Advanced active electronic devices for molecular biological analysis and diagnostics

• US 6,099,803 A
• Filed: 02/20/1998
• Issued: 08/08/2000
• Est. Priority Date: 07/07/1994
• Status: Expired due to Fees

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen, Inc.
• Inventors: Ackley, Donald E., Graham, Scott O., Butler, William F., Swanson, Paul D., Mather, Elizabeth L., LeClair, Timothy L.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US09/026,618
• Time in Patent Office: 900 Days
• Field of Search: 422/50, 422/68.1, 422/69, 422/82.05, 422/129, 422/131, 435/6, 435/286.1, 435/286.2, 435/286.5, 435/287.1, 435/287.3, 435/289.1, 436/501, 536/25.3
• US Class Current: 422/68.1
• 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 2219/00626 Covalent
• 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 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00713 Electrochemical synthesis
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B01J 2219/00731 Saccharides
• CPC Class Codes: B01L 2200/0647 Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2200/0689 : Sealing
• CPC Class Codes: B01L 2200/12 : Specific details about manufacturing devices
• CPC Class Codes: B01L 2300/0636 : Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0645 : Electrodes
• CPC Class Codes: B01L 2300/0654 : Lenses; Optical fibres
• CPC Class Codes: B01L 2300/0877 : Flow chambers
• CPC Class Codes: B01L 2400/0415 : electrical forces, e.g. electrokinetic
• 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 3/502761 : 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: 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 1/045 : using devices to improve synthesis, e.g. reactors, special vessels
• 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: F04B 19/006 : Micropumps F04B43/043 and F04B43/095 take precedence
• CPC Class Codes: G01N 27/44743 : Introducing samples
• 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

Abstract

Methods of manufacture and devices for performing active biological operations utilize various structures to advantageously collect and provide charged biological materials to an array of microlocations. In one embodiment, a device includes focusing electrodes to aid in the direction and transport of materials from a collection electrode to an array. Preferably, one or more intermediate transportation electrodes are utilized, most preferably of monotonically decreasing size between the collection electrode and the array, so as to reduce current density mismatches. In another aspect, a flow cell is utilized over devices to provide containment of solution containing materials to be analyzed. Preferably, the volume of the flow cell is more advantageously interrogated through use of relatively large collection and return electrodes, such as where the area of those electrodes relative to the footprint of the flowcell is at least 40%. In yet another embodiment, a first collection electrode is disposed adjacent an array, with a second collection electrode disposed on the at least an opposite portion of the array. Preferably, the combined area of the collection electrodes is a substantial fraction, preferably at least 50% of the area of the footprint of the flow cell. In yet another embodiment, a concentric ring design is provided. Various flip chip embodiments are disclosed.

Claims

1. An electronic device for performing active biological operations comprising:

a support substrate,

an array of microlocations disposed on the substrate,

a collection electrode disposed on the substrate,

first and second focusing electrodes disposed on the substrate, the first and second electrodes being disposed at least in part adjacent the array of microlocations, the distance between the first and second focusing electrodes adjacent the array being smaller than the distance between the first and second electrodes in yet another region disposed away from the array, and

a counter electrode disposed on the substrate.

2. The electronic device for performing active biological operations of claim 1 further including at least one transport electrode, the transport electrodes being disposed on the substrate, and positioned between the collection electrode and the array.

3. The electronic device for performing active biological operations of claim 2 wherein there are at least two transport electrodes.

4. The electronic device for performing active biological operations of claim 3 wherein the transport electrodes are of a different size.

5. The electronic device for performing active biological operations of claim 4 wherein the ratio of the sizes of the largest to the smallest transport electrodes is at least 2:

1.

6. The electronic device for performing active biological operations of claim 4 wherein the ratio of the size of the largest to the smallest transport electrodes is at least 3:

1.

7. The electronic device for performing active biological operations of claim 4 wherein the ratio of the size of the largest to the smallest transport electrodes is at least 4:

1.

8. The electronic device for performing active biological operations of claim 4 wherein the transport electrodes generally decrease in size the closer they are to the array.

