Module for an automated biological laboratory system with an interface for transferring microplates or labware - Patent application

Abstract

To provide microplates or lab-ware used in automated biological systems, or to provide modules for processing or storing other means.SOLUTION: Provided is a module 100 for an automated biology laboratory system having: a housing 102; a storage device having a plurality of plate slots 110 for receiving microplates or lab-ware with footprint identical to that of the microplate, or containers and formed as a carousel 108 rotatably located within the housing; a transfer slot assigned to the storage device 108 to transfer the microplates, lab-ware, or containers between an inside of the module and an outside of the module, of the plurality of plate slots; and alignment means to facilitate the alignment of the transfer slot with a transfer interface comprising an aperture of the housing.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention comprises a housing and a storage device disposed within the housing, the storage device having a plurality of plate slots for receiving plates or containers for carrying cell cultures, labware, or liquids; a transfer slot for transferring said plates or containers between the inside of the module and the outside of the module; indexing means for facilitating alignment of the transfer interface with the opening in the housing and the transfer slot; and connecting means for fixedly connecting the transport interface of a module to the transport interface of an adjacent module.

[0002] The present invention relates to a method for handling plates or containers for carrying cell cultures, labware or liquids stored in an archive module of an automated biological system. [Background technology]

[0003] An automated biological laboratory system is disclosed in US Pat. No. 5,399,633.

[0004] Patent Document 2 discloses a machine for automatically filling a plurality of microplates in a biological laboratory system.

[0005] An automated chemical or biological sample analyzer is disclosed in US Pat. No. 5,399,633.

[0006] A sample rack transport device for automated chemical analysis is disclosed in US Pat. No. 5,399,633.

[0007] US Patent No. 5,999,333 shows a system for facilitating biological communication between two or more cell culture devices. A fluid collection device has a tip that engages with an output or input port of the fluidic device. A plurality of fluidic devices are stored on a carousel.

[0008] US Pat. No. 5,399,433 shows a cell culture device including an incubator for accommodating culture containers in a closed system.

[0009] US Patent No. 5,399,633 shows an automated cell culture operator having a storage device for storing cell cultures and labware, and a robotic arm capable of three-dimensional movement for handling microplates and labware.

[0010] Patent Document 8 discloses an automatic culture system equipped with a transfer means for transferring a microplate for automatic maintenance.

[0011] US Pat. No. 5,399,433 discloses an automated robotic system for the maintenance of microcell cultures.

[0012] Other microfluidic cell culture systems are known from US Pat. No. 5,399,623, US Pat. No. 5,499,633, US Pat. No. 5,599,623 or US Pat. No. 5,599,633.

[0013] Cell culture requires advanced technology, but is time-consuming and complicated, which increases labor costs. In addition, the workflow is difficult, complicated, and can take weeks, resulting in low reproducibility. Therefore, attempts are being made to automate cell culture.

[0014] Cells are cultured in plasticware (flasks, round dishes, bottles, multi-well plates) in an incubator. The usual procedure for passaging cells includes: pre-warming the medium, PBS, and trypsin (stored in the refrigerator) stored in the refrigerator, defrosting additives such as fetal bovine serum (FBS) and special additives such as growth factors stored in the freezer; preparing new plasticware (new plates, serological pipettes, pipette tips); transferring the cells from the incubator to a flow hood (i.e., under sterile conditions, but preferably with minimal time outside the incubator); checking the cells under a microscope; washing the cells with PBS; removing and suspending the cells with trypsin, taking an aliquot, and counting the cell concentration on a microscope counting slide; adding the appropriate amount of cells, and any medium; and returning the cells to the incubator. Large volume liquid transfers are performed with a serological pipette and small volumes with a micropipette with disposable pipette tips.

[0015] There are existing systems for automating cell biology. These systems consist of assembling different pieces of lab equipment (liquid handlers, automated incubators, refrigerators, etc.) from different vendors in different formats that are not generally designed to work together. These are often assembled by bolting the equipment to a table or other machine bed, which is then integrated with a 3D robotic arm. US Pat. No. 5,399,633 discloses a storage device for cell cultures that includes a carousel with radially arranged plate slots, each level of the carousel having a door for accessing the plate slots. US Pat. No. 5,399,633 discloses a storage unit having a housing defining a storage compartment comprised of an annular shelf. A modular chemical analysis device is disclosed in US Pat. No. 5,399,633. Patent Document 16 discloses an automatic biochemical analyzer that is composed of a process module equipped with a turntable and a plurality of storage modules. An analytical device equipped with rubber is disclosed in US Pat. No. 5,399,633. US Pat. No. 5,399,633 discloses an automated diagnostic analyzer. US Pat. No. 5,399,633 discloses a cryogenic storage system with two storage modules. US Pat. No. 5,399,633 discloses a modular sample repository. US Pat. No. 5,399,633 discloses an automated micro-well plate handling device for removing micro-well plates from a stack. US Pat. No. 5,399,633 discloses an automated storage device with a cylindrical rack having a center well in which a robot is positioned. US Pat. No. 5,399,633 discloses a carrier for carrying bottles for other labware. US Pat. No. 5,399,633 discloses a liquid handling system for biological cell culture. US Pat. No. 5,399,633 discloses a robot handling device equipped with a gripper arm having protrusions. US Pat. No. 5,399,433 discloses an incubator with a robotic handling device. US Pat. No. 5,399,633 discloses a robotic handling device for opening bottles. US Pat. No. 5,399,633 discloses an apparatus for culturing cells using a pipetting device. Patent Document 29 discloses a robot system. US Pat. No. 5,399,633 discloses a bottle decapper. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] Chinese Patent No. 104777321 [Patent Document 2] U.S. Patent No. 6,360,792 [Patent Document 3] U.S. Patent No. 7,670,553 [Patent Document 4] Japanese Patent Application Publication No. 1-1189561 [Patent Document 5] US Patent Application Publication No. 2016 / 0145555 [Patent Document 6] US Patent Application Publication No. 2018 / 0044624 [Patent Document 7] U.S. Pat. No. 7,883,887 [Patent Document 8] US Patent Application Publication No. 2016 / 0201022 [Patent Document 9] U.S. Pat. No. 8,652,829 [Patent Document 10] U.S. Pat. No. 9,388,374 [Patent Document 11] US Patent Application Publication No. 2017 / 0145366 [Patent Document 12] U.S. Patent No. 9,057,715 [Patent Document 13] WO 03 / 008103 [Patent Document 14] International Publication No. 93 / 03891 [Patent Document 15] European Patent Application Publication No. 2 068 155 [Patent Document 16] U.S. Patent No. 6,146,592 [Patent Document 17] European Patent Application Publication No. 3 229 028 [Patent Document 18] US Patent Application Publication No. 2014 / 0273242 [Patent Document 19] US Patent Application Publication No. 2018 / 0202908 [Patent Document 20] International Publication No. 2011 / 047710 [Patent Document 21] US Patent Application Publication No. 2007 / 0059205 [Patent Document 22] European Patent Specification No. 1 573 340 [Patent Document 23] European Patent Application Publication No. 1 900 806 [Patent Document 24] European Patent Application Publication No. 2 733 196 [Patent Document 25] JP 2009-291869 A [Patent Document 26] JP 2004-166558 A [Patent Document 27] US Patent Application Publication No. 2017 / 036833 [Patent Document 28] European Patent Application Publication No. 3 078 736 [Patent Document 29] US Patent Application Publication No. 2005 / 0058574 [Patent Document 30] International Publication No. 2016 / 130964 Summary of the Invention [Problem to be solved by the invention]

[0017] It is an object of the present invention to provide a module for handling or storing microplates, labware, or other instruments used in automated biological systems.

[0018] It is a further object of the present invention to provide a method for handling such microplates or other means used in processes for the maintenance of cell cultures. [Means for solving the problem]

[0019] This object is achieved by the invention specified in the claims, each claim essentially representing an independent solution of the object of the invention stated above.

[0020] The module of the invention comprises a housing, a rotatable storage device with a number of plate slots, a transfer slot and an indexing means for easily aligning the transfer slot with the transfer interface. Since the two modules are fixedly connected by a connecting means, the transfer direction when transferring a plate or container from one module to the other can be limited to a single horizontal direction. To transfer the plate or container in the housing, the robot handling device can move further in a vertical direction. It is not necessary to rotate the robot handling device. To connect the two modules airtight, a sealing element can be used.

