WO2010078177A1

WO2010078177A1 - Robotic pipette system

Info

Publication number: WO2010078177A1
Application number: PCT/US2009/069348
Authority: WO
Inventors: Charles D. Lemme; William Richards
Original assignee: Ventana Medical Systems, Inc.
Priority date: 2008-12-31
Filing date: 2009-12-22
Publication date: 2010-07-08

Abstract

A robotic pipette system is used to process specimen-bearing microscope slides. The system includes a filling station, carousels, and a transport apparatus that loads pipettes filled at the filling station into the carousels. The carousels position the pipettes above the specimen-bearing slides such that fluids dispensed from the pipettes are applied to the specimens. Each carousel can hold a series of pipettes that are used to perform a multi-step process.

Description

ROBOTIC PIPETTE SYSTEM

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U. S. C. § 119(e) of U.S. Provisional Patent Application No. 61/142,126 filed on December 31 , 2008. This provisional application is incorporated herein by reference in its entirety.

BACKGROUND

Technical Field

The present invention relates generally to robotic pipette systems. More specifically, the invention relates to robotic pipette systems capable of processing specimen-bearing microscope slides.

Description of the Related Art

Pipettes are used to hold and dispense measured volumes of reagents onto specimens carried by microscope slides. Many staining protocols involve applying a series of different reagents to a specimen using a robotic apparatus capable of carrying a single pipette. Conventional robotic apparatuses commonly perform two-step "sip and spit" processes for each pipette. A robotic apparatus often carries a pipette to a reagent bottle to sip reagent out of the bottle into the pipette. The robotic apparatus then carries the pipette to a staining instrument and spits the reagent from the pipette onto a slide in the staining instrument. The robotic apparatus carries the empty pipette away from the staining instrument. This two-step process is repeated to dispense a series of reagents.

Conventional staining systems often have a single robotic apparatus for delivering pipettes to multiple staining instruments. Unfortunately, staining procedures are often performed in series because the robotic apparatus carries a single pipette through the entire sip and spit process. If multiple staining instruments have specimens ready to receive reagents, the robotic apparatus delivers one reagent at a time to one of the staining instruments while the other staining instruments wait for reagents. This results in relatively inefficient processing because many of the specimens may wait significant lengths of time for reagents. Additionally, lines of slides may form at the staining instruments because of the relative low handling volume of the robotic apparatus. At other times {e.g., when the staining instruments simultaneously bake specimens), the robotic apparatus can be idle. Consequently, the robotic apparatus may be used infrequently and inefficiently and may limit the productivity of the staining instruments.

BRIEF SUMMARY

Certain embodiments disclosed herein are directed to a robotic pipette system having a plurality of processing stations. Each station is capable of receiving a plurality of dispensers used to deliver substances onto a specimen carried on a substrate. The stations can minimize, limit, or substantially eliminate at least some of the inefficiencies often associated with robotic apparatuses capable of carrying a single pipette. A robotic handler, in some embodiments, can load each processing station with a plurality of dispensers in the form of pipettes. The processing stations can rapidly apply the substances to the specimens.

Pipettes can be queued at the processing stations in order to perform a wide range of different protocols. The queued pipettes successively apply reagents to the specimens. The reagents can be delivered independent of the operation of the robotic handler. In some embodiments, reagents are immediately applied to specimens at the end of each exposure period to reduce overall processing times. After completing a protocol {e.g., a baking through staining protocol), the robotic handler can reload the processing station. In some embodiments, the robotic handler continuously replaces spent pipettes with filled pipettes as the processing station treats the specimen. The robotic pipette system can be automated in order to process microscope slides without human intervention. A user can manually place specimen-bearing slides into the processing stations. The robotic pipette system obtains information about the slides and determines an appropriate protocol for each slide. The processing stations are automatically loaded with pipettes based on the protocol while avoiding or limiting queuing of the pipettes to be carried by the robotic apparatus, thereby reducing or substantially eliminating wait times for reagent deliveries. The robotic pipette system is adapted to execute different protocols for different microscope slides. In some embodiments, a processing station includes a rotatable pipette holder and an air injection apparatus. The pipette holder is capable of holding a generally circular array of pipettes. The air injection apparatus outputs air that causes fluid to flow from a pipette mated with the air injection apparatus. The pipette can be proximate to and/or aligned with an outlet of the air injection apparatus. In certain embodiments, the pipette holder is in the form of a carousel positioned to process a specimen carried by a microscope slide. The carousel sequentially positions the pipettes over the specimen to dispense fluids onto the specimen. The dispensed fluid can flow directly onto the specimen, spread over the specimen, or the like. In some embodiments, a system for processing microscope slides comprises a pipette filling station, a first carousel, a second carousel, and a transport apparatus. The first carousel is configured to move a first pipette to a first delivery position for delivering a liquid to a first microscope slide. The first carousel includes a first plurality of pipette receivers. A second carousel is configured to move a second pipette to a second delivery position for delivering a liquid to a second microscope slide. The second carousel includes a second plurality of pipette receivers. The transport apparatus is adapted to load both the first plurality of pipette receivers and the second plurality of pipette receivers with pipettes filled at the pipette filling station. In certain embodiments, the carousels have at least five pipette receivers in order to stage a sufficient number of pipettes to minimize or limit wait times for reagents. In some embodiments, a system for processing microscope slides includes a filling station, a first carousel, a second carousel, and a transport apparatus. The first carousel includes a first plurality of pipette receivers, each movable to a first delivery position for delivering liquid to a first microscope slide. The second carousel includes a second plurality of pipette receivers, each movable to a second delivery position for delivering liquid to a second microscope slide. The transport apparatus is adapted to load both the first plurality of pipette receivers and the second plurality of pipette receivers with pipettes that were filled at the filling station. In certain embodiments, the first and second carousels concurrently process microscope slides. The transport apparatus can prepare and deliver the pipettes to the carousels during specimen processing.

