Systems and methods for the active electronic control of biological reactions

• US 20010026778A1
• Filed: 05/04/2001
• Published: 10/04/2001
• Est. Priority Date: 11/01/1993
• Status: Active Grant

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen, Inc.
• Inventors: Ackley, Donald E., Graham, Scott O.
• Granted Patent: US 7,425,308 B2
• Time in Patent Office: Days
• US Class Current: 422/129
• 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 2219/00617 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 2219/00637 by coating it with another layer
• 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 2219/00695 Synthesis control routines, e.g. using computer programs
• 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 2219/0072 : 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: B01L 2200/025 : Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/027 : for microfluidic devices
• 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 2300/0816 : Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0877 : Flow chambers
• CPC Class Codes: B01L 2300/0887 : Laminated structure
• CPC Class Codes: B01L 2400/0415 : electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/0421 : electrophoretic flow
• CPC Class Codes: B01L 3/5027 : by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• 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 3/50273 : characterised by the means or forces applied to move the fluids micropumps F04B19/006, of the membrane type F04B43/043
• 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: B01L 9/527 : for microfluidic devices, e.g. used for lab-on-a-chip
• 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: 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

A system useful in performing active biological reactions includes an array of unit cells arranged in rows and columns. Row lines are coupled to row contacts of unit cells of the array. A row selector is coupled to the row lines to provide a row select voltage. Column lines are coupled to column contacts of the array. A column selector is coupled to the column lines to provide more than two column voltage states on the column lines. The unit cells are coupled to a supply and to an electrode, the row select and column select voltage states provides variable current output from the electrode of the unit cell. A return electrode is coupled to a potential and adapted to contact conductive solution including charged biological materials, wherein in the presence of the conductive solution, current is provided between various unit cells and the return electrode.

Claims

1. A system for the active electronic control of biological reactions in a multiple site environment comprising:

an array of unit cells, the cells being arranged in rows and columns,

a row selector external to the array and operatively connected to the array for selective addressing of rows of the array,

a column selector external to the array and operatively connected to the array for providing an indication of output values and for selective addressing of the columns of the array,

an input adapted to receive unit cell selection information, the input coupled to the row selector and the column selector,

current circuitry for receiving an input current and coupling a signal to the unit cells for current generation thereof, and

power source connectors adapted to receive power, the connectors supplying power to the unit cells.

2. The system of

claim 1

for the active electronic control of biological reactions wherein the row selector includes a memory.

3. The system of

claim 2

for the active electronic control of biological reactions wherein the memory is a shift register memory.

4. The system of

claim 3

for the active electronic control of biological reactions wherein the shift register is in a by one configuration.

5. The system of

claim 1

for the active electronic control of biological reactions wherein the row selector includes a decoder.

6. The system of

claim 1

for the active electronic control of biological reactions wherein the column selector includes a memory.

7. The system of

claim 6

for the active electronic control of biological reactions wherein the memory is a shift register memory.

8. The system of

claim 7

for the active electronic control of biological reactions wherein the shift register memory is in a by one configuration.

9. The system of

claim 7

for the active electronic control of biological reactions wherein the shift register memory is in a by four configuration.

10. The system of

claim 1

for the active electronic control of biological reactions wherein the column selector includes a decoder.

11. The system of

claim 1

for the active electronic control of biological reactions further including a variable current waveform generator.

12. The system of

claim 1

for the active electronic control of biological reactions further including a current mirror system for receipt of current at a first value and outputting current at a second value.

13. The system of

claim 12

for the active electronic control of biological reactions wherein the second value is smaller than the first value.

14. The system of

claim 13

for the active electronic control of biological reactions wherein the second value is at least twenty times less than the first value.

15. The system of

claim 1

for the active electronic control of biological reactions further including multiplexers for the alternative input of row and column selection.

16. The system of

claim 1

for the active electronic control of biological reactions wherein the input current comprises a current waveform.

17. The system of

claim 16

for the active electronic control of biological reactions wherein the current waveform is a static, direct current waveform.

18. The system of

claim 16

for the active electronic control of biological reactions wherein the current waveform is a square wave.

19. The system of

claim 18

for the active electronic control of biological reactions wherein the current waveform is an asymmetric square wave.

20. The system of

claim 16

for the active electronic control of biological reactions wherein the current waveform is a sinusoidal wave.

21. The system of

claim 16

for the active electronic control of biological reactions wherein the current waveform is a sawtooth wave.

22. A system for the selective provision of current in an active biological matrix device adapted to receive a conductive solution including charged biological materials, comprising:

an array of unit cells, each unit cell including a row contact and a column contact, row lines, the row lines being coupled to the row contacts of the array,

a row selector, the row selector being coupled the row lines to provide a row select voltage.

column lines, the column lines being coupled to the column contacts of the array,

a column selector, the column selector being coupled to the column lines to provide more than two column voltage states on the column lines,

the unit cells being coupled to a supply and to an electrode, the row select voltage and the column voltage states providing a variable current output from the electrode of the unit cell, and

a return electrode coupled to a potential and adapted to contact the conductive solution,

whereby in the presence of the conductive solution current is provided between various unit cells, including the return electrode.

