Automated pipette tip organization for fluid handling systems - Patents.com

Abstract

A method for automatically defragmenting pipette tips in a tip tray during performance of a procedure defined by a protocol stored in a memory of a fluid handling system, the method comprising the steps of determining the location of an empty receptacle in the tip tray in which no pipette tip is present, determining the location of a filled receptacle in the tip tray in which a pipette tip is present, and using the fluid handling system to move the pipette tip from the filled receptacle to the empty receptacle to complete a series of filled receptacles in the tip tray.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 277,396, filed November 9, 2021, the entire contents of which are incorporated herein by reference.

[0002] This application relates generally to fluid handling systems, such as, but not limited to, those that may be used in a variety of applications for combining reagents (e.g., liquid reagents and solvents) or other fluids. More specifically, this application relates to systems and methods for arranging pipette tips loaded into a robotic fluid handling system, such as to improve access to pipette tips by moving parts of the fluid handling system and to facilitate the execution of protocols and operations performed by the fluid handling system. [Background technology]

[0003] Many fluid handling systems are configured to be loaded with containers of liquid to perform library construction (e.g., libraries of DNA or RNA fragments for sequencing) using multiple reagents and solvents. To perform library construction on samples using a fluid handling system such as a liquid handler, the fluid handling system is typically set up by an operator or user. The set up may include loading various items onto the deck of the fluid handling system, including samples, library construction reagents, and various items of labware such as pipette tips, plate lids, and liquid containers of various types and configurations, including reservoirs, microtiter plates, test tubes, vials, microcentrifuge tubes, and the like, according to a protocol programmed into the fluid handling system to perform library construction.

[0004] Pipette tips can be provided by the manufacturer or arranged by the user in boxes, trays, or racks. A typical arrangement includes a rectangular array of rows and columns of pipette tips loaded into individual sockets or receptacles in the rack. The pipette tips can be appropriately spaced to allow each of multiple mandrels of a multi-channel pipetting instrument of the fluid handling system to access the pipette tips. Each mandrel of a single or multi-channel pipetting instrument can be loaded with a clean pipette tip from the rack before using the pipetting instrument in a pipetting operation. Used pipette tips can then be dropped into a waste container before the pipetting instrument is moved back to the rack and an unused pipette tip is retrieved. Unused pipette tips can be removed from the rack in various numbers and from disparate locations to perform different pipetting operations using different pipetting instruments. Thus, after the fluid handling system has performed a complete protocol, the rack of pipette tips can be partially used while leaving unused pipette tips in random locations throughout the rack. Using unused pipette tips for a subsequent operation typically requires the user to manually reload a box or tray with sufficient pipette tips to perform the next operation. Such a task can be labor intensive and time consuming, and can lead to contamination of unused pipette tips due to their manual handling. Summary of the Invention [Means for solving the problem]

[0005] The inventors have recognized that, inter alia, a problem to be solved in preparing a fluid handling system for performing a protocol involving pipetting operations includes the need for direct operator interaction required to check the fluid handling system for partial pipette tip containers, e.g., racks, bins, and trays, either at the beginning or end of the protocol, and to reload the containers to capacity. Frequently, one partially filled pipette tip container is used to reload another partially filled pipette tip container.

[0006] The present subject matter can provide solutions to these and other problems, such as by providing a fluid handling system that can automatically perform a pipette tip-container defragmentation and reformatting procedure to reduce or eliminate empty pipette tip locations within a container, or strategically generate a series of pipette tips that facilitate protocol execution or improve access to pipette tips. In various embodiments, the defragmentation and reformatting operation can be initiated before, during, or after a protocol. In various embodiments, the defragmentation and reformatting operation can include tracking and mapping the consumption of pipette tips in real time, such that unused pipette tips can be loaded into the empty locations. In various embodiments, the defragmentation and reformatting operation can utilize imaging to identify empty locations that need to be refilled with unused pipette tips. In various embodiments, the defragmentation and reformatting operation can sense the presence of locations within a pipette tip container where a pipette tip is located, and determine locations where unused pipette tips need to be reloaded.

[0007] In one embodiment, a method for automatically defragmenting pipette tips in a tip tray during performance of a procedure defined by a protocol stored in a memory of a fluid handling system includes the steps of determining the location of an empty receptacle in the tip tray in which no pipette tip is present, determining the location of a filled receptacle in the tip tray in which a pipette tip is present, and using the fluid handling system to move the pipette tip from the filled receptacle to the empty receptacle to complete a series of filled receptacles in the tip tray.

[0008] In one embodiment, a method for automatically defragmenting pipette tips in a tip tray during performance of a procedure defined by a protocol stored in a memory of a fluid handling system includes determining locations of empty receptacles in the tip tray where no pipette tips are present, determining locations of filled receptacles in the tip tray where a pipette tip is present, and using the fluid handling system to move pipette tips from the filled receptacles to the empty receptacles to generate a pattern of filled receptacles in a row of the tip tray according to tip usage as defined in the protocol.

[0009] In another example, a method for automatically defragmenting pipette tips in a first tip tray during performance of a procedure defined by a protocol stored in a memory of a fluid handling system can include determining the location of an empty receptacle in the first tip tray in which no pipette tip is present, determining the location of a filled receptacle in the first tip tray in which a pipette tip is present, and using the fluid handling system to move a pipette tip from the filled receptacle to the empty receptacle in a second tip tray to complete a series of filled receptacles in the first tip tray. [Brief description of the drawings]

[0010] [Figure 1]FIG. 1 is a block diagram of a robotic fluid handling system according to one embodiment of the present disclosure.

[0011] [Diagram 2] FIG. 2 is a perspective view of the exemplary robotic fluid handling system of FIG. 1 including a housing, a carousel, a reaction vessel, a thermal cycler module, and an imaging device positioned relative to a deck.

[0012] [Diagram 3] FIG. 3 is a schematic diagram illustrating the items of labware, labware receivers, transport devices, and imaging devices positioned relative to the deck, further illustrated in FIGS.

[0013] [Figure 4] FIG. 4 is a plan view of the deck of FIG. 3 with various items of labware, including reaction vessels, a carousel, and a thermal cycler reaction vessel holder, positioned on the deck for loading into the enclosure of FIG. 2.

[0014] [Diagram 5] FIG. 5 is a plan view of the deck of FIG. 4 without any articles of labware loaded thereon to show a bulk reaction vessel holder, a labware holder for reaction vessels, a labware holder for pipette tip containers or microplates, and a thermal cycler reaction vessel holder.

[0015] [Figure 6] FIG. 6 is a perspective view of a manifold that may be coupled to a transfer device of a fluid handling system of the present disclosure.

[0016] [Figure 7] FIG. 7 is a cross-sectional view of the manifold of FIG. 6 taken at section 7-7, showing the circuit board, mandrel, pipette tip, plunger, and connector pins.

[0017] [Figure 8]FIG. 8 is a perspective view of a pipette tip rack at full capacity of unused pipette tips.

[0018] [Figure 9A] 9A-9E illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step after a protocol initiation step. [Figure 9B] 9A-9E illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step after a protocol initiation step. [Figure 9C] 9A-9E illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step after a protocol initiation step. [Figure 9D] 9A-9E illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step after a protocol initiation step. [Figure 9E] 9A-9E illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step after a protocol initiation step.

[0019] [Figure 10A] 10A-10F illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step during initiation of a protocol. [Figure 10B] 10A-10F illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step during initiation of a protocol. [Figure 10C] 10A-10F illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step during initiation of a protocol. [Figure 10D] 10A-10F illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step during initiation of a protocol. [Figure 10E]10A-10F illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step during initiation of a protocol. [Figure 10F] 10A-10F illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step during initiation of a protocol.

[0020] [Figure 11A] 11A-11C illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step prior to initiation of a protocol. [Figure 11B] 11A-11C illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step prior to initiation of a protocol. [Figure 11C] 11A-11C illustrate schematic maps of the pipette tip rack of FIG. 8 showing an example of a defragmentation step prior to initiation of a protocol.

[0021] [Figure 12A] 12A and 12B illustrate a diagram showing steps for automatically performing pipette tip defragmentation or reformatting on the pipette tip rack of FIGS. 8-11C using the robotic fluid handling system of FIGS. 1-7. [Figure 12B] 12A and 12B illustrate a diagram showing steps for automatically performing pipette tip defragmentation or reformatting on the pipette tip rack of FIGS. 8-11C using the robotic fluid handling system of FIGS. 1-7.

[0022] [Figure 13A] FIG. 13A is a side view of the deck of FIG. 4 taken along the Y direction to show locations for the tip racks, which are arranged in a stadium configuration to facilitate access by the manifold.

[0023] [Figure 13B]FIG. 13B is a side view of the deck of FIG. 4 taken along the X direction to show locations for tip racks, which are arranged in tiers of the arena configuration to facilitate access by the manifold. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description FIG. 1 is a high-level block diagram of a processing system 100 according to an embodiment of the present disclosure. The processing system 100 can include a liquid or fluid handling system with which the pipette tip defragmentation or reformatting procedure of the present disclosure can be performed. The processing system 100 can include a control computer 108 operably coupled to the structure 140, the transport device 141, the processing device 101, and the thermal cycler system 107. Input / output interfaces can be present in each of these devices to allow data transmission between the illustrated devices and external devices. The processing system 100 can include a robotic fluid handling system as described herein. The fluids can include various liquids such as reagents and the like. Exemplary processing systems in which the present disclosure can be implemented are the Biomek i7 automated workstation and the Biomek NGeniuS automated workstation, each of which is commercially available from Beckman Coulter, Inc. (Brea, California).

[0025] For purposes of illustration, the processing system 100 will be described primarily as a system for processing and analyzing biological samples, such as preparing libraries of nucleic acid fragments (e.g., libraries of fragments derived from DNA or RNA molecules), including next generation sequencing (NGS) libraries. For example, embodiments of the present disclosure can include thermal cycling and incubating reagents in reaction vessels loaded into a thermal cycling system, where a single reaction vessel and a single thermal cycling system can perform multiple different heating functions for different liquids loaded therein. The processing system 100 can additionally represent other types of fluid handling systems.

[0026] To properly process reagents and samples in system processing modules (e.g., reaction vessels) and provide other functionality of the fluid handling system, liquids can be moved around and combined within the fluid handling system using pipette tips attached to a pipetting instrument or manifold via a mandrel. Typically, pipette tips are disposable and configured to be used once to avoid contamination. Thus, the pipetting instrument or manifold repeatedly self-loads with clean, unused pipette tips from a storage container within the fluid handling system, performs a pipetting operation, disposes of dirty, used pipette tips in a waste container, and reloads with new pipette tips. The present disclosure describes systems and methods for monitoring consumption of pipette tips from a pipette tip container, retrieving unused pipette tips from other containers, and re-arranging unused pipette tips within the container, and organizing unused pipette tips into an arrangement that may facilitate rapid execution of a current protocol and accelerate the execution of subsequent protocols. Thus, the processing system 100 can be used to verify the location of pipette tips, monitor the consumption of pipette tips, and track the location of free and filled pipette tip receptacles so that unused pipette tips can be added and organized within the pipette tip container to facilitate subsequent operations and protocols. Partially used pipette tip containers can be reformatted or defragmented. Reformatting can include fully refilling the pipette tip container to capacity or arranging the container to include a pattern of pipette tips to facilitate performance of various pipetting operations within a protocol. Defragmenting can include arranging a block or series of contiguous pipette tips to eliminate or reduce empty space.