In other embodiments, a system for processing microscope slides includes a first carousel having a first plurality of pipette receivers, a second carousel having a second plurality of pipette receivers, and a transport apparatus. The transport apparatus is configured to move at least one pipette to the first carousel while the second carousel is used treat a specimen carried by a microscope slide.

In yet other embodiments, an apparatus for processing microscope slides includes first and second slide holders and first and second carousels. The first carousel has a first plurality of pipette receivers and is movably coupled to the first slide holder. The second carousel has a second plurality of pipette receivers and is movably coupled to the second slide holder. In certain embodiments, a controller is used to independently rotate the first and second carousels.

In some embodiments, a processing station includes a microscope slide holder, a carousel, and a dispensing apparatus. The microscope slide holder includes a chamber and a delivery port. The carousel has pipette receivers that are positioned to be successively aligned with the delivery port. The dispensing apparatus is operable to cause one of the pipettes generally aligned with the delivery port to output fluid through the delivery port onto a specimen in the chamber.

In some embodiments, a method of processing microscope slides using a plurality of processing stations is provided. The method includes determining substances to be applied to microscope slides. Each processing station is adapted to hold a microscope slide and includes a movable carousel. At least one of the carousels is loaded with a plurality of pipettes based on the determination of substances. After loading the carousel with pipettes, substances are delivered from the pipettes onto a microscope slide held by the processing station. In certain embodiments, additional processing stations are coupled to the plurality of processing stations. The additional processing stations may or may not include movable carousels.

In yet other embodiments, a method for processing microscope slides includes filling a plurality of pipettes at a filling station. The pipettes are delivered to a plurality of independently movable carousels. After delivering the pipettes, fluids are outputted from the pipettes onto microscope slides. In certain embodiments, each carousel uses three or more queued pipettes to apply reagents to a specimen.

In some embodiments, a method for processing microscope slides includes filling a plurality of pipettes at a filling station. The plurality of pipettes are delivered to a first carousel and a second carousel. After delivering the plurality of pipettes, fluid is outputted from at least one pipette carried by the first carousel to a first microscope slide and fluid from at least one pipette carried by the second carousel is outputted onto a second microscope slide. In some embodiments, a processing station includes a substrate holder and a means for holding a plurality of pipettes. The means for holding the plurality of pipettes is movably coupled to the substrate holder. In certain embodiments, the means for holding the plurality of pipettes includes a carousel with a plurality of integral pipette receivers. Pipettes held by the pipette receivers deliver fluids towards a substrate held by the holder. The integral pipette receivers can be through-holes in a unitary cylindrical body. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Non-limiting and non-exhaustive embodiments are described with reference to the following drawings. The same reference numerals refer to like parts or acts throughout the various views, unless otherwise specified. Figure 1 is a plan view of a robotic pipette system, in accordance with one embodiment.

Figure 2 is a pictorial view of a processing station loaded with pipettes and a specimen-bearing microscope slide, in accordance with one embodiment. Figure 3 is an exploded view of the processing station of Figure 2.

Pipettes are shown removed from a carousel.

Figure 4 is another pictorial view of the processing station of Figure 2.

Figure 5A is a cross-sectional view of a processing station in Figure 1 taken along a line 5A-5A. A pipette is ready to dispense a fluid.

Figure 5B is a cross-sectional view of the processing station in Figure 1 taken along a line 5B-5B. The pipette is delivering the fluid onto a specimen.

Figure 6 is a flowchart of one method of processing specimens. Figure 7 is a top plan view of a processing station, in accordance with another embodiment.

Figure 8 is a side elevational view of the processing station of Figure 7.