[0021] In a further embodiment, a module for an automated biological laboratory system is provided, the module having: a housing having at least one plate slot for holding labware or microplates; at least one interface within the housing for transporting labware or microplates in and out of the housing; indexing means for rotationally aligning the carousel with a handler or interface; optional indexing means for vertically aligning the handler with the plate-loading slot; an interface of the module and a connecting means for the interface; and connecting means positioned relative to the interface to facilitate connection of the interface with a module's interface having a matching connecting means when positioned adjacent to the module, the connecting means being suitable for locking the module to an adjacent module when the connecting means is aligned. An interface is a location through which plates move between modules. An interface has a defined location - all or most modules have the interface in the same location, such as the same height position on the housing. Modules can be more or less secured together at the interface, which is a function of the interface. An interface is a controlled location where plates are exchanged. The connecting means is configured to be capable of engaging with a corresponding or matching connecting means on an adjacent module, and the position of the connecting means relative to the interfaces is such that when a module is connected to an adjacent module with a relative position of the interface and connecting means that is the same as the relative position of the interface and connecting means on the module, the two interfaces of the module and the adjacent module are aligned to allow the passage of microplates or labware between the modules. Thus, when the modules are connected to the same module, the interfaces are aligned to allow labware to be passed between the modules without any obstruction beyond that which would occur in such a passage through one interface of a single module. It will be appreciated that the two modules may have identical connection means that interact with each other in the connection manner described above, but alternatively the connection means may be configured such that they are adapted to perform the connection function. For example, one module may have a frame with one or more flanges that have surfaces for engaging with surfaces of one or more flanges of the other module, such engaging surfaces of that module facing away from the interface, while the corresponding engaging surfaces of the other module facing towards the interface of that other module. It is further understood that while a module may have locking means that lock with identical locking means provided on the same adjacent module, the locking means may alternatively be configured to lock with matching locking means in the opposite orientation. In other words, the modules are configured to connect and lock to the same module for alignment of the respective interfaces. In that case, modules may be considered to be capable of connecting and locking to the same module even if the identity between modules does not extend to having identical connecting means and / or locking means, but merely has matching connecting means and / or locking means in a manner that ensures alignment of the interfaces. Preferably, the module has a rotatable carousel electrically driven and controlled by a controller such as a computer that includes at least one plate slot. Preferably, one or more of the at least one plate slot on the carousel is indexed to align with the interface. The modules are indexed to align with each other and the carousel is indexed to align the plate slot thereon. This ensures that the plate slot is in the correct position for transfer into and out of the interface. Preferably, at least one connection means is located horizontally to the interface at a distance from the interface equal to or less than the width of the interface, and / or vertically to the interface at a distance from the interface equal to or greater than the height of the interface. Having the connection close to or on the interface maintains alignment where required. This has the advantage over connecting the module to a floor or base plate that has a tolerance stack-up, which would cause movement or misalignment as the plate moves in and out of the module. Preferably, the interface includes alignment means for orienting process plates transferred through the interface between modules, thereby also compensating for misalignment between modules or by robotic handling equipment. Preferably, the alignment means defines a width of the interface that decreases with increasing distance from the center of the module, so that the labware can be gently rotated or oriented as it passes through such a decrease in size of the alignment means. Preferably, the alignment means includes gradually sloping walls that define the transition from the wider interface width to the narrower interface width. Preferably, plate slots are formed by recesses in a rotatable carousel to form channels for holding microplates or labware that ensure that the plates or labware do not rotate by being constrained to a location on the carousel or on the transfer level of the carousel and are always oriented for processing or handling by the robotic device. Preferably, the channel has plate slot alignment means which define a width of the channel or portion thereof for the plate slot that increases with increasing distance from the center of the module. Again, the alignment means of the channel itself ensures that the plate or labware is correctly oriented as it enters the channel, which also ensures that if some misalignment occurs, the plate or labware will move to fit within the channel instead of hitting the wall of the carousel. Preferably, the channel has side walls whose sides are alignable with the width of the interface, ensuring a consistent channel through which plates or labware can pass from the plate slot through the interface and into the plate slot of an adjacent module, all in the same channel and in the correct alignment. The modular nature also allows for this. Preferably, the module further comprises a robotic handling device arranged therein, the robotic handling device comprising gripper fingers for gripping the microplates or labware, the maximum lateral width of the gripper fingers being less than or equal to the width of the channel and / or less than or equal to the width of the interface. A computer-generated controller may be provided for controlling the movement of the robotic handling device, in particular the gripper fingers. The controller may also control the movement of the storage device. If a robotic device is used to pass through the interface, the robotic device is also aligned with the channel. In some cases, the channel can have grooves for the gripper fingers of the robotic device to pass through so that the labware or plates are still aligned with the sides of the channel. If a gripper plate is used, the channel can have an additional groove on its bottom surface so that the gripper plate can be aligned and the plates are all aligned with the same channel. Preferably, the module further comprises a robot handling device disposed within the module, where horizontal movement of the robot handling device is restricted to a direction between the position of the robot handling device and the center of the interface. Preferably, the module further comprises a horizontal rail extending partially or fully along the plate slot and / or interface for guiding horizontal movement of the robot handling device in use. This provides a further means for ensuring that the robot handling device remains aligned and has simple movements. Preferably, the interface is located on the top and / or bottom wall of the housing, which allows modules to be stacked vertically with interfaces on the bottom and top of the modules. Preferably, the module further comprises a robotic handling device arranged therein, the module further comprising a vertical rail, in which case the robotic handling device is configured to move vertically along the rail, the rail allowing the robotic device to remain in a constrained location without shifting out of position. Preferably, there is provided a system having a plurality of modules as described above, wherein the connected interfaces of adjacent modules are rigidly constrained by at least one connecting means extending between the housings of the adjacent modules, thereby providing a system made up of a plurality of modules. Preferably, the connecting means exerts a compressive force across the connected interfaces of adjacent modules, thereby further constraining the assembled modules into rigid alignment. Preferably, the system includes two modules as described above connected to each other such that their respective interfaces are aligned with each other, where the interfaces are hermetically sealable to each other, the sealed system allowing consistent processing of biological material within the modules. Preferably, the system includes two modules as described above, where the two modules are arranged one above the other and the interfaces of the modules are provided in mutual registration on the respective upper and lower faces of the respective modules, and the system includes one or more robotic handling devices arranged to move vertically between the modules via the connected interfaces to reach the plate slots of either module. The robotic device may travel the entire height of the module, or may move like a horizontal transfer, stopping at a slot, such as a buffer slot, to deposit the plate after which another robotic device takes the plate to where it is needed. In a further embodiment, a method is provided for operating a biological laboratory system including a module aligned with an adjacent module using an indexing means, the modules coupled together by an interface within the housing of the module secured to an interface of the adjacent module, the modules including a plate transfer slot and / or a plate receiving slot, the method including: aligning the plate transfer slot of the module with the interface using the indexing means of the module; aligning the plate receiving slot of the adjacent module with the interface using the indexing means of the adjacent module; and transferring labware or a plate between the plate transfer slot and the plate receiving slot via the connected interfaces. At the module level, a module has its own interface (it can have several), which at the module level is an opening (optionally with a door). At the system level, there is an interface between each pair of modules that exchange plates, and each interface consists of two connected interfaces / openings, so the interfaces of the modules are combined to form a single interface between the modules. A further object of the present invention is a method for handling plates, the method comprising the steps of: moving, by a first robot handling device, a plate or container from a plate slot at a level other than the level having the buffer slot to a buffer slot; temporarily storing the plate or container in the buffer slot; and moving, by a second robot handling device, the plate or container via a transport interface to an adjacent module. A further object of the invention is a method, the method comprising the steps of: moving one of the plates or containers from a plate slot on a first level to a transfer slot located on a second level different from the first level; aligning the transfer slot with the transfer interface by rotating the storage device; and moving the plate or container from the transfer slot through an opening in the interface and out of the module. The control device has a program for automatically executing the method. These and other aspects of the invention will now be described in further detail, purely by way of example, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows a schematic plan view of an embodiment of a module. [Diagram 2] FIG. 2 shows a schematic plan view of the modules of FIG. 1 formed into a system of modules. [Figure 3A] FIG. 3A shows a schematic plan view of the modules of FIGS. 1 and 2 formed into a system in a different configuration. [Figure 3B] FIG. 3B shows a schematic plan view of the system according to FIG. 3B in a different configuration. [Figure 4A] FIG. 4A shows a schematic plan view of the interfaces between the modules. [Figure 4B] FIG. 4B shows a schematic plan view of the interfaces between the modules. [Figure 4C] FIG. 4C shows a schematic plan view of the interfaces between the modules. [Diagram 5] FIG. 5 shows a schematic cross-sectional side view of the plate slots, plates and grippers of the module. [Figure 6] FIG. 6 shows a schematic cross-sectional side view of the interface according to FIGS. 4A, 4B and 4C. [Figure 7A] FIG. 7A shows a schematic plan view of a further embodiment of an interface between modules. [Figure 7B]FIG. 7B shows a schematic plan view of a further embodiment of an interface between modules. [Figure 8] FIG. 8 shows a schematic plan view of a further embodiment of an interface between modules. [Figure 9] 9A and 9B show schematic cross-sectional side views of two vertically stacked modules. [Figure 10] FIG. 10 shows a schematic side view of vertically and horizontally oriented modules. [Figure 11] 11A and 11B show schematic plan views of a buffer slot between two modules. [Figure 12] 12A-12F show schematic plan views of steps using buffer slots of three modules. [Figure 13] 13A and 13B show schematic side views of labware according to one embodiment. [Figure 14] FIG. 14 shows a schematic plan view of the labware. [Figure 15A] FIG. 15A shows a schematic cross-sectional side view of the storage module and the process module. [Figure 15B] FIG. 15B shows a schematic plan view of the storage module and process module of FIG. 15A. [Figure 16] FIG. 16 shows a schematic side view of the process module and air handler. [Figure 17] FIG. 17 shows a schematic side view of the plate and plate slots. [Figure 18] FIG. 18 shows a schematic plan view of the interface between modules with sensing means. [Figure 19] FIG. 19 shows a schematic plan view of the plate transfer steps between modules. [Figure 20] FIG. 20 shows a schematic plan view of the plate transfer steps between modules. [Figure 21] FIG. 21 shows schematic top and side views of a handling device and plate according to one embodiment. [Figure 22]FIG. 22 shows a schematic plan view of the handling device and plate slot of FIG. 21 and further handling devices. [Diagram 23] FIG. 23 shows a schematic plan view of the handling device and plate slot of FIG. 21 and further handling devices. [Figure 24] FIG. 24 shows schematic top and side views of labware for use with the handling device of FIG. [Diagram 25] FIG. 25 shows a schematic side view of a bottle for use in the handling device of FIG. [Figure 26] FIG. 26 shows schematic top and side views of a handling device according to one embodiment. [Figure 27] FIG. 27 shows a schematic top and side view of labware with interfaces for handling with caps and lids. [Figure 28A] FIG. 28A shows a schematic plan view of a system of modules with a central robotic handler according to one embodiment. [Figure 28B] FIG. 28B shows a schematic side view of a system of vertically stacked modules with a central robotic handler according to one embodiment. [Figure 29A] FIG. 29A shows a schematic plan view of the system of FIG. 28A with an additional carousel. [Figure 29B] FIG. 29B shows a schematic side view of the system of FIG. 28B with an additional carousel. [Diagram 30] FIG. 30 shows a schematic close-up side view of the robotic handling equipment and rack of the module. [Figure 31A] FIG. 31A shows a schematic side view of a rotatable robotic handling device according to one embodiment. [Figure 31B] FIG. 31B shows a schematic side view of a rotatable robotic handling device according to one embodiment. [Diagram 32] FIG. 32 shows a schematic side view of a robotic handling device with a magazine rack and modules according to one embodiment. [Diagram 33]FIG. 33 shows a schematic plan view of a system of modules and a robotic device on rails according to one embodiment. [Diagram 34] FIG. 34 shows a schematic plan view of transferring plates between modules in vertically stacked modules according to one embodiment. [Diagram 35] FIG. 35 shows a plan view similar to FIG. 1 in a further embodiment of the invention. [Diagram 36] FIG. 36 shows a single well plate for containing liquid media. [Figure 37] FIG. 37 shows a single well plate for containing liquid media. [Figure 38] FIG. 38 shows two adjacent modules connected with a sealing element 311. [Figure 39] FIG. 39 shows two adjacent modules connected with a sealing element 311. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] 15A and 15B, there is shown a process module 120 connected to an additional module 100, which may be any of the modules described herein. The process module 120 has a rotating element 108 or turntable. However, in some cases, the turntable 108 in the process module 120 may be a single surface and not have various vertical racks 210. Instead, the top surface of the turntable 108 forms the working deck 330 or at least a portion of the working deck 330. The turntable working deck has multiple slots for labware and can be aligned with a functional module (e.g., a liquid handling robot) within the process module and with an interface where plates are transferred horizontally onto the turntable working deck from another module. Thus, the turntable working deck serves as a very compact, integrated, and simple means for transferring plates into the module and between multiple functional elements.

