Graphene FET devices, systems, and methods of using the same for sequencing nucleic acids

• US 9,618,474 B2
• Filed: 03/09/2016
• Issued: 04/11/2017
• Est. Priority Date: 12/18/2014
• Status: Active Grant

• Current Assignee: Cardea Bio, Inc.
• Original Assignee: Edico Genome Inc.
• Inventors: van Rooyen, Pieter, Lerner, Mitchell, Hoffman, Paul
• Primary Examiner(s): Fan, Michele
• Application Number:
  US15/065,744
• Publication Number:
  US 20160265047A1
• Time in Patent Office: 398 Days
• Field of Search: None
• CPC Class Codes: B01L 2300/0627 Sensor or part of a sensor is integrated
• CPC Class Codes: B01L 2300/0858 Side walls
• CPC Class Codes: B01L 2300/0887 Laminated structure
• CPC Class Codes: B01L 2300/12 Specific details about materials
• CPC Class Codes: B01L 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502761 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• 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 27/414 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 27/4146 involving nanosized elements, e.g. nanotubes, nanowires
• 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 27/085 including field-effect components only
• CPC Class Codes: H01L 29/1606 Graphene
• CPC Class Codes: H01L 29/24 including, apart from doping materials or other impurities, only semiconductor materials not provided for in groups H01L29/16, H01L29/18, H01L29/20, H01L29/22 including organic materials H10K99/00

Abstract

Provided herein are devices, systems, and methods of employing the same for the performance of bioinformatics analysis. The apparatuses and methods of the disclosure are directed in part to large scale graphene FET sensors, arrays, and integrated circuits employing the same for analyte measurements. The present GFET sensors, arrays, and integrated circuits may be fabricated using conventional CMOS processing techniques based on improved GFET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense GFET sensor based arrays. Improved fabrication techniques employing graphene as a reaction layer provide for rapid data acquisition from small sensors to large and dense arrays of sensors. Such arrays may be employed to detect a presence and/or concentration changes of various analyte types in a wide variety of chemical and/or biological processes, including DNA hybridization and/or sequencing reactions. Accordingly, GFET arrays facilitate DNA sequencing techniques based on monitoring changes in hydrogen ion concentration (pH), changes in other analyte concentration, and/or binding events associated with chemical processes relating to DNA synthesis within a gated reaction chamber of the GFET based sensor.

Claims

1. An integrated circuit for performing a sequencing reaction, the sequencing reaction involving the sequencing of strands of nucleic acids, the integrated circuit comprising:

a substrate;

an array of graphene field effect transistors arranged on the substrate, each of the graphene field effect transistors comprising;

a primary layer forming a base layer;

a secondary layer over the primary layer, the secondary layer being formed of a first nonconductive material and comprising a source and a drain formed in the first nonconductive material, the source and drain being separated one from the other by a channel, the source and the drain being formed of an electrically conductive material; and

a tertiary layer over the secondary layer, the tertiary layer comprising a gate formed over the channel to electrically connect the source and the drain, the channel being formed of a graphene layer, the tertiary layer further comprising a surface structure that overlaps the source and the drain in the secondary layer, the surface structure further defining a well having side walls and a bottom that extends over at least a portion of the graphene layer of the channel so as to form a reaction chamber for the performance of the sequencing reaction; and

a chemically-sensitive bead provided in one or more wells of the array of graphene field effect transistors, each chemically-sensitive bead being configured with one or more reactants to interact with portions of the strands of nucleic acids such that the associated graphene field effect transistor detects a change in ion concentration of the reactants by a change in current flow from the source to the drain via an activation of the graphene layer.

2. The integrated circuit in accordance with claim 1, further comprising an ion sensitive layer disposed over the portion of the graphene layer at the bottom of the well, the ion sensitive layer being formed of an ion sensitive material.

3. The integrated circuit in accordance with claim 1, wherein the chemically-sensitive bead is provided to each well in a fluid solution.

4. The integrated circuit in accordance with claim 1, wherein the primary layer is formed of silicon.

5. The integrated circuit in accordance with claim 1, wherein the electrically conductive material that forms the source and/or the drain is selected from the group of electrically conductive materials that consist of:

copper, damascene, aluminum, platinum, and gold.