23. The system of

claim 22

wherein the return electrode is a unit cell of the array.

24. The system of

claim 22

wherein the row selector includes memory.

25. The system of

claim 24

wherein the memory includes a shift register memory.

26. The system of

claim 24

wherein the shift register memory is in a by one configuration.

27. The system of

claim 22

wherein the row selector includes a decoder.

28. The system of

claim 22

wherein the column selector includes memory.

29. The system of

claim 28

wherein the memory includes shift register memory.

30. The system of

claim 29

wherein the shift register memory includes multiple bits per column of unit cells.

31. The system of

claim 30

wherein there are at least four bits per column of unit cells.

32. The system of

claim 22

wherein each unit cell further includes a second row contact and a second row line coupled to the second row contact.

33. The system of

claim 22

further including a second row selector.

34. The system of

claim 22

wherein each unit cell further includes a second column contact and second column line coupled to the second column contact.

35. The system of

claim 22

further including a second column selector.

36. A system for the active electronic control of biological reactions in a multiple site environment comprising:

an array of unit cells, the unit the cells being arranged in rows and columns, each unit cell being driven or un-driven;

a first column selector external to the array and operatively connected to the array for providing an indication of first output values to the unit cells operatively connected to selected columns of the array, said first column selector selectively addressing individual columns of the array;

a first row selector external to the array and operatively connected to the array for selectively addressing individual rows of the array;

a second column selector external to the array and operatively connected to the array for providing an indication of second output values to the unit cells operatively connected to selected columns of the array, said second column selector selectively addressing individual columns of the array;

a second row selector external to the array and operatively connected to the array for selectively addressing individual rows of the array; and

wherein each unit cell within the array is driven at one of the first output values, the second output values, or is un-driven.

37. A system according to

claim 36

, wherein the first column selector has a plurality of states, and wherein each plurality of states produces different first output values.

38. A system according to

claim 37

, wherein the plurality of states are voltage states.

39. A system according to

claim 38

, wherein the plurality of states are positive voltage states.

40. A system according to

claim 36

, wherein the second column selector has a plurality of states, and wherein each plurality of states produces different second output values.

41. A system according to

claim 40

, wherein the plurality of states are voltage states.

42. A system according to

claim 41

, wherein the plurality of states are negative voltage states.

43. A system according to

claim 36

, wherein the first output values vary as a function of time.

44. A system according to

claim 36

, wherein the second output values vary as a function of time.

45. A system for the active electronic control of biological reactions in a multiple site environment comprising:

an array of unit cells arranged in rows and columns;

a first column selector external to the array and operatively connected to the array for providing an indication of first output values to the unit cells operatively connected to selected columns of the array, the first column selector selectively addressing the columns of the array;

column lines coupling the first column selector to each unit cell within a column of the array;

a first row selector external to the array and operatively connected to the array for selectively addressing the rows of the array;

row lines coupling the first row selector to each unit cell within a row of the array;

a second column selector external to the array and operatively connected to the array for providing an indication of second output values to the unit cells operatively connected to selected columns of the array, the second column selector selectively addressing the columns of the array;

column lines coupling the second column selector to each unit cell within a column of the array;

a second row selector external to the array and operatively connected to the array for selectively addressing the rows of the array;

row lines coupling the second row selector to each unit cell within a row of the array; and

wherein each unit cell within a single selected column is driven at a value corresponding to the output values of the first column selector, the second column selector, or is un-driven.

46. A system according to

claim 45

, wherein the first column selector has a plurality of states, and wherein each plurality of states produces different first output values.

47. A system according to

claim 46

, wherein the plurality of states are voltage states.

48. A system according to

claim 47

, wherein the plurality of states are positive voltage states.

49. A system according to

claim 45

, wherein the second column selector has a plurality of states, and wherein each plurality of states produces different second output values.

50. A system according to

claim 49

, wherein the plurality of states are voltage states.

51. A system according to

claim 50

, wherein the plurality of states are negative voltage states.

52. A system according to

claim 45

, wherein the first output values vary as a function of time.

53. A system according to

claim 45

, wherein the second output values vary as a function of time.

54. A method of driving an array of unit cells, wherein each unit cell, when driven, is driven at a specific output value, said method comprising the steps of:

addressing at least one column of the array with at least one column selector, the at least one column selector operatively connected to selected columns of the array via column lines;

addressing at least one row of the array with at least one row selector, the at least one row selector operatively connected to the array via row lines for addressing selected rows of the array; and

sending an output value to at least one unit cell addressed by one of the at least one row selectors, the output value being sent by one of the at least one column selectors.

55. A method of selectively controlling the electrical characteristics of an array of individual electrode sites through the use of column and row lines, the method including the steps of:

addressing at least one electrode site within the array, the at least one electrode site addressed via a column selector and a row selector, the column selector operatively connected to selected columns of the array, the row selection operatively connected to selected rows of the array; and

activating the column containing the at least one addressed electrode site with an output value, wherein the at least one addressed electrode site within the column is driven at a value corresponding to the output value on the column.