Multiplexed active biologic array

• US 5,965,452 A
• Filed: 07/09/1996
• Issued: 10/12/1999
• Est. Priority Date: 07/09/1996
• Status: Expired due to Term

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen, Inc.
• Inventors: Kovacs, Gregory T. A.
• Primary Examiner(s): Soderquist, Arlen
• Application Number:
  US08/677,305
• Time in Patent Office: 1,190 Days
• Field of Search: 204/413, 204/412, 204/435, 204/290 R, 422/68.1, 422/82.01, 422/82.03, 422/82.02, 422/82.05, 436/73, 436/79, 436/86-90, 436/93-95, 436/106-113, 436/127-132, 436/149-151, 436/164, 436/172, 436/501, 436/503, 436/508, 436/512, 436/513, 436/518 , 436/527
• US Class Current: 436/149
• 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 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel 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 2219/00617 by chemical means
• 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 2219/00653 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 2219/00722 Nucleotides
• CPC Class Codes: G01N 27/27 Association of two or more measuring systems or cells, each measuring a different parameter, where the measurement results may be either used independently, the systems or cells being physically associated, or combined to produce a value for a further parameter
• CPC Class Codes: G01N 27/3276 being a hybridisation with immobilised receptors using a FET type sensor G01N27/4145; concerning the hybridisation C12Q1/68
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: Y10T 436/142222 Hetero-O [e.g., ascorbic acid, etc.]
• CPC Class Codes: Y10T 436/143333 Saccharide [e.g., DNA, etc.]
• CPC Class Codes: Y10T 436/144444 Glucose
• CPC Class Codes: Y10T 436/17 Nitrogen containing
• CPC Class Codes: Y10T 436/170769 N-Nitroso containing [e.g., nitrosamine, etc.]
• CPC Class Codes: Y10T 436/171538 : Urea or blood urea nitrogen
• CPC Class Codes: Y10T 436/173845 : Amine and quaternary ammonium
• CPC Class Codes: Y10T 436/20 : Oxygen containing
• CPC Class Codes: Y10T 436/200833 : Carbonyl, ether, aldehyde or ketone containing
• CPC Class Codes: Y10T 436/203332 : Hydroxyl containing

Abstract

An improved biologic electrode array and methods for manufacturing and using the same. In one aspect, a matrix of electrodes each coupled to a respective sample-and-hold circuit is provided. The electrodes and sample-and-hold circuits are integral and form an array within a single semiconductor chip, such that each sample-and-hold circuit may be loaded with a predefined voltage provided by a single, timeshared digital-to-analog converter (DAC). Further, all of the sample-and-hold circuits may be accessed through a multiplexer which may be scanned through some or all of the electrode locations. Each sample-and-hold circuit may comprise a capacitor and one or more transistor switches, the switch(es), when closed, providing electrical communication between the capacitor and a source line formed in the matrix.

Claims

1. A biologic electrode matrix comprising:

a plurality of addressable biologic electrode sites, wherein each electrode site resides on a common integrated circuit chip and comprises an electrode, an output amplifier circuit having an output coupled to said electrode, a capacitor coupled to an input of said output amplifier circuit for driving said output amplifier circuit, and at least one switch coupled to said capacitor.

2. The biologic electrode matrix of claim 1, wherein each biologic electrode site further comprises a voltage amplifier having an input coupled to said electrode for sensing a voltage of said electrode.

3. The biologic electrode matrix of claim 1, wherein each biologic electrode site further comprises a current sensing circuit having an input coupled to said electrode for sensing a current flowing through said electrode.

4. The biologic electrode matrix of claim 1, wherein said plurality of biologic electrode sites are arranged in a plurality of rows and columns,

each row of biologic electrode sites is coupled to a distinct row select line,

each column of biologic electrode sites is coupled to a distinct column select line, and

each biologic electrode site comprises switching circuitry responsive to a coincidence of select signals on respective row and column select lines, said switching circuitry providing an electrical connection between said capacitor and an analog programming signal upon receiving select signals on both of said respective row and column select lines.