[0027] The structure 140 can include a housing (e.g., housing 202 in FIG. 2), legs or casters for supporting the housing, a power source, a deck 105 loadable into the housing, and any other suitable features. The deck 105 can hold a permanently mounted module (processing device 101) for automated performance of multiple sample preparations or assays, such as those that can be used in library construction for next generation sequencing. In addition, the deck 105 can include a physical surface, such as a planar physical surface (e.g., platform 212 in FIG. 2), on which components can be reversibly installed and accessed for experiments, analyses, and processes. In some cases, the deck 105 can be a floor or tabletop surface. The deck 105 can be subdivided into multiple discrete deck locations (e.g., locations L1-L16 in FIG. 4) for installing different components. The locations can be directly adjacent, or spaced apart from each other. Each deck location may include dividers, inserts, and / or any other support structure to separate different deck locations and contain components, as shown in FIG. 5. For illustrative purposes, FIG. 1 shows a first location 105A, a second location 105B, and a third location 105C on deck 105, but additional locations may also be included. One or more of locations 105A-105C may be loaded with one or more microtiter plates or reaction vessels (e.g., reaction vessel 205 in FIG. 2), which may include a carousel (e.g., carousel 204 in FIG. 2), or space for holding one or more components, such as liquids or vials of liquid. For the present application, deck 105 may include one or more locations for placement of pipette tip boxes, racks, or trays.

[0028] The transport device 141 may comprise a wheeled gurney, bridge, or carrier system having movement capabilities in the X and Y directions and hoisting capabilities in the Z direction (see FIG. 3). The transport device 141 may represent multiple transport devices, capable of preparing and / or transporting components between the deck 105 and the processing equipment 101 and between different locations on the deck 105. Examples of transport devices may include conveyors, cranes, sample trucks, pick-and-place grippers, independently movable laboratory transport elements (e.g., pucks, hubs, or pedestals), robotic arms, and other tube or component handling mechanisms. The transport device 141 may comprise a mandrel (e.g., the distal mandrel 256 in FIG. 3). The mandrel may be equipped with a working instrument and presence sensing capabilities such as a capacitance sensor. In some examples, the working instrument mounted on the transport device 141 comprises a fluid dispenser, such as a pipetting head, configured to transport liquid. The pipetting head can comprise a single channel or multi-channel pipettor configured to deliver liquids using pipette tips that are reversibly attached to a pipette tip mandrel of the pipettor. A multi-channel pipettor can include a single displaceable piston configured to actuate each channel simultaneously via coupling to a manifold. Pipette tips can be attached to the pipetting head and can be discarded after each use. The pipetting head can also include a gripper suitable for gripping or releasing other labware, such as a microwell plate.

[0029] The processing device 101 may include any number of machines or instruments for performing any suitable process. For example, the processing device 101 may include an analyzer, which may include any suitable instrument capable of analyzing a sample, such as a biological sample. Examples of analyzers include a spectrophotometer, a luminometer, a mass spectrometer, an immunoanalyzer, a hematology analyzer, a microbiology analyzer, a flow cytometer, and / or a molecular biology analyzer. In some examples, the processing device 101 may include a sample staging device. The sample staging device may include a sample presentation unit for receiving a sample tube with a biological sample, a sample storage unit for temporarily storing the sample tube or sample holding container, a means or device for aliquoting the sample, such as an aliquoter, a means for holding at least one reagent pack comprising reagents required for the analyzer, and any other suitable features. The processing device 101 may further include a device for mixing the sample, a shaker or agitator for stirring or mixing liquids and reagents, and the like.

[0030] The thermal cycler system 107 can be positioned relative to the deck 105 and can be configured to receive a liquid container, such as a reaction vessel 205 (FIG. 2). The liquid container can be loaded into the thermal cycler system 107 manually or via a transport device 141. The thermal cycler system 107 can be configured to provide a number of different heating zones that can heat different portions of the reaction vessel 205 to different temperatures. Thus, for example, depending on the amount and type of liquid placed in the reaction vessel 205, different amounts of heat can be applied to perform thermal cycling, incubation processes, and the like.

[0031] The processing system 100 may include an imaging system, e.g., a camera such as imaging device 206 (FIG. 2), for viewing the presence of labware items loaded on the deck 105, pipette tips loaded in a tip tray, and reading labels of reagent vials loaded on the labware items. The imaging system may ensure that all portions of the workspace of the deck 105 are within the field of view of at least one camera. The imaging device may be any suitable device for capturing an image of the deck 105 and any components on the deck 105, or the entire structure 140. The imaging device may comprise one of a number of imaging devices mounted on or near the structure 140 for obtaining multiple views of the labware and reagent vials disposed on the deck 105. For example, the imaging device may be any suitable type of camera, such as an optical camera, a video camera, a three-dimensional image camera, an infrared camera, etc. Some embodiments may also include a three-dimensional laser scanner, infrared optical depth sensing technology, or other instrument for creating a three-dimensional surface map of an object and / or a room. In an embodiment, the imaging devices can be used to facilitate setup of the processing system 100, such as by verifying the proper location of labware or other components within an enclosure (e.g., enclosure 202 of FIG. 2) or on deck 105, and by providing input regarding the presence or location of labware or components to the control computer 108. In additional embodiments, one or more imaging devices 206 can be used to monitor pipette tip location and dissipation before, during, and after performing a protocol, facilitating defragmentation and reformatting procedures, where a protocol is a list of instructions for the fluid handling system to perform a procedure, including pipetting operations.

[0032] The control computer 108 can use the processing device 101 according to stored protocols to perform pipette tip organization for pipette tips loaded on the deck 105, including the transport device 141, and control processes initiated on the processing system 100. The control computer 108 can control and / or transmit messages to the processing device 101, the transport device 141, and / or the thermal cycler system 107. The control computer 108 can comprise a data processor 108A, a non-transitory computer readable medium 108B and a data storage component 108C coupled to the data processor 108A, one or more input devices 108D, and one or more output devices 108E. Although the control computer 108 is depicted in FIG. 1 as a single entity, it should be understood that the control computer 108 can exist in a distributed system or in a cloud-based environment. Additionally, embodiments allow for some or all of the control computer 108, processing unit 101, transport device 141, and / or thermal cycler system 107 to be combined as components within a single device.

[0033] The output device 108E may comprise any suitable device capable of outputting data. Examples of the output device 108E may include a display screen, a video monitor, a speaker, audio and visual alarms, and a data transmission device. The input device 108D may comprise any suitable device capable of inputting data into the control computer 108. Examples of the input device may include a button, a keyboard, a mouse, a touch screen, a touch pad, a microphone, a video camera, and a sensor (e.g., a light sensor, a position sensor, a speed sensor, a proximity sensor). In addition, the input device 108D may comprise a sensor that may receive input from the transport device 141. In an example, the input device 108D may comprise a capacitance sensor (e.g., capacitance sensor 616 of FIG. 7) that may be in electronic communication with the tip mandrel 256 (FIG. 3) of the transport device 141. Thus, capacitance sensed at the tip mandrel 256 or an instrument loaded therein can be relayed to or sensed in conjunction with a capacitance sensor located in the control computer 108. In an additional embodiment, the input device 108D can be located on the transport device 141 and include one or more encoders for providing location information, such as X, Y, Z coordinates, to the control computer 108 regarding the location of the tip mandrel 256 and an instrument loaded therein relative to the workspace of the deck 105.

[0034] The data processor 108A may include any suitable data computing device or combination of such devices. An exemplary data processor may include one or more microprocessors that cooperate to perform desired functions. The data processor 108A may include a CPU that includes at least one high-speed data processor suitable for executing program components to execute user and / or system generated requests. The CPU may be a microprocessor such as an AMD Athlon, Duron, and / or Opteron, IBM and / or Motorola PowerPC, IBM and Sony Cell processors, Intel Celeron, Itanium, Pentium, Xeon, and / or XScale, and / or similar processors. The data processor system may include a means for communicating to an external device such as a USB drive to load a user panel or services such as the Beckman Connect instrument diagnostic service.

[0035] The computer readable medium 108B and data storage component 108C can be any suitable device or devices capable of storing electronic data. Examples of memory can include one or more memory chips, disk drives, etc. Such memory can operate using any suitable electrical, optical, and / or magnetic modes of operation.

[0036] The computer readable medium 108B may comprise code executable by the data processor 108A to perform any suitable method. For example, the computer readable medium 108B may comprise code executable by the processor 108A to cause the processing system 100 to perform an automated process, including a pipette tip defragmentation and reformatting process, and to control the thermal cycler system 107, the structure 140, the transport device 141, and / or the processing device 101 to perform process steps for one or more processes described herein, in particular those described with reference to Figures 8-14B and the Examples section below, which describes a pipette tip defragmentation and reformatting method.

[0037] The computer readable medium 108B can comprise code executable by the data processor 108A to receive and store process steps for one or more pipette tip organization procedures (e.g., procedures for arranging or rearranging, formatting or reformatting, and / or defragmenting pipette tips within one or more containers). Thus, the computer readable medium 108B can include three dimensional location data, such as X, Y, Z coordinates described below, for the locations of individual pipette tip sockets or receptacles for pipette tip containers loaded onto the deck 105.

[0038] The computer readable medium 108B may also include code executable by the data processor 108A for receiving results from the processing device 101 (e.g., results from analyzing a biological sample) and for transferring the results or using the results for additional analysis (e.g., diagnosing a patient).

[0039] Additionally, the computer readable medium 108B may comprise code executable by the data processor 108A to acquire an image of the deck 105, identify information in the image of the deck 105 (e.g., the presence of labware or the location of a pipette tip), identify a piece of labware or a pipette tip on the deck 105 by comparing the location information stored in the computer readable medium 108B with the location information acquired from the imaging process, and perform a pipette tip organization process of the processing system 100 accordingly.

[0040] The data storage component 108C can be internal or external to the control computer 108. The data storage component 108C can include one or more memories, including one or more memory chips, disk drives, etc. The data storage component 108C can also be used with Microsoft SQL, Oracle TM , or Sybase TM The data storage component 108C may include a conventional, fault-tolerant, relational, scalable, and secure database, such as those commercially available from Microsoft Corporation. In some embodiments, the data storage component 108C may store the protocol 108F and the images 108G. The data storage component 108C may additionally include instructions for the data processor 108A, including the protocol. The computer readable medium 108B and the data storage component 108C may comprise any suitable storage device, such as non-volatile memory, magnetic memory, flash memory, volatile memory, programmable read-only memory, and the like.

[0041] The protocol 108F in the data storage component 108C can include information about one or more protocols. A protocol can include one or more processing steps to complete (e.g., pipetting processes, procedures, or operations), components to be used during a process (e.g., pipette tips), component location layouts (e.g., X, Y, Z coordinate locations for pipette tips), loading of the thermal cycler system 107, information about heating levels of the thermal cycler system 107, and / or any other suitable information for completing a process. For example, a protocol can include one or more ordered steps for processing a biological sample or processing a DNA library. A protocol can also include steps for preparing a list of components before starting a process, such as the number of pipette tips to be used in each pipetting operation. Components can be mapped to specific locations within a reaction vessel (e.g., reaction vessel 205 in FIG. 2) or within a carousel (e.g., carousel 204 in FIG. 2) or deck (e.g., deck 105) or pipette tip container (e.g., pipette tips 702 in tip rack 700 in FIG. 8) from which the transport device 141 may retrieve them for transporting the components or the containers in which they are loaded to the processing device 101 or thermal cycler system 107. This mapping can be encoded as instructions to operate the transport device 141, such as instructions directing a pipettor, including a pipette tip, to aspirate a volume of liquid from a reaction vessel in the carousel and dispense that volume to a predetermined destination, and the mapping can also be represented by a virtual image shown to a user as the user places components on the deck 105, reaction vessel, and carousel. An embodiment allows the processing system 100 to be used for multiple processes (e.g., multiple different sample processes or preparation procedures). Thus, information about multiple protocols 108F can be stored and retrieved when needed.As described herein, the components on deck 105, particularly the pipette tips, reaction vessels, and carousels, can be automatically rearranged, changed, and / or replenished as necessary when changing from a first process to a second process within a protocol, or when resuming a first process within a protocol, or when changing from a first protocol to a second protocol. In order to properly execute a protocol, it is desirable for control computer 108 to know how to manipulate transport device 141 to move work implements to desired three-dimensional locations within the workspace of deck 105.