[0024] Within the process module 120 is a liquid handling robot 340. The liquid handler 340 is located above the turntable 108. In the illustrated embodiment, the liquid handler 340 does not occupy the entire area above the working deck 330 as shown in Figures 15A and 15B. As shown in Figure 15B, the turntable 108 is rotated so that five plate slots 110 are located below the liquid handler 340. The liquid handler can be configured to have a liquid discharge point for each of the plate slots 110 located below it, or for a selected number as needed. The actual size of the liquid handler can vary depending on the required functionality of the system 99. In a given embodiment, it is positioned to access all plate slots 110 of the working deck 330.

[0025] As mentioned above, the turntable 108 and thus the rotating work deck 330 in the process module 120 has radially arranged plate slots 110 that can hold a variety of items, such as cell culture plates 116 and plates containing consumables such as pipette tips and media bottles. While eight slots may be sufficient for a general purpose cell culture system, the total number of plate slots 110 can be varied as needed, for example, the plate slots 110 can be adapted to hold two or more plates adjacent to each other.

[0026] FIG. 15B shows a microscope placed in the plate slot 110 of the process module 120 so that the turntable 108 can be rotated therein. The microscope has a lens below the plate (to view the cells through the bottom side of the plate) and a light source, e.g. a high power LED array, above the plate. Any position in the work deck 330 where it is desired to scan the plate 116 with the microscope 342 must therefore have a cutout to expose the bottom side of the plate 116 to the microscope lens. Alternatively, the plate can be lifted by a handling means from the rotating work deck and transferred to the microscope. The microscope can view or scan the entire plate 116 by moving or scanning in the x and y directions. The turntable 108 indexes the microscope 342 so that it always remains in the same position, ensuring high quality inspection of the plate and contents below. As shown, the microscope 342 is located at the position where the plate 116 is transferred to and from the incubator 124. This allows the plate 116 to be transferred in and out of the plate slot 110 beneath the microscope 342 without rotating the turntable 108 of the process module 120, thereby not interrupting other processes taking place on the turntable working deck 330. Other embodiments are possible, for example, the microscope 342 could be located in a different slot on the working deck 330.

[0027] Microscope 342 is typically used to monitor the state of the cells (such as confluent) so that one knows how fast the cells are growing and when they need to be passaged next or where there are enough cells to start another process. In another embodiment, microscope 342 can also detect the pH of the medium (carrying a dye that acts as a pH indicator) and / or detect gross microbial contamination (making the medium acidic (more yellow) and cloudy).

[0028] In another embodiment, the microscope 342 is indexed to the turntable 108 or positioned to view an area larger than the area of ​​the required plate 116 or plate slot 110 and is programmed to ignore features outside this field of view or use them to correct for misalignment in the plate 116.

[0029] An optional decapper robot 344 is shown and positioned to be above the plate slot 110 when the turntable 108 is rotated into position. The decapper 344 decaps the vials 321 and bottles 323. Vials 321 and bottles 323 that need to be decapped have their plate slot 110 rotated by the turntable 108 to a decap position below the decapper 344. The turntable 108 can then rotate the decapped plate slot 110 into a position required for the liquid handler 340 (e.g., a pipette robot).

