Advanced active circuits and devices for molecular biological analysis and diagnostics

• US 6,331,274 B1
• Filed: 01/29/1999
• Issued: 12/18/2001
• Est. Priority Date: 11/01/1993
• Status: Expired due to Fees

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen, Inc.
• Inventors: Ackley, Donald E., Graham, Scott O.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US09/239,598
• Time in Patent Office: 1,054 Days
• Field of Search: 422/50, 422/68.1, 435/5, 435/6, 435/7.1, 435/7.2, 435/283.1, 435/286.1, 435/287.1, 435/287.2, 435/287.3, 435/287.7, 435/287.9, 435/288.7, 435/289.1, 436/501
• 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 2219/00617 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

Devices for performing active biological operations utilize various structures to advantageously collect and provide charged biological materials to an array of microlocations. An active biological matrix device includes an array of unit cells, each unit cell including a variable current control element, a select switch, and a return electrode. The output of the select switch is preferably adapted to contact a conductive solution including charged biological materials. The return electrode is preferably connected to a second potential and adapted to contact the conductive solution. In the presence of the conductive solution, current is provided between the return electrode and the output of the select switch. The variable current control element includes a control element that is adapted to receive a first control signal via, preferably, a first column line. The select switch includes a control element that is adapted to receive a second control signal via, preferably, a first row line. In another aspect, a current control system is used with a unit cell circuit to variably provide current between a first electrode and the return electrode.

Claims

1. A unit cell circuit for providing current in an active biological matrix device adapted to receive a conductive solution including charged biological materials, the active biological matrix device comprising an array of unit cells, the unit cell circuit comprising:

a variable current control element including an input, an output and a control element, the control element being adapted to receive a first control signal via a first column line,

a select switch having an input, an output and a control element, the input being connected to the output of the variable current element, thereby providing a series connection between the variable current control element and the select switch, the control element being adapted to receive a second control signal via a first row line, the input of the variable current control element being connected to a first potential and the output of the select switch being adapted to contact the conductive solution, and

a return electrode, the return electrode being connected to a second potential and adapted to contact the conductive solution,

whereby in the presence of the conductive solution current is provided between the return electrode and the output of the select switch, said unit cell circuit being located on the biological matrix device.

2. The unit cell circuit of claim 1 wherein the variable current control element is a transistor.

3. The unit cell circuit of claim 2 wherein the transistor is a MOSFET.

4. The unit cell circuit of claim 1 wherein the select switch is a transistor.

5. The unit cell circuit of claim 4 wherein the transistor is a MOSFET.

7. The unit cell circuit of claim 1 further including a second variable current control element including an input, an output and a control element, the control element being adapted to receive a third control signal via a second column line,

a second select switch having an input, an output and a control element, the input being connected to the output of the second variable current element, thereby providing a series connection between the second variable current control element and the second select switch, the control element being adapted to receive a fourth control signal via a second row line, the input of the second variable current control element being connected to a third potential and the output of the second select switch being adapted to contact the conductive solution.

8. The unit cell circuit of claim 7 wherein the second variable current control element is a transistor.

9. The unit cell circuit of claim 8 wherein the transistor is a MOSFET.

10. The unit cell circuit of claim 7 wherein the first variable current control element is of a first dopant type and the second variable current control element is of an opposite dopant type.

11. The unit cell circuit of claim 7 or 10 wherein the second variable current control element is a p-channel element.

12. The unit cell circuit of claim 7 wherein the first variable current control element and the second variable current control element are selected to have similar performance characteristics.

13. The unit cell circuit of claim 12 wherein the circuit parameter is device gain.

14. The unit cell circuit of claim 7 wherein a series connection is provided in the following order:

the first potential, the variable current control element, the select switch, the second select switch, the second variable current control element and the third potential.

15. The unit cell circuit of claim 1 further including a second variable current control element including an input, an output, and a control element, the control element being adapted to receive a third control signal via a second column line,

a second select switch having an input, an output, and a control element, the input being connected to the output of the second variable current element, thereby providing a series connection between the second variable current control element and the second select switch, the control element being adapted to receive a fourth control signal via a second row line, the input of the second variable current control element being adapted to contact the conductive solution and the output of the second select switch being connected to a third potential.