[0042] The images 108G in the data storage component 108C can include real-world visual representations of the deck 105, pipette tips, reaction vessels, and carousel, and components disposed on or within the deck 105, pipette tip containers, reaction vessels, and carousel, and labels disposed on those components. In each image, the deck 105, reaction vessels, and carousel can be shown in a ready state to begin a process, with components for carrying out the protocol located in locations accessible to the transport device 141. Each of the images 108G can be associated with a specific protocol from the stored protocols 108F. In some embodiments, there can be a single image for a protocol. In other embodiments, there can be multiple images for a protocol (e.g., from different angles, with different lighting levels, or containing acceptable labware surrogates in several locations). The images 108G can be stored as image files of various types or formats, including JPEG, TIFF, GIF, BMP, PNG, and / or RAW image files, and AVI, WMV, MOV, MP4, and / or FLV video files. The images 108G can thus provide information to the control computer 108 regarding the presence and proper positioning of labware and pipette tips on the deck 105, and the quantities of such components that are available, and the number of vacant locations or receptacles for such components.

[0043] Deck 105 can be subdivided into multiple discrete deck locations to stage different components. The discrete locations can be of any suitable size. An example of a deck 105 with multiple locations is shown loaded with labware in FIG. 4 and unloaded in FIG. 5. Deck 220 in FIG. 4 shows separate areas numbered L1-L16 and a thermal cycler system 208, which can act as separate locations for separate types of components or packages of components. Deck 105 can have additional or fewer locations as desired. These locations can be numbered or named, but they may or may not be physically labeled or marked on deck 105 in the physical embodiment of the system.

[0044] As discussed herein, the processing system 100 can execute a pipette tip organization procedure for the processing system 100, including steps of performing a reformatting and defragmentation procedure using the transport device 141 (FIG. 2) and the pipetting device 600 (FIG. 6). In particular, as described in more detail with reference to FIGS. 14A and 14B, the processing system 100 can 1) determine a starting set of pipette tips to be used for a protocol, 2) determine the locations of all pipette tips in the starting set, 3) monitor the consumption of pipette tips during the performance of the protocol, 4) record the locations of unfilled or empty pipette tip receptacles in a pipette tip container, 5) move pipette tips from within a pipette tip receptacle to a different receptacle, 6) move pipette tips from within a different pipette tip container to a receptacle in the pipette tip container, and 7) organize pipette tips within the receptacles of the pipette tip container to reduce free space and increase efficient pipette tip loading onto the pipetting device. The knitting procedures described herein can be performed by the processing system 100 without or with minimal assistance of operator intervention and with reduced time compared to typical procedures.

[0045] FIG. 2 is a perspective view of a fluid handling system 200, which may comprise an embodiment of the processing system 100 of FIG. 2. The fluid handling system 200 may comprise a housing 202, a carousel 204, a reaction vessel 205, an imaging device 206, and a thermal cycler system 208. It should be noted that the components of FIG. 2 are not necessarily drawn to scale for illustrative purposes. The housing 202 may comprise a number of walls or panels forming an enclosure within which the carousel 204 and the reaction vessel 205 may be positioned. The enclosure may have an opening across which a cover panel 210 may be positioned to encapsulate the carousel 204, the imaging device 206, and the thermal cycler system 208 within the enclosure. The housing 202 may additionally include a platform 212 upon which a deck, such as deck 105 (FIG. 1) or deck 220 (FIG. 3), may be positioned. The deck can include various sockets, slots, or receptacles (e.g., receptacles 300, 302, 304, and 306 in FIG. 5) for receiving the carousel 204 and one or more of the reaction vessels 205, pipette tip racks, and the like. In an embodiment, the sockets, slots, or receptacles can be configured to hold the carousel 204, reaction vessels 205, pipette tips, and the like in a predetermined or known position relative to the transport device 141 (FIGS. 1, 3) and the imaging device 206. The platform 212 can hold the deck and contents therein in a predetermined or known position relative to the housing 202. The housing 202 can additionally include space for holding a controller 214, such as that of the control computer 108 (FIG. 1). The controller 214 can be configured to communicate with a network 216, such as via wireless or wired communication lines.

[0046] The imaging device 206 can be located in the housing 202 at a fixed location. However, the imaging device 206 can be movable or have an adjustable field of view. One or more imaging devices 206 can be configured to face a single location or multiple locations in the housing 202. At the same time, the dispenser tip 258 (FIG. 3) of the transport device 141 and the processing device 101 (FIG. 1) can be located in the housing 202 to access locations on the platform 212. The transport device 141 can additionally be configured to move reaction vessels 205 into the thermal cycler system 208 and other items of labware to any of the locations L1-L16 (FIG. 4). The carousel 204 can swivel or rotate to present different locations to the fluid dispenser, e.g., the dispenser tip 258 (FIG. 3) or the pipette tip 608 (FIG. 6), and the imaging device 206. In other embodiments, a single imaging device 206 may be mounted within the housing 202 and the viewing area may be moved throughout different portions of the interior of the housing 202 .

[0047] Fluid handling system 200 may further comprise a transport device 141 (FIG. 1), which may comprise a system for moving fluid dispensers to different three-dimensional locations within housing 202, as described with reference to FIGS. 3-5. The organizing procedures described herein may be performed by transport device 141 to move fluid dispensers within housing 202, move unused pipette tips between locations within one or more pipette tip containers, assemble fragmented pipette tips, or format pipette tips into useful patterns from pipette tips that may be scattered within one or more pipette tip containers due to implementation of a protocol, as described in more detail with reference to FIGS. 8-14B.

[0048] FIG. 3 is a schematic diagram illustrating the platform 212 of FIGS. 4 and 5 with the lab equipment piece 230 positioned in a receptacle 232 of the deck 220 and relative to the transport device 141 and the imaging device 206. The receptacle 232 may include walls 234A-234D. The transport device 141 may include an overhead crane system having rails 240A and 240B extending across the length of the platform 212 and a bridge 242 that may span the width of the platform 212. The bridge 242 may be configured to slide on the rails 240A and 240B via wheels 244A and 244B or the like. A carriage 246 may be coupled to the bridge 242 and configured to move along the bridge 242 across the width of the platform 212. The bridge 242 and the carrier 246 are operatively coupled to one or more motors 248 and power sources (not shown) and controller 214 ( FIG. 2 ) or control computer 108 ( FIG. 1 ) for movement according to the reformatting or defragmentation procedure. The carrier 246 can comprise a wheeled gurney 250 having wheels 252A and 252B, a fluid dispenser 254, and a tip mandrel 256. In the illustrated embodiment, the tip mandrel 256 is reversibly coupled to a dispenser tip 258. In an embodiment, the dispenser tip 258 can comprise a pipette tip, such as pipette tip 702 of FIG. 8 . The dispenser tip 258 can be configured to move axially in the Z direction via the telescopic action of the tip mandrel 256, the carrier 246 can be configured to move axially in the X direction on the bridge 242, and the bridge 242 can be configured to move axially in the Y direction on the rails 240A and 240B. In some embodiments, the fluid dispenser 254 is coupled to a robotic arm configured to move the fluid dispenser 254 axially in the Z direction and provide vertical movement and positioning of the dispenser tip 258.Thus, the dispenser tip 258 can be moved to engage the receptacle 232 and the labware piece 230 and move liquid from the labware piece 230 to other locations on the deck 220 and from other locations on the deck 220 to the labware piece 230. The motor 248 can comprise one or more motors for moving the wheeled gurney 250 by activating wheels 252A and 252B, moving the bridge 242 by activating wheels 244A and 244B, moving the tip mandrel 256 relative to the fluid dispenser 254 by moving a linear actuator, etc. The motor 248 can include a stepper motor, where the position of a component of the motor 248 relative to the rest of the motor 248 can be converted to an X, Y, or Z position in a coordinate system.

[0049] According to the present disclosure, the transport device 141 can be operated by the controller 214 to engage the tip of the dispenser tip 258 or the tip mandrel 256 of the fluid dispenser 254 when the dispenser tip 258 is not disposed within the tip mandrel 256 to sense the presence of items located on the deck 220, such as liquids, labware, and pipette tips, by using a capacitance sensing system or the like. The fluid dispenser 254, the tip mandrel 256 extending therefrom, and the dispenser tip 258, and other conductive or semiconductor implements attached to the tip mandrel 256, can be configured to be in electrical communication with a capacitance sensor located, for example, within the controller 214 (FIG. 2), the carrier 250, the fluid dispenser 254, or elsewhere within or on the housing 202. In one embodiment, the fluid dispenser 254 and associated capacitance sensor can be configured as the tip mandrel 606 and capacitance sensor 616 of FIGS. 6 and 7. In an embodiment, the capacitance sensor may include a CapSense® sensor manufactured by Cypress Semiconductor. In an additional embodiment, the pipette or pipette tip attached to the tip mandrel 256 may be fabricated from a plastic into which a conductive material is injected or embedded. Thus, the processing system 100 may utilize the conductive tip to sense the magnitude of capacitance between the tip and a container of conductive fluid to be measured. This magnitude may be correlated with data stored in memory available to the processing system 100 to determine the level of the liquid surface. Similarly, the processing system 100 may determine whether the tip mandrel 256 is in contact with a conductive pipette tip to determine the presence or absence of a pipette tip at a location (e.g., an X, Y, Z coordinate position) within the pipette tip container.Examples of capacitive sensing circuits are described in U.S. Patent No. 4,912,976, entitled "Liquid level sensing apparatus" by Labiola, II, U.S. Patent No. 4,736,638, entitled "Liquid level sensor" by Okawa et al., and U.S. Patent No. 7,275,430, entitled "Method and apparatus for detecting liquid levels in liquid-storage containers" by Zuleta et al., each of which is incorporated herein by reference in their entirety. In other embodiments, the processing system 100 can determine the presence or absence of a pipette tip at a location (e.g., an X, Y, Z coordinate location) within a pipette tip container using the imaging device 206, as described elsewhere herein. In yet other embodiments, the presence or absence of a pipette tip at a specific location can be determined by detecting a change in the resistance of motion of the tip mandrel 256 as the tip mandrel 256 is lowered to engage a pipette at that specific location. This change in resistance can be detected by a pressure sensor, by a position encoder indicating a reduction in movement compared to the commanded movement, or by any other suitable means. In yet another embodiment, the locations of free pipette tip receptacles and filled tip receptacles within the pipette tip container may be determined by assuming that the pipette tip container was full at the start of the activation and monitoring the consumption of pipette tips according to the protocol being activated.

