Electronic detection of hybridization on nucleic acid arrays

Abstract

A method of detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: measuring the temperature at a plurality of locations on the surface of the nucleic acid probe array; applying an oscillating level of energy to the surface of the nucleic acid probe array, thereby causing the temperature at the surface of the nucleic acid probe array to oscillate; and detecting a decreased range of temperature oscillation at at least one of the plurality of locations on the nucleic acid probe array, thereby indicating an increased heat capacity caused by latent heat of hybridization between at least one target in the fluid sample and at least one nucleic acid probe disposed on a surface of the nucleic acid probe array.

What is claimed is:  
     
         1 . A method of detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: 
 measuring the temperature at a plurality of locations on the surface of the nucleic acid probe array;    applying an oscillating level of energy to the surface of the nucleic acid probe array, thereby causing the temperature at the surface of the nucleic acid probe array to oscillate; and    detecting a decreased range of temperature oscillation at at least one of the plurality of locations on the nucleic acid probe array, thereby indicating an increased heat capacity caused by latent heat of hybridization between at least one target in the fluid sample and at least one nucleic acid probe disposed on a surface of the nucleic acid probe array.    
     
     
         2 . A method of detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: 
 measuring the temperature at a plurality of locations on the surface of the nucleic acid probe array;    applying energy to the surface of the nucleic acid probe array, thereby causing the temperature at the surface of the nucleic acid probe array to increase; and    detecting a decrease in the rate of temperature change at at least one of the plurality of locations on the nucleic acid probe array, thereby indicating an increased heat capacity caused by latent heat of hybridization between at least one target in the fluid sample and at least one nucleic acid probe disposed on a surface of the nucleic acid probe array.    
     
     
         3 . A method of detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: 
 measuring the temperature at a plurality of locations on the surface of the nucleic acid probe array;    decreasing the temperature of the surface of the nucleic acid probe array; and    detecting a decrease in the rate of temperature change at at least one of the plurality of locations on the nucleic acid probe array, thereby indicating an increased heat capacity caused by latent heat of hybridization between at least one target in the fluid sample and at least one nucleic acid probe disposed on a surface of the nucleic acid probe array.    
     
     
         4 . The method of  claim 1  or  2 , wherein applying energy to the surface of the nucleic acid probe array is accomplished by at least one heater disposed under the nucleic acid probe array.  
     
     
         5 . The method of  claim 4 , wherein the at least one heater comprises an array of heaters, each heater being disposed under a patch of probes.  
     
     
         6 . The method of  claim 1 , wherein the at least one heater comprises an array of heaters, each heater being disposed under a patch of probes, further comprising: 
 adjusting the temperature at each patch of probes to a temperature approximately equal to the temperature at which hybridization occurs between the patch of probes and the targets.    
     
     
         7 . The method of  claim 1 , further comprising: 
 providing an optically absorbing layer under the probe array;    providing a thermal insulation layer under the optically absorbing material; and    providing a substrate under the thermal insulation layer.    
     
     
         8 . The method of  claim 7 , wherein the substrate comprises a material selected from the group consisting of a ceramic, silicon or glass.  
     
     
         9 . The method of  claim 1  or  2 , wherein applying an oscillating or varying level of energy to the surface of the nucleic acid probe array comprises: 
 directing the output of a first laser at the surface of the nucleic acid probe array.  
 
     
     
         10 . The method of  claim 9 , wherein applying an oscillating or varying level of energy to the surface of the nucleic acid probe array further comprises: 
 directing the output of a second laser at the surface of the nucleic acid probe array, wherein the output of the first laser is greater than the output of the second laser.    
     
     
         11 . The method of  claim 10 , wherein the first laser is adapted to control the average temperature at the probe array, and the second laser is adapted to fine tune the temperature at the probe array.  
     
     
         12 . The method of  claim 7 , wherein the optically absorbing layer comprises a thin nickel film.  
     
     
         13 . The method of  claim 7 , wherein an infrared scanner is used to measure the temperature at a plurality of locations on the surface of the nucleic acid probe array.  
     
     
         14 . A system for detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: 
 a nucleic acid probe array;    at least one heater disposed under the nucleic acid probe array; and    a temperature monitoring system for measuring the temperature at a plurality of locations on the nucleic acid probe array.    
     
     
         15 . The system of  claim 14 , wherein the at least one heater comprises an array of heaters.  
     
     
         16 . The system of  claim 14 , wherein the temperature monitoring system comprises: 
 an infrared scanning system.    
     
     
         17 . The system of  claim 14 , wherein the heaters are made of polycrystalline silicon formed on suspended diaphragms of silicon nitrate.  
     
     
         18 . The system of  claim 14 , further comprising: 
 an optically absorbing layer disposed under the probe array;    a thermal insulation layer disposed under the optically absorbing material; and    a substrate disposed under the thermal insulation layer.    
     
     
         19 . A method of detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: 
 positioning an electrode in the target liquid;    providing an insulating layer under the nucleic acid array;    providing a n-p-n junction under the insulating layer;    directing a laser beam at the underside of the n-p-n junction, thereby forming a circuit between the n-p-n junction and the electrode in the target liquid; and    measuring the impedance of the circuit.    
     
     
         20 . The method of  claim 19 , further comprising: 
 scanning the laser beam across the underside of the n-p-n junction, thereby measuring the impedance of the circuit at a plurality of locations on the nucleic acid array.    
     
     
         21 . The method of  claim 19 , wherein the insulating layer comprises silicon nitride.  
     
     
         22 . A system for detecting locations on a nucleic acid probe array at which hybridization occurs between targets in a fluid sample and nucleic acid probes disposed on a surface of the nucleic acid probe array, comprising: 
 an electrode adapted to be disposed in the target liquid;    an insulating layer disposed under the nucleic acid array; and    a n-p-n junction disposed under the insulating layer.    
     
     
         23 . The system of  claim 22 , further comprising: 
 a laser adapted to direct a laser beam at the underside of the n-p-n junction, thereby forming a circuit between the n-p-n junction and the electrode in the target liquid.