DETAILED DESCRIPTION Figure 1 shows a robotic pipette system 100 that generally includes a holding station 110, a filling station 120, a transport apparatus 130, and a microscope slide processing system 140. The processing system 140 includes a plurality of stations 150a, 150b, 150c, 15Od (collectively "150") that have carousels 160a, 160b, 160c, 16Od (collectively "160"), respectively, capable of receiving and carrying dispensers in the form of pipettes. A microscope slide 170a carrying a specimen 172a is ready to be inserted into the processing station 150a. The processing stations 150b, 150c, 15Od hold the microscope slides 170b, 170c, 17Od, respectively. The carousels 160 can rotate counterclockwise or clockwise to move pipettes to appropriate positions for fluid delivery.

Each station 150 can perform a tissue preparation process. Such tissue preparation processes can include, without limitation, baking a specimen, incubating a specimen, deparaffinizing a specimen, conditioning a specimen, staining a specimen, performing antigen retrieval, performing immunohistochemistry (IHC), and/or performing in situ hybridization (ISH), as well as other processes for preparing specimens for microscopy, microanalyses, mass spectromethc methods, or the like. The specimens can be in the form of biological samples (e.g., samples of tissue such as sections of an organ, tumor sections, bodily fluids, smears, frozen sections, cytology preparations, or cell lines). Tissue can be any collection of cells mountable on a slide.

The carousels 160 can serve as staging areas to provide a significantly enhanced processing capacity of the system 100. Each carousel 160 can hold a plurality of pipettes used to successively dispense fluids. Each carousel 160 of Figure 1 carries six pipettes and is capable of applying six different fluids without accepting additional pipettes from the transport apparatus 130. The transport apparatus 130 can reload the carousels 160 to keep the carousels 160 ready to dispense the next fluid. Because the transport apparatus 130 can stage pipettes at the stations 150 well before the pipettes are needed, the system 100 can have a greater productivity than conventional systems and can be especially well suited for use in high-volume laboratories. The transport apparatus 130 can move a pipette from the holding station 110 to the filling station 120. At the filling station 120, the pipette is filled with a desired volume of fluid. The transport apparatus 130 loads the fluid- carrying pipette into one of the carousels 160. In this manner, the carousels 160 can be loaded with pipettes. The transport apparatus 130 can keep the stations 150 filled with fluid-carrying pipettes to ensure that fluids are ready to be dispensed onto specimens.

With continued reference to Figure 1 , the holding station 110 includes a plurality of empty pipettes 200 and a receptacle 210. The receptacle 210 can contain any number of pipettes and can include, without limitation, an open container, a table, a box, a rack, or any other structure suitable for holding a desired number of pipettes. The illustrated receptacle 210 holds thirty pipettes. The holding station 110 can also include, without limitation, one or more conveyors or delivery mechanisms capable of delivering pipettes to the transport apparatus 130.

The filling station 120 includes a plurality of containers 131. To fill a pipette at the filling station 120, the transport apparatus 130 can insert the pipette into one of the containers 131 and can draw a desired volume of a substance (e.g., a liquid) into the pipette. The containers 131 can be bottles, jars, vials, or other containers suitable for holding substances used to process specimens. The substances in the containers 131 may be reagents, probes, rinses, and/or conditioners and may be in the form of a fluid {e.g., gases, liquids, or gas/liquid mixtures). The fluids can be solvents (e.g., polar solvents, non-polar solvents, etc.), solutions (e.g., aqueous solutions or other types of solutions), or the like. Reagents include, but are not limited to, stains, wetting agents, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, etc.), antigen recovery fluids (e.g., aqueous-based antigen retrieval solutions, antigen recovery buffers, etc.), or combinations thereof. Stains include, without limitation, dyes, hematoxylin stains, eosin stains, conjugates, or other types of substances for imparting color and/or for enhancing contrast. Substances from the containers 131 can be used to perform different protocols, such as staining protocols (e.g., primary staining, special staining, IHC, ISH, or the like), antigen retrieval protocols, or the like.

The transport apparatus 130 includes a robotic handler 250 and a rail assembly 254. The robotic handler 250 includes a robotic arm 251 with an end effector 256. The robotic arm 251 is reconfigurable in order to move the end effector 256 to a desired location and/or along a desired path. The illustrated robotic arm 251 is a three-axis robotic arm capable of reaching any one of the carousels 160. Other types of robotic arms can also be used. For example, the robotic arm 251 can be a two-axis robotic arm to reduce the number of motors used to move the arm. In some embodiments, the robotic handler 250 includes two or more robotic arms capable of simultaneously preparing pipettes to further increase processing capacity. The degrees of freedom, number of components, and dimensions of the robotic handler 250 can be selected based on the desired positional accuracy, desired processing capacity of the system 100, or other operating parameters.

The end effector 256 is capable of manipulating pipettes (including picking up pipettes, carrying pipettes, and/or releasing pipettes), sipping fluids into pipettes, spitting fluids from pipettes, or the like. The end effector 256 can have one or more gripping mechanisms for carrying pipettes and one or more lines for sipping fluids into pipettes and/or for spitting fluids from pipettes.