[0050] As discussed in more detail below, the controller 214 (FIG. 2) can be configured to perform a pipette tip defragmentation or reformatting procedure to reduce or eliminate the need for an operator to manually replenish or organize pipette tips left behind after a protocol is initiated when pipette tips are loaded into a container. In an embodiment, the controller 214 can be configured to operate the transport device 141 to contact a sensor connected to or mounted on the transport device 141 with a pipette tip in a container loaded onto the platform 212 or deck 220. For example, the fluid dispenser 254 or the dispenser tip 258 can be equipped with a sensor, such as a capacitance sensor. Unique structural features of a pipette tip loaded into a tip tray disposed on the deck 220 can be contacted and the location of the tip mandrel 256 in three-dimensional X, Y, Z coordinates can be recorded such that the controller 214 can know the location of the pipette tip in that specific location. If the fluid dispenser 254 does not contact the pipette tip, no capacitance reading occurs and the controller 214 can know that no pipette tip is present at that location.

[0051] Thus, contact of the pipette tip can establish that the receptacle in the container is occupied, and absence of contact with the pipette tip can establish that the receptacle in the container is empty. Occupancy / empty information read from these sensors can be compared to information obtained from the network 216 (FIG. 2) connected to the control computer 108 (FIG. 1) or stored in a computer readable medium such as medium 108B of FIG. 1, or information provided by the operating method. The information stored in the computer readable medium can include protocol information, including the number and location of pipette tips to be used in the protocol, where they should be read, and the number or location of pipette tips that may be left or remain at any time after or during the execution of the protocol. In addition, complete geometric information (e.g., dimensions, sizes, tolerances, etc.) regarding the pieces of labware and pipette tips that may be positioned in each of the receptacles 300, 302, 304, and 306 can be stored in the medium 108B of FIG. 1 or made available via the network 216 (FIG. 2).

[0052] The controller 214 (FIG. 2) can be configured to perform different pipette tip organization procedures, such as filling containers, filling rows or columns in an array of container receptacles, formatting pipette tips into patterns or groupings that facilitate performance of steps of a protocol, and defragmenting groups of pipette tips or individual pipette tips to eliminate or reduce gaps between pipette tips. Examples of organization procedures are discussed with reference to FIGS. 8-14B.

[0053] Figure 4 is a plan view of deck 220 for loading onto platform 212 of enclosure 202 of Figure 2 with labware loaded thereon. Figure 5 is a plan view of deck 220 of Figure 3 without labware loaded thereon. Unless specifically noted otherwise, Figures 4 and 5 are discussed in parallel.

[0054] Deck 220 can include spaces or locations L1-L16 for various components, including carousel 204, reaction vessels 205, pipette tip rack (or microtip rack) 218, millitip rack 221, bulk reservoir 222, and waste container 224. Other locations can also be provided for other items of labware, such as tube holders and reagent tube holders. Deck 220 can also be configured to represent an embodiment with multiple modules with predetermined fixed operable locations, and these modules may comprise complete subsystems performing dedicated functions. For example, a module may perform washing of a sample or prepared sample, while another may present a primary sample to transport device 141 for sample aliquoting.

[0055] One or more imaging devices 206 can be mounted within the housing 202 relative to the platform 212 such that the imaging devices can generate a field of view that encompasses all of the platform 212. Similarly, a transport system, such as the transport device 141 of FIGS. 1 and 3, can be configured to move the fluid dispenser 254 around the entire periphery of the platform 212.

[0056] 4 shows deck 220 including locations numbered L1-L16 that may act as separate locations for separate types of components or packages of components, as well as other components, such as thermal cycler system 208. An embodiment of deck 220 may have additional or fewer locations, as desired. These locations may be numbered or named, but the locations may or may not be physically labeled or marked on deck 220 in a physical embodiment of fluid handling system 200. In an embodiment of fluid handling system 200, some or all of the locations may be occupied by predefined types of components according to a protocol. For example, locations L1-L10 may be loaded with microtip racks or pipette tip racks. Specifically, in an embodiment, locations L1-L4 may comprise storage locations for pipette tip racks or microtip racks 218, locations L5-L10 may comprise storage locations for millitip racks 221 that may be loaded with components of a package or a reagent kit or components as defined by a protocol, and location L11 may be loaded with carousel 204. Racks 218 and 221 may be used in place of reaction vessels 205, with reference to FIG. 2, and in place of labware pieces 230, with reference to FIG. 3. Racks 218 and 221 may additionally comprise instances of pipette tip racks 700 of FIG. 8, in which racks 218 and 221 may serve as a source of unused pipette tips and / or a location for receiving or discarding used pipette tips. Location L12 may comprise a cold reagent storage area for reaction vessels 205. Location L13 may comprise a warm reagent storage area for reaction vessels 205. Location L15 may comprise a storage area for bulk reservoir 222. Location L14 may comprise an RV stack storage area for reaction vessels 205. Locations L14 and L15 may be interchangeable in various systems. Location L16 may comprise a waste storage area for receptacles 224, such as where used pipette tips may be discarded or where liquid from used pipette tips may be discarded.In an example, used pipette tips can be discarded in other items of labware, such as tip trays designated for used pipette tips. Some of the locations L1-L16 can contain components of the same type. The components can include test tubes, microwell or microtiter plates, pipette tips, plate lids, reservoirs, or any other suitable labware components. The components can also include items of lab equipment, such as shakers, agitators, mixers, temperature incubators, vacuum manifolds, magnetic plates, thermal cyclers, or the like.

[0057] One or more of the locations L1-L16 can be programmed to the processing system 100 to be locations for receiving trays, boxes, or racks of pipette tips. Such receiving trays, boxes, or racks may contain unused pipette tips for performing a pipetting operation, or may contain used pipette tips that are placed in the receiving tray, box, or rack after a pipetting operation. The processing system 100 can include X, Y, Z coordinates of the locations L1-L16 and the geometry of labware configured to be stored in the locations L1-L16. For example, the geometry of a pipette tip rack, including sockets or receptacles for pipette tips, can be translated into X, Y, Z coordinates that are stored in memory. Thus, the processing system 100 can be configured to know the three-dimensional position of the socket or receptacle relative to the deck 220 such that the position of the pipette tip within the socket or receptacle, or the absence of a pipette tip in such a socket or receptacle, can be determined and recorded in memory, such as by using an imaging or sensing system of the fluid dispenser.

[0058] Each of locations L1-L16 can be accessed by transport device 141 (FIG. 1). For example, locations L1-L16 and thermal cycler system 208 can be physically separate from structure 140 or deck 220. As shown in FIG. 5, locations L1-L16 can include sockets, slots, or receptacles in which other components, such as labware and tip trays, can be positioned and steadily held in known locations relative to transport device 141.

[0059] For example, bulk reservoir 222 (FIG. 4) can be positioned in bulk reaction vessel receptacle 300 (FIG. 5), reaction vessels 205 (FIG. 3) can be positioned in reaction vessel receptacle 302 (FIG. 5), milli-tip rack 221 (FIG. 4) can be positioned in rack receptacle 304 (FIG. 5), and thermal cycler reservoir 205T (FIG. 4) can be positioned in thermal cycler reaction vessel receptacle 306 (FIG. 5). In addition, pipette tip rack 700 of FIG. 8 can be positioned in one of the rack receptacles 304 (FIG. 5).

[0060] The imaging device 206 can be configured to recognize, for example, the presence of one or more components at each of locations L1-L16, the presence of the carousel 204 at location L11, and the presence of reaction vessels 205 at locations L12, L13, and L14. Components, for example, vials of liquid, can be loaded into the carousel 204 in a desired manner, for example, according to a protocol, and liquid from there or from another location can be loaded into one of the reaction vessels 205 for loading into the thermal cycler system 208 according to the protocol. The imaging device 206 can be used to identify components loaded onto the deck 220 and verify that the identified components are the expected components. In further examples, the imaging device 206 can indicate that a component other than the expected component has been loaded, or that the expected component has been loaded improperly (such as being bent). In examples, the imaging device 206 can be used to confirm the presence, shape, and proper loading of components.

[0061] In an embodiment, imaging device 206 can be used to identify items on deck 220 and the location of such items on deck 220 in accordance with the principles and methods described in WO 2021 / 041216 to Davis et al., which is incorporated herein by reference in its entirety.

[0062] As a specific non-limiting example of component validation, a deck setup configuration may require that a particular size and / or type of pipette tip container, such as a 96 or 384-pipette tip box, be arranged at a particular location on the deck 220. Machine learning or artificial neural networks may be used to scan an image of the deck 220 for locations where pipette tip containers are desired. The machine learning or artificial neural networks may be trained, programmed, or otherwise configured to determine whether an item is located at a particular location on the deck 220. In particular, the machine learning or artificial neural networks may determine whether the item on the deck 220 is (1) a 96-pipette tip box, (2) a 384-pipette tip box, or (3) a different item. If the item is determined to be a 96-pipette tip box, the location may be determined to be filled. If the item is determined to be a different item, an error may be recorded and an operator may be alerted that the item is incorrect.

[0063] Additionally, in some embodiments, machine learning or artificial neural networks can determine whether an article on deck 220 is configured or arranged exactly where a particular configuration or arrangement of components is required or desired. For example, it can be determined whether an article on deck 220 is (1) a 96-pipette tip box without a lid, (2) a 96-pipette tip box with a lid, (3) a 384-pipette tip box without a lid, (4) a 384-pipette tip box with a lid, or (5) a different article. If it is determined that the article on deck 220 is the correct box but contains a lid or other covering, an error can be logged and an operator can be alerted to remove the lid for processing.

[0064] In addition, if the deck setup configuration requires that a box contain a particular number and / or configuration of tips or tipless openings, template matching can be used, for example, to identify and count the number of tips or openings in an image of the box. FIG. 9A shows a close-up view of an example pipette tip rack having several tips 702 and a receptacle 706 for holding the tips 702. Template matching can be used to compare an image of the deck 220 with one or more stored template images of tips or tip openings. Thus, for example, template matching can be used to compare an image of the deck 220 with x stored template images of tips or tip openings, where "x" corresponds to the number of tips or tip openings. Using x stored template images can be useful, for example, in situations where deck lighting casts different shadows on tips within the same tip box and / or camera perspective distortion results in different views of tips within the same tip box. Thus, template matching can be employed to identify each vacant receptacle 706 of an article on the deck 220, count the total number of openings, and determine whether the bin contains the correct number and / or pattern of openings (and thus, by extension, the correct number and / or pattern of tips). In other embodiments, the tips 702 may be identified and counted instead of or in addition to the openings. Those skilled in the art will recognize that the ability to count the total number of openings may be determined, at least in part, by the angle of the camera mounting. For example, depending on the camera angle, some of the tip openings may be blocked by adjacent tips. As a result, when a camera angle is used that causes one or more tips to block the view of one or more adjacent openings, it may be useful to use the tips as templates instead of the openings in the tip bin.

[0065] In some examples, deck setting instructions may be dynamically modified in response to component validation. For example, if an operator is instructed to load a particular number of tips onto the deck and the operator loads fewer than the particular number of tips, the system of the present disclosure may calculate the additional number of tips still needed and instruct the operator to load the additional number of tips. As a specific example, if a particular run or method to be performed calls for 96 tips and the operator loads two boxes, each containing 48 tips, the system may validate the appropriate deck setting for that component or location on the deck. However, if the operator loads two partial boxes, each containing only 20 tips, the system may calculate that 56 tips are still needed in response to counting the number of tips present. The system may then instruct the operator to load the additional 56 tips.

[0066] As another specific, non-limiting example of component validation, a deck setup configuration may require that a particular size and / or type of pipette tip container, such as a 384-pipette tip box, be arranged at a particular location on the deck 220. Machine learning or artificial neural networks may be used to review deck images for locations on the deck 220 where a pipette tip container is required. The machine learning or artificial neural network can be trained, programmed, or otherwise configured to identify whether an article arranged in a location on the deck 220 is (1) a 384-pipette tip box without a lid, (2) a 384-pipette tip box with a lid, or (3) a different article. Template matching can be used to identify and count within each tip within a bin to determine if the bin contains the correct number and / or pattern of openings. In other examples, each opening can be identified and counted using template matching.