[0030] An optional delidder station 346 is also shown, which is provided for deliding plates 116, e.g., cell culture plates. In the art, consumables such as pipette tip boxes and pipette tip stacks, or plates such as microplate reservoirs, are housed on the deck of a liquid handler. In the system described herein, it is desirable to allow the process module to randomly access a wide range of consumables that a human would use in a laboratory. To this end, the process module is interfaced with an automated incubator, an automated refrigerator, and an automated plasticware store, allowing for flexible movement of consumables or cell culture plates to and from the process module as needed. To enable this, a system that allows the lids of the pipette tip boxes and microplate reservoirs to be opened and closed is desirable. In the art, the lids of the pipette tip boxes are adapted for human use, are hinged to the box, are somewhat flexible, and are usually made of a polymer such as polypropylene. The microplate reservoirs, if they have lids, also have somewhat flexible polymer lids. Pipette tip boxes or other labware (such as microplate reservoirs) can also be de-lidded with the de-lidder if they have lids that can be handled by the de-lidder. Such lids are known in the art for cell culture plates, are generally made of materials such as polycarbonate, and require rigidity. It is an added advantage if the lids are glossy, as is known in the art. The de-lidder 346 can be positioned over one of the plate slots 110 carrying a plate that needs to have its lid removed by rotating the turntable 108.

[0031] 15B, an exemplary process module 120 can be configured with one microscope 342, one de-lidder 346, and one de-capper 344, all located on the work deck 330. Other configurations are possible depending on the needs of the system. For example, more than one microscope 342 may be required, or a configuration may not require a de-capper 344.

[0032] As an example, the working deck 330 holds a cell culture plate 116 in a plate slot 110, a rack with vials 320 (e.g., vials containing reagents or growth factors) and bottles 322 (e.g., bottles containing cell culture medium or trypsin), and a pipette tip box 324 with two different sizes of pipette tips. The working deck 330 may be stationary while the liquid handler 340 performs liquid transfers, or may rotate to conveniently present various dishes and other consumables to the liquid handler 340 at various times. Additionally, there may be other items, such as a cell culture plate 116, below the microscope 342, delidder 346, or decapper 344. If the mechanisms for the microscope 342, delidder 346, and decapper 344 were located above the plate slots 110 on the working deck 330, in most cases this would prevent the liquid handler 340 from reaching the items in those plate slots 110. Items within the plate slot 110 below the microscope 342, delidder 346 or decapper 344 can be exposed to the liquid handler 340 when required by rotating the working deck 330.

[0033] The turntable 108 for the work deck 330 has eight radially arranged plate slots 110 for cell culture plates 116 having a Society for Laboratory Automation and Screening (SLAS) microplate footprint and can be small, e.g., less than 80 cm in diameter, allowing the process module 120, or other modules 100 having a similarly sized turntable, to be compact and easily pass through doors, such as laboratory clean room doors. This makes installation of the system 99 generally simple, fast and economical, since the modules can be assembled in the factory and then assembled on-site.

[0034] 15B, a carousel 108 with a rack system 210, such as the carousel 108 of the incubator 124 shown in FIG. 15B, can be positioned adjacent to the work deck 330 of the process module 120, such that labware 300, such as cell culture plates 116, can be transferred by a simple horizontal movement from the plate slots 110 of the carousel 108 of the incubator 124 to the plate slots 110 of the work deck 330. A robotic device 160 for transferring the plates 116 can be provided within the incubator 124.

[0035] An external solid waste receptacle 348 with a robotic grabber 160 is provided in association with the process module 120. Solid waste from the process module 120 (e.g. used cell culture plates, empty pipette tip boxes, empty bottles) can be transferred to the solid waste receptacle 348. The solid waste receptacle 348 does not have to be the size of the module 100, but can have a smaller capacity, possibly requiring its contents to be emptied into bags and transported outside the laboratory. A sealing means 311 formed by a piece of pipe connects the modules 100, 120 airtight. The sealing means 311 can be used to rigidly connect the two modules 100, 120.

[0036] 16 is a schematic diagram of the air flow through the process module 124. An air handler 350 is provided. It is located above the process module 124 to conserve floor space. However, the air handler 350 may be located in other locations as appropriate for a given system 99. The air handler supplies clean air 352 to the process module 124, which is routed across (i.e., horizontally) the process module 124 to an exhaust where the exhaust air 354 is returned to the air handler 350.

[0037] Preferably, HEPA filtered air is blown through the process module 124. Blowing the air horizontally minimizes particle fall-out into open cell culture plates 116 or reagent vials or bottles. HEPA air can be recirculated through the system 99 via a HEPA filter as a way to reduce particulates and reduce exhaust air from the system 99. Recirculating air may be preferred for process steps where it is not desirable to exhaust air into the room, such as in systems dealing with lentivirus. In some cases, it may be preferable not to recirculate air in a given system.

[0038] In one embodiment, the process module 124 further comprises some means for periodic sterilization, such as hydrogen peroxide vapor, ozone, ethylene oxide, or UV light, such as a UV LED, arranged to irradiate the surfaces of interest.

[0039] FIG. 17 shows two versions of a plate slot 110. In one version, the plate 116 or other labware 300 rests in a channel or trough 156 formed by a slot side 152 and a bottom 154 that is generally perpendicular to the slot side 152. As mentioned above, the plate 116 or other labware 300 has a footprint 360 that is wider than the width of the plate 116 or other labware 300 itself. This can be used to allow the grabber 164 to slide into the trough 156. However, in the channel 156 shown in the plate slot 110 on the right side of FIG. 17, the slot side 152 has a wider portion at the bottom of the channel 156 and a narrower portion at the opening of the channel 156. The width of the trough in this situation is such that footprint 360 is wider than the narrow portions (but can fit between the wide portions) and plate 116 is vertically constrained within plate slot 110. This allows for alignment of labware 300 and prevents the labware from being dropped or lost.

[0040] Such a configuration may be particularly useful, for example, at locations on the work deck 330 of the process module 120. If the grabbers 164 and thus the gripper fingers 168 do not extend down the sides of the plate 116 in the slot 110, then either additional grooves in the channel walls (e.g., FIG. 5) or labware grooves 370 (FIG. 19A) are required to accommodate the gripper fingers. Alternatively, a robotic handling device 160 is required. This can be accomplished by a gripper handling the front side of the plate 116, or by the plate 116 being pushed in and out of the plate slot 110.

[0041] Chamfers 362 are provided on the upper edges of the slot sides 152 at the openings of the channels 156. These chamfers 362 can assist in vertically aligning the plate 116 placed in the plate slot 110. The features described above, such as the chamfers 362 and the slot sides 152, which provide various widths for the channels 156, can be combined with features of FIG. 5, such as the side grooves 166.

[0042] 18, the end of the plate slot 110 is provided with an engagement means 362. The engagement means 362 is actuated or otherwise triggered by the placement of the plate 116 to indicate the presence of the plate 116 within the slot 110. In one embodiment, the engagement means 362 is a spring that retracts into the wall of the plate slot 110 when the plate 116 is present. This activates a proximity or pressure switch, notifying the control system that a plate is present or properly positioned within the plate slot 110.

[0043] Alternatively, the engagement means 362 may be a recess, a press fit, or a spring that engages the labware 300. The engagement means 362 can provide feedback (e.g., read by the motor driving the gripper 164) when the means 362 is initially engaged by the labware 300, and provide further feedback when the labware 300 is fully engaged in the plate slot 110. Generation of such a signal as a function of the position of the plate 116 in the slot 110 can be done by various means, such as impedance strips, or by proximity sensors located at the front and back ends of the plate 116 that are triggered by contact with the engagement means 362. Alternatively, variations in the shape of the plate 116 from front to back can result in different forces being applied to the engagement means 362. For example, the plate can be narrower at the front, and therefore the engagement means 362 will retract less than wider portions of the plate 116 which will cause the engagement means 362 to retract more. This requires consistent alignment of the plate 116 and therefore corresponding engagement means 362 may be provided at the entrance to the plate slot 110.

[0044] A sample process will now be described with reference to Figure 19 and its sub-figures A, B and C. Here, the replacement of nutrient medium in a cell culture plate 116 is described.

[0045] While the cells are growing, the cell culture plate 116 with nutrient medium is in the incubator 124. Due to waste products or lack of nutrients, the medium needs to be changed. In FIG. 19A, the plate 116 is transferred to the work deck 330 with the pipette tips 324 and new medium (which may be in a deep well plate 364 or alternatively in a bottle in an adapter rack or in a bottle with a microplate footprint). The associated plate 116 with cells is removed from the plate slot 110 of the plate hotel / rack 210 in the carousel 108 by the robotic device 160. The vertical movement of the robotic device 160 and the rotation of the carousel 108 present the correct plate 116 to the robotic device 160, which removes the plate 116 from the plate slot 110. The robotic device 160 then moves vertically to align with the door 130 of the incubator 324, which is aligned with a slot on the rotating work deck 330. The carousel 108 / rotating work deck 330 rotates to align the target plate slot 110 on the rotating deck 330 (i.e., where the plate 116 is to be transferred) with the door 130 of the incubator 324, and the robotic device 160 transfers the plate 116 horizontally to the target plate slot 110 on the rotating work deck 330. The plate 116 is de-lidded, for example, by rotating the rotating work deck 330 until it is aligned with the de-lidder station 346, which then removes and stores the lid.