The rail assembly 254 can position the robotic handler 250 alongside each station 150 and can include a rail 260 and a carriage 262. The carriage 262 carries the robotic handler 250 and can be moved linearly along the rail 260 in the directions indicated by arrows 264, 266.

The type and configuration of the transport apparatus 130 can be selected based on the spatial relationship between components of the system 100. For example, the transport apparatus 130 can include, without limitation, one or more robotic handlers, X-Y-Z transport systems, conveyors, combinations thereof, or other automated mechanisms capable carrying pipettes between locations, if needed or desired. processing system 11 OOThe processing system 140 includes the stations 150, a drive assembly 300 for rotating the carousels 160, and a dispensing assembly 310 for forcing fluids from pipettes. The drive assembly 300 of Figure 1 includes a plurality of motors 320a, 320b, 320c, 32Od (collectively "320") connected to the carousels 160a, 160b, 160c, 16Od, respectively. The motors 320 can be alternating current electric motors, direct current electric motors, or other types of motors that use electrical energy to produce mechanical energy. For example, the motors 320a, 320b, 320c, 32Od can be stepper motors capable of rotating drive shafts 330a, 330b, 330c, 33Od, respectively, in response to signals from the controller 280. Additionally or alternatively, the drive assembly 300 can include, without limitation, one or more drive trains, drive belts, or other subassemblies suitable for imparting motion to the carousels 160, as well as other components of the stations 150. The dispensing assembly 310 includes a line 321 , a pressurization device 332, and a plurality of valves 340a, 340b, 340c, 34Od coupled to output lines 348a, 348b, 348c, 348d, respectively. The pressurization device 332 can deliver pressurized air through the line 321. The pressurization device 332 can include, without limitation, one or more air compressors capable of taking in air at atmospheric pressure and delivering it at a higher pressure into the line 321. The valves 340 are operable to selectively deliver the pressurized air to the stations 150.

The stations 150 can perform parallel processing of specimens. Parallel processing generally refers to, without limitation, to simultaneously processing different specimens in different stations 150. By way of example, two different series of reagents can be simultaneously applied to two specimens. Parallel processing between stations 150 can be accomplished by maintaining queues of pipettes in the carousels 160. The stations 150 can be generally similar to each other and, accordingly, the following description of one of the stations applies equally to the others, unless indicated otherwise. Figures 2 and 3 show the station 150a including a slide holder

340, the carousel 160a movably coupled to the slide holder 340, and a drive mechanism 350. The slide holder 340 is configured to hold the microscope slide 170a (shown removed in Figure 3) underneath at least one of the pipettes carried by the carousel 160a. The drive mechanism 350 includes a rigid support 380 fixedly coupled to the slide holder 340. The support 380 includes an output line holder 386 for retaining the output line 348a and a bearing region 390 for holding the drive shaft 330a in engagement with the carousel 160a. The output line holder 386 includes a through hole 384 that receives the output line 348a such that an outlet 364 is positioned below the holder 386.

The carousel 160a generally includes a main body 400, a plurality of pipette receivers 41 Oa-f (collectively "410"), and a circumferential drive feature 430. The main body 400 can be a cylinder that is rotatable about an axis of rotation 460. A bore 440 of the main body 400 receives in a rigid shaft 450 of the slide holder 340 to allow rotation of the main body 400 with respect to the slide holder 340. The pipette receivers 410 can be through-holes in the main body

400 and can be angularly spaced (evenly or unevenly) about a longitudinal axis 441 of the main body 400. Pipettes can be inserted into the pipette receivers 410 to position outwardly extending flanges of the pipettes on an upper face 470 of the main body 400. In some embodiments, the pipette receivers 410 are holders coupled to the main body 400. The holders can be in the form of sleeves, clamps, or retainers coupled to the main body 400 by fasteners, adhesives, or combinations thereof.

The drive feature 430 includes teeth circumstantially spaced about the main body 400. These teeth contact an engagement section 480 of the drive shaft 330a. When the drive shaft 330a rotates about an axis of rotation 495 (indicated by an arrow 496 in Figure 2), the carousel 160a rotates about the axis of rotation 460 (indicated by an arrow 498 in Figure 2).

Referring to Figures 3 and 4, an element 500 can evaluate one or more measurable parameters and can send one or more signals indicative of the measurable parameters to the controller 280. The measurable parameters can include the angular position of the carousel 160a, the angular acceleration of the carousel 160a, rational speed of the carousel 160a, or the like. The controller 280 positions the carousel 160a based on the signals. The element 500 and controller 280 can also cooperate to index the pipettes using various techniques, thereby ensuring that the pipettes can be accurately located in the appropriate delivery position to dispense liquids. Various techniques can be used to index the pipettes. If the carousel 160a has a number n of generally evenly spaced apart pipette receivers 410, the carousel 160a can be rotated in increments of 360 degrees/n to successively position the pipette receivers 410 in a delivery position. In the illustrated embodiment, the carousel 160a can be incrementally rotated 60 degrees about the axis of rotation 460 to successively mate the pipettes to the outlet 364 with a high degree of precision and repeatability.