[0067] 6 is a perspective view of a pipetting device 600 that may be coupled to the transport device 141. In an embodiment, the pipetting device 600 may be connected to a carrier 250 (FIG. 3) so as to be movable within a workspace in the fluid handling system 200 (FIG. 2). The pipetting device 600 may include various cables and connectors for electronically coupling the pipetting device 600 and its components to the controller 214. For example, the pipetting device 600 may include a cable 602 that may connect a circuit board 604 to the controller 214. A tip mandrel 606 may be connected to the pipetting device 600, which may include space for coupling to multiple pipette tips 608. In the illustrated embodiment, the pipetting device 600 may hold eight pipette tips 608.

[0068] Figure 7 is a cross-sectional view of the pipetting device 600 of Figure 6 taken at section 7-7, showing the circuit board 604, tip mandrel 606, pipette tip 608, plunger 610, and connector pin 612. Figures 6 and 7 will be discussed in parallel.

[0069] The tip mandrel 606 can include a device to which a pipette tip 608 can be connected. In an embodiment, the tip mandrel 256 of FIG. 3 can be configured similarly to the tip mandrel 606. The tip mandrel 606 can include a sealed cap 614 through which a shaft 611 of a plunger 610 can extend. The plunger 610 can be activated by the pipetting device 600, such as via the controller 214, to draw a vacuum within the pipette tip 608, similar to a syringe. Each tip mandrel 606 can be connected to a plunger 610 such that all of the pipette tips 608 can be actuated simultaneously, regardless of whether they are each actually performing a pipetting function. Thus, the transport device 141 can move the pipetting device 600 around the working space so that the pipette tip 608 can be inserted into a volume of liquid, and the plunger 610 can be retracted (moved upwards, referring to FIG. 7 ) to draw liquid into the pipette tip 608 and moved to another position where the liquid can be dispensed by moving the plunger 610 downwards.

[0070] The circuit board 604 can include a liquid level sensor board configured to sense capacitance. Thus, the circuit board 604 can include a capacitance sensor 616 that can be in electrical communication with the connector pin 612. The connector pin 612 can provide an electrical connection between the tip mandrel 606 and a pipette tip 608 coupled thereto. In an embodiment, the connector pin 612 can include a pogo pin. For example, the capacitance sensor 616 can be used to sense the level of liquid in a vial or container into which the pipette tip is inserted, as can be understood by one of ordinary skill in the art. Furthermore, the capacitance sensor 616 can be used to sense the position of the tip mandrel 606 when it is contacted with a conductive surface. Additionally, if a conductive pipette tip 608 is coupled to the mandrel 606, capacitance sensing can be performed using the pipette tip 608.

[0071] As can be seen in Fig. 6, the pipetting device 600 can further comprise gripper arms 618A and 618B, which can be coupled to the pipetting device 600 at pivot points 620A and 620B, respectively. The gripper arms 618A and 618B can include gripping features 622A and 622B, such as teeth, flanges, or fingers, respectively, which can couple to an item of labware. For example, the gripping features 622A and 622B can hook onto an edge of an item of labware such that the transport device 141 can be used to move the item of labware around the workspace. The gripper arms 618A and 618B can be electronically coupled to the capacitance sensor 616. The gripper arms 618A and 618B can be motorized to be automatically controlled with the control computer 108 (Fig. 1) to implement the protocol.

[0072] Incorporating a capacitance sensor 616 into the pipetting device 600 in electrical communication with the tip mandrel 606 can enable configurations that facilitate the performance of various features described herein, including the reformatting and defragmentation processes.

[0073] As shown in Figures 6 and 7, some embodiments of the present disclosure can include a pipettor or liquid dispenser that includes multiple channels. Each of these liquid conducting channels can be coupled to a different capacitance sensor, e.g., a separate instance of capacitance sensor 616, allowing for independent checking or calibration of each channel. For example, each of the pipette tips 608 shown in Figure 6 can be electronically coupled to an instance of capacitance sensor 616, allowing independent functional check operations to be performed with each pipette tip 608.

[0074] 8 is a perspective view of a pipette tip rack 700 at a full capacity of unused pipette tips 702. The pipette tip rack 700 can include a body 704 having receptacles 706. The pipette tip rack 700 can be configured to hold a plurality of pipette tips 702 in a predetermined array or pattern such that the pipetting device 600 can be guided by the control computer 108 to a location where the pipette tips 702 can be brought together. In the illustrated example, the rack 700 includes an 8×12 rectangular array of pipette tip receptacles 706.

[0075] The body 704 of the rack 700 can comprise, for example, a rectilinear body configured to fit within one of the rectilinear spaces L1-L10. The periphery of the body 704 can be configured to nest between a barrier or wall of one of the receptacles 304 (FIG. 5) such that the body 704 can be reproducibly positioned at the same location on the deck 220. Thus, as a pipette tip rack 700 is emptied or depleted of pipette tips 702, a new pipette tip rack 700 full of clean, unused pipette tips 702 can be installed on the deck 220 at a geographic location where the pipette tips 702 are in the same X, Y, Z location.

[0076] The pipette tip 702 can comprise a pipetting shaft 708 and a collar 710. The collar 710 can comprise a proximal end of the pipette tip 702 having an inner diameter configured to engage the tip mandrel 606 (FIG. 7). The pipetting device 600 (FIG. 6) or the tip mandrel 606 can be moved up or down in the Z direction to engage the collar 710 and remove the pipette tip 702 from the rack 700. The pipetting device can additionally include features for removing the pipette tip 702 from the tip mandrel 606. For example, the shaft 611 of the plunger 610 can be fully extended to push the pipette tip out of the tip mandrel 606. Alternatively, the pipetting device 600 can include a shack plate configured to engage the collar 710 and push the pipette tip out of the tip mandrel 606. A shaft 708 can comprise the distal end of the pipette tip 702 having an internal lumen configured to fluidly connect to a fluid passage in the tip mandrel 606. A shaft 611 of a plunger 610 (FIG. 7) can be inserted into the shaft 708 to draw fluid into the shaft 708 to perform pipetting operations.

[0077] The receivers 706 may comprise cylindrical slots or bores in the body 704 that may receive the shafts 708 of the pipette tips 702. The collars 710 of the pipette tips 702 may rest on the body 704 such that they are engageable by the tip mandrel 606. The receivers 706 may be arranged in a pattern to maximize the cross-sectional area of ​​the body 704 to receive as many pipette tips 702 as possible, given the size of the pipette tips 702. In an embodiment, the receivers 706 may be arranged in a rectangular array of rows and columns. In the illustrated embodiment, the receivers 706 may be arranged in an array of 8 rows and 12 columns, as shown in FIG. 9A.

[0078] 9A is a schematic map of the pipette tip rack 700 of FIG. 8 showing the location of receptacles 706 for placement of unused pipette tips 702 within the pipette tip rack 700. FIG. 9A also diagrammatically illustrates an embodiment of a pipetting device 600 having eight tip mandrels 606. The pipetting device 600 is oriented such that the tip mandrels 606 are aligned in the Y direction. The pipetting device 600 can move in the X and Y directions to position the tip mandrels 606 above the receptacles 706. In some embodiments, the pipetting device 600 of the illustrated embodiment can be moved in the Z direction to simultaneously engage and capture eight pipette tips 702 located within the receptacles 706. In other embodiments, each tip mandrel 606 of the illustrated pipetting device 600 is independently movable in the Z direction such that any number of the eight tip mandrels 606 may be lowered to simultaneously engage and capture pipette tips 702.

[0079] As shown in FIG. 9A, the columns are labeled 1-12 and the rows are labeled AH. Note that grid lines are shown in FIG. 9A for illustrative purposes. As can be seen in FIG. 9A, each of the receptacles 706 is shown diagrammatically as being occupied by a pipette tip 702, indicated by cross-hatched lines. FIG. 9A can illustrate the state of the pipette tip rack 700 as being full, or at maximum capacity, such that each of the receptacles 706 is occupied by a pipette tip 702. Thus, FIG. 9A can represent a packaged, brand new box from the manufacturer, with a full array of pipette tips 702, or a pipette tip tray or rack 700 that has been filled by an operator using a partial pipette tip box, rack, or tray. FIG. 9A illustrates a typical configuration of a starting set for the pipette tip rack 700 at the start of a protocol to be performed by the processing system 100 and the fluid handling system 200, i.e., a full state. Thus, the pipette tip rack 700 is fully formatted and the pipette tips 702 are not fragmented. However, over the course of the steps of performing a protocol, as the pipette tips 702 are consumed, the pipette tip rack 700 may become partially populated with fragmented pipette tips 702 throughout disparate and unconnected, e.g., non-adjacent, receptacles 706.

[0080] An example of pipette tip defragmentation and reformatting is described below in connection with Figures 9B-11C.

[0081] Figure 9B illustrates the use of pipette tips 702 in the fully loaded pipette tip rack 700 of Figure 9A according to an exemplary protocol. The pipette tip rack 700 thus includes filled receptacles 706 and empty receptacles 706. The filled receptacles 706 are indicated by cross-hatched circles and may represent locations where the fluid handling system 200 has not removed a pipette tip 702 from the complete array of pipette tips 702 during performance of the protocol. The empty receptacles 706 are indicated by unfilled circles and may represent locations where the fluid handling system 200 has removed a pipette tip 702 from the array to perform a pipetting procedure of the protocol.

[0082] In this exemplary protocol, a first pipetting operation is performed that includes two successive pipetting steps using a single channel pipetting device 600 in which a different pipette tip 702 is used for each step, thereby removing pipette tips A1 and B1 from the pipette tip rack 700.

[0083] A situation may arise where rows 1-12 have fewer pipette tips 702 available than required in the protocol. Thus, the pipetting device 600 may need to move to a different row where sufficient pipette tips are available for the next pipetting operation, even if the pipette tips 702 remain in the previous row. For example, in the second pipetting operation of the protocol, an 8-channel pipetting device 600 is used to remove eight pipette tips 702. However, row 1 has insufficient pipette tips 702. Thus, the pipetting device 600 moves to row 2, thereby removing rows A2-H2 of pipette tips in the pipette tip rack 700.

[0084] Finally, in the third pipetting operation of the protocol, a multichannel pipetting device 600 is used that is configured to remove every other pipette tip 702 in row 3 of the pipette tip rack 700. In an embodiment, the multichannel pipetting device 600 used to perform this third pipetting operation is an 8-channel pipettor in which every other tip mandrel 606 is lowered in the Z direction independently relative to the other tip mandrels 606 of the 8-channel pipettor such that only the lowered tip mandrels 606 engage the pipette tips 702 in the pipette tip rack 700. Figure 9B illustrates the status of the pipette tip rack 700 upon completion of this exemplary protocol.

[0085] Thus, the pipette tip rack 700 of FIG. 9B is fragmented, as accomplished in the illustrated embodiment, to perform three different pipetting operations using different types of pipetting devices.

[0086] In an additional example of how the pipette tip rack 700 may become fragmented, it may be possible that unused pipette tips 702 are left at the bottom edge or in the center portion of rows 1-12 due to the need for the pipetting device 600 to be able to access the pipette tips 702 in the rack 700 and then subsequently insert the loaded pipette tips 702 into the labware on the deck 220. For example, the labware may be arranged on the deck 220 such that a pipette tip 702 loaded on the bottom side of the pipetting device 600 (relative to the orientation of FIG. 9A ) may not be able to access a desired location within a reaction vessel 205 at location L13 due to the presence of other reaction vessels 205 on the deck 220 at location L13. It may therefore be advantageous for the pipetting device 600 to fill the upper portion of the mandrel 606 with pipette tips 702.

