Methods and Apparatus for Measuring Analytes Using Large Scale FET Arrays

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.

1 - 106 . (canceled) 
     
     
         107 . A method for sample analysis comprising:
 (a) disposing a plurality of samples at discrete locations on a substrate associated with a semiconductor based sensor array comprising at least 10 3  sensors, wherein each discrete location is associated with at least one sensor comprising a field-effect transistor configured to provide output signals representative of sample reaction products detected proximate thereto;   (b) introducing one or more known sample reaction components at the discrete locations;   (c) providing conditions sufficient to permit the sample reaction components to produce sample reaction products;   (d) detecting at least one of the sample reaction products formed or brought in proximity to the at least one sensor;   (e) outputting at least one signal indicative of the at least one sensor detecting the at least one sample reaction products.   
     
     
         108 . The method of  claim 107  wherein the sensors of the sensor array have a chemically sensitive portion responsive to one or more of the sample reaction products and disposed in proximity to the substrate such that the at least one sample reaction products diffuse or contact the sensors to thereby be detected. 
     
     
         109 . The method of  claim 108  wherein the chemically sensitive portion of the sensors of the sensor array is responsive to a plurality of different sample reaction products. 
     
     
         110 . The method of  claim 109  wherein the chemically sensitive portion is responsive to one or more biomolecules. 
     
     
         111 . The method of  claim 110  wherein the biomolecules comprise at least one chemical moiety selected from the group consisting of nucleic acids, proteins, and polysaccharides. 
     
     
         112 . The method of claim  3  wherein the chemically sensitive portion is responsive to changes in ion concentration resulting from the presence or generation of the sample reaction products. 
     
     
         113 . The method of  claim 109  wherein the chemically sensitive portion is responsive to changes in hydrogen ion concentration formed by the presence or generation of the sample reaction products. 
     
     
         114 . The method of  claim 107  wherein the sample reaction components comprise sample nucleic acids reacted under conditions where known nucleotides are incorporated into the sample nucleic acids resulting in sample reaction production formation comprising hydrogen ions that are detected by the at least one sensor. 
     
     
         115 . The method of  claim 107  wherein the output signals for the sensors of the sensor array are configured to be similar in response to similar amounts of detected sample reaction products. 
     
     
         116 . The method of  claim 107  wherein the discrete locations are disposed within individual reaction chambers. 
     
     
         117 . The method of  claim 116  wherein the sample analysis is conducted in a fluidic environment. 
     
     
         118 . A method for sample analysis comprising:
 (a) disposing a plurality of samples at discrete locations on a substrate associated with a semiconductor based sensor array comprising at least 10 3  sensors, wherein the sensors of the sensor array comprise field-effect transistors configured to provide output signals in response to samples detected proximate thereto;   (b) detecting at least a portion of the samples when brought in proximity to sensors of the sensor array;   (c) outputting signals indicative of at least a portion of the sensors detecting the presence of the samples.   
     
     
         119 . The method of  claim 118  wherein the sensors of the sensor array have a chemically sensitive portion responsive to the samples and disposed in proximity to the substrate such that the samples diffuse or contact the sensors to thereby be detected. 
     
     
         120 . The method of  claim 119  wherein the chemically sensitive portion of the sensors of the sensor array is responsive to a plurality of different samples. 
     
     
         121 . The method of  claim 120  wherein the chemically sensitive portion is responsive to one or more biomolecules. 
     
     
         122 . The method of  claim 121  wherein the biomolecules comprise at least one chemical moiety selected from the group consisting of nucleic acids, proteins, and polysaccharides. 
     
     
         123 . The method of  claim 119  wherein the chemically sensitive portion is responsive to changes in ion concentration resulting from sample presence. 
     
     
         124 . The method of  claim 119  wherein the chemically sensitive portion is responsive to changes in hydrogen ion concentration formed by sample presence. 
     
     
         125 . The method of  claim 118  wherein the output signals for the sensors of the sensor array are configured to be similar in response to similar amounts of detected sample. 
     
     
         126 . The method of  claim 118  wherein the discrete locations are disposed within individual chambers. 
     
     
         127 . The method of  claim 118  wherein the sample analysis is conducted in a fluidic environment.