16. The unit cell circuit of claim 1 wherein the potential is VDD.

17. The unit cell circuit of claim 7 wherein the first potential is the supply potential.

18. The unit cell circuit of claim 17 wherein the supply voltage is in the range from substantially 0 to 10 volts.

19. The unit cell circuit of claim 17 wherein the supply voltage is substantially 5 volts.

20. The unit cell circuit of claim 7 wherein the second potential is substantially ½

of the supply potential.

21. The unit cell circuit of claim 7 wherein the third potential is ground.

22. The unit cell circuit of claim 21 wherein the second potential is between the supply potential and ground.

23. The unit cell circuit of claim 22 wherein the second potential is substantially ½

the supply potential.

25. The unit cell circuit of claim 7 wherein one of the first control signal and the third control signal is a square wave signal.

26. The unit cell circuit of claim 7 wherein one of the first control signal and the third control signal is an asymmetric square wave signal.

27. The unit cell circuit of claim 7 wherein one of the first control signal and the third control signal is a sinusoidal wave signal.

28. The unit cell circuit of claim 7 wherein one of the first control signal and the third control signal is a sawtooth wave signal.

6. A unit cell circuit for providing current in an active biological matrix device adapted to receive a conductive solution including charged biological materials, the active biological matrix device comprising an array of unit cells, the unit cell circuit comprising:

a variable current control element including an input, an output, and a control element, the control element being adapted to receive a first control signal via a first column line,

a select switch having an input, an output, and a control element, the input being connected to the output of the variable current element, thereby providing a series connection between the variable current control element and the select switch, the control element being adapted to receive a second control signal via a first row line, the input of the variable current control element being adapted to contact the conductive solution and the output of the select switch being connected to a first potential, and

a return electrode, the return electrode being connected to a second potential and adapted to contact the conductive solution,

whereby in the presence of the conductive solution current is provided between the return electrode and the input of the variable current control element, said unit cell circuit being located on the biological matrix device.

29. A current control system used with a unit cell circuit for providing current in an active biological matrix device adapted to receive a conductive solution including charged biological materials, the current control system comprising:

a first variable current source having an output,

a voltage divider having an input adapted to receive a first potential and a second input coupled to the output of the first variable current source, and an output node adapted to supply a second potential which varies as a function of the output of the first variable current source,

a unit cell coupled to the output node, the unit cell comprising;

a variable current control element having an input, an output and a control element, the control element coupled to a column line that is coupled to the output node adapted to supply the second potential, the input being coupled to a third potential, and

a select switch having an input, an output, and a control element, the input being connected to the output of the variable current element, thereby providing a series connection between the variable current control element and the select switch, the control element being adapted to receive a control signal via a row line, the output being coupled to a first electrode adapted to contact the conductive solution,

a return electrode, the return electrode being connected to a return potential,

whereby in the presence of the conductive solution current is variably provided between the return electrode and the first electrode.

24. The unit cell circuit of claim 33 wherein the first control signal is a static signal.

30. The current control system of claim 29 wherein the first variable current source includes a switched source.

31. The current control system of claim 30 wherein the first variable current source includes a plurality of switched current sources.

32. The current control system of claim 31 wherein the switched current sources are controlled by memory.

33. The current control system of claim 32 wherein the memory is a bi-state memory.

34. The current control system of claim 33 wherein the bi-state memory is a flip-flop.

35. The current control system of claim 32 wherein the memory includes a shift register.

36. The current control system of claim 29 wherein the voltage divider includes a switchable resistive element.

37. The current control system of claim 36 wherein the switchable voltage divider includes a series connected transistor.

38. The current control system of claim 37 wherein the series connected transistor is controlled by logic.

39. The current control system of claim 38 wherein the logic receives memory state outputs as inputs.

40. The current control system of claim 38 wherein the logic controls inclusion of resistance in the voltage divider if any memory is on.

41. The current control system of claim 38 wherein the logic is a NAND gate.

42. The current control system of claim 31 wherein the outputs of the switched current sources are summed.

43. The current control system of claim 29 wherein the first potential equals the second potential.

44. The current control system of claim 43 wherein the first potential and second potential are the supply potential.

45. The current control system t of claim 29 further including at least one current mirror to supply current to the first variable current source.

46. The current control system of claim 29 further including test transistors to provide a series connection between the third potential and the output being coupled to a first electrode adapted to contact the conductive solution.