[0087] Also, the pipetting actions of the loaded protocol may not require all of rows 1-12 to be used, such that a complete row of pipette tips remains, as shown by rows 4-12 in FIG. 9B.

[0088] Thus, at the end of completing all pipetting operations for a protocol, the pipette tip rack 700 may be left with a scattering of pipette tips 702 within the matrix of receptacles defined by columns 1-12 and rows AH. The pipette tips 702 may be fragmented into clumps or individual pipette tips, leaving pipette tips 702 that are too few to perform another protocol or that would require the manifold 600 to perform additional operations to capture unused pipette tips, thereby slowing down the performance time for the protocol. Thus, it may be desirable to organize the pipette tips 702, such as by defragmenting or reformatting the array of pipette tips 702 within the pipette tip rack 70.

[0089] Reformatting can be performed after a protocol is executed, as discussed with reference to Figures 9C-9E. Reformatting can also be performed during the execution of a protocol, as discussed with reference to Figures 10A-10F. Reformatting can also be performed before a protocol is executed, as discussed with reference to Figures 11A-11C. In addition, the reformatting step can be performed during times when the robotics components of system 100 or fluid handling system 200 are idle, to minimize extending the time required to complete a protocol. Similarly, the reformatting step can be performed so as not to interrupt time-critical pipetting operations. That is, the reformatting can be performed so as not to interrupt sequential or consecutive pipetting operations that should, need to, or are advantageously performed with minimal time delay between operations. "Time-critical" can be defined as a chemical reaction time that is less than the time it takes to perform the reformatting step. Defragmentation can be performed at a time that minimizes or eliminates any increase in procedure run time, such as during reaction incubation or any other time when the robotics components are idle.

[0090] 9C-9E illustrate three examples of steps for defragmenting and / or reformatting the pipette tip rack 700 after performing an exemplary protocol.

[0091] 9C, unused (pipette tips C11-H12) from the filled receptacles 706 in rows 11 and 12 of the pipette tip rack 700 are moved to fill the empty receptacles 706 in rows 1 and 3 of the pipette tip rack 700. This provides a reformatted pipette tip rack 700 with a continuous series of filled receptacles 706, starting with A1, and a maximum number of rows that are completely filled.

[0092] 9D, unused pipette tips in columns 1 and 3 of pipette tip rack 700 are moved to fill vacant receptacles 706 in columns 2 and 3, reformatting pipette tip rack 700 so that the pipette tip rack 700 has a continuous series of filled receptacles 706 from the end of the pipette tip rack at H12 back to tip G2. This provides a reformatted pipette tip rack 700 that is equivalent to that of FIG. 9C after the pipette tip rack 700 has been rotated 180 degrees and reloaded onto deck 220 by the user prior to starting a book or another protocol.

[0093] In Figure 9E, the unused pipette tips 702 in rows 1, 3, and 12 are moved as illustrated in Figure 9B to create the pattern of filled receptacles 706 utilized by the exemplary protocol. In this manner, the reformatted pipette tip rack 700 is optimally formatted for once again performing the exemplary protocol.

[0094] 10A-10E illustrate certain examples of steps for defragmenting and / or reformatting a pipette tip rack 700 during performance of the exemplary protocol of FIG. 9B.

[0095] FIG 10A illustrates one example of a pipette tip rack 700 before the exemplary protocol of FIG 9B is initiated. In this example, the pipette tip rack 700 starts with 16 unused pipette tips 702 occupying rows 1 and 2 of the pipette tip rack 700. FIG 10B illustrates the status of the pipette tip rack 700 after a first pipetting operation of the exemplary protocol is performed in which the single channel pipetting device 600 removes the pipette tips 702 that occupied the receptacles 706 at locations A1 and A2. FIG 10C illustrates the status of the pipette tip rack 700 after a second pipetting operation is performed using the 8-channel pipetting device 600 to remove the pipette tips 702 that occupied row 2 of the pipette tip rack 700. At this stage, the multichannel pipetting device 600 is configured to remove every other pipette tip 702 in a row of the pipette tip rack 700, so that there are no partial rows of unused pipette tips 702 in the pipette tip rack 700 accessible to the multichannel pipetting device 600 used for the third pipetting operation of the protocol. Thus, the pipetting device 600 reformats the pipette tip rack 700 by moving the unused pipette tips 702 in location D1 to an empty receptacle in location A1 of the pipette tip rack 700. Thus, after this reformatting, the third pipetting operation of the exemplary protocol can be performed, resulting in the removal of pipette tips 702 in locations A1, C1, E1, and G1 of the pipette tip rack 700. FIG. 10E illustrates the status of the pipette tip rack 700 after completion of the exemplary protocol.

[0096] In another example, as illustrated in Figure 10F, the pipette tip rack 700 of Figure 10C can be reformatted after performing the second pipetting operation of the exemplary protocol by moving four of the unused pipette tips 702 in row 1 of the pipette tip rack 700 to alternating positions A3, C3, E3, and G3 in row 3 of the pipette tip rack 700. In this manner, the third pipetting operation of the exemplary protocol can be performed originally as illustrated in Figure 9B (i.e., using row 3 of the pipetting tip rack 700). However, in this embodiment, the pipette tip rack 700 has been reformatted to empty every other receptacle 706 in row 3 of the pipette tip rack 700, so that the third pipetting operation of the exemplary protocol can be performed using a typical 8-channel pipettor (i.e., each tip mandrel 606 remains in a fixed Z position relative to the other tip mandrels 606), thereby eliminating the need for a multi-channel pipetting device 600 having tip mandrels 606 that are independently movable in the Z direction.

[0097] The methods of reformatting or defragmenting the pipette tip rack 700 performed during the performance of a protocol, as described herein, can also be combined with any suitable methods of reformatting or defragmenting the pipette tip rack 700 performed after the performance of a protocol, as described herein.

[0098] 11A-11C illustrate an example of defragmenting and / or reformatting a pipette tip rack 700 prior to performing the exemplary protocol of FIG 9B. In this example, the pipette tip rack 700 starts with 16 unused pipette tips 702 occupying columns 1 and 2 of the pipette tip rack 700, as illustrated in FIG 11A. Prior to starting the protocol, the pipette manipulation device 600 moves four unused pipette tips 702 from locations E1-H1 of the pipette tip rack 700 to locations A3, C3, E3, and G3, as illustrated in FIG 11B. Following this reformatting, the exemplary protocol described in connection with Fig. 9B is performed, including the use of a multi-channel pipetting device 600 configured to remove every other pipette tip 702 in row 3 of the pipette tip rack 700 within a third pipetting operation of the protocol, resulting in the status of the pipette tip rack 700 after completion of the protocol as illustrated in Fig. 11C. In another embodiment, following the reformatting illustrated in Fig. 11B, the exemplary protocol is performed, except that a typical 8-channel pipettor is used to perform the third pipetting operation instead of the multi-channel pipetting device 600 configured to remove every other pipette tip 702 in row 3 of the pipette tip rack 700. More generally, the disclosed reformatting methods can be used to attach pipette tips 702 to any number and combination of tip mandrels 606 of a multi-channel pipetting device 600, thereby eliminating the need for a separate pipetting device 600 with tip mandrels 606 that are independently movable in the Z (or X or Y) direction.

[0099] The methods described herein for reformatting and / or defragmenting the pipette tip rack 700 either before, during, and / or after performing a protocol may be combined in any suitable manner or combination.

[0100] In some embodiments, the pipette tip rack 700 is used as a source of unused pipette tips 702 for a selected protocol. In some embodiments, the pipette tip rack 700 is used to receive and isolate used pipette tips 702 from unused pipette tips 702. In some embodiments, the reformatting and / or defragmentation methods described herein can be used separately, in any suitable combination, on pipette tip racks 700 used as a source of unused pipette tips 702 and on pipette tip racks 700 used to receive used pipette tips 702.

[0101] 12A and 12B illustrate a diagram 800 showing steps and operations for automatically performing pipette tip organization of pipette tips 702 in the pipette tip rack 700 of FIG. 9A. Diagram 800 may illustrate an embodiment of the reformatting and defragmentation described above. The procedure described with reference to diagram 800 may be performed using the processing system 100 and robotic fluid handling system 200 of FIGS. 1-7, such as by being controlled by control computer 108 (FIG. 1) using instructions stored in computer readable medium 108B.

[0102] Step 802 may include starting fluid handling system 200 (FIG. 2). An operator may power on or otherwise prepare fluid handling system 200 for performance of a protocol or another operation. The operator may interface with input device 108D (FIG. 1) or controller 214 (FIG. 2) to start fluid handling system 200.

[0103] Step 804 may include preparing the fluid handling system 200 for performing a procedure involving pipetting. Thus, a protocol may be programmed into the input device 108D (FIG. 1) or the controller 214 (FIG. 2). The protocol may include one or more substeps including pipetting operations with the pipetting device 600, where a different set of pipette tips 702 is utilized in each pipetting operation, thereby causing the pipetting device 600 to travel multiple times to the tip rack 700 (FIG. 8) to obtain the required number of pipette tips 702 to be used in each pipetting operation. Thus, the tip mandrel 606 may be repeatedly loaded and unloaded with pipette tips 702 in different combinations to perform the pipetting operations.

[0104] Step 806 may include determining a starting set of pipette tips 702 to be loaded into the fluid handling system 200. The control computer 108 can determine the starting set of pipetting tips 702 in a number of ways, as described with reference to steps 806A-806D. The control computer 108 can perform one, multiple, or all of steps 806A-806D to determine the starting set. The starting set of pipette tips 702 can be determined in different ways with redundancy to help ensure that the correct number of pipette tips 702 are properly determined.

[0105] Step 806A may include the processing system 100 assuming that the pipette tip rack 700 loaded on the deck 220 is full. In an embodiment, the processing system 100 may recognize the presence of the pipette tip rack 700 on the deck 220 using the imaging device 206, and then assign unused pipette tips 702 to each receptacle 706 in the pipette tip rack 700. In an embodiment, the processing system 100 may read the type of pipette tip rack 700 used in the protocol stored in the computer readable medium 108B, determine from the computer readable medium 108B the number and location of receptacles 706 for pipette tips 702 in the pipette tip rack 700, and then assign unused pipette tips 702 to each receptacle 706 in the pipette tip rack 700.

[0106] Step 806B may include the processing system 100 reading the number and locations of pipette tips 702 loaded on the deck 220 from a protocol stored in the computer readable medium 108B. For example, the protocol stored in the computer readable medium 108B may directly enumerate the number and locations of receptacles 706 for the pipette tip racks 700, and further enumerate the receptacles 706 that contain pipette tips 702 that are not in use.

[0107] Step 806C may include using the imaging device 206 (FIGS. 2 and 3) to view the pipette tips 702 in the pipette tip rack 700 such that the processing system 100 may utilize image recognition software, algorithms, or procedures to count the number of pipette tips 702 in the rack 700. For example, the digital image of the deck 220 may be analyzed for shapes or patterns that match stored shapes and patterns in the computer-readable medium 108B of the pipette tips 702. Thus, the number of shapes or patterns in the digital image may be counted to determine a starting set of pipette tips 702.

