IP Library › Granted Patent US 12,372,521
Granted Patent B2
US 12,372,521 · App. 17/402,361 · Granted Jul 29, 2025

Chemically differentiated sensor array

Inventor: Brett Goldsmith (San Diego, CA)
Assignee: Cardea Bio, Inc.
G01N33/54373C12Q1/6869G01N27/4145G01N27/4148G01N33/02G01N33/4836G01N33/49G01N33/493G01N33/5438
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Quick Facts
Patent No.
US 12,372,521
App. No.
17/402,361
Granted
Jul 29, 2025
Kind
B2
Abstract

Apparatuses, systems, and methods are disclosed for chemically differentiated sensor arrays and methods of manufacturing and using the same. In one or more examples. An integrated circuit chip includes a chemically differentiated array of graphene field effect transistors with one or more wells configured to receive a volume of biological sample liquid comprising a plurality of different types of biological substances to be distinguished using electrical measurements of output signals of the graphene field effect transistors. At least one electrode is configured to apply a changing gate bias voltage (V G s) that increases and decreases within a predetermined range to the sample liquid and at least one electrode is configured to monitor measurement vectors including slopes of drain current measurements relative to the voltage measurements and differences in slope of the measurement vectors distinguish different biological substances in the sample liquid. Systems and methods utilize the integrated circuit chip.

Claims (50)

1. An integrated circuit chip comprising:

a chemically differentiated array of graphene field effect transistors, the graphene field effect transistors individually including a source, a drain, and a graphene channel;

one or more wells that are formed above one or more groups of the graphene field effect transistors of the array and are configured to receive a volume of biological sample liquid comprising a plurality of different types of biological substances to be distinguished using electrical measurements of output signals of the graphene field effect transistors;

a first type of biomolecule that functionalizes graphene channels of a first group of the one or more groups of graphene field effect transistors, the first type of biomolecule selected to bind to a first type of biological substance comprised in the sample liquid;

a second type of biomolecule that functionalizes graphene channels of a second group of the one or more groups of graphene field effect transistors, the second type of biomolecule selected to bind to a second type of biological substance comprised in the sample liquid and different from the first type of biological substance;

one or more electrodes disposed on a top surface of the chip and offset horizontally from channels of any of the graphene field effect transistors in the array, wherein at least one of the one or more electrodes is configured to apply a changing gate bias voltage (V Gs ) to the sample liquid and at least one of the one or more electrodes is configured to monitor a reference voltage (V REF ) of the sample liquid, wherein the gate bias voltage increases and decreases within a predetermined range;

wherein in response to the changing gate bias voltage being applied to the sample liquid, the graphene field effect transistors are operable to output:

a first set of one or more output signals for obtaining first measurement vectors indicative of binding between the first type of biomolecule functionalizing the first group of graphene field effect transistors and the first type of biological substance in the sample liquid; and

a second set of one or more output signals for obtaining one or more second measurement vectors, different from said first measurement vectors and indicative of binding between the second type of biomolecule above the second group of graphene field effect transistors and the second type of biological substance in the sample liquid, wherein:

said measurement vectors individually comprise voltage measurements of the V REF of the sample liquid, current measurements of the graphene field effect transistor output signal, and slopes of drain current measurements relative to the voltage measurements; and

differences in slope of said measurement vectors are operable to distinguish binding between the first type of biomolecule and the first type of biological substance in the sample liquid from binding between the second type of biomolecule and the second type of biological substance in the sample liquid.

2. The integrated circuit chip of claim 1 , wherein at least one of the one or more electrodes is disposed on the top surface of the integrated circuit chip between the first and second groups of graphene field effect transistors.

3. The integrated circuit chip of claim 1 , wherein the one or more electrodes comprise a first electrode configured to apply the gate bias voltage (V Gs ) to the sample liquid and a second electrode configured to measure the reference voltage (V REF ) of the sample liquid, wherein the first electrode, the second electrode, and graphene channels of the first and second groups of graphene field effect transistors are disposed such that an imaginary line passes through a region separating the graphene channels of the first and second groups of graphene field effect transistors from portions of the first and second electrodes that contact the sample liquid.

