INTEGRATED PHOTONIC ELECTRONIC SENSOR ARRAYS FOR NUCLEIC ACID SEQUENCING

• US 20150184237A1
• Filed: 12/27/2013
• Published: 07/02/2015
• Est. Priority Date: 12/27/2013
• Status: Active Grant

• Current Assignee: Intel Corporation
• Original Assignee: Su Xing
• Inventors: SU, XING, Oldham, Mark
• Granted Patent: US 9,593,371 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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: C12Q 2521/101 DNA polymerase
• CPC Class Codes: C12Q 2521/543 Immobilised enzyme(s)
• CPC Class Codes: C12Q 2537/157 A reaction step characterised by the number of molecules incorporated or released
• CPC Class Codes: C12Q 2563/116 electrical properties of nucleic acids, e.g. impedance, conductivity or resistance
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: G01N 27/00 Investigating or analysing materials by the use of electric, electrochemical, or magnetic means G01N3/00 – G01N25/00 take precedence; measurement or testing of electric or magnetic variables or of electric or magnetic properties of materials G01R
• CPC Class Codes: G01N 27/4145 specially adapted for biomolecules, e.g. gate electrode with immobilised receptors

Abstract

Devices and methods for detecting, identifying, and sequencing, compounds, complexes, and molecules are described. Electronic detection is combined with optical excitation to determine the presence or identity of an analyte of interest. Embodiments of the invention additionally provide devices and methods that allow highly parallel nucleic acid sequence determination.

Claims

1. A device comprising,

a substrate having a surface wherein the substrate comprises an integrated circuit chip,

an array of sensors on the substrate surface wherein the sensors are coupled to the electronics of and individually addressable through the integrated circuit chip and wherein the sensors are capable of sensing an electron transfer event that occurs proximate to the sensor surface,

an array of light harvesting antennas on the substrate surface wherein the light harvesting antennas are associated with the array of sensors such that at least one antenna is capable of localizing energy from light illuminating the antenna into a sensor region on the substrate surface for each of the sensors of the array of sensors.

2. The device of claim 1 wherein at least four antennas are capable of localizing light illuminating the substrate surface into a sensor region for each of the sensors of the array of sensors.

3. The device of claim 1 wherein the sensor is a field effect transistor or an extended gate field effect transistor.

4. The device of claim 3 wherein the field effect transistor or the extended gate field effect transistor has a surface and the surface comprises surface-attached molecules that are electron acceptors.

5. The device of claim 1 wherein the sensor is an electrode.

6. The device of claim 1 wherein the sensor is a high band gap semiconductor coated electrode.

7. The device of claim 1 wherein the sensor has an interface and the interface is comprised of a semiconducting material.

8. The device of claim 1 wherein the sensor region is 10 to 100 nm wide in its widest dimension.

9. The device of claim 1 wherein the light harvesting antennas are comprised of aluminum.

10. The device of claim 1 wherein the sensor region comprises an immobilized enzyme.

11. A method for sequencing a nucleic acid comprising,

on a substrate surface wherein the substrate comprises an integrated circuit chip and the substrate surface comprises an array of sensors and an array of light harvesting antennas, wherein a polymerase is immobilized in a sensor region for at least a subset of the sensors of the array, wherein a DNA molecule to be sequenced and a primer DNA molecule are complexed to the immobilized polymerase,

providing a solution comprising a plurality of different nucleotides labeled with at least two uniquely identifiable labels, wherein the uniquely identifiable labels comprise photosensitizers, to the substrate surface under conditions that allow immobilized polymerase to bind a labeled nucleotide complementary to a base of the DNA molecule to be sequenced,

exposing the surface of the substrate to light that causes a uniquely identifiable label of a nucleotide bound to polymerase to transition into an excited state,

detecting the presence of a uniquely identifiable label that transitioned into an exited state of a nucleotide bound to polymerase through the detection of electron transfer events by the sensor, and

determining the identity of a nucleotide complementary to a base of a DNA molecule to be sequenced through the detection of the presence of the uniquely identifiable label that transitioned into an excited state of a nucleotide bound to polymerase.

12. The method of claim 11 wherein the electron acceptor is provided in the solution comprising a plurality of different nucleotides labeled with at least two different uniquely identifiable labels.

13. The method of claim 11 wherein the sensor is an electrode and the detection of electron transfer events at the sensor comprises detecting a change in current at the sensor.

14. The method of claim 11 wherein the sensor is a field effect transistor or an extended gate field effect transistor and the detection of electron transfer events at the sensor comprises detecting a change in charge of an electron acceptor or an electron donor on the surface of the field effect transistor.

15. The method of claim 11 wherein the sensor is an ion sensitive field effect transistor or a chemical field effect transistor.

16. The method of claim 11 wherein the plurality of different nucleotides is four different nucleotides and each one is labeled with a different uniquely identifiable label, wherein the uniquely identifiable labels comprise photosensitizers.

17. The method of claim 11 wherein the sensor region is 10 to 100 nm wide in its widest dimension.

18. The method of claim 11 wherein the light harvesting antennas are comprised of aluminum.

19. A method for sequencing a nucleic acid comprising,

on a substrate surface wherein the substrate comprises an integrated circuit chip and the substrate surface comprises an array of sensors, wherein a polymerase is immobilized in a sensor region for at least a subset of the sensors of the array, wherein a DNA molecule to be sequenced and a primer DNA molecule are complexed to the immobilized polymerase,

providing a solution comprising a plurality of different nucleotides labeled with at least two uniquely identifiable labels, wherein the uniquely identifiable labels comprise photosensitizers, to the substrate surface under conditions that allow immobilized polymerase to bind a labeled nucleotide complementary to a base of the DNA molecule to be sequenced,

exposing the surface of the substrate to light that causes a uniquely identifiable label of a nucleotide bound to polymerase to transition into an excited state,

detecting the presence of a uniquely identifiable label that transitioned into an exited state of a nucleotide bound to polymerase through the detection of electron transfer events by the sensor, and

determining the identity of a nucleotide complementary to a base of a DNA molecule to be sequenced through the detection of the presence of the uniquely identifiable label that transitioned into an excited state of a nucleotide bound to polymerase.

20. The method of claim 19 wherein the electron acceptor is provided in the solution comprising a plurality of different nucleotides labeled with at least two uniquely identifiable labels.

21. The method of claim 19 wherein the sensor is an electrode and the detection of electron transfer events at the sensor comprises detecting a change in current at the sensor.

22. The method of claim 19 wherein the sensor is a field effect transistor or an extended gate field effect transistor and the detection of electron transfer events at the sensor comprises detecting a change in charge of an electron acceptor or an electron donor on the surface of the field effect transistor.

23. The method of claim 19 wherein the sensor is an ion sensitive field effect transistor or a chemical field effect transistor.

24. The method of claim 19 wherein the plurality of different nucleotides is four different nucleotides and each one is labeled with a uniquely identifiable label, wherein the uniquely identifiable labels comprise photosensitizers.

25. The method of claim 19 wherein the sensor region is 10 to 100 nm wide in its widest dimension.