Manufacture of arrays with reduced error impact

Abstract

Methods and apparatus are disclosed for synthesizing a plurality of compounds such as biopolymers on the surface of supports. The synthesis comprises a plurality of steps in which reagents for conducting the synthesis are deposited on the surface of the support to form precursors of the chemical compounds and, ultimately, the chemical compounds themselves. An error in the deposition may occur in one or more of the plurality of steps. A reagent for forming the chemical compounds is deposited on the surface of the support. A determination is made as to whether an error occurred in the depositing of the reagent. If an error is detected, the support is treated to re-deposit at least some of those reagents that were not correctly deposited. In one approach the support is treated to stabilize precursors of the chemical compounds, the source of the error is corrected, and the reagent applied above is re-deposited on the surface.

1 . A method for synthesizing an array of chemical compounds on the surface of a support wherein said synthesis comprises a plurality of steps in which reagents for conducting said synthesis are deposited on the surface of the support to form precursors of said chemical compounds and wherein one or more of said plurality of steps may comprise an error in said deposition, said method comprising: 
 (a) depositing, on multiple locations on said surface, reagents for forming said chemical compounds,    (b) repeating step (a) in one or more cycles so as to form said chemical compounds, wherein the reagents deposited in different cycles at the same locations on said surface may or may not be the same;    the method additionally comprising in at least one selected cycle,    (c) determining whether an error occurred in the depositing of said first reagents in the selected cycle to one or more of said multiple locations,    (d) if an error occurred, 
 (i) correcting the source of said error, and  
 (ii) re-depositing on said surface at least some of those of said same reagents that were not correctly deposited in the selected cycle.  
   
     
     
         2 - 3 . (canceled)  
     
     
         4 . A method for synthesizing a plurality of biopolymers on the surface of a support wherein said synthesis comprises a plurality of steps in which reagents for conducting said synthesis are deposited on the surface of the support to form precursors of said biopolymers and wherein one or more of said plurality of steps may comprise an error in said deposition, said method comprising:  
       (a) depositing on said surface a reagent for forming said biopolymers, 
 (b) repeating step (a) in one or more cycles so as to form said biopolymers wherein the reagents deposited in different cycles at the same locations on said surface may or may not be the same;  
 the method additionally comprising in at least one selected cycle,  
 (c) determining using an imaging system, whether an error occurred in the depositing of said reagent in the selected cycle,  
 (d) if an error occurred, 
 (i) treating said support to stabilize precursors of said biopolymers,  
 (ii) correcting the source of said error, and  
 (iii) re-depositing on said surface the same reagent of step (a) that was not correctly deposited in the selected cycle, and  
 
 (e) preparing the support for the next depositing step.  
 
     
     
         5 . A method according to  claim 4  wherein said reagents are delivered to said surface as plurality of drops.  
     
     
         6 . A method according to  claim 5  wherein said reagents are delivered by means of a plurality of nozzles.  
     
     
         7 . A method according to  claim 5  wherein said error is determined by means of comparing an imprint of the delivered spots to a predetermined imprint.  
     
     
         8 . A method according to  claim 7  wherein said imprint of said delivered spots is determined by means of a camera.  
     
     
         9 . A method according to  claim 7  wherein said comparing is carried out by means of a computer.  
     
     
         10 - 11 . (canceled)  
     
     
         12 . A method according to  claim 4  wherein said treating comprises applying an oxidizing agent to said surface.  
     
     
         13 . A method according to  claim 12 , which comprises washing said surface.  
     
     
         14 . A method for synthesizing an array of biopolymers on the surface of a support wherein said synthesis comprises a plurality of steps wherein reagents comprising biopolymers subunits are deposited on the surface of the support and wherein one or more of said plurality of steps may comprise an error in said deposition, said method comprising: 
 (a) placing a support having a functionalized surface into a reaction chamber,    (b) dispensing, to multiple locations on said surface from a plurality of nozzles, a plurality of drops of a reagent comprising a biopolymers subunit,    (c) repeating steps (a) and (b) in one or more cycles so as to form said biopolymers, wherein the reagents deposited in different cycles at the same locations on said surface may or may not be the same;    the method additionally comprising in at least one selected cycle,    (d) determining, using an imaging system, whether an error occurred in the dispensing of said reagent in the selected cycle,    (e) if an error occurred, 
 (i) removing said support from said reaction chamber and placing said support in a holding chamber,  
 (ii) stabilizing the surface of said support in said holding chamber,  
 (iii) correcting the source of said error,  
 (iv) returning said support to said reaction chamber, and  
 (v) dispensing, to said surface from a plurality of nozzles, a plurality of drops of the same reagent for the cycle in which the error occurred and  
   (f) subjecting said support to reagents for preparing said support for a subsequent dispensing step.    
     
     
         15 . A method according to  claim 14  wherein said error is determined by means of comparing an imprint of the delivered spots to a predetermined imprint.  
     
     
         16 . A method according to  claim 15  wherein said imprint of said delivered spots is determined by means of a camera.  
     
     
         17 . A method according to  claim 16  wherein said comparing is carried out by means of a computer.  
     
     
         18 . A method according to  claim 14  wherein said biopolymers are polynucleotides or polypeptides.  
     
     
         19 . A method according to  claim 14  wherein said stabilizing comprises applying an oxidizing agent to said surface.  
     
     
         20 . A method according to  claim 19 , which comprises washing said surface.  
     
     
         21 . A method according to  claim 20  wherein said washing is carried out in more than one step.  
     
     
         22 . A method according to  claim 14  for the synthesis of polynucleotides on said surface comprising subsequent to step (d) subjecting said surface to an oxidizing agent and subjecting said surface to an agent for removing a protecting group.  
     
     
         23 . (canceled)  
     
     
         24 . A method according to  claim 14  further comprising exposing the array to a sample and reading the array.  
     
     
         25 . A method according to  claim 24  comprising forwarding data representing a result obtained from a reading of the array.  
     
     
         26 . A method according to  claim 25  wherein the data is transmitted to a remote location.  
     
     
         27 . A method according to  claim 24  comprising receiving data representing a result of an interrogation obtained by the reading of the array.  
     
     
         28 . A method according to  claim 1  for synthesizing an array of biopolymers on the surface of a support, said method utilizing an apparatus comprising: 
 (a) a reaction chamber,    (b) a mechanism for moving a support to and from said reaction chamber,    (c) a controller for controlling the movement of said mechanism of (b),    (d) one or more fluid dispensing stations in fluid communication with said reaction chamber,    (e) a mechanism for determining the correct operation of said fluid dispensing stations, said mechanism being in communication with said controller for controlling the movement of said mechanism of (b),    (f) a controller for controlling said mechanism of (e), and    (g) a stabilization chamber for subjecting said support to stabilization reagents.    
     
     
         29 - 30 . (canceled)  
     
     
         31 . A method according to  claim 28  wherein said mechanism for determining the correct operation of said fluid dispensing stations is an inspection system comprising a camera.  
     
     
         32 - 38 . (canceled)