[0108] Step 806D may include sensing the number of pipette tips 702 in the pipette tip rack 700. The processing system 100 may move the pipetting device 600 to the location of the pipette tip rack 700 and contact one of the tip mandrels 606 with each of the receptacles 706 in the pipette tip rack 700. If the tip mandrel 606 obtains a capacitance reading at the expected location of the pipette tip rack 700, the computer readable medium 108B may be updated to record the location of the pipette tip 702. If the tip mandrel 606 does not obtain a capacitance reading at the expected location of the pipette tip rack 700, the computer readable medium 108B may be updated to record the absence of the pipette tip 702. In an additional embodiment, the processing system 100 can recognize Z height differences in terms of capacitance signal readings to distinguish between a higher Z location where the pipette tip 702 is located or a lower Z location where contact is made with the empty receptacle 706. Additionally, the processing system 100 can recognize Z height differences through the use of a pressure sensor.

[0109] Step 808 may include obtaining new pipette tips 702 using the pipetting device 600. The processing system 100 may start to perform the first pipetting operation of the protocol from step 804. The pipetting device 600 may be moved to the location of the pipette tip rack 700 to obtain a pipette tip 702. The pipetting device 600 may be moved downward in the Z direction to engage the tip mandrel 606 with the collars 710 of a selected number of pipette tips 702 to be loaded onto the pipetting device 600 to perform the pipetting procedure.

[0110] Step 810 may include performing a pipetting operation using a new pipette tip 702 loaded onto the tip mandrel 606. The pipette tips 702 collected in step 808 may be moved across one or more articles of labware loaded onto the deck 220 (FIG. 4). Fluids or liquids may be drawn from those articles of labware with the pipette tips 702 loaded onto the tip mandrel 606 by the plunger 610 moving upwards and then transported to another article of labware where the plunger 610 may be pushed downwards to dispense the fluid or liquid into the second article of labware. As a result of such a dispensing process, the pipette tips 702 loaded onto the tip mandrel 606 may become dirty, thereby making it desirable to unload such pipette tips 702 in favor of unused, clean pipette tips 702 for the next pipetting operation to avoid contamination, etc.

[0111] Step 812 may include disposing of the soiled pipette tip 702 used in step 810. The pipetting device 600 may be moved from the second item of labware in step 810 to a waste storage area L16 for the container 224 (FIG. 4). The tip mandrel 606 may expel the soiled pipette tip 702 into the container 224 by moving the plunger 610 further downward and pushing the used pipette tip 702 on the tip mandrel 606.

[0112] Step 814 may include updating the starting set of pipette tips 702 of step 806 to remove used pipette tips. The starting set of pipette tips can be updated in a number of ways, which are described with reference to steps 814A-814D. The control computer 108 can perform one, multiple, or all of steps 814A-814D to determine the updated set. The updated set of pipette tips 702 can be determined in different ways with respect to redundancy to help ensure that the correct number of pipette tips 702 is properly determined.

[0113] Step 814A may include removing the number of pipette tips 702 used and discarded in steps 810 and 812 from the starting or complete set of pipette tips provided by steps 806A-806D, etc. The number of pipette tips 702 used in step 808 may be read from a protocol stored in computer readable medium 108B. The protocol may include a list of the number of pipette tips 702 used in each sub-step or pipetting operation of the protocol. Thus, the control computer 108 may maintain a running ledger of pipette tips by continually subtracting the number of used pipette tips from the starting total. The computer readable medium 108B may be updated with the remaining number and locations of clean and unused pipette tips 702.

[0114] Step 814B may include reading a memory of the fluid handling system 200 to determine the number of pipette tips 702 remaining after a particular pipetting procedure is performed in step 810. For example, the control computer 108 may reference the protocol loaded in step 804 and determine the number of pipette tips 702 and their locations that should remain after steps 810 and 812 are performed. The protocol may maintain a running ledger of pipette tips for the protocol after each sub-step or pipetting operation of the protocol. The computer readable medium 108B may be updated with the remaining number and locations of clean and unused pipette tips 702.

[0115] Step 814C may include using the imaging device 206 (FIG. 2) to take a digital photograph of the pipette tip rack 700 from which the pipette tips 702 of step 808 were acquired. The control computer 108 may use image recognition software algorithms stored in computer readable medium 108B to recognize receptacles 706 in the occupied pipette tip rack 700, such as those described with reference to step 806C. The computer readable medium 108B may be updated with the remaining number and locations of clean and unused pipette tips 702.

[0116] Step 814D can include using the tip mandrel 606 to sense the pipette tips in the pipette tip rack 700. As described with reference to step 806D, the pipetting device 600 can be moved around the pipette tip rack 700 to engage the tip mandrel 606 with the pipette tips 702 and receptacles 706 and determine the occupied receptacles 706. The computer readable medium 108B can be updated with the remaining number and locations of clean and unused pipette tips 702.

[0117] After step 814, steps 808-814 can be repeated as necessary to complete the protocol loaded in step 804 until all necessary pipetting operations have been performed.

[0118] Step 816 may include completing the protocol loaded in step 804 and all pipetting procedures called for therein. The processing system 100 may be switched to a completed state in which the user may operate the controller 214 and cover panel 210 to obtain the desired outcome of the protocol, e.g., library building. However, before or after operation of the processing system 100 is handed over to user control, the control computer 108 may be used to perform a pipette tip organization procedure as described herein. Such a pipette tip organization procedure may be performed automatically by the control computer 108 without user intervention. However, in an embodiment, the user may load a new, fully or partially filled pipette tip rack 700 into the processing system 100 to make new pipette tips available for the organization procedure. In either case, the fluid handling system 200 may be operated to locate unused pipette tips on the deck 220 by using image recognition or the like, to perform sensing with the mandrel 606, or to reference information stored in the computer readable medium 108B.

[0119] Step 818 may include moving the pipetting device 600 to a space in the pipette tip rack 700 where the unused pipette tip 702 is located from the location determined in step 816 .

[0120] Step 820 may include moving the pipetting device 600 to collect unused pipette tips 702 by engaging the pipette tips 702 with the tip mandrel 606. New or clean pipette tips 702 may be collected from occupied receptacles 706 in the same pipette tip rack 700 in step 820A, or from occupied receptacles 706 in a different pipette tip rack 700 used to perform steps 806-816 in step 820B. In an embodiment, an additional pipette tip rack 700 partially or fully loaded with pipette tips 702 may be positioned on the deck 220 in step 802 such that performance of the protocol is not interrupted. In an additional embodiment, an additional pipette tip rack 700 partially or fully loaded with pipette tips 702 may be positioned on the deck 220 after step 816.

[0121] Step 822 can include moving the pipetting device 600 to a space in the pipette tip rack 700 where no pipette tips are located. The pipetting device 600 can then use the mandrel 606 to eject the pipette tips 702 collected in 820 into an unoccupied receptacle 706.

[0122] Step 824 may include defragmenting the pipette tips 702 of the pipette tip rack 700 used in steps 806-816 by repeating steps 818-822. Step 824A may include defragmenting the pipette tips 702 by filling a row or column of the pipette tip rack 700 used in steps 806-816. Step 824B may include defragmenting the pipette tips 702 by completing a series of pipette tips 702. Step 824C may include defragmenting the pipette tips 702 by generating a pattern of pipette tips 702, such as a pattern of pipette tips accessed by a pipetting device according to a selected protocol. Other defragmentation and reformatting procedures may be performed in addition.

[0123] Step 826 may include terminating operation of the processing system 100. Thus, the defragmentation process of steps 818-824 may be completed. All of the pipetting operations of steps 808-814 may be completed, and the protocol loaded in step 804 may be completed. Thus, the processing system 100 may obtain the results of the most recently completed protocol, be returned to user control for preparing the processing system 100 for a subsequent protocol, etc., without having to manually realign, reformat, or defragment the pipette tip 702.

[0124] Figure 13A is a side view of the deck 220 of Figure 4 taken along the Y direction to show locations L2-L10 for the tip racks 221 arranged in a arena configuration to facilitate access by the pipetting device 600. Figure 13B is a side view of the deck 220 of Figure 4 taken along the X direction to show locations L4, L7, and L10 for the tip racks 221 arranged in tiers for a arena configuration to facilitate access by the pipetting device 600. Figures 13A and 13B will be discussed in parallel.

[0125] A deck 220 can be positioned on the platform 212. The deck 220 can provide a raised area to provide access for the pipetting device 600 to various items, such as the carousel 204, the thermal cycler system 208, the bulk reaction vessel holder 300, and other items and devices described herein. The reaction vessels 205 can be located in the bulk reaction vessel holder 300. The milli-tip racks 221 can be loaded into the receivers 304.

[0126] As can be seen in Fig. 13B, locations L10, L7, and L4 can be arranged in a hierarchy with location L10 closest to platform 212, location L4 furthest from platform 212, and location L7 positioned between locations L10 and L4 in the Z direction. As can be seen in Fig. 11A, locations L2, L5, and L8 and L3, L6, and L9, respectively, can additionally be grouped in such a hierarchy. Furthermore, in other embodiments, all of locations L1-L10 can be provided at the same distance from platform 212 in the Z direction. However, hierarchy of locations on platform 212 can facilitate access by pipetting device 600 to more receptacles in tip rack 221. As explained above, due to the orientation of the series of tip mandrels 606 (see FIGS. 9A and 13B) and the presence of adjacent tip racks 221 relative to the tip rack 221 desired to be accessed, it may be difficult, if not impossible, for each tip mandrel 606 of the pipetting device 600 to access every pipette tip located in the tip rack 221. For example, it may be difficult, if not impossible, for a tip mandrel 606 at the right end of the manifold 600 in the X direction (relative to the orientation of FIG. 13B) to capture a pipette tip at the left end of location L4 due to interference between the tip mandrel 606 at the left end of the pipetting device 600 interfering with the pipette tip at the right end of location L7. Thus, layering the locations L10, L7, and L4 such that the pipette tip at the right end of location L7 is positioned below the tip mandrel 606 at the left end of the pipetting device 600 as shown in FIG. 13B, may alleviate this problem.

[0127] The reformatting and defragmenting methods of the present disclosure are not limited to protocols involving pipetting operations. The defragmenting and reformatting methods, operations, and procedures described herein can be used more generally in dedicated reformatting and defragmenting protocols. In an embodiment, the reformatting and defragmenting protocols of the present disclosure can recognize the type and number of tip boxes loaded on the deck, the number and position of tips in each box, by using a camera or capacitance or pressure sensing, etc., can recognize and handle tip boxes with or without lids, and can automatically reformat or defragment to generate full or partial boxes that are more optimized for future use. In an embodiment, the reformatting and defragmenting protocols can also be initiated by other machines than the liquid or fluid handling systems described herein.

[0128] Working Example Example 1 is a method for automatically defragmenting pipette tips in a tip tray during performance of a procedure defined by a protocol stored in the memory of a fluid handling system, the method including the steps of determining the location of an empty receptacle in the tip tray in which no pipette tip is present, determining the location of a filled receptacle in the tip tray in which a pipette tip is present, and using the fluid handling system, moving the pipette tip from the filled receptacle to the empty receptacle to complete a series of filled receptacles in the tip tray.

[0129] In Example 2, the subject matter of Example 1 optionally includes the steps of removing pipette tips from filled receptacles in the tip tray using one or more tip mandrels of a pipetting device of the fluid handling system, performing a pipetting operation with the pipetting device using the removed pipette tips, the pipetting operation being performed according to a protocol, and disposing of the removed pipette tips after performing the pipetting operation to generate empty receptacles in the tip tray.

[0130] In Example 3, the subject matter of Example 2 optionally includes the step of determining the locations of the empty and filled receptacles in the tip tray including the steps of viewing the locations of the empty and filled receptacles with a camera, recognizing the empty and filled receptacles in the tip tray in an image of the tip tray, and mapping the empty and filled receptacles to a tip tray map stored in a memory of the fluid handling system.

