ACTIVE CHEMICALLY-SENSITIVE SENSORS

• US 20120326767A1
• 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 8,698,212 B2
• Time in Patent Office: Days
• US Class Current: 327/509
• 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 comprising:

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

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

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

2. The apparatus of claim 1, wherein the gate of the first transistor is coupled to a select signal conductor.

3. The apparatus of claim 1, wherein the output conductor is a column bus, and the gate of the first transistor is coupled to a row select signal conductor.

4. The apparatus of claim 1, wherein a voltage on the output conductor is a function of a threshold voltage of the chemFET.

5. The apparatus of claim 4, wherein the threshold voltage of the chemFET is based on an ion-concentration of an analyte solution coupled to the sensor surface of the chemFET.

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

7. The apparatus of claim 6, wherein a voltage on the output conductor indicates an ion-concentration of an analyte solution coupled to the floating gate via the passivation layer.

8. 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.

9. The apparatus of claim 1, wherein the sensor consists of the chemFET, the first transistor, the second transistor and the third transistor, and corresponding conductors.

10. The apparatus of claim 1, wherein the current source conductor couples the second conduction terminal of the first transistor to a current source operated in sub-threshold mode.

11. The apparatus of claim 10, wherein the current source provides current exclusively to the sensor in the array of sensors.

12. The apparatus of claim 1, wherein the chemFET detects a reaction proximate to the sensor surface.

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

connecting current sources to the chemFETs in a row of the sensors;

amplifying a voltage on a conduction terminal of a chemFET in a particular sensor using the source follower amplifier in the particular sensor to produce a sensor output voltage; and

coupling the sensor output voltage to an output conductor coupled to sensors in the array.

14. The method of claim 13, wherein the connecting includes turning on a first transistor in the sensor coupled between the conduction terminal of the chemFET in the particular sensor and a current source in response to a row select signal, and the amplifying includes coupling the conduction terminal of the chemFET in the particular sensor to the gate of a second transistor in the source follower amplifier of the particular sensor and turning on a third transistor in the particular sensor coupled between a conduction terminal of the second transistor and the output conductor, in response to the row select signal.

15. The method of claim 13, including disposing a chemical sample in chemical sample wells coupled to the plurality of sensors, to produce voltages on conduction terminals of the chemFETs.

16. The method of claim 15, wherein the voltages on the conduction terminals of the chemFETs indicate sequencing reactions detected by the sensors.

17. The method of claim 15, wherein:

the disposing the chemical sample includes disposing a plurality of template nucleic acids in the chemical sample wells, and introducing a known nucleotide into the chemical sample wells; and

the voltages on the conduction terminals of the chemFETs indicate incorporation of the introduced known nucleotide into one or more primers that are hybridized to at least one of the template nucleic acids.

18. The method of claim 13, wherein the chemFET in the particular sensor includes a floating gate and a passivation layer, and a sensor surface on the passivation layer over the floating gate.

19. The method of claim 18, wherein a voltage on the output conductor indicates an ion-concentration of an analyte solution coupled to the floating gate via the passivation layer.

20. The method of claim 13, wherein the sensors in the array include chemical sample wells, and including applying an analyte solution to the chemical sample wells, and coupling a reference electrode to the analyte solution.