Multiplexed active biologic array

• US 6,258,606 B1
• Filed: 07/30/1999
• Issued: 07/10/2001
• 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:
  US09/364,676
• Time in Patent Office: 711 Days
• Field of Search: 204/290.R, 204/412, 204/413, 204/435, 422/68.1, 422/82.01, 422/82.02, 422/82.03, 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, time-shared 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.

In another aspect, a memory (for example, a random access memory (RAM)), a digital-to-analog converter (DAC) coupled to the memory, a counter, a row decoder coupled to the counter and to the memory, a column decoder coupled to the counter and to the memory, and a matrix of active biologic electrodes coupled to the row decoder and t he column decoder are provided on a single semiconductor chip for carrying out a series of reactions.

In another aspect, provision is made for the fabrication of an entire active array surface on a thermally-isolated membrane containing at least one on-board, controllable heating element. By cycling the temperature of the heating element(s), it is possible to carry out DNA amplification in situ, if suitable reagents are present.

Finally, in still another aspect, provision is made for the incorporation of optical fluorescence or transmittance detection circuitry within a biologic electrode array matrix.

Claims

1. A biologic electrode array assembly formed on an integrated circuit chip, said biologic electrode array assembly comprising:

a row decoder,

a column decoder,

a counter coupled to said row decoder and said column decoder,

a matrix of active biologic electrodes coupled to said row decoder and said column decoder such that individual electrode sites within said matrix may be selectively addressed by said row decoder and said column decoder, and

a memory coupled to said row decoder, said column decoder, and a digital to analog converter, said digital to analog converter being coupled to said matrix of active biologic electrodes, and said memory enabling on-chip storage of digital values corresponding to a controllable characteristic of a stimulus to be applied at selected ones of said individual electrode sites.

2. The biologic electrode array assembly of claim 1, wherein said controllable characteristic is a voltage level.

3. The biologic electrode array assembly of claim 1, wherein said controllable characteristic is a current level.

4. A biological electrode array assembly formed on an integrated circuit chip, said biological electrode array assembly comprising:

a plurality of rows of biological electrode sites, wherein each row is coupled to a distinct row line;

a plurality of columns of biological electrode sites, wherein each column is coupled to a distinct column line;

a driving element coupled to each of the biological electrode sites for delivering an electrical stimulus to each biological electrode site; and

a local memory coupled to said driving element for each of the biological electrode sites for storing signal information corresponding to the magnitude of the electrical stimulus that is to be applied to each site.

5. A biological electrode array according to claim 4, further comprising:

a row decoder;

a column decoder; and

a counter coupled to said row decoder and said column decoder, wherein individual biological electrode sites are selectively addressed by said row decoder and said column decoder.

6. A biological electrode array according to claim 5 further comprising a memory coupled to said row decoder, said column decoder, and a digital-to-analog converter, said memory enabling on-chip storage of digital values corresponding to a controllable characterization of a stimulus to be applied at individual electrode sites.

7. A biological electrode array according to claim 4, further comprising a source line coupled to said local memory for input of the signal information.

8. A biological electrode array according to claim 7, wherein the source line is a voltage source line.

9. A biological electrode array according to claim 4, wherein said local memory is an EEPROM.

10. A method of selectively controlling the electrical characteristics of individual electrode sites in an array arranged in rows and columns, the method comprising the steps of:

addressing at least one electrode site in the array;

storing signal information corresponding to the electrical characteristics of the at least one addressed electrode site at a sample-and-hold circuit coupled with each addressed electrode site; and

driving each electrical site via a driving element in response to said stored signal information.

11. A method of controlling the electrical characteristics of individual electrode sites in an array arranged in rows and columns, the method comprising the steps of:

addressing a first group of electrode sites within the array, the first group of electrode sites addressed via a plurality of column select lines and row select lines;

storing first signal information corresponding to the electrical characteristics of the first group of addressed electrode sites at a sample-and-hold circuit coupled with each addressed electrode site;

driving each electrode site within the first group via individual driving elements in response to said stored first signal information;

addressing a second group of electrode sites within the array, the second group of electrode sites addressed via said plurality of column select lines and row select lines;

storing second signal information corresponding to the electrical characteristics of the second group of addressed electrode sites at a sample-and-hold circuit coupled with each addressed electrode site; and

driving each electrode site within the second group via individual driving elements in response to said stored second signal information.

12. A method according to claim 11, wherein the first signal information corresponds to voltage.

13. A method according to claim 11, wherein the first signal information corresponds to current.

14. A method according to claim 11, wherein said first signal information is different from said second signal information.

15. A method according to claim 11, wherein the second signal information corresponds to voltage.

16. A method according to claim 11, wherein the second signal information corresponds to current.

17. A method according to claim 11, wherein the address information, the first signal information, and the second signal information are stored within a memory.

18. A method according to claim 17, wherein the memory is an on-chip memory.

19. A method according to claim 11, further including the step of updating the first group of addressed electrode sites, said updating comprising the step of again storing said first information corresponding to the electrical characteristics of the first group of addressed electrode sites at the sample-and-hold circuit coupled with each addressed electrode site within the first group.

20. A method according to claim 11, further including the step of updating the second group of addressed electrode sites, said updating comprising the step of again storing said second information corresponding to the electrical characteristics of the second group of addressed electrode sites at the sample-and-hold circuit coupled with each addressed electrode site within the second group.

21. A method of selectively controlling the electrical characteristics of an array of individual electrode sites arranged in rows and columns through the use of a column select line, a row select line, and a signal line, the method comprising the steps of:

addressing a first group of electrode sites via said column select line and said row select line;

sending first group signal information via said signal line to the first group of electrode sites, said first group of signal information being stored at a sample-and-hold circuit coupled to each electrode site within the first group;

driving each electrode site within the first group via a driving element in response to the stored first group of signal information;

addressing a next group of electrode sites via said column select line and said row select line;

sending next group signal information via said signal line to the next group of electrode sites, said next group of signal information being stored at a sample-and-hold circuit coupled to each electrode site within the next group; and

driving each electrode site within the next group via a driving element in response to the stored next group of signal information.

22. A method according to claim 21 further including the steps of addressing via said column select lines and said row select lines additional groups of electrode sites, sending signal information via said signal line to these additional groups of electrode sites, and driving via driving elements, the additional groups of electrode sites.

23. A method of selectively controlling the electrical voltages of individual electrode sites in an array arranged in rows and columns, the method comprising the steps of:

storing binary values within a memory, said binary values representing voltages to be applied at the various electrode sites;

addressing at least one electrode site within the array;

retrieving the binary value from the memory for each addressed electrode site;

converting the binary value to a voltage stored in a sample-and-hold circuit for each addressed electrode site; and

driving each electrode site via a driving element in response to the stored voltage.

24. A method of selectively controlling the electrical voltages of individual electrode sites in an array arranged in rows and columns, the method comprising the steps of:

storing binary values within a memory, said binary values representing voltages to be applied at the various electrode sites;

addressing at least one electrode site within the array;

retrieving the binary value from the memory for each addressed electrode site;

storing a voltage signal in a local memory, the voltage signal corresponding to the binary values stored in the memory; and

driving each electrode site via a driving element in response to the stored voltage signal in the local memory.