Integrated sensor arrays for biological and chemical analysis

• US 8,936,763 B2
• Filed: 10/22/2009
• Issued: 01/20/2015
• Est. Priority Date: 10/22/2008
• Status: Active Grant

• Current Assignee: GM Global Technology Operations Incorporated (Motors Liquidation Co. GUC Trust), Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Inventors: Rothberg, Jonathan, Bustillo, James, Milgrew, Mark, Schultz, Jonathan, Marran, David, Rearick, Todd, Johnson, Kim
• Primary Examiner(s): GORDON, MATTHEW E
• Application Number:
  US13/125,133
• Publication Number:
  US 20110263463A1
• Time in Patent Office: 1,916 Days
• Field of Search: 422/82.05, 422/502, 422/504, 436/164, 250/370.14, 257/253, 257/E23.08, 438/10
• US Class Current: 422/407
• 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: C12Q 2565/607 being a sensor, e.g. electrode
• 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: H01L 21/82 to produce devices, e.g. integrated circuits, each consisting of a plurality of components

Abstract

The invention is directed to apparatus and chips comprising a large scale chemical field effect transistor arrays that include an array of sample-retaining regions capable of retaining a chemical or biological sample from a sample fluid for analysis. In one aspect such transistor arrays have a pitch of 10 μm or less and each sample-retaining region is positioned on at least one chemical field effect transistor which is configured to generate at least one output signal related to a characteristic of a chemical or biological sample in such sample-retaining region. In one embodiment, the characteristic of said chemical or biological sample is a concentration of a charged species and wherein each of said chemical field effect transistors is an ion-sensitive field effect transistor having a floating gate with a dielectric layer on a surface thereof, the dielectric layer contacting said sample fluid and being capable of accumulating charge in proportion to a concentration of the charged species in said sample fluid. In one embodiment such charged species is a hydrogen ion such that the sensors measure changes in pH of the sample fluid in or adjacent to the sample-retaining region thereof. Apparatus and chips of the invention may be adapted for large scale pH-based DNA sequencing and other bioscience and biomedical applications.

Claims

1. An apparatus comprising:

an array of sensors, a sensor in the array including

a chemically-sensitive field effect transistor generating a sensor signal at a circuit node during a first time interval in response to a reaction occurring within a reaction well, and

a first switch between the chemically-sensitive field effect transistor and the circuit node to couple a terminal of the chemically-sensitive field effect transistor to the circuit node in response to a select signal;

a reference circuit including a second switch directly connected to the circuit node for coupling a reference signal to the circuit node in response to a timing signal during a second time interval; and

a sampling circuit producing an output signal as a function of a first sample obtained during the first time interval and a second sample obtained during the second time interval.

2. The apparatus of claim 1, wherein the output signal indicates a characteristic of the reaction.

3. The apparatus of claim 2, wherein the characteristic of the reaction is a concentration of a charged species in a sample fluid.

4. The apparatus of claim 3, wherein the chemically-sensitive field effect transistor has a floating gate with a dielectric layer on a surface thereof.

5. The apparatus of claim 4, wherein the dielectric layer comprises a metal oxide.

6. The apparatus of claim 5, wherein the metal oxide is selected from the group consisting of aluminum oxide, tantalum oxide, silicon nitride, silicon oxynitride, tantalum pentoxide, tin oxide, and stannic oxide.

7. The apparatus of claim 1, wherein the output signal is based on a difference between the first and the second samples.

8. The apparatus of claim 1, wherein the sampling circuit includes a sample and hold capacitor, and a difference circuit that stores a difference between the first sample and the second sample on the sample and hold capacitor.

9. The apparatus of claim 1, wherein the sampling circuit includes an amplifier having an input coupled to the circuit node and an output coupled by a switch to a sample and hold capacitor, and a feedback circuit between the input and output of the amplifier.

10. The apparatus of claim 9, wherein the feedback circuit provides a first feedback path between the input and output of the amplifier during the first time interval, and provides a second feedback path between the input and output of the amplifier during the second time interval.

11. The apparatus of claim 10, wherein:

the first feedback path includes a first switch; and

the second feedback path includes a feedback capacitor in series with a second switch.

12. An apparatus, comprising:

an array of sensors, a sensor in the array including a chemically-sensitive field effect transistor to generate a sensor signal in response to a reaction occurring within a reaction well, and a switch coupled between the chemically-sensitive field effect transistor and a circuit node to couple a terminal of the chemically-sensitive field effect transistor to the circuit node;

a buffer coupled between the switch and the circuit node; and

a sampling circuit coupled to the circuit node to take a first sample when the switch is closed, to take a second sample when the switch is open, and to produce an output signal based on a difference between the first sample and the second sample; and

a second switch between the circuit node and a reference signal.

13. The apparatus of claim 12, wherein the second sample is based on a reference signal coupled to the circuit node when the switch is open.

14. The apparatus of claim 12, wherein the sampling circuit takes the first sample when the second switch is open, and takes the second sample when the second switch is closed.

15. The apparatus of claim 12, wherein the sensor signal is based on a threshold voltage of the chemically-sensitive field effect transistor.

16. The apparatus of claim 12, wherein the sensor signal is a voltage at a conduction terminal of the chemically-sensitive field effect transistor, and the switch is coupled between the conduction terminal and the circuit node.