Methods and apparatus for measuring analytes using large scale fet arrays

• US 20120034607A1
• Filed: 09/26/2011
• Published: 02/09/2012
• Est. Priority Date: 12/14/2006
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Inventors: ROTHBERG, Jonathan M., Hinz, Wolfgang, Johnson, Kim L., Bustillo, James
• Granted Patent: US 9,269,708 B2
• Time in Patent Office: Days
• US Class Current: 435/6.11
• 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

1-106. -106. (canceled)

107. An apparatus comprising:

an array of electronic sensors arranged in a plurality of rows and a plurality of columns, wherein each sensor in the array of electronic sensors comprises a field-effect transistor (FET);

a plurality of microwells, wherein each microwell is disposed on at least one sensor; and

a column circuit configured to provide a drain current and a drain-to-source voltage to each of the FETs in a column of the array of electronic sensors.

108. The apparatus of claim 107, further comprising:

at least one row select shift register configured to enable at least one row in the plurality of rows;

at least one column shift register configured to acquire an output signal from at least one FET in the array of electronic sensors; and

an output driver.

109. The apparatus of claim 108, wherein the at least one row select shift register comprises a plurality of row select shift registers configured to simultaneously select at least two rows from the plurality of rows.

110. The apparatus of claim 108, wherein the at least one column shift register comprises a plurality of column shift registers configured to simultaneously acquire a plurality of output signals from a plurality of respective FETs from at least two columns of the plurality of columns.

111. The apparatus of claim 108, wherein the output driver comprises:

at least one buffer amplifier; and

at least one switch configured to couple at least two columns from the plurality of columns to the at least one buffer amplifier, wherein an output of the at least one buffer amplifier comprises an array output signal based on a plurality of output signals from a plurality of respective FETs.

112. The apparatus of claim 111, wherein the array output signal constitutes a frame of data, and wherein the output driver is configured to generate multiple frames of data at a rate of at least 10 frames per second.

113. The apparatus of claim 108, wherein the output signal is a voltage signal measured in reference to a voltage of a reference electrode.

114. The apparatus of claim 108, wherein a plurality of output signals from a respective plurality of sensors constitutes a frame of data, and wherein the output driver is configured to generate multiple frames of data at a rate of at least 10 frames per second

115. The apparatus of claim 107, wherein the FET is an ion-sensitive field-effect transistor (ISFET) with a threshold voltage that changes based on a chemical reaction occurring in at least one microwell.

116. The apparatus of claim 115, wherein the chemical reaction comprises a hydrogen ion concentration byproduct and an output signal of the ISFET represents one or more changes in the hydrogen ion concentration in the at least one microwell.

117. The apparatus of claim 107, wherein the column circuit comprises a plurality of amplifiers and a diode-connected FET arranged in a Kelvin bridge configuration with a respective sensor to provide the drain-to-source voltage.

118. An apparatus comprising:

an array of electronic sensors with more than 256 sensors, wherein each sensor in the array of electronic sensors comprises a field-effect transistor (FET);

a plurality of microwells, wherein each microwell is disposed on at least one sensor; and

a control circuit coupled to the array of electronic sensors and configured to generate at least one array output signal to provide multiple frames of data from the array of electronic sensors.

119. The apparatus of claim 118, wherein the array of sensors is arranged in a plurality of rows and a plurality of columns.

120. The apparatus of claim 119, wherein the plurality of rows comprises at least 512 rows and the plurality of columns comprises at least 512 columns.

121. The apparatus of claim 119, wherein each of the columns in the plurality of columns comprises a column circuit configured to provide a drain current and a drain-to-source voltage to each of the FETs in a column of the array of electronic sensors.

122. The apparatus of claim 118, wherein the FET is an ion-sensitive field-effect transistor (ISFET) with a threshold voltage that changes based on a chemical reaction occurring in at least one microwell.

123. The apparatus of claim 122, wherein the chemical reaction comprises a hydrogen ion concentration byproduct and an output signal of the ISFET represents one or more changes in the hydrogen ion concentration in the at least one microwell.

124. The apparatus of claim 122, wherein the control circuit comprises an output driver circuit configured to generate multiple frames of data at a rate of at least 10 frames per second.

125. A method comprising:

providing a drain current and a drain-to-source voltage to each field effect transistor (FET) in an array of electronic sensors arranged in a plurality of rows and a plurality of columns, wherein each sensor in the array of electronic sensors comprises a microwell disposed on at least one sensor;

generating at least one array output signal to provide a plurality of frames of data from the array of electronic sensors.

126. The method of claim 125, wherein the FET is an ion-sensitive field effect transistor (ISFET), and wherein the generating comprises detecting a change in threshold voltage of the ISFET based on a chemical reaction occurring in at least one microwell.