[0046] The pipette tips 324 and cell culture media (in deep well plates 364) are transferred in a similar manner from the other storage 122 to the target plate slot 110 on the rotating working deck 330 by vertical movement of the robotic device 160, rotation of the carousel 108, and alignment of the associated target plate slot 110 on the working deck 330 with the door 130 of the associated storage 122. In Figure 19B, all the necessary materials, i.e., plate 116, media, and tips, are in the process module 120.

[0047] The liquid handling robot 340 picks up a new disposable sterile pipette tip 324. Disposable pipette tips are used to prevent the medium and cells from being contaminated with microorganisms or excess chemicals from previous pipetting steps. The liquid handler aspirates the used medium from the plate and disposes of it as waste. The pipette tip 324 is then discarded and a new pipette tip 324 is picked up. The liquid handler 340 then aspirates fresh medium from a reservoir (e.g., a deep well plate) and dispenses the medium into the plate with the cells. The plate can be a single-well plate or a multi-well plate, in which case the pipette dispenses into a row of wells, and this operation is repeated until all wells are filled with fresh medium. Re-cap the plate 116 with fresh medium: The rotating work deck 330 is rotated until the plate 116 is aligned with the de-lidder 346 housing the lid that was removed from the plate 116, which re-caps the plate 116 and returns the plate 116 to the incubator 124. If no longer needed, the medium and pipette tips are returned to storage 122.

[0048] FIG. 19C shows the plate 116, pipette tips 324, and deep well plate 364 returned to their original positions in the system 99.

[0049] An exemplary sample process is further described with reference to Figures 20A, B, C. Cells are typically passaged when they are, for example, 80% confluent. In this example process, the following are transferred to the rotating work deck 330: 1. A plate containing cells that are usually close to confluent. 2. A box of 1 ml pipette tips 324. The tips may preferably be wide bore tips. 3. Deep well plate containing PBS (phosphate buffered saline) + EDTA (or equivalent reagent) 4. Deep well plate containing trypsin (or equivalent reagent) 5. Deep-well plate 364 with fresh medium 6. Two new plates for transferring cells 116

[0050] The initial position of the materials is shown in Figure 20A. The liquid may optionally be pre-heated by transferring the plate 116 to the incubator 124 for a suitable period of time. This may be achieved by transferring the plate 116 from storage 122 to the rotating work deck 330 and then from the rotating work deck 330 to the incubator 124, as previously described.

[0051] 20B, when the required material is on the rotating work deck 330 and the lid of the associated plate 116 is removed, the liquid handling head 340 picks up a new pipette tip 324 and aspirates the old media from the passing plate 116. The media is discarded into liquid waste 366.

[0052] Residual medium (including serum) is then washed away. The liquid handler 340 picks up a new pipette tip, aspirates PBS, and pipettes it into the wells of the plate 116. The PBS is then removed and discarded. This rinse can be repeated to further reduce the amount of residual medium and serum.

[0053] Trypsin is then added. Note that in Figure 20B, multiple plates are beneath a diagonally oriented delidder apparatus 346. The delidder apparatus 346 is not fixed to the rotating working deck 330, so that the decapper 344 and delidder 346 remain in fixed positions as the deck rotates. Also, a diagonal position may be inconvenient for the pipetting head. Therefore, in this example, the rotating working deck 330 can be rotated to present the plates 116 in any convenient orientation or position.

[0054] After the liquid handler 340 picks up a new pipette tip, the work deck 330 is rotated so that the liquid handler 340 aspirates the necessary (usually minimal) amount of trypsin for the associated plate. The work deck 330 is rotated again to return the plate 116 with cells to a position where the pipetting head can easily pipette and add trypsin to the wells of the plate. The plate is then incubated for a few minutes to allow the trypsin to detach the cells. In some methods, the plate is incubated at room temperature, which can be achieved by leaving it on the rotating work deck 330. In other methods, the plate is incubated at 37° C. while the cells are detached - this can be achieved by returning the plate to the incubator 124. Various methods can be used to select the incubation time with trypsin, for example, the incubation time can be predicted based on past results with a given cell line. Alternatively, an automated microscope can be used to monitor the detachment of the cells.

[0055] Once the cells are sufficiently detached, the liquid handler 340 adds medium, typically containing serum, to quench the trypsin (by rotating the work deck 330 as necessary, as described above for trypsin). Alternatively, there are modified trypsins and similar reagents known in the art that do not require quenching with serum. The liquid handler picks up a new pipette tip, aspirates the required amount of medium, and pipettes it into the well containing the detached cells. The detached cells are resuspended (to reduce shear stress on the cells), e.g., by gently pipetting up and down, e.g., with a wide-bore pipette tip.

[0056] The required number of cells are then transferred to two fresh plates 116 to achieve a target confluence of the freshly seeded plates, for example 20% confluence.

[0057] A variety of methods can be used to determine the volume of cell mixture to be transferred. For example, the cells may be counted with an automated cell counter, or the cell number may be estimated based on confluency just prior to passaging. In either case, the pipetting head aspirates the required volume of cell suspension (containing the required number of cells) and seeds the cells into a fresh plate. The wells of the new plate are replenished with new medium as necessary to ensure the correct amount of medium per well. The freshly seeded plate is then recapped and returned to the incubator. The old plate is discarded, and the medium, PBS, and trypsin can be returned to the plate hotel storage location on the associated carousel 108, as shown in Figure 20C.

[0058] In the handling strategy briefly described, all necessary materials (fresh plates, PBS, trypsin, media, pipette tips) are all loaded onto the rotating work deck 330 at the beginning of the process. Other movement sequences are possible. For example, pre-heated liquids may be loaded onto the work deck 330 only when needed.

[0059] As discussed above, there is a need for automated equipment that handles more complete and integrated workflows. Currently, there is a need to create equipment that handles a wide variety of traditional human-optimized labware that is difficult to handle in automated systems. Provided herein is a labware set and method for its use that allows end-to-end automation of complex cell culture workflows using essentially only labware that conforms to the SLAS microplate footprint, thereby adapting the workflow to a format that can be easily handled by the automated equipment. Also provided is a universal format for handling the labware set, including robotic handlers, racks, and slots, and storage that conforms to this format.

[0060] As mentioned above, labware having a footprint compatible with the microplate footprint 116 will be grabbed by the grabber arm 164, and more specifically by the gripper fingers 168. Thus, a standardized form of plate 116 is used for one robotic device 160 to access all storage modules (i.e., refrigerator 128, freezer 126, plasticware and room temperature reagents 122, etc.). Microplates or microtiter plates 116 are often used in cell culture processes.

[0061] The terms "microplate" and "plate" are used interchangeably herein to mean "labware with an SBS / SLAS microplate footprint" and are comprised of a set of labware including microplates, microplate reservoirs, single-well cell culture plates, multi-well cell culture plates, microtiter plates, bottles, pipette tip boxes, vials and / or adapter racks for bottles, all of which use the same bottom footprint and can therefore be manipulated within module 100 by the same robotic device handler 160. Additionally, all of this labware can have the microplate bottom footprint and are interchangeable.

[0062] 13A, a set of labware 300 is provided arranged in a rack 310. The rack 310 is arranged as a vertical stand 314 with rack rails 312 disposed between two vertical stands 314 and extending slightly into the interior area of ​​the rack 310. Because these rack rails 312 extend only a portion of the interior area, when a plate 116 is placed on the rails 312, it only interacts with a portion of the plate 116 (or labware) and does not limit the height as it does not extend across the rack stand 314. The gripper fingers 164 can still interact with the plate 116 and other labware 300 as they grip the top of the rack rails 312, as will be described in more detail below with reference to FIG. 13B.

[0063] 13A, a microplate 116 (or the like) is shown seated on rails 312 of a rack 310. Also shown is a vial plate 320 seated on the rails 312. However, in this embodiment, the vials 321 of the vial plate 320 extend beyond the height of the next rail 312 placed above it. The vials 321 can extend beyond the height of the next rail 312 because the rails 312 do not extend into the interior area of ​​the rack 310 more than far enough for the footprint of the plate 116 or vial plate 320 to be placed on the rails 312.