4. The integrated circuit chip of claim 2 , wherein one or more groups of the graphene field effect transistors individually comprise five graphene channels arranged along an imaginary line.

5. The integrated circuit chip of claim 4 , wherein the five graphene channels within a group are functionalized with the same biomolecule for detecting the same biological substance in the sample liquid.

6. The integrated circuit chip of claim 4 , wherein the five graphene channels within a group are functionalized with differing biomolecules for detecting the different biological substances in the sample liquid.

7. The integrated circuit chip of claim 1 , wherein the graphene field effect transistors in the array are operable to obtain the differences in slope of the measurement vectors when the gate bias voltage applied to the sample liquid increases and decreases between −1 volt and +1 volt.

8. The integrated circuit chip of claim 1 , wherein the graphene channels of the graphene field effect transistors in the array comprise scattering sites formed of sp 3 hybridized carbon that are chemically prepared to enable covalent bonding of biomolecule for functionalizing the graphene by applying an oxidizing agent selected from sulfuric acid, potassium permanganate, or hydrogen peroxide.

9. The integrated circuit chip of claim 1 , wherein the first type of biomolecule and the second type of biomolecule different from the first type of biomolecule are selected from proteins and antibodies, selected to bind respectively to antibodies and proteins in the biological substance types comprised in the sample liquid.

10. The integrated circuit chip of claim 1 , wherein a third group of the graphene field effect transistors is functionalized with a third type of biomolecule different from the first and second types of biomolecules, wherein the first, second, and third type of biomolecule are selected from proteins, antibodies, and nucleic acid probes chosen respectively to bind to antibodies, proteins, and complementary nucleic acid sequences in the biological substance types comprised in the sample liquid.

11. A graphene transistor based system for multiplexed analysis of biological samples comprising:

an integrated circuit chip comprising:

a chemically differentiated array of graphene field effect transistors, the graphene field effect transistors individually including a source, a drain, and a graphene channel;

one or more wells that are formed above one or more groups of the graphene field effect transistors of the array and are configured to receive a volume of biological sample liquid comprising a plurality of different types of biological substances to be distinguished using electrical measurements of output signals of the graphene field effect transistors;

a first type of biomolecule that functionalizes graphene channels of a first group of the one or more groups of graphene field effect transistors, the first type of biomolecule selected to bind to a first type of biological substance comprised in the sample liquid;

a second type of biomolecule that functionalizes graphene channels of a second group of the one or more groups of graphene field effect transistors, the second type of biomolecule selected to bind to a second type of biological substance comprised in the sample liquid and different from the first type of biological substance;

one or more electrodes disposed on a top surface of the chip and offset horizontally from channels of any of the plurality of graphene field effect transistors in the array, wherein at least one of the one or more electrodes is configured to apply a changing gate bias voltage (V Gs ) to the sample liquid and at least one of the one or more electrodes is configured to monitor a reference voltage (V REF ) of the sample liquid, wherein the gate bias voltage increases and decreases within a predetermined range;

a computing device configured to perform measurements of current output of the graphene transistors in the array, the computing device comprising:

a processor, memory, and program code, the program code being configured to be executable by a processor to perform operations comprising:

obtaining first measurement vectors indicative of binding between the first type of biomolecule that functionalizes the first group of graphene field effect transistors and the first type of biological substance in the sample liquid; and

obtaining second measurement vectors, different from said first measurement vectors and indicative of binding between the second type of biomolecule that functionalizes the second group of graphene field effect transistors and the second type of biological substance in the sample liquid, wherein:

said measurement vectors individually comprise voltage measurements of the V REF of the sample liquid, current measurements of the graphene field effect transistor output signal, and slopes of drain current measurements relative to the voltage measurements; and

distinguishing binding between the first type of biomolecule and the first type of biological substance in the sample liquid from binding between the second type of biomolecule and the second type of biological substance in the sample liquid based at least in part on differences in slope of said measurement vectors.

