INTEGRATED SENSOR ARRAYS FOR BIOLOGICAL AND CHEMICAL ANALYSIS

• US 20110263463A1
• Filed: 10/22/2009
• Published: 10/27/2011
• 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: Milgrew, Mark, Rearick, Todd, Rothberg, Jonathan M., Bustillo, James, Johnson, Kim, Schultz, Jonathan, Marran, David
• Granted Patent: US 8,936,763 B2
• Time in Patent Office: Days
• US Class Current: 506/39
• 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 a chemical field effect transistor array in a circuit-supporting substrate, such transistor array having disposed on its surface an array of sample-retaining regions capable of retaining a chemical or biological sample from a sample fluid, wherein such transistor array has a pitch of 10 μ

m 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.

2. The apparatus of claim 1 wherein said 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 related to a concentration of the charged species in said sample fluid.

3. The apparatus of claim 2 wherein said dielectric layer has a thickness selected to maximize capacitance thereacross.

4. The apparatus of claim 3 wherein said thickness of said dielectric layer is between 1 and 1000 nanometers.

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

6. The apparatus of claim 5 wherein said 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 4 wherein said dielectric layer comprises a bilayer consisting of a charge-sensitive layer in fluid contact with said sample fluid and an adhesion layer disposed on said floating gate for bonding the charge-sensitive layer to said floating gate.

8. The apparatus of claim 7 wherein said charge-sensitive layer is tantalum oxide and said adhesion layer is aluminum dioxide.

9. The apparatus of claim 1 wherein said array of sample-retaining regions is an array of microwells formed on and integral with said chemical field effect transistor array, each microwell of the array having walls enclosing a microwell volume and each microwell volume being capable of containing said chemical or biological sample.

10. The apparatus of claim 9 wherein said array of microwells is enclosed by a flow cell sealingly attached to said chemical field effect transistor array, the flow cell being configured to deliver reagents to said microwells and the flow cell having an inlet, an outlet, and forming a chamber with the array that defines a flow path for the reagents, such that each microwell is in fluid communication with the chamber.

11. The apparatus of claim 10 wherein said chamber is configured to provide a flow rate of said reagents which is substantially equal at each of said microwells.

12. The apparatus of claim 11 wherein said circuit-supporting substrate further includes control circuitry coupled to said chemical field effect transistor array to receive samples of said output signals from said chemical field effect transistors at a rate of at least one frame per second.

13. An integrated sensor array comprising:

a plurality of sensors formed in a circuit supporting substrate, each sensor comprising a chemical field-effect transistor, the sensors being in a planar array of greater than 256 sensors at a density greater than 100 sensors per mm², each sensor of the array being configured to provide at least one output signal related to a concentration or presence of a chemical or biological sample proximate thereto, such output signal being substantially the same for each sensor of the array in response to the same concentration or presence of the same chemical or biological sample.

14. The integrated sensor array of claim 13, further including a plurality of sample-retaining regions in said circuit supporting substrate, each sample-retaining region on and operationally associated with at least one of said sensors.

15. The integrated sensor array of claim 14 wherein said concentration includes 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 a sample fluid containing said chemical or biological sample and being capable of accumulating charge in proportion to a concentration of the charged species in the sample fluid adjacent thereto.

23. The integrated sensor array of claim 14 wherein said array of sample-retaining regions is an array of microwells formed on and integral with said chemical field effect transistor array, each microwell of the array having walls defining a microwell volume and each microwell volume being capable of containing said chemical or biological sample and wherein said array of microwells is enclosed by a flow cell sealingly attached to said chemical field effect transistor array, the flow cell being configured to deliver reagents to said microwells and the flow cell having an inlet, an outlet, and an interior that defines a flow path for the reagents, such that each microwell is in fluid communication with the interior of the flow cell.

24. The integrated sensor array of claim 23 wherein said interior of said flow cell is configured to provide a flow rate of said reagents which is substantially equal at each of said microwells.

16-22. -22. (canceled)

25. A single chip chemical assay device comprising:

a sensor array formed in a circuit supporting substrate, each sensor of the array comprising a chemical field-effect transistor and being configured to provide at least one output signal related to a concentration or presence of a chemical or biological sample proximate thereto, such output signal being substantially the same for each sensor of the array in response to the same concentration or presence of the same chemical or biological sample;

a plurality of sample-retaining regions in the circuit supporting substrate, each sample-retaining region disposed on at least one sensor; and

control circuitry in the circuit supporting substrate coupled to the sensor array to receive samples of the output signals from said chemical field effect transistors at a rate of at least one frame per second.

26. The assay device of claim 25 wherein said concentration includes 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 a sample fluid containing said chemical or biological sample and being capable of accumulating charge in proportion to a concentration of the charged species in the sample fluid adjacent thereto.

31. The assay device of claim 26 wherein said plurality of sample-retaining regions is an array of microwells formed on and integral with said chemical field effect transistor array, each microwell of the array having walls enclosing a microwell volume and each microwell volume being capable of containing said chemical or biological sample.

27-30. -30. (canceled)

32-36. -36. (canceled)