The element 500 can include, but is not limited to, one or more sensors, reed switches, limit switches, or other devices used to evaluate measurable parameters. In some embodiments, the element 500 is a senor {e.g., a proximity sensor, a Hall effect sensor, an optical sensor, a capacitance sensor, a rotary encoder, or the like). The element 500 can be embedded in the main body 400, which protects the element 500 from external forces. In other embodiments, the element 500 is coupled to an external surface of the main body 400 and can be conveniently replaced or inspected, if needed or desired. In some embodiments, the element 500 is a magnet embedded in the main body 400 that is sensed by a Hall effect sensor carried by the support 380 or other component of the slide holder 340. In some embodiments, the positioning element 500 includes a pin that extends outwardly from the main body 400. The pin can contact a stop 510 to limit rotation of the carousel 160a. Referring again to Figures 2 and 3, the drive shaft 330a can be a worm screw or other type of mechanical device capable of imparting rotary motion to the carousel 160a. The engagement section 480 of the drive shaft 330a can include external threads that mate with the drive feature 430. Other types of features can also be used to rotate the carousel 160a.

Figure 5A is a cross-sectional view of the station 150a of Figure 1 after the microscope slide 170a has been inserted through an entrance 520 of the slide holder 340. The specimen 172a is positioned below a pipette 360 in a delivery position. The pipette 360 is generally aligned with a delivery port 536 such that fluid from the pipette 360 can pass through the delivery port 536 and onto the specimen 172a. An alignment feature 530, illustrated as a narrowed region of the pipette receiver 41 Od, keeps a tip 540 of the pipette 360 generally concentric with the delivery port 536. The outlet 364 can deliver air into the pipette 360, as shown in Figure 5B, to force fluid 560 out of the pipette 360. The air can flow lengthwise through the entire pipette 360. Such pneumatically dispensed open- ended pipettes can reliably dispense metered volumes of fluids. The flow rate of the air can be increased or decreased to increase or decrease the flow rate of fluid 560 flowing through an opening 541 at the tip 540.

The tip 540 of Figures 5A and 5B has a relatively small opening 541 and a small angle of taper to prevent liquid from escaping while the pipette 360 is carried between locations but allowing forced air to readily push the fluid 560 out of the tip 540. The diameter of the opening 541 can be equal to or less than about 0.5 mm, 0.4 mm, 0.3 mm, or 0.2 mm. The angle of taper can be equal to or less than about 10 degrees, 5 degrees, or 3 degrees. In some embodiments, the diameter of the opening 541 is about 0.4 mm and the angle of taper is about 5 degrees. Other types of pipettes can also be utilized with the station 150a. For example, standard glass or plastic pipettes, such as disposable pipette tips routinely used with hand-held, adjustable pipettors, can be used. The holding capacity of the pipette 360 can be in a range of about 10 microliters to about 10 ml_, but more typically, the pipette 360 will have a capacity in the range of about 100 microliters to about 1 ml_. Of course, the amount of substance held in the pipette can be less than the capacity so that a single type of pipette can be used to deliver a range of volumes.

Anti-evaporation feature 547 has a relatively small opening to minimize, limit, or substantially prevent any significant evaporative losses. In some embodiments, including the illustrated embodiment, the anti-evaporation feature 547 is an inwardly extending annular member coupled to a tapered main body 549 of the pipette 360. The main body 549 includes an outwardly extending upper flange 551 for resting on the upper surface 470 of the main body 440. The station 150a can include a wide range of different types of holders with thermal elements {e.g., resistive heaters, conductive heaters, etc.), plumbing (e.g., drains, fluid lines, etc.), nozzles, sensors [e.g., temperature sensors, proximity sensors, etc.), or other components used to process specimens. The holder 340 of Figures 4 and 5 includes a chamber 562 in which the specimen 172a is positioned while the microscope slide 170a is in the entrance 520.

The microscope slide 170a is a generally flat transparent substrate capable of carrying the specimen 172a for examination using equipment, such as optical equipment (e.g., a microscopic or other optical device). In some embodiments, the microscope slide 170a may be a generally rectangular piece of a transparent material having a front face for receiving the specimen 172a. The slide 170a can have a length of about 3 inches (75 mm) and a width of about 1 inch (25 mm) and, in certain embodiments, may include a label and such label can include characters and/or other machine-readable codes such as a barcode or an RFID tag. In other embodiments, information can be etched into the microscope slide or included within the microscope slide. In some embodiments, the slide 170a has a length of about 75 mm, a width of about 25 mm, and a thickness of about 1 mm. Other dimensions are also possible. The microscope slide 170a can be in the form of a standard microscope slide made of glass. Other types of substrates capable of carrying specimens can also be utilized. The holder 340 can thus be configured to hold other types of substrates capable of carrying specimens in the form of cytological preparations, micro-arrays, tissue arrays, or the like Figure 6 is a flowchart of one method of processing specimens.