12. The system of claim 11 , wherein at least one of the one or more electrodes is disposed on the top surface of the integrated circuit chip between the first and second groups of graphene field effect transistors.

13. The system of claim 12 , wherein one or more groups of the graphene field effect transistors individually comprise five graphene channels arranged along an imaginary line.

14. The system of claim 13 , wherein the five graphene channels within a group are functionalized with the same biomolecule for detecting the same biological substance in the sample liquid.

15. The system of claim 13 , wherein the five graphene channels within a group are functionalized with differing biomolecules for detecting the different biological substances in the sample liquid.

16. The system of claim 11 , wherein the graphene field effect transistors in the array are operable to obtain the differences in slope of the measurement vectors when the gate bias voltage applied to the sample liquid changes up and down between −1 volt and +1 volt.

17. The system of claim 11 , wherein the first type of biomolecule and the second type of biomolecule different from the first type of biomolecule are selected from proteins and antibodies, selected to bind respectively to antibodies and proteins in the biological substance types comprised in the sample liquid.

18. The system of claim 11 , wherein a third group of the graphene field effect transistors is functionalized with a third type of biomolecule different from the first and second types of biomolecules, wherein the first, second, and third type of biomolecule are selected from proteins, antibodies, and nucleic acid probes chosen respectively to bind to antibodies, proteins, and complementary nucleic acid sequences in the biological substance types comprised in the sample liquid.

19. A method for electronic biological sample analysis comprising:

delivering a biological sample liquid to one or more wells that are formed above one or more groups of a chemically differentiated array of graphene field effect transistors, the wells being configured to receive a volume of biological sample liquid comprising a plurality of different types of biological substances to be distinguished using electrical measurements of output signals of the graphene field effect transistors, wherein:

the graphene channels of a first group of one or more transistors in the array are functionalized with a first type of biomolecule selected to bind to a first biological substance in the sample liquid; and

the graphene channels of a second group of one or more transistors in the array are functionalized with a second type of biomolecule selected to bind to a second biological substance in the sample liquid;

applying a supply voltage (V D ) to the drain of the graphene field effect transistors in the array;

applying a changing gate bias voltage (V Gs ) to the sample liquid using a first electrode that is disposed on a top surface of the chip and offset horizontally from the channel of any of the plurality of transistors in the array, wherein the gate bias voltage increases and decreases within a predetermined range;

monitoring a reference voltage (V REF ) of the liquid using a second electrode that is disposed on a top surface of the chip and offset horizontally from the channel of any of the plurality of transistors in the array;

determining measurement vectors for the individual transistors of the array, the measurement vectors individually comprising output current (I D ) measurements of the transistor, measurements of the changing V REF voltage of the liquid, and slope measurements of the current outputs of the transistors relative to the changing V REF voltage of the liquid; and

distinguishing binding between the first type of biomolecule and the first biological substance in the sample liquid from binding between the second type of biomolecule and the second type of biological substance in the sample liquid based at least in part on differences in slope of said measurement vectors.

20. The method of claim 19 , wherein a third group of the graphene field effect transistors is functionalized with a third type of biomolecule different from the first and second types of biomolecules, wherein the first, second, and third type of biomolecule are selected from proteins, antibodies, and nucleic acid probes chosen respectively to bind to antibodies, proteins, and complementary nucleic acid sequences in the biological substance types comprised in the sample liquid.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 19, 2022
From: GOLDSMITH, BRETT
To: CARDEA BIO, INC.
Reel/Frame 061472/0325 →
Continuity (5)
Continuation 15589942 · May 8, 2017
Continuation 14884705 · Oct 15, 2015
Continuation In Part 14684283 · Apr 10, 2015
Continuation In Part 14263954 · Apr 28, 2014
Related Publication 20210382046A1 · Dec 9, 2021
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