[0064] The vertical stands 314 can be arranged such that each column can be arranged side by side to form a row of racks 310, with the rails 312 extending from both sides of the vertical stands 314. This allows for a compact rack 310, since each vertical stand 314 can form part of a rack 310 in a further rack 310. In this arrangement, the robotic device 160 needs to be able to move not only in a single horizontal dimension, i.e., towards and away from the rack 310, but also in a second horizontal dimension, left and right, thus in the z-axis and y-axis, to access adjacent racks 310. When the racks 210 are arranged on the carousel 108, one vertical stand 314 cannot be used for two racks 210, since the racks are arranged radially.

[0065] A bottle tray 322 is shown in FIG. 13A where the footprint of the microplate 116 is provided with a tray suitable for holding a number of bottles 323. As with the vial plate 320, the bottles 323 are shown to extend beyond the height of the rails 312 above them. This is possible because the rails 312 extend into the interior area of ​​the rack 310 only a distance to hold the microplate footprint, and are therefore not height limiting. A pipette tip tray 324 is also shown, and as with the other examples, the footprint of the microplate 116 may be accommodated in a rack 310 where the height between the rails 312 is less than the height of the pipette tip tray 324 while having a pipette rack capable of holding a number of pipettes.

[0066] Two examples of large bottles 326, 327 are shown in FIG. 13A. The large bottles 326, 327 are manufactured to have the same footprint as the plate 116 or trays 322, 324. Therefore, the bottles are not placed on a microtiter footprint rack as is the case with other labware 330. The base of the bottle 326 is provided with an extension 328 having a width greater than the width between the rails 312 and less than the width between adjacent vertical stands 314 of the rack 310 so that the bottles 326, 327 are suspended by the rails of the rack. A bottle narrower than the width between the two rails 312 extends from the extension 328. The bottle 327 is also provided with an upper extension 329 that reaches between the rails 312 of the rack 310 so that it is suspended by the rails 312. However, the upper extension 329 is located at the mid-height of the bottle so that the bottle 327 extends from the extension 329 in both directions (i.e., up and down). Thus, the bottle 329 can be placed on a higher rail 312 and extend upward while still being suspended downward. This contrasts with the bottle 326, which has an extension 328 at its base that extends upward relative to the height of the rack 310. This allows the bottle 326 to be placed on the lowest rail 312 of the rack 310 and pass the rail 312 above it.

[0067] The extensions 328, 329 and / or bottles 326, 327 can be shaped to have a horizontally circular cross section, i.e., to form the outline of a circle when viewed from above, allowing bottles of a conventional shape to be held on the rail 312. Alternatively, the extensions 328, 329 can have flat sides that run along the length of the rail 312, providing a larger support area for hanging the bottles 326, 327. The bottles can be circular or similarly shaped with flat sides, in which case the more rectangular shaped bottles (when viewed from above) can be a more efficient use of space and are often used in cell culture work.

[0068] This provides a versatile rack solution by eliminating the need for specially sized plate slots 110 for various labware, instead the plate slots 110 are universally capable of accommodating many types of labware. Additionally, in some embodiments, the plate slots 110 do not need to be specially sized for a particular height of content, instead the plate slots 110 can accommodate items of labware 300 that are taller than the set of rails 312 because the set of rails 312 does not intrude into the height of the plate slots 110 and thus the racks 210, 310.

[0069] The racks 210, 310 mentioned above are located on the carousel 108. In some cases, the rack 210 can be completely removed from the carousel 108 and a new rack 210, 310 can be loaded. This allows a new set of plasticware 300 or plates 116 to be preloaded and replaced in the rack. Access to the rack 210, 310 can be via a user-accessible door. The height of the door should be the same as the height of the rack 210, 310 that is being removed or placed in the module 100. The exchange of the rack 210, 310 can be combined with a load lock to avoid contamination of the module or changes in the environment. In some cases, only the module 100 used for storing plasticware and for storage at room temperature can be accessed for the exchange of the rack 210, 310.

[0070] The carousel 108 has been described in the singular for each module 100. However, multiple rotating disks can be provided to form a carousel that holds the racks 210, 310. For example, a lower turntable and an upper turntable can have space between them for the racks 210, 310 to seat. In some embodiments, the rows of plate slots 110 are seated on separate carousels 108 that rotate independently within the same module 100.

[0071] When researchers want to culture a large number of cells, they will use a large number of flasks. On the other hand, plates are used when users need multi-well plates to perform multiple cultures or experiments in parallel. Single-well plates can have a large liquid surface area, such as 77 cm2, similar to T75 flasks. Single-well plates are inconvenient and unusual for humans to use, but robotic devices 160 can use them. This simplifies mechanical handling in automated systems.

[0072] FIG 13B shows a set of labware 300 as shown in FIG 13A. However, gripper fingers 168 are shown interacting with the various labware 300. In the case of plate 116, gripper fingers 168 grip each side of plate 116 (except for the footprint which rests on rails 312). Because it is the sides of the plate that are gripped, gripper fingers 168 do not encroach on the area above (or below) plate 116. This does not limit the height of the plate or contents; the only height limitation may be the height of the rack 310 (or module 100) in which the labware 300 is to be placed, or the height of the interface 134 through which the labware 300 is to pass.

[0073] For the vial plate 320, bottle tray 322, pipette tip tray 324, and large bottle 326, the gripper fingers 168 all grip the labware 300 above a footprint that rests on the rails 312. It is worth noting that when placed on the rack 310, there is enough space between the vertical stand 314 and the side of the plate 116 or other piece of labware 300 that the gripper fingers 168 can fit into. This is because the footprint of the labware 300 (extensions 328, 329 in the case of large bottles 326, 327) is wider than the width between the sides of the labware 300. For the large bottle 327, because extension 329 rests on rail 312, the gripper fingers can instead grip the bottle 327 at a lower level than extension 329.

[0074] The system described above handles cell culture plates 116, liquid media (typically in bottles 323, 326, 327), liquid additives (such as growth factors) in e.g. 2 ml vials 321, sample plates 116 (for storing samples taken from cells), pipette tips (in pipette tip box 324), etc. These different objects can be handled differently in the same system 99 using the robotic device 160. This allows for a highly autonomous automated cell culture system 99 that can withstand long hours of operation.

[0075] 3A and 3B, a process module 120 is shown in which various labware 300 is shown on the working deck of the carousel 108 in accordance with the above description. It is noted that because the plate slots 110 are the same size and configuration throughout the system 99, such as those on the working deck of the carousel 108, all labware (e.g., plasticware) 300, including vials 321, bottles 323, 326, 327, and pipette tip boxes 324, are handled by the same gripper fingers 168, are housed in the same types of racks 210, 310 and carousel 108, and are seated in the same types of docks 110 on the rotating working deck.

[0076] Vials usually contain 0.2-2ml of liquid. They are often screw-capped, but other methods are possible. Vials can be cryovials, with caps ranging from 0.2-2ml.

[0077] Because pipette tips take up a large amount of space, and because the system 99 uses such a large number of pipette tips, they are typically stored in space-saving stacks (magazines). However, it is advantageous to have a variety of tips available, such as 10ul, 100ul, and 1ml tips. In addition, it may be advantageous to have other tips, such as 100ul and 1ml wide bore tips, and aerosol resistant versions of those tips. If multiple tip boxes 324 were preloaded on the deck or there were magazines for the boxes, this flexibility would require multiple slots 110 and magazines. This may require a large or complex deck. Thus, although handling tips in one box 324 may seem to use a large amount of limited space, in reality it provides a good availability of the system 99, as the simplified mechanism allows for greater flexibility and less downtime. It also requires less manpower to replace tips when needed. Variations of these embodiments can be employed depending on the requirements of the system 99.

[0078] 14 shows plan views of different trays or plates 116 for different functions, for example, on the left is shown a bottle tray 322 with four defined areas for bottles 323, and on the right is shown a vial plate 320 with 48 slots for vials 321. However, the central tray 325 shows a combination of slots or areas so that bottles and vials can be accommodated on one tray 325. Various combinations for the trays 325 can be provided depending on the requirements of the system 99.