Generally, the controller 280 determines substances to be applied to each of the specimens. Pipettes are filled with the appropriate substances and loaded into the carousels 160. The substances are delivered from the pipettes onto the specimens. The transport apparatus 130 can prepare pipettes, load carousels, and unload carousels to ensure that the appropriate substances are available when needed. At 600, the controller 280 can determine an appropriate executable program for each of the slides 170. Different programs can be used to perform tissue conditioning, staining, antigen retrieval, immunohistochemistry (IHC), in situ hybridization (ISH), or the like. The programs can be determined based on information about the slides 170 and the available reagents. For example, a program can be determined based on the available reagents at the filling station 120, tissue composition of the specimen, or the like. If the slides 170 include labels that include barcodes, RF ID tags, transponders, or the like that contain information that can be acquired by the stations 150 (e.g., by readers, scanners, or other devices), the stations 150 can acquire and send information about the slides 170 to the controller 280, which in turn determine an appropriate program.

A user can also input information into the controller 280. The controller 280 can determine a program for operating the components based, at least in part, on the inputted information. The inputted information can include, without limitation, parameters to be optimized, processing times, specimen characteristics, or the like. The user can also select a stored program to perform a desired protocol.

At 610, the transport apparatus 130 alternately fills pipettes and delivers the pipettes to the appropriate carousel 160. The end effector 256 can pick up a pipette at the holding station 110 and can carry the pipette to the filling station 120. At the filling station 120, the pipette is inserted into one of the containers 131 and filled with a desired volume of fluid. The filled pipette (either partially or completely filled) is removed from the container 131 and carried towards the system 140. The end effector 256 inserts the pipette into the appropriate pipette receiver. The end effector 256 releases the pipette. This process can be repeated to deliver additional pipettes to any of the carousels 160. The transfer apparatus 130 can thus load empty pipette receivers of the carousels 160 at any time to minimize, limit, or substantially eliminate idling of the transfer apparatus 130. Each station 150 can be loaded with pipettes for performing a certain protocol. By way of example, the transport apparatus 130 can deliver a series of reagents for a staining protocol to the carousel 160a and can deliver a different series of reagents for an antigen retrieval protocol to the carousel 160b. Each of the carousels 160a, 160b can be rotated at different times and at different speeds to provide flexible processing.

At 620, the stations 150 process the specimens. The carousels 160 can be independently rotated to perform parallel processing. In some embodiments, the stations 150 perform the same protocols. In other embodiments, the stations 150 perform different protocols. For example, the stations 150 can perform different staining protocols that may involve different numbers of reagents, different volumes of reagents, different processing times, or the like. The volumes and types of fluids applied to specimens can be selected based on various characteristics of the specimens. Once processing at a particular station is complete, the specimen can be removed (manually or automatically) and another specimen can be placed into the station for processing.

At 630, the transport apparatus 130 can remove the spent pipettes from the carousels 160. The pipettes can then be discarded or reused. To reuse the pipettes, the transport apparatus 130 can deliver the pipettes to a cleaning apparatus for cleaning and sterilizing.

The method of Figure 6 can be used to process different types of specimens. If the specimen 172a is a paraffin-embedded tissue section, the station 150a can perform a deparaffinization process. The deparaffinization process may include, without limitation, applying a deparaffinization liquid {e.g., limonene, xylene, surfactant containing solution, or the like) to the specimen 172a to effectuate deparaffinization. Any number of deparaffinization liquids can be applied until a desired amount of paraffin has been removed. After the deparaffinization process, the specimen 172a can be washed one or more times with, for example, washing liquids, such as ethanol or water. The holding capacity of the pipettes with the rinse solutions can be selected based on the size of the specimen and whether the rinse solution is drained by gravity or by blowing air towards the specimen 172a. The station 150a may also have separate fluid lines to deliver rinse solutions onto the specimen 172a. Figures 5A and 5B show a fluid line 523 that can deliver rinse solutions or other fluids onto the specimen 172a.

The specimen 172a can then be exposed to one or more stains for an extended period of time to ensure through staining. If the specimen 172a is stained using a hematoxylin dye, the hematoxylin stained specimen 172a may then be blued using an acidic bluing solution. The specimen 172a is then exposed to an eosin solution and washed. Each of these liquids is dispensed using a different pipette. Any number of rinsing operations can be performed between staining procedures to minimize, limit, or substantially prevent unwanted residual reagent.

