Methods and Apparatus for Measuring Analytes Using Large Scale FET Arrays

• US 20120129728A1
• Filed: 02/02/2011
• Published: 05/24/2012
• 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 8,264,014 B2
• Time in Patent Office: Days
• US Class Current: 506/16
• 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:

a sensor array of at least 10⁵ sensors each comprising at least one chemFET having a gate oxide with a characteristic thickness, a floating gate, and a characteristic threshold voltage, wherein the characteristic threshold voltage of each chemFET is affected by trapped charge; and

wherein each sensor comprises a trapped-charge-reducing element configured to reduce trapped charge in the chemFET.

108. The apparatus of claim 107, wherein the trapped-charge reducing element forms a temporary electrical connection between the floating gate and a substrate associated with a respective sensor.

109. The apparatus of claim 107, wherein the trapped-charge-reducing element comprises a transistor.

110. The apparatus of claim 107, wherein the floating gate for a respective sensor is coupled to a gate of the trapped-charge-reducing element.

111. The apparatus of claim 107, where the characteristic threshold voltage for a respective chemFET sensor is similar to the characteristic threshold voltages of other chemFETs in the sensor array.

112. The apparatus of claim 107, further comprising control circuitry configured to detect output signals from the sensors, where the output signals are dependent on the respective threshold voltages of the sensors.

113. The apparatus of claim 112, wherein the output signals from the sensors are substantially similar in response.

114. The apparatus of claim 112, wherein the control circuitry further comprises at least one analog-to-digital converter.

115. The apparatus of claim 107, wherein the sensors of the sensor array are substantially similar in sensitivity.

116. The apparatus of claim 107, further comprising an array of reaction chambers coupled to the array of sensors.

117. The apparatus of claim 116, wherein output signals are created in response to the presence of analytes in the reaction chambers.

118. The apparatus of claim 117, wherein the analytes comprise hydrogen ions.

119. The apparatus of claim 117, wherein the analytes comprise byproducts of a chemical reaction.

120. The apparatus of claim 119, wherein the chemical reaction comprises nucleotide incorporation into a sample nucleic acid template.

121. A method of reducing trapped charge in a chemFET sensor comprising:

providing a sensor array of at least 10⁵ sensors each comprising at least one chemFET having

a substrate, a floating gate, and a characteristic threshold voltage, wherein the characteristic threshold voltage of each chemFET is affected by trapped charge; and

wherein at least one sensor or the sensor array comprises a trapped-charge-reducing element; and

causing the trapped-charge-reducing element in the at least one sensor to form a temporary electrical connection between the gate and the substrate of the first sensor thereby reducing the trapped charge in the at least one sensor.

122. The method of claim 121, where the trapped-charge-reducing element comprises a transistor coupled to the gate and substrate of the first sensor.

123. The method of claim 121, further comprising disconnecting the trapped-charge-reducing element from the gate and the substrate of the at least one sensor.

124. The method of claim 121, wherein the floating gate for the at least one sensor is coupled to a gate of the trapped-charge-reducing element.

125. The method of claim 121, further comprising configuring the characteristic threshold voltage for a respective sensor to be similar to the characteristic threshold voltages of other sensors in the sensor array.

126. The method of claim 121, further comprising detecting output signals from the sensors, where the output signals are dependent on the respective threshold voltages of the sensors.

127. A chemFET sensor array comprising:

an array of at least 10⁵ chemFET sensors each comprising a substrate, a floating gate, and a characteristic threshold voltage, wherein the characteristic threshold voltage of each chemFET is affected by trapped charge; and

wherein the chemFETs comprise a trapped-charge-reducing element configured to reduce trapped charge in the chemFETs where an electrical connection between the gate and the substrate reduces the trapped charge in the chemFETs.

128. The chemFET sensor array of claim 127, where the characteristic threshold voltage for a respective chemFET is similar to the characteristic threshold voltages of other chemFETs in the sensor array.

129. The chemFET sensor array of claim 127, further comprising control circuitry configured to detect output signals from the chemFETs, where the output signals are dependent on the respective threshold voltages of the chemFETs.

130. The chemFET sensor array of claim 129, wherein the output signals are substantially similar in response.