ACTIVE CHEMICALLY-SENSITIVE SENSORS WITH CORRELATED DOUBLE SAMPLING

• US 20120329044A1
• Filed: 08/30/2012
• Published: 12/27/2012
• Est. Priority Date: 05/29/2009
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Inventors: MILGREW, Mark
• Granted Patent: US 8,742,469 B2
• Time in Patent Office: Days
• US Class Current: 435/6.1
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• CPC Class Codes: C12Q 1/6874 involving nucleic acid arrays, e.g. sequencing by hybridisation
• 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 27/414 Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
• CPC Class Codes: G01N 27/4145 specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
• CPC Class Codes: G01N 27/4148 Integrated circuits therefor, e.g. fabricated by CMOS processing CMOS processing per se H01L21/82
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: Y10T 29/49002 Electrical device making

Abstract

Methods and apparatus relating to FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.

Claims

1. An apparatus, comprising:

an array of sensors, a sensor in the array including;

a chemically-sensitive field effect transistor (chemFET) having a first conduction terminal, a second conduction terminal coupled to a first supply voltage conductor, and a sensor surface;

a first transistor having a first conduction terminal coupled to the second conduction terminal of the chemFET, a second conduction terminal coupled to a second supply voltage conductor, and a gate coupled to a bias voltage conductor; and

a second transistor having a gate coupled to a first control signal conductor, a first conduction terminal coupled to the first conduction terminal of the chemFET, and a second conduction terminal coupled to an amplifier node;

a reset circuit coupled to the amplifier node and having an input coupled to a second control signal conductor, the reset circuit to reset the amplifier node to a reference voltage in response to a signal on the second control signal conductor;

an amplifier having an input connected to the amplifier node and having an output coupled to an output conductor; and

a controller to cause the amplifier to provide a first output while the amplifier node is reset to the reference voltage, and to cause the amplifier to provide a second output while the chemFET is coupled to the amplifier node.

2. The apparatus of claim 1, wherein the reset circuit includes a third transistor having a gate coupled to the second control signal conductor, a first conduction terminal coupled to the amplifier node, and a second conduction terminal coupled to a supply voltage conductor.

3. The apparatus of claim 1, wherein the amplifier includes:

a third transistor having a gate coupled to the amplifier node, a first conduction terminal coupled to a third supply voltage conductor, and a second conduction terminal; and

a fourth transistor having a gate coupled to a select signal conductor, a first conduction terminal coupled to the second conduction terminal of the third transistor, and a second conduction terminal coupled to the output conductor.

4. The apparatus of claim 3, wherein the output conductor is a column bus, and the select signal conductor is a row select signal conductor.

5. The apparatus of claim 1, wherein the bias conductor is coupled to a source of a bias voltage having a level setting the first transistor is a sub-threshold mode.

6. The apparatus of claim 1, wherein the bias conductor is coupled to a source of a bias voltage having a level setting the first transistor is a reverse-biased diode mode.

7. The apparatus of claim 1, wherein the first supply voltage conductor is coupled to ground, and the second supply voltage conductor is coupled to a positive supply voltage.

8. The apparatus of claim 1, wherein the chemFET includes a floating gate and a passivation layer, and the sensor surface is a surface of the passivation layer over the floating gate.

9. The apparatus of claim 8, wherein a difference between the first output of the amplifier and the second output of the amplifier indicates an ion-concentration of an analyte solution coupled to the floating gate via the passivation layer.

10. The apparatus of claim 1, including a chemical sample well including the sensor surface of the chemFET, and reference electrode coupled to an analyte solution in fluid flow communication with the chemical sample well.

11. A method of operating an apparatus comprising an array of chemically sensitive sensors arranged in rows and columns, the sensors including chemically-sensitive field effect transistors (chemFETs) and amplifiers, the method comprising:

coupling an output of an amplifier in a given sensor in the array of sensors to an output conductor in response to a select signal, the amplifier having an input coupled to an amplifier node;

coupling the amplifier node to a reference to produce a reference output signal at the output of the amplifier;

inducing a flow of current in the chemFET in the given sensor in the array, and connecting the chemFET to the amplifier node; and

producing a sensing output signal of the amplifier in response to a reaction proximate the chemFET.

12. The method of claim 11, wherein the connecting the amplifier node to a reference includes using a pull up transistor coupled to the amplifier node.

13. The method of claim 11, wherein the inducing includes using a transistor coupled to the chemFET in the given sensor biased in a current limiting mode.

14. The method of claim 13, wherein the inducing includes applying a sub-threshold voltage to the transistor in the given sensor.

15. The method of claim 13, wherein the inducing includes biasing the transistor in a reverse-bias diode mode.

16. The method of claim 11, wherein the coupling the output of the amplifier includes connecting the amplifier node to a gate of a first transistor in the amplifier, and turning on a second transistor coupled between a conduction terminal of the first transistor and the output conductor, in response to the select signal.

17. The method of claim 11, wherein the connecting the chemFET to the amplifier node includes coupling a conduction terminal of the chemFET via a switch transistor to the amplifier node.

18. The method of claim 11, including applying a chemical sample to chemical sample wells coupled to the plurality of sensors.

19. The method of claim 11, wherein the chemFET includes a floating gate and a passivation layer, and a sensor surface on the passivation layer over the floating gate.

20. The method of claim 19, wherein a difference between the first output signal and the second output signal indicates an ion-concentration of an analyte solution coupled to the floating gate via the passivation layer.

21. The method of claim 11, the sensors in the array including chemical sample wells, and including applying an analyte solution to the chemical sample wells, and coupling a reference electrode to the analyte solution.