6. The integrated circuit in accordance with claim 1, wherein the surface structure of the tertiary layer is formed of a second nonconductive material selected from the group of second nonconductive materials that consist of:

polymide, BCB, silicon dioxide, silicon oxynitride, and silicon carbide.

7. The integrated circuit in accordance with claim 1, wherein the channel has a length of between 0.05 microns and 3 microns.

8. The integrated circuit in accordance with claim 1, wherein the channel has a width of between 0.05 microns and 2 microns.

9. The integrated circuit in accordance with claim 2, wherein the ion sensitive material includes an oxide material.

10. The integrated circuit in accordance with claim 9, wherein the oxide material is selected from the group of oxide materials that consist of:

aluminum oxide, silicon dioxide, hafnium dioxide, hafnium silicate, zirconium silicate, zirconium dioxide, lanthanum oxide, tantalum oxide, titanium oxide, iron oxide, and yttrium oxide.

11. An integrated circuit for performing a sequencing reaction, the sequencing reaction involving the sequencing of strands of nucleic acids, the integrated circuit comprising:

a substrate;

an array of graphene field effect transistors arranged on the substrate, each of the graphene field effect transistors comprising;

a primary layer forming a base layer;

a secondary layer over the primary layer, the secondary layer being formed of a first nonconductive material and comprising a source and a drain formed in the first nonconductive material, the source and drain being separated from each other by a channel, the source and the drain being formed of an electrically conductive material; and

a tertiary layer over the secondary layer, the tertiary layer comprising a gate formed over the channel, the channel to electrically connect the source and the drain, the channel being formed of a graphene layer, the tertiary layer further comprising a surface structure that overlaps the source and the drain in the secondary layer, the surface structure further defining a well having side walls and a bottom that extends over at least a portion of the graphene layer of the channel so as to form a reaction chamber for the performance of the sequencing reaction;

where one or more of the graphene field effect transistors of the integrated circuit is configured for detecting a change in ion concentration by a change in current flow from the source to the drain via an activation of the graphene layer resulting from the performance of the sequencing reaction.

12. The integrated circuit in accordance with claim 11, further comprising an ion sensitive layer disposed over the portion of the graphene layer at the bottom of the well, the ion sensitive layer being formed of an ion sensitive material.

13. The integrated circuit in accordance with claim 11, wherein the electrically conductive material that forms the source and/or the drain is selected from the group of electrically conductive materials that consist of:

copper, damascene, aluminum, platinum, and gold.

14. The integrated circuit in accordance with claim 11, further comprising an ion selective permeable membrane positioned over the graphene layer.

15. The integrated circuit in accordance with claim 11, wherein the gate is configured as a solution gate.

16. An integrated circuit for performing a sequencing reaction, the sequencing reaction involving the sequencing of strands of nucleic acids, the integrated circuit comprising:

a substrate;

an array of graphene field effect transistors arranged on the substrate, each of the graphene field effect transistors comprising;

a primary layer forming a base layer;

an intermediary layer over the primary layer, the intermediary layer being formed of a first nonconductive material and comprising a source and a drain formed in the first nonconductive material, the source and drain being separated from each other by a channel, the source and the drain being formed of an electrically conductive material; and

a tertiary layer over the secondary layer, the tertiary layer comprising a gate formed over the channel, the channel to electrically connect the source and the drain, the channel being formed of a graphene layer, the tertiary layer further comprising a surface structure that overlaps the source and the drain in the secondary layer, the surface structure further defining a well having side walls and a bottom that extends over at least a portion of the graphene layer of the channel so as to form a reaction chamber for the performance of the sequencing reaction.

17. The integrated circuit in accordance with claim 16, further comprising an ion sensitive layer disposed over the portion of the graphene layer at the bottom of the well, the ion sensitive layer being formed of an ion sensitive material.

18. The integrated circuit in accordance with claim 16, wherein the electrically conductive material that forms the source and/or the drain is selected from the group of electrically conductive materials that consist of:

copper, damascene, aluminum, platinum, and gold.

19. The integrated circuit in accordance with claim 16, further comprising an ion selective permeable membrane positioned over the graphene layer.

20. The integrated circuit in accordance with claim 16, wherein the gate is configured as a solution gate.