The station 150a, in some embodiments, performs an immunohistochemical (IHC) procedure by deparaffinizing the specimen 172a. The specimen 172a is then rinsed one or more times. After rinsing, an inhibitor solution, such as a hydrogen peroxide solution, is used to reduce non-specific background staining. A primary antibody contacts the specimen 172a and is incubated. A secondary anti-antibody binds to the primary antibody that also includes a signal generating moiety such as an enzyme (for example, horseradish peroxidase or alkaline phosphatase) conjugated thereto. A combination of antibody conjugates that specifically bind the primary and the secondary antibodies is applied to the specimen 172a. Once antibodies that are not specifically bound are rinsed from the specimen 172a, a buffered wash solution is dispensed onto the specimen 172a. A diaminobenzidine

(DAB)/hydrogen peroxide solution is contacted to the specimen 172a and allowed to incubate, during which time enzymes of the secondary anti-antibody conjugate converts the soluble DAB into an insoluble brown precipitate at the sites in the specimen 172a where the primary antibody is specifically bound. After treatment to darken the hue of the DAB precipitate, the specimen 172a is washed with buffer, followed by one or more rinses with ethanol, and one or more rinses with limonene to ready the specimen 172a for subsequent processing, such as coverslipping.

The system 100 of Figure 1 may have a significantly higher productivity as compared to standard systems because the robotic handler 250 can keep a large number of carousels 160 loaded with pipettes. The illustrated processing system 140 includes four stations 150, but a greater or lesser number of stations can be used. For example, the process system 140 can include more than four connected or spaced apart stations 150 that can rapidly process slides without waiting for the robotic handler 250 to deliver pipettes. The stations 150 can be spaced apart from one another to reduce or eliminate vibrations caused by adjacent stations.

Figures 7 and 8 show a unit 698 including a drive assembly 700 and a processing station 710 carrying the drive assembly 700. The drive assembly 700 includes a motor 715 and a bracket 720 fixedly coupling the motor 715 to a slide holder 730. The bracket 720 includes a first rigid arm 736 and a second rigid arm 738 fixed to the slide holder 730. A carousel 740 is positioned between the arms 736, 738. In some embodiments, the carousel 740 is directly coupled to an output shaft of the motor 715. In other embodiments, the carousel 740 is indirectly coupled to the output shaft of the motor 715 by one or more mechanical components.

A user can insert a specimen-bearing microscope slide through an entrance 750 to position a specimen beneath the carousel 740. A pipette carried by the carousel 740 can be mated with an outlet 760. For example, the motor 715 can rotate the carousel 740 clockwise to position a pipette receiver 762 (shown empty in Figure 7) underneath the outlet 760. Air is passed through a line 770 and exits the outlet 762 to dispense fluid from the pipette 762.

Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open, inclusive sense, that is as "including, but not limited to." It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a sensor" includes a single sensor and/or a plurality of sensors. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

Various methods and techniques described above provide a number of ways to carry out the invention. There is interchangeability of various features from different embodiments disclosed herein. Similarly, the various features and acts discussed above, as well as other known equivalents for each such feature or act, can be mixed and matched by one of ordinary skill in this art to perform methods in accordance with principles described herein. Additionally, the methods which are described and illustrated herein, such as methods of installation, programming, calibration, and the like, are not limited to the exact sequence of acts described, nor are they necessarily limited to the practice of all of the acts set forth. Other sequences of events or acts, or less than all of the events, or simultaneous occurrence of the events, may be utilized in practicing the embodiments of the invention.

These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS What is claimed is:

1. A system for processing microscope slides, the system comprising: a pipette filling station; a first carousel configured to move a first pipette to a first delivery position for delivering a liquid to a first microscope slide, the first carousel including a first plurality of pipette receivers; a second carousel configured to move a second pipette to a second delivery position for delivering a liquid to a second microscope slide, the second carousel including a second plurality of pipette receivers; and a transport apparatus adapted to load both the first plurality of pipette receivers and the second plurality of pipette receivers with pipettes filled at the pipette filling station.

2. The system of claim 1 , further comprising: a first processing station having a first microscope slide holder and the first carousel, the first carousel is rotatably coupled to the first microscope slide holder such that the pipette receivers of the first carousel move sequentially to the first delivery position as the first carousel rotates; and a second processing station having a second microscope slide holder and the second carousel, the second carousel is rotatably coupled to the second microscope slide holder such that the pipette receivers of the second carousel move sequentially to the second delivery position as the second carousel rotates.

3. The system of claim 2, further comprising: a drive assembly coupled to the first processing station and the second processing station and adapted to independently rotate the first carousel and the second carousel.

4. The system of claim 1 , further comprising a controller communicatively coupled to the transport apparatus, the controller configured to command the transport apparatus to load the first carousel with a plurality of pipettes while the second carousel holds a plurality of pipettes for staining a specimen carried on the second microscope slide.

5. The system of claim 4, wherein the controller is configured to determine a carousel loading sequence for staging pipettes in the first and second carousels to increase throughput of the system.

6. The system of claim 1 , wherein the pipette filling station includes a plurality of containers holding reagents.

7. The system of claim 1 , wherein the first plurality of pipette receivers includes a plurality of through-holes angularly spaced from one another with respect to an axis of rotation of the first carousel.

