Apparatus and method for biological sample processing

Abstract

An apparatus and method are described that achieve independent and simultaneous processing of a plurality of substrate-supported biological samples. In one embodiment, substrate holders arranged in a minor arc are independently moveable between a processing position and an access position, and reagents are delivered to substrates held in the substrate holders through a nozzle plate that moves along the arc of substrate holders. The disclosed apparatus and method are particularly suited for implementation of lean processing of biological samples.

1 . An automated biological sample processing apparatus, comprising:
 a plurality of substrate holders, each substrate holder automatically and independently movable between a different processing position and a different access position; and,   a movable substrate processor configured to simultaneously process two or more substrates held on two or more substrate holders in their different processing positions.   
     
     
         2 . The apparatus of  claim 1 , wherein the plurality of substrate holders comprise independent thermal control units. 
     
     
         3 . The apparatus of  claim 2 , wherein the independent thermal control units comprise conductive heating platforms. 
     
     
         4 . The apparatus of  claim 2 , wherein the independent thermal control units comprise radiant heating platforms. 
     
     
         5 . The apparatus of  claim 2 , wherein the independent thermal control units comprise heating and cooling platforms. 
     
     
         6 . The apparatus of  claim 5 , wherein the heating and cooling platforms comprise Peltier platforms. 
     
     
         7 . The apparatus of  claim 2  further comprising a non-contact temperature sensor positioned to measure a temperature of at least one of an upper surface of a substrate, a biological sample on the upper surface of the substrate, and a volume of liquid covering at least a portion of the upper surface of the substrate. 
     
     
         8 . The apparatus of  claim 7 , wherein the non-contact temperature sensor is connected in a feedback loop with a power supply for the thermal control unit. 
     
     
         9 . The apparatus of  claim 2 , wherein the independent thermal control units comprise a source of air flow past one or more of the substrate holders. 
     
     
         10 . The apparatus of  claim 9 , wherein each of the plurality of substrate holders has a separate source of air flow. 
     
     
         11 . The apparatus of  claim 10 , wherein the air flow past each of the substrate holders is separated. 
     
     
         12 . The apparatus of  claim 11 , wherein the air flow past each of the substrate holders is directed toward a common point at a distance beyond the substrate holders. 
     
     
         13 . The apparatus of  claim 1 , wherein the plurality of substrate holders in their different processing positions are arranged in substantially the same plane and substantially along a minor arc having a minor arc radius, and the substrate processor is rotatably mounted at a center of the minor arc and moves along a path parallel to and in a plane above the minor arc. 
     
     
         14 . The apparatus of  claim 13 , wherein the substrate processor comprises an elongate nozzle plate having a first end at which it is mounted and a second end, the second end located along a length of the nozzle plate toward the minor arc of the substrate holders, and the nozzle plate comprising a plurality of nozzles arranged in a plate arc, the plate arc having substantially the same radius as the minor arc along which the substrate holders are arranged. 
     
     
         15 . The apparatus of  claim 14 , wherein the plate arc of nozzles is smaller in length than the minor arc along which the substrate holders are arranged. 
     
     
         16 . The apparatus of  claim 14 , wherein the substrate processor further comprises a reagent carousel rotatably mounted on the nozzle plate. 
     
     
         17 . The apparatus of  claim 16 , wherein a plurality of dispensers are arranged around the circular profile of a cylindrical reagent carousel mounted with its axis perpendicular to the nozzle plate. 
     
     
         18 . The apparatus of  claim 14 , wherein the plurality of nozzles includes two or more of a vortex mixing nozzle, a bulk reagent dispense nozzle, a jet-drain nozzle, a rinse nozzle, and a railed aspirator. 
     
     
         19 . The apparatus of  claim 1  further comprising an enclosure housing the substrate holders in the different processing positions, from which enclosure the substrate holders are extended outside of the enclosure to the different access positions. 
     
     
         20 . The apparatus of  claim 1 , wherein processing of biological samples held on one or more substrate holders in different processing positions automatically continues while one or more of the sample holders are in different access positions. 
     
     
         21 . An automated biological sample processing apparatus, comprising:
 a plurality of substrate holders arranged in substantially the same plane along a minor arc of a circle, the circle having a first radius;   an elongate nozzle plate rotatably mounted at the center of the circle and extending toward the minor arc in a plane above the plurality of substrate holders and along a radial line of the minor arc; and   a cylindrical reagent dispenser carousel rotatably mounted on the elongate nozzle plate, the cylindrical carousel having an axis and a second radius, the second radius being smaller than the first radius, the cylindrical carousel mounted on the elongate nozzle plate such that a reagent dispenser on the carousel can be positioned over a substrate holder along the minor arc through a combination of rotational movement of the nozzle plate around the center of the circle and rotational movement of the carousel around its axis.   
     
     
         22 . The apparatus of  claim 21 , wherein each of the plurality of substrate holders is independently extendable outward from the minor arc along separate radial lines of the minor arc. 
     
     
         23 . The apparatus of  claim 21 , wherein ambient air is directed along radial lines of the minor arc past two or more of the substrate holders. 
     
     
         24 . The apparatus of  claim 23 , wherein the ambient air is directed past the substrate holders toward the center of the circle of which the minor arc is part. 
     
     
         25 . The apparatus of  claim 23 , wherein ambient air directed past a first substrate holder is substantially separated from ambient air directed past a second substrate holder. 
     
     
         26 - 36 . (canceled) 
     
     
         37 . A method for improving the coordination of biological sample processing with biological sample preparation, comprising:
 cutting a tissue section;   placing the tissue section on a substrate, the substrate including a machine-readable code that specifies a pre-determined set of sample processing steps for the tissue section;   placing the tissue section on the substrate into an unoccupied substrate support unit of a biological sample processing apparatus, the apparatus having a plurality of separate substrate support units where each of the substrate support units are automatically and independently movable between a separate processing position and a separate access position, the unoccupied substrate support unit held in the access position to receive the substrate;   causing the substrate support unit to move to the processing position; and   initiating processing of the sample without interrupting the processing of other samples already being processed by the apparatus.   
     
     
         38 . The method of  claim 37  further comprising alerting a user that a substrate support unit of the apparatus is unoccupied and ready to receive a substrate supporting a tissue sample, or alerting the user that a substrate supporting a tissue sample for which processing is completed can be retrieved from the apparatus to provide the unoccupied substrate support unit. 
     
     
         39 . A method for controlling the operation of a biological sample treatment system to provide opportunities to replenish or change reagents on the system, wherein each of a plurality of samples is independently being processed by the system, comprising:
 determining pause point steps for each sample of the plurality of samples;   calculating a landing zone by aligning the pause points for all of the plurality of samples; and,   automatically stopping processing of samples at the landing zone and automatically providing access to a plurality of reagent containers held on the system so that the reagent containers can be removed, replaced or changed.   
     
     
         40 . A system for processing biological samples, the system comprising:
 a biological sample processing system for independent processing of a plurality of samples coupled to a computer; and,   instructions for performing the method of  claim 39  stored on the computer.   
     
     
         41 . A program storage device readable by a machine tangibly embodying a program of instructions readable by the machine to perform the method of  claim 39 .