[0079] Various labware 300 may have computer readable means, such as bar codes, RFID, NFC chips, etc., to record the tray or plate type and configuration on the system. A reader may be present on the robotic device 160 to detect trays or plates as they are selected.

[0080] A cell culture plate typically requires 10-15 ml of medium. This medium is typically pipetted from a 100-500 ml bottle with a 15-20 ml serological pipette. Serological pipettes were originally designed for manual use and are usually made of polymers such as polycarbonate, are highly rigid, and have an inner diameter that is widest in the middle of the length of the body and narrows at the tip, and also at the end where it connects to the mechanism that applies air pressure to aspirate or dispense the liquid. For this reason, traditionally, automated systems were required to handle bottles and serological pipettes, which tended to result in complex and malfunction-prone robots. On the other hand, traditional pipetting robots are mature and reliable, but their heads generally only handle up to 1 ml, and long pipetting steps are required to transfer 10-15 ml of medium. Pipetting robots generally have a piston and often operate with air exchange. Disposable pipette tips are used, which are somewhat compliant and generally made of polymers such as polypropylene so that they can be attached in a sealing manner to the outside of the pipette's "cone." The pipette tip has a significantly larger inner diameter where it attaches to the pipette cone.

[0081] It should also be noted that instead of bottles 323, 326, 327, deep well plates 116 can be used as medium storage containers. Deep well plates can be used in the present system, making handling easier with the automated robotic system 99. Additionally, deep well plates 116 can be sealed with a film (to prevent liquids from leaking during shipping) that can be broken by the pipette. Alternatively, the plate lid may be sealed or have a gasket. A 96 well plate with 2 ml wells can hold 192 ml of medium, similar to the bottles, making efficient use of space. Unlike bottles, deep well plates are accessible to a multichannel pipette head, as are trough reservoirs. An 8 channel pipette head with 1 ml pipettes can pipette 8 ml at a time from a deep well plate, so filling a single well plate with up to 16 ml of medium requires only two pipetting steps. Although filling plates with medium using a multichannel pipette head may seem inefficient at first glance, using deep-well plates as large-volume liquid reservoirs and pipetting with a multichannel pipette can greatly reduce the mechanical complexity of automated systems and increase the occupancy rate (i.e., efficient use) of the system due to its space efficiency and flexibility. Single-well plates can be used by robots instead of T75 flasks. T75 flasks have a large culture area of ​​75 cm2 and are useful for maintaining cell stocks, but are preferred by humans and are not suitable for robots. On the other hand, single-well plates exist, but are rarely used because they are difficult for humans to use and easily tilt, spilling medium. However, single-well plates are suitable for robots and can have a culture area of ​​75 cm2 or more. It is further advantageous for automated systems to increase storage density by making the plate height 15 mm or less, or even 10 mm or less.Normally this would be a disadvantage for human use, as tilting the plate would make the liquid more likely to spill.

[0082] In an example of using the system, a user loads the system with the liquids required by the system 99. The liquids may be transferred from bottles 326, 327 to the deep well plate (e.g., by an automated liquid handler or dispenser) or may have been provided to the deep well plate by a supplier as described above. The user may load the deep well plate containing media, PBS (Phosphate Buffered Saline), and trypsin, for example, into racks 210, 310 in the carousel 108 of the refrigerator 128 of the system 99. When the system 99 is ready to passage cells, the robotic device 160 in the refrigerator 128 retrieves the media, PBS, and trypsin from the racks 210, 310 in the refrigerator 128 and transfers them to an empty rack 210, 310 in the incubator 124 to warm for 5 minutes. After 5 minutes, the system transfers a box of 1 ml pipette tips 324 and at least one fresh cell culture plate 116 to the work deck 108. The robotic device 160 in the plasticware storage 122 retrieves the tip box 324 from the slot 110 in the carousel 108 and passes it onto the slot 110 in the work deck 108 that has been rotated to align with the door 130 of the plasticware storage 122, where it passes the tip box 324 and also passes a fresh tissue culture plate 116 in a similar manner. The work deck 108 then rotates to align the slot 110 that receives the PBS, medium, and trypsin with the door 130 of the incubator 124, and the robotic device 160 in the incubator 124 passes those liquids (which are in the deep well plate 116) to the appropriate slot 110 in the turntable 108. The robotic device 160 then passes the plate 116 with the cells that need to be passaged.

[0083] 21, an improved interface of the robotic device 160, specifically the interface between the handler or gripper fingers 168 and the plate 116 or other compatible labware 300, is shown.

[0084] Typically, the interface consists of a combination of a handler and a "dock & key" feature on the labware, e.g. beveled or conical, that allows the labware to be aligned on the handler during pick-up and compensate for misalignment of a few millimeters. The handling interface allows the labware to be held more securely. This feature allows the system to detect and reject labware that does not have a handling interface and is the wrong size.

[0085] In FIG. 21A, plate 116 is shown having a footprint 360 with a groove 370 extending through its sidewall. In particular, groove 370 begins at an end of footprint 360 and extends along the length of plate 116. In some embodiments, the length of groove 370 is no more than half the length of plate 116, and is the same length (or longer) as the length of gripper fingers 168. Groove 370 is closed at the top and bottom of footprint 360. However, groove 370 can be open on the sidewall of footprint 360 closest to the open side to form a channel. Groove 370 is also provided at the opposite end (i.e., across the width of plate 116). The two grooves 370 are sized so that a pair of gripper fingers 168 can slide along groove 370 to manipulate plate 116. The labware 300 other than plate 116 preferably has a footprint similar or identical to plate 116. Thus, grooves 370 can be provided on all labware 300.

[0086] The upper and lower surfaces of the grooves 370 limit the vertical movement of the plate 116 relative to the gripper fingers 168. As a result, not only must the gripper fingers 168 rely on horizontal forces to manipulate the plate 116, but the plate is also constrained vertically, reducing the likelihood of dropping the plate 116. An identical pair of grooves 370 can be provided from opposite ends of the plate 116, allowing the gripper fingers 168 associated with the robotic device 160 to manipulate the plate 116 from both sides and pass the plate 116 to one another.

[0087] Alternatively, groove 370 may be enclosed on the sides or open on the bottom. Also, groove 370 may be of a different shape, for example, square or circular in cross section. This feature may be reversed so that instead of gripper fingers 168 aligning with groove 370, the flanges of labware 300 align with beveled grooves in gripper fingers 168 or rack 210.

[0088] 21B shows a set of gripper fingers 168 having conical or pyramidal projections 372 and a plate 116 having corresponding conical or pyramidal recesses 374. The conical projections 372 are located on the faces of the gripper fingers 168 that grip against the sides of the plate 116. Corresponding conical or pyramidal recesses 374 are located on the outer edge of the plate 116 opposite the gripper fingers 168. In operation, the gripper fingers 168 extend along a designated length of the plate 116 and close against the plate 116 to grip the plate 116. The designated length is such that the recesses 374 and the projections 372 align. Small amounts of misalignment between the plate 116 and the gripper fingers 168 are automatically corrected by moving the plate 116 so that the conical or pyramidal protrusions 372 move into the recesses 374 and into proper alignment with the gripper fingers 168.

[0089] Corresponding conical or pyramidal projections 372 and conical or pyramidal recesses 374 are provided on the gripper fingers 168 on the other side of the plate 116. It should be noted that the projections 372 and recesses 374 do not have to be aligned horizontally. By providing two different heights for the projections and recesses, it is possible, for example, to handle the plate without making a mistake in its orientation. Furthermore, if the projections 372 and recesses 374 are not aligned horizontally across the width of the plate 116, the plate 116 cannot rotate around the recess. In FIG. 21B, there are two projections 372 and recesses 374 arranged on one side at the end of the gripper fingers 168, i.e., one is arranged towards the end of the gripper fingers 168 and the other is arranged at the beginning of the end of the plate 116. On the other side, there is a single projection 372 and recess 374 arranged horizontally between the projections 372 and recesses 374 of the other gripper finger 168. The conical or pyramidal shape allows for alignment and also aids in gripping not only due to the inward force of the gripper fingers 168 required to hold the plate 116, but also due to the vertical component provided by the conical or pyramidal shape to reduce the chance of the plate being dropped by the robotic device 160.

[0090] Other shapes than a cone or pyramid can be used, such as semicircular projections 372 and depressions 374. Any number of projections 372 and depressions 374 can be provided as desired. For example, both gripper fingers 168 can have no projections 372 and no depressions 374.