8. The system of claim 1 , wherein the transport apparatus includes a robotic handler with an end effector operable to fill a pipette with a liquid.

9. A system for processing microscope slides, the system comprising: a first carousel having a first plurality of pipette receivers; a second carousel having a second plurality of pipette receivers; and a transport apparatus positioned to load the first plurality of pipette receivers and the second plurality of pipette receivers, the transport apparatus is configured to move at least one pipette to the first carousel to process a first microscope slide while the second carousel is used to process a second microscope slide.

10. The system of claim 9, further comprising: a drive assembly coupled to the first carousel and the second carousel; and a controller communicatively coupled to the drive assembly and the transport apparatus, the controller configured to command the transport apparatus to load the first carousel with pipettes while the drive assembly sequentially positions at least two of the second plurality of pipette receivers for delivering fluids to the second microscope slide.

11. The system of claim 9, further comprising an air injection apparatus configured to force liquid from at least one pipette carried by the first carousel.

12. The system of claim 9, further comprising a drive assembly configured to independently rotate the first carousel and the second carousel based on a first staining protocol and a second staining protocol.

13. An apparatus for processing microscope slides, comprising: a first slide holder; a first carousel having a first plurality of pipette receivers and being movable with respect to the first slide holder to position one of the pipette receivers for fluid delivery to a first microscope slide in the first slide holder; a second slide holder; and a second carousel independently movable with respect to the first carousel, the second carousel having a second plurality of pipette receivers and being movable with respect to the second slide holder to position one of the second plurality of pipette receivers for fluid delivery to a second microscope slide in the second slide holder.

14. The apparatus of claim 13, wherein the first carousel is positioned to successively position each pipette receiver of the first plurality of pipette receivers generally above a specimen carried on the first microscope slide.

15. The apparatus of claim 13, wherein the first carousel includes a cylindrical main body and the first plurality of pipette receivers are through-holes in the main body.

16. The apparatus of claim 13, wherein the first carousel and the second carousel are operable to simultaneously apply a first series of reagents to the first microscope slide and a second series of reagents to the second microscope slide.

17. A processing station for processing a specimen carried by a microscope slide, including: a microscope slide holder including a chamber and a delivery port; a carousel configured to successively align pipettes with the delivery port, the carousel having a plurality of pipette receivers; and a dispensing apparatus operable to cause a pipette that is aligned with the delivery port to output a fluid through the delivery port onto a specimen in the chamber.

18. The processing station of claim 17, wherein the plurality of pipette receivers includes at least five pipette receivers spaced angularly about an axis of rotation of the carousel.

19. The processing station of claim 17, wherein the carousel includes a cylindrical main body and the plurality of pipette receivers are through-holes in the cylindrical main body.

20. The processing station of claim 17, wherein the carousel is rotatably coupled to the microscope slide holder.

21. The processing station of claim 17, wherein the dispensing apparatus is configured to mate with a pipette in one of the plurality of pipette receivers to pneumatically push fluid from the pipette.

22. The processing station of claim 17, further comprising; a sensor adapted to output at least one signal based on a position of the carousel; and a drive assembly adapted to position the carousel based on the at least one signal outputted by the sensor.

23. A method for processing specimen-bearing microscope slides, the method comprising: determining substances to be applied to the specimen-bearing microscope slides; loading a plurality of rotatable carousels with pipettes based on the determination; and after loading the plurality of carousels, delivering substances from the pipettes held by the plurality of carousels onto microscope slides.

24. The method of claim 23, wherein determining the substances to be applied includes determining staining protocols for respective ones of the specimen-bearing microscope slides using a controller.

25. The method of claim 23, further comprising loading the plurality of carousels using a robotic arm.

26. The method of claim 23, wherein delivering substances from the pipettes includes forcing air through the pipettes.

27. The method of claim 23, wherein loading the plurality of carousels includes loading a plurality of pipette receivers of one of the carousels with pipettes.

28. A method for processing microscope slides, the method comprising: filling a plurality of pipettes at a filling station; delivering at least one of the pipettes to a first carousel and at least one of the pipettes to a second carousel; outputting fluid from the at least one pipette carried by the first carousel onto a first microscope slide; and outputting fluid from the at least one pipette carried by the second carousel onto a second microscope slide.

29. The method of claim 28, wherein filling the plurality of pipettes and delivering the pipettes includes alternating filling one of the pipettes and delivering the one of the pipettes to one of the first and second carousels.

30. The method of claim 28, further comprising staining a first specimen on the first microscope slide using the fluid outputted from the at least one pipette carried by the first carousel while a second specimen on the second microscope slide is stained using the fluid outputted from the at least one pipette carried by the second carousel.

31. The method of claim 28, further comprising moving the plurality of pipettes from the filling station using a robotic handler, the robotic handler is configured and positioned to delivery pipettes to both the first carousel and the second carousel.

32. The method of claim 31 , wherein the robotic handler includes a reconfigurable robotic arm.