[0131] In Example 4, the subject matter of any one or more of Examples 2-3 optionally includes the step of determining the locations of the empty and filled receptacles in the tip tray including the steps of obtaining a tip tray map from a protocol stored in a memory of the fluid handling system indicating the locations of the filled receptacles in the tip tray, and removing pipette tips from the filled receptacles as the pipette tips are used during the pipetting operation to create empty receptacles in the tip tray map.

[0132] In Example 5, the subject matter of Example 4 optionally includes the tip tray map defaulting to the fill volume of the tip tray at the start of the procedure.

[0133] In Example 6, the subject matter of any one or more of Examples 4-5 optionally includes that the tip tray map is set according to an initial status indicated in the protocol.

[0134] In Example 7, the subject matter of any one or more of Examples 2-6 optionally includes that the step of determining the locations of the empty and filled receptacles in the tip tray includes the step of sensing for the presence of a pipette tip in each receptacle in the tip tray.

[0135] In Example 8, the subject matter of Example 7 optionally includes that the presence of a pipette tip in each receptacle is determined using a capacitance sensing system associated with the fluid handling system.

[0136] In Example 9, the subject matter of Example 8 optionally includes that the presence of a pipette tip in each receptacle is determined at the start and end of the procedure using a capacitance sensing system associated with the fluid handling system.

[0137] In Example 10, the subject matter of any one or more of Examples 2-9 optionally includes a step of determining the locations of empty and filled receptacles in the tip tray performed at the start of the procedure.

[0138] In Example 11, the subject matter of any one or more of Examples 2-10 optionally includes a step of determining the locations of empty and filled receptacles in the tip tray performed at the end of the procedure.

[0139] In Example 12, the subject matter of any one or more of Examples 2-11 optionally includes a step of determining the locations of empty and filled receptacles in the tip tray performed during the procedure.

[0140] In Example 13, the subject matter of Example 12 optionally includes a step of performing successive time-constrained pipetting operations of the procedure prior to the step of determining the locations of the empty and filled receptacles in the tip tray.

[0141] In Example 14, the subject matter of any one or more of Examples 12-13 optionally includes the steps of determining that a number of consecutive filled receptacles in the tip tray is insufficient to perform a step of the pipetting operation, and moving pipette tips from filled receptacles to empty receptacles in the tip tray to provide a sufficient number of consecutive filled receptacles to perform the step of the pipetting operation before performing the step.

[0142] In Example 15, the subject matter of any one or more of Examples 1-14 optionally includes where moving the pipette tip from a filled receptacle to an empty receptacle to complete the series of filled receptacles in the tip tray includes moving the pipette tip to a less obstructed location in the tip tray.

[0143] In Example 16, the subject matter of any one or more of Examples 1-15 optionally includes where moving pipette tips from filled receptacles to vacant receptacles to complete a series of filled receptacles in the tip tray includes moving all pipette tips in a partial row or column in the tip tray to consecutive, vacant receptacles in another row or column in the tip tray.

[0144] In Example 17, the subject matter of any one or more of Examples 1-16 optionally includes where moving pipette tips from filled receptacles to vacant receptacles to complete the series of filled receptacles in the tip tray includes completely filling a partial row or column of receptacles in the tip tray with pipette tips from other rows or columns in the tip tray.

[0145] Example 18 is a method for automatically defragmenting pipette tips in a tip tray during performance of a procedure defined by a protocol stored in a memory of a fluid handling system, the method including the steps of determining locations of empty receptacles in the tip tray where no pipette tips are present, determining locations of filled receptacles in the tip tray where a pipette tip is present, and using the fluid handling system to move pipette tips from the filled receptacles to the empty receptacles to generate a pattern of filled receptacles in a row of the tip tray according to tip usage as defined in the protocol.

[0146] Example 19 is a method for automatically defragmenting pipette tips in a first tip tray during performance of a procedure defined by a protocol stored in a memory of a fluid handling system, the method including the steps of determining the location of an empty receptacle in the first tip tray where no pipette tip is present, determining the location of a filled receptacle in the first tip tray where a pipette tip is present, and using the fluid handling system, moving a pipette tip from the filled receptacle in a second tip tray to the empty receptacle to complete a series of filled receptacles in the first tip tray.

[0147] In Example 20, the subject matter of Example 19 optionally includes the step of moving pipette tips from filled receptacles to empty receptacles to complete the series of filled receptacles in the second tip tray includes the step of moving pipette tips to a different level of a platform of the fluid handling system.

[0148] (Miscellaneous notes) The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples." Such examples may include elements in addition to those shown or described. However, the inventors also contemplate examples in which only those elements shown or described are provided. The inventors also contemplate examples that use any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof) shown or described herein, or with respect to other examples (or one or more aspects thereof).

[0149] In the event of a conflicting usage between this document and any document so incorporated by reference, the usage in this document shall control.

[0150] The terms "a" or "an" are used herein, as is common in patent documents, to include "one or more than one," independent of any other instance or usage of "at least one" or "one or more." The term "or" is used herein to refer to a non-exclusive "or," such that "A or B" includes "A but not B," "B but not A," and "A and B," unless otherwise indicated. The terms "including" and "in which" are used herein as the plain English equivalents of the respective terms "comprising" and "wherein." Also, in the following claims, the terms "including" and "comprising" are open-ended, i.e., systems, devices, articles, compositions, formulations, or processes that include elements in addition to those listed after such terms in a claim, are still considered to be within the scope of that claim. Also, in the following claims, the terms "first," "second," and "third," etc. are used merely as labels and are not intended to impose numerical requirements on their purposes.

[0151] The method embodiments described herein can be at least partially machine or computer implemented. Some embodiments can include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform the methods as described in the above embodiments. Such method implementations can include code, such as microcode, assembly language code, higher level language code, or the like. Such code can include computer-readable instructions for performing various methods. The code can form part of a computer program product. Furthermore, in some embodiments, the code can be tangibly stored on one or more volatile, non-transitory, or non-volatile tangible computer-readable media, such as during execution or at other times. Examples of these tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memory (RAM), read-only memory (ROM), and the like.

[0152] The above description is intended to be illustrative and not restrictive. For example, the above described embodiments (or one or more aspects thereof) may be used in combination with each other. Other embodiments may also be used by those skilled in the art upon review of the above description. The Abstract is provided to comply with 37 C.FR §1.72(b) to enable the reader to quickly ascertain the nature of the present technical disclosure. It should be considered with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above detailed description, various features may be grouped together to simplify the disclosure. This should not be construed as intending that an unclaimed disclosed feature is essential to any claim. Rather, the subject matter of the invention may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are incorporated herein as examples or embodiments into the detailed description, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments may be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. 1. A method for automatically defragmenting pipette tips in a tip tray during the performance of a procedure defined by a protocol stored in a memory of a fluid handling system (200), the method comprising: determining the location of an empty receptacle (706) within said tip tray (700) where no pipette tips (702) are present; determining the location of a filled receptacle (706) within said tip tray (700) in which a pipette tip (702) resides; using said fluid handling system (200) to move pipette tips (702) from filled receptacles to empty receptacles to complete the series of filled receptacles in said tip tray (700); A method comprising:

2. removing pipette tips (702) from filled receptacles (706) in the tip tray (700) using one or more tip mandrels (606) of a pipetting device (600) of the fluid handling system (200); performing a pipetting operation with said pipetting device (600) using the removed pipette tip (702), said pipetting operation being performed according to said protocol (108F); disposing of the removed pipette tip (702) after performing the pipetting operation and creating the empty receptacle (706) in the tip tray (700); The method of claim 1 further comprising:

3. Determining the locations of empty and filled receptacles in the tip tray includes: visualizing the locations of empty and filled receptacles using a camera (206); identifying empty and filled receptacles of said tip tray in an image (108G) of said tip tray (700); mapping the empty receptacles and the filled receptacles to a top tray map stored in a memory of the fluid handling system (200); The method of claim 2 , comprising:

4. Determining the locations of empty and filled receptacles in the tip tray includes: deriving a tip tray map from the protocol (108F) stored in a memory of the fluid handling system (200) indicating the location of filled receptacles (706) within the tip tray (700); removing pipette tips (702) from the filled receptacles (706) as the pipette tips (702) are used during the pipetting operation to create empty receptacles (706) in the tip tray map; The method of claim 2 , comprising:

5. The leading edge tray map (i) defaulting to the fill volume of the tip tray (700) at the start of the procedure; (ii) be set according to the initial status indicated in said protocol; The method of claim 4, wherein the at least one of

6. 3. The method of claim 2, wherein determining the locations of empty and filled receptacles in the tip tray includes sensing for the presence of a pipette tip in each receptacle in the tip tray.

7. 7. The method of claim 6, wherein the presence of a pipette tip (702) in each receptacle is determined using a capacitance sensing system associated with the fluid handling system (200), preferably the capacitance sensing system being associated with the fluid handling system (200) at the start and end of the procedure.

8. Determining the locations of empty and filled receptacles (706) in the tip tray includes: (i) performed at the start of said procedure; (ii) performed at the end of said procedure; The method of claim 2, wherein the at least one of

9. 3. The method of claim 2, wherein determining the locations of empty and filled receptacles (706) in the tip tray (700) is performed during the procedure.

10. 10. The method of claim 9, further comprising performing successive time-constrained pipetting operations of the procedure prior to determining the locations of empty and filled receptacles in the tip tray (700).

11. determining that the number of consecutive filled receptacles (706) in the tip tray (700) is insufficient to perform a step of the pipetting operation; moving pipette tips (702) from filled receptacles (706) to empty receptacles (706) in said tip tray (700) to provide a sufficient number of successive filled receptacles (706) to perform said step of said pipetting operation before performing said step; 10. The method of claim 9, further comprising:

12. Moving pipette tips from a filled receptacle (706) to an empty receptacle (706) to complete the series of filled receptacles (706) in said tip tray comprises: (i) moving pipette tips (702) to less obstructed locations within said tip tray (700); (ii) moving all pipette tips (702) in a partial row or column in the tip tray to successive free receptacles in another row or column in the tip tray (700); (iii) completely filling a partial row or column of receptacles (706) in said tip tray (700) with pipette tips (702) from other rows or columns in said tip tray (700); The method of claim 1 , comprising at least one of:

13. 1. A method for automatically defragmenting pipette tips (702) in a tip tray (700) during the performance of a procedure defined by a protocol (108F) stored in a memory of a fluid handling system (200), the method comprising: determining the location of an empty receptacle (706) within said tip tray (700) where no pipette tips (702) are present; determining the location of a filled receptacle (706) within said tip tray (700) in which a pipette tip (702) resides; using said fluid handling system (200) to move pipette tips (702) from filled receptacles (706) to empty receptacles (706) to generate a pattern of filled receptacles (706) in a row of said tip tray (700) according to tip usage as defined in said protocol (108F); A method comprising:

14. 1. A method for automatically defragmenting pipette tips (702) in a first tip tray (700) during performance of a procedure defined by a protocol (108F) stored in a memory of a fluid handling system (200), the method comprising: determining the location of an empty receptacle (706) within said first tip tray (700) where no pipette tips (702) are present; determining the location of a filled receptacle (706) within the first tip tray in which a pipette tip (702) resides; using the fluid handling system (200) to move pipette tips (702) from filled receptacles to empty receptacles in a second tip tray to complete the series of filled receptacles in the first tip tray; A method comprising:

15. Moving pipette tips (702) from a filled receptacle to an empty receptacle to complete the series of filled receptacles in said second tip tray includes: Moving pipette tips (702) to different levels of a platform (212) of said fluid handling system (200).

15. The method of claim 14, comprising:

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