METHODS AND APPARATUS FOR MEASURING ANALYTES USING LARGE SCALE FET ARRAYS

• US 20100188073A1
• Filed: 01/22/2010
• Published: 07/29/2010
• Est. Priority Date: 12/14/2006
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: ION Torrent Systems Incorporated (Thermo Fisher Scientific Incorporated)
• Inventors: Rothberg, Jonathan M., Hinz, Wolfgang, Johnson, Kim L., Bustillo, James
• Granted Patent: US 8,426,898 B2
• Time in Patent Office: Days
• US Class Current: 324/123.R
• CPC Class Codes: C12Q 1/6818 involving interaction of two or more labels, e.g. resonant energy transfer
• CPC Class Codes: C12Q 1/6874 involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: C12Q 2533/101 Primer extension
• CPC Class Codes: C12Q 2565/301 Pyrophosphate (PPi)
• 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: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: H01L 27/088 the components being field-effect transistors with insulated gate
• CPC Class Codes: H01L 29/42324 Gate electrodes for transistors with a floating gate
• CPC Class Codes: H01L 29/78 with field effect produced by an insulated gate H01L29/7725, H01L29/775, H01L29/778 take precedence
• CPC Class Codes: H01L 2924/01006 Carbon [C]
• CPC Class Codes: H01L 2924/01013 Aluminum [Al]
• CPC Class Codes: H01L 2924/01015 Phosphorus [P]
• CPC Class Codes: H01L 2924/01073 Tantalum [Ta]
• CPC Class Codes: H01L 2924/14 Integrated circuits
• CPC Class Codes: H01L 2924/1433 Application-specific integrated circuit [ASIC]
• CPC Class Codes: Y10T 436/22 Hydrogen, per se

Abstract

Methods and apparatus relating to very large scale FET arrays for analyte measurements. ChemFET (e.g., ISFET) arrays may be fabricated using conventional CMOS processing techniques based on improved FET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense arrays. Improved array control techniques provide for rapid data acquisition from large and dense arrays. 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. In one example, chemFET 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.

Claims

1. An apparatus, comprising:

an array (100) of CMOS-fabricated sensors (105), each sensor comprising one chemically-sensitive field effect transistor (chemFET) (150) and occupying an area on a surface of the array of approximately ten micrometers by ten micrometers or less.

2. The apparatus of claim 1, wherein the area occupied by each sensor is approximately nine micrometers by nine micrometers or less.

5. The apparatus of claim 1, wherein the plurality of CMOS-fabricated sensors includes more than 256 sensors.

6. The apparatus of claim 5, wherein the array includes a two-dimensional array of at least 512 rows and at least 512 columns of the CMOS-fabricated sensors.

9. The apparatus of claim 5, wherein a collection of chemFET output signals from all chemFETs of the array constitutes a frame of data, and wherein the apparatus further comprises control circuitry (110, 192, 194, 198) coupled to the array and configured to generate at least one array output signal (Vout) to provide multiple frames of data from the array at a frame rate of at least 10 frames per second.

10. The apparatus of claim 9, wherein the control circuitry is configured such that the frame rate is at least 20 frames per second.

13. The apparatus of claim 1, wherein the chemFET of each sensor comprises:

a floating gate structure (170); and

a source (156) and a drain (158) having a first semiconductor type and fabricated in a region (154) having a second semiconductor type, wherein there is no electrical conductor that electrically connects the region having the second semiconductor type to either the source or the drain.

14. The apparatus of claim 13, further comprising at least one first electrical conductor to electrically connect together all regions having the second semiconductor type of all chemFETs in the array.

15. The apparatus of claim 1, wherein each sensor comprises:

a plurality of field effect transistors (FETs), including the chemFET; and

a plurality of second electrical conductors electrically connected to the plurality of FETs,

wherein the plurality of FETs are arranged such that the plurality of second electrical conductors includes no more than four conductors traversing an area occupied by each sensor and interconnecting multiple sensors of the array.

16. The apparatus of claim 1, wherein each sensor comprises three or fewer field effect transistors (FETs), including the chemFET.

17. The apparatus of claim 15, wherein all of the FETs in each sensor are of a same channel type and implemented in the region having the second semiconductor type.

18. The apparatus of claim 1, wherein the chemFET of each sensor is an ion-sensitive field effect transistor (ISFET).

3-4. -4. (canceled)

7-8. -8. (canceled)

11-12. -12. (canceled)

19-50. -50. (canceled)

51. An apparatus, comprising:

an array (100) of CMOS-fabricated sensors (105), each sensor comprising a chemically-sensitive field effect transistor (chemFET) (150), the chemFET comprising;

a floating gate structure (170); and

a source (156) and a drain (158) having a first semiconductor type and fabricated in a region (154) having a second semiconductor type, wherein there is no electrical conductor that electrically connects the region having the second semiconductor type to either the source or the drain.

52. The apparatus of claim 51, further comprising at least one first electrical conductor to electrically connect together all regions having the second semiconductor type of all chemFETs in the array.

53. The apparatus of claim 51, wherein the chemFET is a p-channel chemFET, and wherein the region having the second semiconductor type is formed as an n-type well in a p-type substrate (152) for the array.

54. The apparatus of claim 51, wherein each sensor comprises:

a plurality of field effect transistors (FETs), including the chemFET; and

a plurality of second electrical conductors electrically connected to the plurality of FETs,

wherein the plurality of FETs are arranged such that the plurality of second electrical conductors includes no more than four conductors traversing an area occupied by each sensor and interconnecting multiple sensors of the array.

57. The apparatus of claim 54, wherein all of the FETs in each sensor are of a same channel type and implemented in the region having the second semiconductor type.

58. The apparatus of claim 57, wherein all of the FETs in each sensor are p-channel FETs, and wherein the region having the second semiconductor type is formed as an n-type well (154) in a p-type substrate (152) for the array.

59. The apparatus of claim 51, wherein each sensor occupies an area on a surface of the array of ten micrometers by ten micrometers or less.

62. The apparatus of claim 51, wherein the array includes a two-dimensional array of the CMOS-fabricated sensors arranged in a plurality of rows and a plurality of columns.

63. The apparatus of claim 62, wherein the array includes at least 512 rows and at least 512 columns of the CMOS-fabricated sensors.

64. The apparatus of claim 62, wherein for each column of the plurality of columns, the array further comprises:

column circuitry (110) configured to provide a constant drain current and a constant drain-to-source voltage to respective chemFETs in the column.

65. The apparatus of claim 64, wherein the column circuitry includes two operational amplifiers (107A,B) and a diode-connected FET arranged in a Kelvin bridge configuration with the respective chemFETs to provide the constant drain-to-source voltage.

69. The apparatus of claim 62, further comprising at least one output driver (198), the at least one output driver comprising:

at least one buffer amplifier (199); and

at least one asymmetric switch (191) to couple at least some columns of the plurality of columns to the at least one buffer amplifier so as to provide at least one array output signal (Vout),

wherein the at least one asymmetric switch comprises a CMOS-pair transmission gate having differently-sized FETs.

70. The apparatus of claim 69, wherein a collection of chemFET output signals from all chemFETs of the array constitutes a frame of data, and wherein the at least one row select shift register, the at least one column select shift register, and/or the at least one output driver is/are configured to generate the at least one array output signal so as to provide multiple frames of data from the array at a frame rate of at least 20 frames per second.

55-56. -56. (canceled)

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