5. The biologic electrode matrix of claim 4, wherein each biologic electrode site further comprises an optical detector formed beneath said electrode, and each electrode is at least partially transparent.

6. An electrode site for use in a biologic electrode array, said biologic electrode array being formed on an integrated circuit chip, and said site comprising:

an electrode,

a sample-and-hold circuit, and

an output amplifier coupled to said electrode and said sample-and-hold circuit, said sample-and-hold circuit being configured to provide an electrical signal to said output amplifier for driving said output amplifier.

7. The electrode site of claim 6, wherein said sample-and-hold circuit comprises a capacitor coupled to a switching circuit, said switching circuit being responsive to a coincidence of select signals on respective row and column select lines and providing an electrical connection between said capacitor and an analog programming signal upon receiving select signals on both of said respective row and column select lines.

8. The electrode site of claim 6, wherein said sample-and-hold circuit comprises a capacitor coupled to a switching circuit, said switching circuit being controlled by an output of a two-input logic gate and, when closed, providing electrical communication between said capacitor and a voltage source line of said biologic electrode array.

9. The electrode site of claim 6, wherein said sample-and-hold circuit comprises a capacitor coupled to a pair of CMOS transmission gates, said CMOS transmission gates being configured in series and, when closed, providing electrical communication between said capacitor and a voltage source line formed within said biologic electrode array.

10. An electrode site for use in a biologic electrode array, said biologic electrode array being formed on an integrated circuit chip, and said site comprising:

an electrode and an analog signal storage element coupled to said electrode via an amplifier circuit, said analog signal storage element being configured to provide an electrical input signal to said amplifier circuit for driving said amplifier circuit.

11. The electrode site of claim 10, wherein said analog signal storage element comprises a capacitor coupled to a switching circuit.

12. The electrode site of claim 11, wherein said switching circuit is controlled by an output of a two-input logic gate and, upon receiving a selected output signal from said logic gate, provides electrical communication between said capacitor and a voltage source line of said biologic electrode array.

13. The electrode site of claim 10, wherein said analog signal storage means comprises a capacitor coupled to a pair of CMOS transmission gates, said CMOS transmission gates being configured in series and, when closed, providing electrical communication between said capacitor and a voltage source line formed within said biologic electrode array.

14. A biologic electrode array, comprising:

a memory;

a digital-to-analog converter coupled to said memory;

a counter;

a row decoder coupled to said counter and to said memory;

a column decoder coupled to said counter and to said memory; and

a matrix of active biologic electrodes formed on an integrated circuit chip and coupled to said digital-to-analog converter, said row decoder and said column decoder;

said matrix of active biologic electrodes having a plurality of biologic electrode sites arranged in a plurality of rows and columns;

each said biologic electrode site having an electrode and a sample-and-hold circuit coupled to said electrode via an amplifier circuit such that said sample-and-hold circuit may cause said amplifier circuit to provide an amplified electrical stimulus to said electrode;

said sample-and-hold circuit being coupled to a selected row select line, a selected column select line and a source line of said matrix.

15. The biologic electrode array of claim 14, wherein said memory, said digital-to-analog converter, said counter, said row decoder, said column decoder, and said matrix are formed on a single semiconductor chip.

16. The biologic electrode array of claim 14, further comprising a sense amplifier coupled to each said electrode of said biologic electrode sites.

17. The biologic electrode array of claim 14, wherein an optical detector is disposed beneath at least one electrode of said biologic electrode sites and the electrode located at said at least one of said biologic sites is at least partially transparent.

18. The biologic electrode array of claim 17, wherein said at least one electrode comprises indium tin oxide.

19. The biologic electrode array of claim 17, wherein said at least one electrode comprises a slitted electrode structure for passing light therethrough.

20. The biologic electrode array of claim 17, wherein said at least one electrode comprises a punctuated electrode structure for passing light therethrough.

21. The biologic electrode array of claim 14 further comprising at least one heating element.

22. The biologic electrode array of claim 14 further comprising a plurality of heating elements which may be selectively controlled.

