Thermo-controllable high-density chips for multiplex analyses

Abstract

The present invention provides miniaturized instruments for conducting chemical reactions where control of the reaction temperature is desired or required. Specifically, this invention provides chips and optical systems for performing and monitoring temperature-dependent chemical reactions. The apparatus and methods embodied in the present invention are particularly useful for high-throughput and low-cost amplification of nucleic acids.

1 . A chip for varying and/or maintaining a reaction sample comprising an array of thermo-controllable units, wherein the chip has a surface density of at least about one thermo-controllable unit per 1 mm 2 , and wherein a unit within the array comprises a micro well for receiving and confining the reaction sample and a heating element in thermal contact with said micro well. 
     
     
         2 . The chip of  claim 1 , wherein the micro well is sealed by (a) applying a radiation-curable adhesive along peripheral dimensions defining an open surface of the micro well; (b) placing a cover to encompass the peripheral dimensions that define the open surface of the micro well; and (c) exposing the micro well to a radiation beam to effect the sealing. 
     
     
         3 . The chip of  claim 2 , wherein the radiation-curable adhesive is UV-curable adhesive. 
     
     
         4 . The chip of  claim 1 , wherein the well has a dimension of about 10 mm to about 100 μm in length, about 100 mm to about 100 μm in width, and about 10 mm to about 100 μm in depth. 
     
     
         5 . The chip of  claim 1 , wherein the micro well has a volume of from about 100 μl to about 0.001 μl. 
     
     
         6 . The chip of  claim 1 , wherein the chip comprises a photon-sensing element. 
     
     
         7 . The chip of  claim 1 , wherein the chip is operatively coupled to an optical system that detects optical signals emitted from the reaction sample. 
     
     
         8 . The chip of  claim 1 , wherein the chip has a ramp temperature time about 25° C. or higher per second. 
     
     
         9 . The chip of  claim 1 , wherein each unit further comprises a temperature sensor in thermal contact with the micro well. 
     
     
         10 . The chip of  claim 1 , wherein the heating element is located within the micro well. 
     
     
         11 . The chip of  claim 1  comprising an upper surface and a bottom surface, and two arrays of thermo-controllable units, wherein one array is arranged in one orientation along the upper surface, and wherein the other array is arranged in an opposite orientation along the bottom surface. 
     
     
         12 . An apparatus for conducting a chemical reaction requiring cycling at least two temperature levels, comprising:
 (a) a chip for cycling at least two temperature levels, said array comprising:   an array of thermo-controllable units, wherein the array has a surface density of at least about one thermo-controllable unit per 1 mm 2 , and wherein a unit within the array comprises a micro well for receiving and confining the amplification reagents and a heating element in thermal contact with said micro well;   (b) an optical system operatively coupled to the chip of (a), wherein the optical system detects an optical signal coming from the micro well.   
     
     
         13 . The apparatus of  claim 12 , wherein the micro well is sealed by (a) applying a radiation-curable adhesive along peripheral dimensions defining an open surface of the micro well; (b) placing a cover to encompass the peripheral dimensions that define the open surface of the micro well; and (c) exposing the micro well to a radiation beam to effect the sealing. 
     
     
         14 . The apparatus of  claim 12 , wherein the chemical reaction is nucleic acid amplification reaction. 
     
     
         15 . The apparatus of  claim 12 , wherein the optical system comprises a spectrum analyzer. 
     
     
         16 . The apparatus of  claim 15 , wherein the spectrum analyzer comprises an optical transmission element and a photon-sensing element. 
     
     
         17 . A method of conducting a chemical reaction that involves a plurality of reaction samples and requires cycling at least two temperature levels, comprising:
 (a) providing a chip comprising:   an array of thermo-controllable units, wherein the chip has a surface density of at least about one thermo-controllable unit per 1 mm 2 , and wherein a unit within the array comprises a micro well for receiving and confining the reaction sample and a heating element in thermal contact with said micro well;   (b) placing the plurality of reaction samples into the thermo-controllable units; and   (c) controlling the heating element to effect cycling at least two temperature levels.   
     
     
         18 . The method of  claim 17 , wherein the controlling step comprises processing sensor signals retrieved from a temperature sensor operatively linked to a thermo-controllable unit based on protocol stored on a computer readable medium. 
     
     
         19 . The method of  claim 17 , wherein the chip is operatively coupled to an optical system that detects optical signals emitted from the reaction sample. 
     
     
         20 . The method of  claim 17 , wherein the optical signals are proportional to the amount of product of the chemical reaction.