

17. The electronic system of claim 15 wherein the electronic sample preparation unit includes a DNA selector unit.

18. The electronic system of claim 15 wherein the electronic sample preparation unit includes a restriction fragment selector.

19. The electronic system of claim 15 further including a DNA selector operatively positioned to receive the output of the electronic cell sorter matrix.

20. The electronic system of claim 17 further including a restriction fragment selector operatively positioned to receive the output of the DNA selector.

21. The electronic system of claim 16 further including a restriction fragment selector operatively positioned to receive the output of the electronic cell sorter matrix.

22. The electronic system of claim 19 further including a restriction fragment selector operatively positioned to receive the output of the DNA selector.

23. An electronic system composed of an integrated arrangement of component devices for performing biological sample processing and molecular biological analyses comprising:

a support for the integrated component devices, the support adapted to receive sample containing material to be analyzed,

an active sample preparation component device to which the sample material to be analyzed may be applied, the active sample preparation component device including means for electrophoretically transporting said material within the sample preparation component device, wherein the material is processed to generate relative purified analytes and the resultant analytes are transported to a subsequent integrated component device, and

an active, programmable electronic analytical component device including a plurality of separately addressable microlocations.

24. The system of claim 23 wherein the active, programmable electronic analytical component device comprises an array of electrodes in a row and column format.

25. The system of claim 24 wherein the active, programmable electronic analytical component device further includes an attachment layer for specific binding of biological materials disposed above the electrodes.

26. The system of claim 25 wherein the attachment layer includes capture sequences.

27. The system of claim 23 further including a detector operatively positioned to monitor the active, programmable device.

28. The system of claim 27 wherein the detector comprises an imaging system.

29. The system of claim 28 wherein the imaging system comprises a CCD camera.

30. The system of claim 27 further comprising an analysis system adapted to receive the output of the detection system.

31. The system of claim 23 wherein the sample preparation component device includes a cell sorter.

32. The system of claim 23 wherein the sample preparation component device includes a DNA selector.

33. The system of claim 23 wherein the sample preparation component device includes a restriction fragment selector.

34. The system of claim 23 wherein the sample preparation component device includes an amplification system.

35. The system of claim 34 wherein the amplification system utilizes polymerase chain reaction.

36. The system of claim 23 further including a reagent delivery system.

37. The system of claim 36 wherein the reagent delivery system is an electronic reagent delivery system.

38. The system of claim 36 wherein the reagent delivery system is a fluidic reagent delivery system.

39. The system of claim 23 further including a waste disposal system.

40. The system of claim 39 wherein the waste disposal system is an electronic waste disposal system.

41. The system of claim 39 wherein the waste disposal system is a fluidic waste disposal system.

42. The electronic system of claim 23 further including a sample addition port.

43. The electronic system of claim 23 further including a biological containment structure overlying the component devices.

44. The electronic system of claim 23 wherein the sample preparation component device includes a complexity reduction unit.

45. The electronic system of claim 23 wherein the active sample preparation component device includes an electronic cell sorter matrix and a DNA selector.

46. The electronic system of claim 23 wherein the active sample preparation component device includes an electronic cell sorter matrix and a restriction fragment selector.

47. The electronic system of claim 23 wherein the active sample preparation component device includes a DNA selector and a restriction fragment selector.

48. The electronic system of claim 23 wherein the active sample preparation component device includes an electronic cell sorter matrix, a DNA selector and a restriction fragment selector.

49. The electronic system of claim 23 wherein the active sample preparation component device includes an electronic cell sorter matrix which further comprises electrodes disposed on the support, a permeation layer disposed above the electrodes and an attachment layer disposed above the permeation layer.

50. The electronic system of claim 23 wherein the active sample preparation component device includes an electronic cell sorter matrix comprising a matrix of locations for attachment of biological cells.

51. The electronic system of claim 50 wherein the locations of the matrix in the electronic cell sorter matrix are physically larger than the microlocations in the active programmable electronic analytical device.

52. The electronic device of claim 50 wherein the matrix of locations for attachment of cells includes antibodies.

53. The electronic system of claim 50 wherein the matrix of locations for attachment of cells includes cell adhesion factors.

54. The electronic system of claim 32 wherein the DNA selector includes a capture sequence for binding DNA.

55. The electronic system of claim 23 further including a DNA fragment storage system.

56. An electronic device adapted for performing molecular biological processes comprising:

a support having a first generally planar surface,

a plurality of microlocations disposed on the first surface of the support, the microlocations including an electrode having a contacting portion adjacent the first surface of the support and a permeation layer disposed above the electrode,

individual electrical connections to the electrodes, and

an optical access to the microlocations.

57. The electronic device of claim 56 wherein the optical access is formed through the support so as to access the contacting portion of the electrodes.

58. The electronic device of claims 56 or 57 wherein the optical access includes a fiber optic.

59. The electronic device of claims 56 or 57 wherein the optical access includes a light pipe.

60. The electronic device of claim 56 wherein the access comprises an opening.