Methods and apparatus for measuring analytes

• US 10,718,733 B2
• Filed: 07/01/2019
• Issued: 07/21/2020
• 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, Rothberg, Jonathan, Bustillo, James
• Primary Examiner(s): Ball, J. Christopher
• Application Number:
  US16/459,515
• Publication Number:
  US 20190339228A1
• Time in Patent Office: 386 Days
• 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. A semiconductor device, comprising:

a sensor array formed in columns and rows, wherein each sensor in the sensor array comprises a two-transistor circuit that includes a chemically-sensitive field effect transistor (chemFET), and a row select transistor;

an array of microwells formed on the sensor array, wherein each microwell is capacitively coupled to at least one sensor;

circuitry for reading each chemFET in the sensor array; and

an analog-to-digital converter (ADC) for each column in the sensor array to convert an analog signal from each chemFET in each column to a digital form that is output from the semiconductor device.

2. The semiconductor device of claim 1, wherein the circuitry for reading each chemFET in the sensor array includes a row-addressing circuit to provide a row address for each chemFET in the sensor array.

3. The semiconductor device of claim 1, wherein the sensor array is subdivided into a plurality of sensor array sub-regions;

each sensor array sub-region including;

circuitry for reading each chemFET in the sensor array sub-region; and

an ADC for each column in the sensor array sub-region to convert an analog signal from each chemFET in the sensor array sub-region to a digital form.

4. The semiconductor device of claim 3, wherein the sensor array further comprises a first sensor array sub-region and a second sensor array sub-region.

5. The semiconductor device of claim 4, wherein the semiconductor device further comprises a multiplexer to provide a single digital output stream.

6. The semiconductor device of claim 1, wherein each chemFET is coupled to a reference electrode voltage circuit.

7. The semiconductor device of claim 1, wherein the sensor array comprises at least 6.5 million sensors.

8. The semiconductor device of claim 1, wherein each chemFET has a first terminal that is coupled to a first readout signal line common to each chemFET of a respective column.

9. The semiconductor device of claim 1, wherein each chemFET in the sensor array further comprises a floating gate coupled to a chemically-sensitive passivation layer.

10. The semiconductor device of claim 9, wherein the chemically-sensitive passivation layer is sensitive to ionic species.

11. The semiconductor device of claim 10, wherein the chemically-sensitive passivation layer is sensitive to hydrogen ion.

12. The semiconductor device of claim 11, wherein each chemFET in the sensor array has a pH range for measuring change in hydrogen ion concentration from pH 6 to pH 9.5.

13. The semiconductor device of claim 12, wherein each chemFET in the sensor array has a pH range for measuring change in hydrogen ion concentration from pH 7 to pH 9.

14. The semiconductor device of claim 10, wherein the chemically-sensitive passivation layer is sensitive to pyrophosphate.

15. The semiconductor device of claim 1, wherein each microwell has a contiguous sidewall structure and a bottom surface defining each microwell.

16. The semiconductor device of claim 15, wherein the bottom surface comprises a chemically-sensitive passivation layer coupled to a floating gate.

17. The semiconductor device of claim 16, wherein the chemically-sensitive passivation layer is sensitive to hydrogen ion.

18. The semiconductor device of claim 16, wherein the chemically-sensitive passivation layer is sensitive to pyrophosphate.

19. The semiconductor device of claim 15, wherein the contiguous sidewall structure and the bottom surface defining each microwell includes a buffering inhibitor.