Integrated sensor arrays for biological and chemical analysis

Abstract

The invention is directed to apparatus and chips comprising a large scale chemical field effect transistor arrays that include an array of sample-retaining regions capable of retaining a chemical or biological sample from a sample fluid for analysis. In one aspect such transistor arrays have a pitch of 10 μm or less and each sample-retaining region is positioned on at least one chemical field effect transistor which is configured to generate at least one output signal related to a characteristic of a chemical or biological sample in such sample-retaining region. In one embodiment, the characteristic of said chemical or biological sample is a concentration of a charged species and wherein each of said chemical field effect transistors is an ion-sensitive field effect transistor having a floating gate with a dielectric layer on a surface thereof, the dielectric layer contacting said sample fluid and being capable of accumulating charge in proportion to a concentration of the charged species in said sample fluid. In one embodiment such charged species is a hydrogen ion such that the sensors measure changes in pH of the sample fluid in or adjacent to the sample-retaining region thereof. Apparatus and chips of the invention may be adapted for large scale pH-based DNA sequencing and other bioscience and biomedical applications.

1 .- 36 . (canceled) 
     
     
         37 . A device comprising:
 a flow cell having an fluid inlet and an fluid outlet and a flow chamber extending between the inlet and the outlet, the flow cell including a substrate having a plurality of reaction chambers, each reaction chamber of the plurality of reaction chambers having an aperture that opens onto the flow chamber;   a reaction sensor coupled to the flow cell including an array of pixels that have a fixed position relative to the substrate of the flow cell, the pixels being assigned to select reaction chambers such that activity detected by the pixels indicates that a desired reaction has occurred within the select reaction chamber; and   an exterior surface having a plurality of pins thereon that are communicatively coupled to the pixels, the pins for delivering information to a circuitry identifying a reaction in a reaction chamber.   
     
     
         38 . The device of  claim 37  wherein the pins interface with an array controller. 
     
     
         39 . The device of  claim 38  wherein the array controller is associated with a processor for processing data from the device. 
     
     
         40 . The device of  claim 39  wherein the processor determines the sequence of a nucleic acid from the data. 
     
     
         41 . The device of  claim 39  wherein the data is displayed on a handheld device. 
     
     
         42 . The device of  claim 37  wherein the inlet and the outlet interface with a fluidics assembly having a conduit for delivering fluid to the inlet and a conduit for removing fluid from the outlet. 
     
     
         43 . The device of  claim 37  further including a structure for promoting substantially laminar flow across the plurality of reaction chambers. 
     
     
         44 . The device of  claim 42  wherein the fluidics assembly includes valves for delivering fluids. 
     
     
         45 . The device of  claim 37  wherein the reaction sensor detects voltage. 
     
     
         46 . The device of  claim 37  wherein the reaction sensor detects current. 
     
     
         47 . The device of  claim 37  wherein the reaction sensor further includes a nucleic acid sequence. 
     
     
         48 . The device of  claim 47  wherein the nucleic acid sequence is attached directly to the surface of the reaction sensor. 
     
     
         49 . A method of performing a sequencing reaction comprising:
 providing a device having:
 a flow cell having an fluid inlet and an fluid outlet and a flow chamber extending between the inlet and the outlet, the flow cell including a substrate having a plurality of reaction chambers, each reaction chamber of the plurality of reaction chambers having an aperture that opens onto the flow chamber; 
 a reaction sensor coupled to the flow cell including an array of pixels that have a fixed position relative to the substrate of the flow cell, the pixels being assigned to select reaction chambers such that activity detected by the pixels indicates that a desired reaction has occurred within the select reaction chamber; 
 an exterior surface having a plurality of pins thereon that are communicatively coupled to the pixels, the pins for delivering information to a circuitry identifying a reaction in a reaction chamber; 
   introducing a nucleic acid sequence to the reaction chambers of the device;   amplifying the nucleic acid sequence; and   determining the sequence of the nucleic acid.   
     
     
         50 . The method of  claim 49  wherein the amplifying includes performing emulsion PCR. 
     
     
         51 . The method of  claim 49  wherein the amplifying includes performing bridge PCR. 
     
     
         52 . The method of  claim 50  wherein the determining includes performing sequencing-by-synthesis.