Programmable multiplexed active biologic array

• US 7,267,751 B2
• Filed: 08/20/2002
• Issued: 09/11/2007
• Est. Priority Date: 08/20/2002
• Status: Expired due to Term

• Current Assignee: Ador Diagnostics S.R.L., Nanogen, Inc.
• Original Assignee: Nanogen, Inc.
• Inventors: Swanson, Paul David, Powrie, Don L., Gelbart, Richard
• Primary Examiner(s): SINES, BRIAN J
• Application Number:
  US10/224,750
• Publication Number:
  US 20040038420A1
• Time in Patent Office: 1,848 Days
• Field of Search: 422/50, 422/61, 422/68.1, 422/81, 422/82.01, 422/82.02, 436/43, 436/63, 436/149, 436/150, 436/151, 204/193, 204/400, 204/403.01, 204/403.03, 204/403.13, 204/406, 204/407, 204/409, 204/411, 204/412
• US Class Current: 204/406
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/00653 the compounds being bound to electrodes embedded in or on the solid supports
• CPC Class Codes: B01J 2219/00698 Measurement and control of process parameters
• CPC Class Codes: B01J 2219/00704 integrated with the reactor apparatus
• CPC Class Codes: G01N 27/028 Circuits therefor measuring impedance per se G01R27/02
• 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: Y10T 436/11 Automated chemical analysis

Abstract

The present invention is directed to devices and methods for carrying out and/or monitoring biological reactions in response to electrical stimuli. A programmable multiplexed active biologic array includes an array of electrodes coupled to sample-and-hold circuits. The programmable multiplexed active biologic array includes a digital interface that allows external control of the array using an external processor. The circuit may monitor, digitally control, and deliver electrical stimuli to the electrodes individually or in selected groups.

Claims

1. A digitally programmable array-based electronic chip for carrying out biological reactions in response to electrical stimuli, comprising:

an array of electrode sites, each electrode site including a sample-and-hold circuit coupled to a working electrode;

a plurality of switches for selectively coupling the working electrodes to the output of a digital-to-analog converter (DAC);

a control logic module coupled to the DAC and the plurality of switches;

a measurement circuit comprising one or more electrical output pathways for selectively coupling the array of electrode sites to an analog-to-digital converter (ADC), the ADC coupled to the control logic module;

a current measurement circuit, the current measurement circuit comprising a first selectable connection to the sample-and-hold circuit, a series connected resistor and a second selectable connection to the sample-and-hold circuit, the current measurement circuit operating in a current measurement mode when the first and second selectable connections are closed and in a high impedance mode when the first and second selectable connections are open; and

an external processor that digitally interfaces with the control logic module, wherein the communication between the control logic and the external processor includes a clock signal, a data in signal, and a data out signal.

2. The electronic chip of claim 1, wherein the sample-and-hold circuits may be configured to operate in normal mode, current measurement mode, high-impedance mode, and voltage measurement mode.

3. The electronic chip of claim 1, further comprising a temperature sensor.

4. The electronic chip of claim 1, further comprising a transceiver coupled with the control logic module for enabling the external processor to communicate with the control logic module through a serial interface.

5. The electronic chip of claim 1, further comprising:

a dual port random access memory module, having a plurality of addresses, coupled to the DAC and the control logic module; and

a counter coupled to the dual port random access memory;

wherein the DAC retrieves a value from the memory to produce a corresponding voltage and the counter specifies the address within the memory where the DAC retrieves the value.

6. The electronic chip of claim 1, further comprising a measurement circuit coupled with the array, configured for measuring the voltage and current through the electrodes.

7. The electronic circuit of claim 1, further comprising a reference electrode coupled with the array and an external voltage source coupled with the reference electrode.

8. The electronic chip of claim 1, wherein the measurement circuit is capable of measuring temperature.

21. The electronic chip of claim 1, wherein the measurement circuit is capable of measuring voltage.

22. The electronic chip of claim 21, wherein the measurement circuit further comprises an external resistor and two nodes coupled with two voltage sense amplifiers.

9. A method for carrying out biological reactions in response to electrical stimuli applied to a plurality of electrodes, comprising the steps of:

providing a chip having an array of electrode sites, each electrode site containing a sample-and-hold circuit coupled to a working electrode, a digital-to-analog converter (DAC), a plurality of switches for selectively coupling the DAC to the working electrodes, and a control logic module coupled to the DAC and the plurality of switches;

providing an external processor that digitally interfaces with the chip;

providing a measurement circuit comprising one or more electrical output pathways for selectively coupling the array of electrodes to an analog-to-digital converter (ADC), the ADC coupled to the control logic module;

providing a current measurement circuit, the current measurement circuit comprising a first selectable connection to the sample-and-hold circuit, a series connected resistor and a second selectable connection to the sample-and-hold circuit, the current measurement circuit operating in a current measurement mode when the first and second selectable connections are closed and in a high impedance mode when the first and second selectable connections are open; and

driving the working electrodes in accordance with instructions contained in the external processor.

10. The method of claim 9, wherein the external processor interfaces with the chip using a transceiver, the transceiver communicating with the chip using a data in signal, a data out signal, and a clock signal.

11. The method of claim 9, wherein the working electrodes are driven at a constant voltage.

12. The method of claim 9, wherein the working electrodes are driven at a constant current.

13. The method of claim 9, wherein the working electrodes are driven at a voltage that is offset from a reference voltage.

14. The method of claim 9, further comprising the step of providing a temperature sensor adjacent to the chip and measuring the temperature of a solution contained on the chip.

15. The method of claim 9, further comprising the step of measuring the current running through an individual electrode or a selected group of electrodes.

16. The method of claim 9, further comprising the step of measuring the voltage running through an individual electrode or a selected group of electrodes.

17. The method of claim 13, further comprising the step of monitoring a user programmable offset between the reference voltage and the voltage of an individual electrode or a selected group of electrodes.

18. The method of claim 9, further comprising the step of sequentially refreshing the sample-and-hold circuits.

19. The method of claim 18, wherein the sample-and-hold circuits are refreshed synchronously with a clock signal having a frequency of approximately 10 MHz.

20. The method of claim 18, wherein the sample-and-hold circuits are refreshed using the DAC, and wherein the DAC is coupled to a dual port random access memory that is further coupled to a counter.