9. The electronic device for performing active biological operations of claim 8 wherein the decrease in size is monotonic.

10. The electronic device for performing active biological operations of claim 2 wherein at least one transport electrode is smaller than the collection electrode.

11. The electronic device for performing active biological operations of claim 10 wherein the ratio of the area of the collection electrode to the area of the smallest transport electrode is at least 4:

1.

12. The electronic device for performing active biological operations of claim 1 further including capture sequences.

13. The electronic device for performing active biological operations of claim 12 wherein the capture sequences are disposed adjacent the collection electrode.

14. The electronic device for performing active biological operations of claim 12 wherein the collection electrode is a complexity reduction electrode.

15. The electronic device for performing active biological operations of claim 1 further including a second power supply for connection to the focusing electrodes.

16. The electronic device for performing active biological operations of claim 1 wherein the focusing electrodes are biased negative.

17. The electronic device for performing active biological operations of claim 1 wherein the focusing electrodes are actively biased to zero.

18. The electronic device for performing active biological operations of claim 1 further including a flow cell, the flow cell having a footprint.

19. The electronic device for performing active biological operations of claim 18 wherein the counterelectrode and the collection electrode are disposed for interrogating a substantial fraction of the volume of the flow cell.

20. The electronic device for performing active biological operations of claim 19 wherein the fraction is at least 50%.

21. The electronic device for performing active biological operations of claim 19 wherein the fraction is at least 75%.

22. The electronic device for performing active biological operations of claim 19 wherein the counterelectrode and the collection electrode are disposed along substantially all of the periphery of the footprint of the flow cell.

23. The electronic device for performing active biological operations of claim 22 wherein the counterelectrode and collection electrode are disposed along at least 80% of the periphery of the flow cell footprint.

24. The electronic device for performing active biological operations of claim 19 wherein the counterelectrodes and collection electrode are disposed at substantially opposite ends of the flow cell footprint.

25. The electronic device for performing active biological operations of claim 18 wherein the combined area of the collection electrode and counter electrodes in proportion to the footprint of the flow cell is at least 40%.

26. The electronic device for performing active biological operations of claim 18 wherein the combined area of the collection electrode and counter electrodes in proportion to the footprint of the flow cell is at least 50%.

27. The electronic device for performing active biological operations of claim 18 wherein the combined area of the collection electrode and counter electrodes in proportion to the footprint of the flow cell is at least 60%.

28. The electronic device for performing active biological operations of claim 18 wherein the flow cell includes an inlet.

29. The electronic device for performing active biological operations of claim 18 wherein the flow cell includes an outlet.

30. A method for analysis of a biological sample, utilizing the electronic device for performing active biological operations of claim 1, comprising the steps of:

providing the sample to the device,

placing the collection electrode attractive for the desired charged biological materials, thereby concentrating desired charged biological materials on the collection electrode,

placing the focusing electrodes at a potential so as to provide a component of force transverse to the line disposed between the collection electrode and the array of microlocations, and

transporting material from the collection electrode to the array of microlocations.

31. The method for analysis of a biological sample of claim 30 wherein the focusing electrodes are actively biased.

32. The method for analysis of a biological sample of claim 31 wherein the active bias of the focusing electrodes is to zero.

33. The method for analysis of a biological sample of claim 31 wherein the bias is negative.

34. The method for analysis of a biological sample of claim 30 further including the step of providing attractive bias to the transport electrodes relative to the desired sample.

35. The method for analysis of a biological sample of claim 30 wherein the transport electrodes are biased attractive relative to the desired sample material after the desired sample has been provided to the collection electrode.

36. The method for analysis of a biological sample of claim 30 wherein the transport electrodes are sequentially biased.

37. The method for analysis of a biological sample of claim 30 wherein the collection electrode is biased repulsive to the desired sample at a point after the desired materials have been collected at the collection electrode.

38. The method for analysis of a biological sample of claim 30 further including the step of actively biasing at least certain microlocations in the array of microlocations attractive to the desired biological materials.