23. A site for use in a biologic electrode array, said biologic electrode array being formed on an integrated circuit chip, and said site comprising:

an electrode;

a driving element coupled to said electrode for applying an electrical stimulus to said electrode; and

a local memory coupled to said driving element for receiving and storing a signal indicative of a magnitude of said electrical stimulus to be applied to said electrode.

24. The site of claim 23, wherein said driving element comprises an amplifier and said local memory comprises a capacitor.

25. The site of claim 24, wherein said capacitor is coupled to a signal source line of said biologic electrode array via a pair of switches, one switch being coupled to a row select line of said biologic array, and the other switch being coupled to a column select line of said biologic array.

26. A method of controlling an electrical characteristic of an electrode within a biologic electrode array, said biologic electrode array being formed on an integrated circuit chip, and said method comprising the steps of:

retrieving from a memory a digital value representing a voltage to be stored on at least one sample-and-hold circuit formed within said biologic electrode array, said sample-and-hold circuit being coupled to said electrode of said biologic electrode array via an output amplifier such that an output of said sample-and-hold circuit may drive said output amplifier causing said output amplifier to apply an electrical stimulus signal to said electrode;

providing said retrieved digital value to a digital-to-analog converter, said digital-to-analog converter generating a voltage proportional to said retrieved digital value and providing said voltage to a conductor in electrical communication with said at least one sample-and-hold circuit;

storing said voltage on said at least one sample-and-hold circuit; and

allowing said sample-and-hold circuit to drive said output amplifier in response to receiving and storing said voltage.

27. The method of claim 26 wherein said steps of retrieving, providing and storing are periodically repeated to ensure that said voltage stored on said sample-and-hold circuit remains within a preselected range of voltages.

28. A method of controlling an electrical characteristic of an electrode within a biologic electrode array, said biologic electrode array being formed on a single substrate, and said method comprising the steps of:

addressing an electrode site within said biologic electrode array;

providing to a sample-and-hold circuit located at said addressed electrode site an electrical signal indicative of an electrical stimulus to be applied to and electrode located at said electrode site; and

allowing said sample-and-hold circuit located at said electrode site to cause said electrical stimulus to be applied to said electrode via a driving element.

29. The method of claim 28, wherein said biologic electrode array includes a plurality of row select lines and column select lines, said electrode site is coupled to a selected row select line and a selected column select line, and said addressing step is performed by providing electrical signals on said selected row and column select lines.

30. A method of controlling an electrical characteristic of an electrode within a biologic electrode array, said biologic electrode array being formed on at least one substrate, and said method comprising the steps of:

addressing an electrode site within said biologic electrode array;

providing to a local memory circuit located at said electrode site an electrical signal indicative of an electrical stimulus to be applied to an electrode located at said electrode site; and

allowing said local memory circuit to communicate with a driving element located at said electrode site to control said electrical stimulus to be applied to said electrode.

31. An electronic device adapted to receive a solution including electrolytes and one or more charged specific binding entities, the device being adapted to affect the electrophoretic transport of the specific binding entities in the solution to selected locations on the device surface, the device comprising:

a plurality of addressable biologic electrode sites formed on a single integrated circuit chip,

wherein each electrode site comprises an electrode, an output amplifier circuit coupled to said electrode for providing an electrical stimulus to said electrode, an analog storage element coupled to said output amplifier circuit for controlling said output amplifier circuit, and a switching circuit coupled to said analog storage element,

wherein the electrode of each electrode site has formed on a surface thereof a permeation layer for providing transport of counter-ions between the electrode and the solution, and

wherein the permeation layer of each electrode site has formed thereon a biologic attachment layer for enabling coupling with one or more selected binding entities from within the solution.

32. The electronic device of claim 31, wherein

said plurality of biologic electrode sites are arranged in a plurality of rows and columns,

each row of biologic electrode sites is coupled to a distinct row select line,

each column of biologic electrode sites is coupled to a distinct column select line, and

the switching circuit of each biologic electrode site is responsive to a coincidence of select signals on respective row and column select lines and provides an electrical connection between the analog storage element coupled thereto and an analog programming signal upon receiving select signals on both of said respective row and column select lines.