Active chemically-sensitive sensors with correlated double sampling

Abstract

Methods and apparatus relating to FET arrays for monitoring chemical and/or biological reactions such as nucleic acid sequencing-by-synthesis reactions. Some methods provided herein relate to improving signal (and also signal to noise ratio) from released hydrogen ions during nucleic acid sequencing reactions.

What is claimed is: 
     
         1 . A method of operating an apparatus comprising an array of chemically sensitive sensors arranged in rows and columns, the sensors including chemically-sensitive field effect transistors (chemFETs) and amplifiers, the method comprising:
 coupling an output of an amplifier in a given sensor in the array of sensors to an output conductor in response to a select signal, the amplifier having an input coupled to an amplifier node;   coupling the amplifier node to a reference to produce a reference output signal at the output of the amplifier;   inducing a flow of current in the chemFET in the given sensor in the array, and connecting the chemFET to the amplifier node; and   producing a sensing output signal of the amplifier in response to a reaction proximate the chemFET.   
     
     
         2 . The method of  claim 1 , wherein the connecting the amplifier node to a reference includes using a pull up transistor coupled to the amplifier node. 
     
     
         3 . The method of  claim 1 , wherein the inducing includes using a transistor coupled to the chemFET in the given sensor biased in a current limiting mode. 
     
     
         4 . The method of  claim 3 , wherein the inducing includes applying a sub-threshold voltage to the transistor in the given sensor. 
     
     
         5 . The method of  claim 3 , wherein the inducing includes biasing the transistor in a reverse-bias diode mode. 
     
     
         6 . The method of  claim 1 , wherein the coupling the output of the amplifier includes connecting the amplifier node to a gate of a first transistor in the amplifier, and turning on a second transistor coupled between a conduction terminal of the first transistor and the output conductor, in response to the select signal. 
     
     
         7 . The method of  claim 1 , wherein the connecting the chemFET to the amplifier node includes coupling a conduction terminal of the chemFET via a switch transistor to the amplifier node. 
     
     
         8 . The method of  claim 1 , including applying a chemical sample to chemical sample wells coupled to the plurality of sensors. 
     
     
         9 . The method of  claim 1 , wherein the chemFET includes a floating gate and a passivation layer, and a sensor surface on the passivation layer over the floating gate. 
     
     
         10 . The method of  claim 9 , wherein a difference between the first output signal and the second output signal indicates an ion-concentration of an analyte solution coupled to the floating gate via the passivation layer. 
     
     
         11 . The method of  claim 1 , the sensors in the array including chemical sample wells, and including applying an analyte solution to the chemical sample wells, and coupling a reference electrode to the analyte solution.