[0091] 21C, a similar arrangement of protrusions 372 and recesses 374 is shown as in FIG. 21B. However, the additional recess 374 is provided on a side of the plate 116 that cannot be reached by the gripper fingers 168 when approaching from one side. Furthermore, the recess 374 is mirrored both horizontally and vertically; that is, the recess 374 is in a position that allows the plate to be picked up by a robotic device 160 having the protrusions 372 from either side of the plate 116. This allows a plate 116 or other labware 300 having such a recess to be handled by two robotic devices 160 simultaneously and to be handed off between robotic devices 160 or modules 100.

[0092] 23 illustrates such a handoff between a pair of robotic devices 160, where two sets of gripper fingers 168 can simultaneously engage the plate 116 to provide a handoff in which positive control of the plate 116 is maintained throughout.

[0093] 22, a dock or plate slot 110 for labware 300 is provided to interact with a recess 374 to allow the robotic device 160 to deliver the plate slot 110. Here, instead of providing a protrusion 372 in the plate slot 110, a feedback means 378 is provided in a position where, when a plate 116 is placed in the plate slot 110, the feedback means 378 extends into the recess 374 of the plate 116 to provide feedback that the plate 116 is fully placed in the plate slot 110.

[0094] The feedback means 378 in the plate slot 110 can provide mechanical feedback such as: i) when the labware 300 begins to engage the plate slot 110, ii) that the labware 300 is fully engaged, and iii) that the labware 300 is in the correct orientation and has the correct handling interface. The feedback means can be in a similar manner to that described above with reference to FIG. 18, i.e., a contact is triggered when the feedback means 378 is in the recess 374. Alternatively, the feedback can be based on the depression of a spring or other resilient means in the feedback means 378 when depressed by the plate 116 and when in the recess 374.

[0095] The feedback is reversed when the operation is reversed, i.e., when the robotic device 160 is removing the labware 300 from the plate slot 110. Each of the plate slots 110 on the working deck 330 or in the rack 210 can have these features. In one embodiment, one or more or all of these features are combined with the engagement means 362 described with reference to FIG. 18.

[0096] The plate 116 and gripper fingers 168 of FIG. 21C have a single protrusion 372 and recess 374 on each side of the plate 116. However, additional recesses 374 are provided on the front and rear faces 116 of the plate, respectively. Furthermore, a protrusion 372 is provided on a beam 376 of the grabber 162 that runs vertically between and connects the two gripper fingers 168. Such protrusions 372 and recesses 374 provide further alignment of the plate 116. As mentioned above, the number or shape of both the protrusions 372 and recesses 374 on the beam 376 or gripper fingers 168 are not limited to those mentioned above. In one embodiment, recesses are provided at off-center positions on each end face of the plate 116 to restrict handling of the plate 116 when it is positioned in the correct way.

[0097] 21D, protrusions 372 and recesses 374 are shown positioned on the footprint 360 of plate 116. This further reinforces that these protrusions 372 and recesses 374 do not encroach on the interior volume of plate 116 or labware 300, which have a larger footprint 360 area to aid in handling. For example, given the standardized footprint 360 described above with reference to FIGS. 13A and 13B, protrusions 372 and recesses 374 are compatible with all labware 300 described above.

[0098] The two types of features, grooves 370 and protrusions 372 and recesses 374 , may be combined in one interface or plate 116 .

[0099] The conical fit of the protrusions 372 and recesses 374 tends to self-align the plate 116 even if it is misaligned with the gripper fingers 168 by a few millimeters. Both of the above mentioned fit features (groove 370 or cones 372, 374) also allow the gripper fingers 168 to hold the plate more securely and reliably by preventing the labware 300 from slipping or dropping vertically off the gripper fingers 168. The three recesses 374 in Figures 21B and 21C allow the unique orientation of the plate 116. The protrusions 372 and recesses 374 align the plate to the gripper fingers 168 in three dimensions. This can be used as feedback that the plate was correctly oriented.

[0100] Both the grooves 370 and the recesses 374 allow the gripper fingers 168 to determine if the labware 300 has the correct handling interface. This allows the system to reject labware 300 that does not have the interface, which in turn allows the system 99 to reject labware 300 that is the incorrect size. This increases the reliability of the system and allows the system to reject third party trays that have poor tolerances. This can be used to build a partially closed system and more easily control the reliability of the system 99.

[0101] A plate incorporating grooves 370 and protrusions 372 and depressions 374 can still conform to the footprint of a microplate (SLAS plate).

[0102] As mentioned above, the interface of Figures 21A-D can be used with any labware 300, not just plates 116. Referring to Figure 24, there is shown a bottle tray 322 with protrusions 372 and recesses 374. In particular, it can be seen that the bottle tray 322 has recesses 374 that are located in the footprint 360 of the bottle tray 322. Thus, this can be adapted for any type of labware 300.

[0103] 25, a large bottle 326 is provided that has the width of the plate 16. It provides a conical fit of protrusions 372 and recesses 374, and the bottle itself has recesses 374 in the body of the bottle. This allows the gripper fingers 168 to grip the sides of the bottle 326 without the use of a tray for the bottle 326 to sit on. In one embodiment, the bottle 326 is held in a rack 210 that has protrusions 372 to hold it in place.

[0104] Trays, plates, and boxes for vials and pipettes adapted to function with groove 370 and conical mating interfaces are similarly envisioned.

[0105] Although a pair of gripper fingers has been described above, in other embodiments, additional means for picking the plate can be used, while the protrusions and recesses described above can be used as an option. Referring to FIG. 26, a plate 116 is provided having a standard microplate footprint 360. The plate 116 can be labware 300 as described above. Instead of active or passive gripper fingers, the robotic handler can have an end effector having a passive handling plate 260 that extends under the plate 116 to manipulate and move the plate 116. The handling plate 260 is shown extending across the width of the plate 116, approaching the plate 116 from that width. However, other embodiments are envisioned. The handling plate 260 has protrusions 372 that extend upward from the handling plate 260 towards the footprint 360 of the plate 116 when the footprint 360 is placed thereon. The plate 116 is provided with corresponding recesses 374 and protrusions 372 in its footprint 360.

[0106] The handling plate 260 also has alignment features 262 that allow for alignment of the plate 116 when it is placed on the handling plate 260. These alignment features 262 extend along the preferred location of the plate 116 on the handling plate 260 and are angled or tapered to encourage the plate 116 to slide into the correct position when placed on the handling plate 260.

[0107] The protrusions 372 and recesses 374 are shown positioned eccentrically relative to the centerline of the plate 116. However, as discussed above with respect to the gripper fingers, various configurations are possible. For example, the plate 116 could have multiple recesses 374 so that the plate 116 can be picked up by handling plates 260 approaching from different directions. Also, the protrusions 372 and recesses 374 could be reversed. Also, additional protrusions 372 and recesses 374 could be provided.

[0108] Since the handling width of the handling plate 260 is smaller than that of the plate 116, the use of the handling plate 260 allows the width of the interface 134, the rack 210, and the plate slot 110 to be minimized to the width or length of the plate 116 without having to consider the handling width. The handling plate 260 also provides a solid base to increase the stability of the plate loading operation.

[0109] Referring to FIG. 27, a decapper interface is shown that is integrated into a bottle or vial. A bottle 326 is provided with a lid 380. The lid 380 has a capping interface 382 on the top surface of the lid 380. The capping interface 382 is a hexagonal shaped recess such that a correspondingly shaped protrusion can interface with (i.e., reside inside) the capping interface 382. This interface provides a rotation lock such that rotating the lid 380 rotates the male protrusion and vice versa. The use of this protrusion in the decapper 344 provides a more reliable decapping or capping than gripping or unscrewing a conventional lid without the interface 382.

[0110] Multiple shapes and interfaces can be used for the capping interface 382. Additionally, the decapper can have a female interface and the bottle can have a male interface, which is more common due to the conventional auto-mating capping process.

[0111] The vial 321 also has a lid 384 with a recess on its top surface to form a vial capping interface 386. Similar to the bottle lid 380, the vial capping interface 386 is shown to have a hexagonal shape when viewed from above, allowing a correspondingly shaped protrusion to rotatably lock with the vial lid 384 to produce a reliable capping or decapping process.

[0112] Similar to the bottle 326, various shapes of the capping interface 386 may be used. For example, another polygonal shape may be used to provide a rotation lock.

[0113] The bottle 326 has a bottom interface 388, in which a recess similar to that of the capping interface 382 is provided and extends from the bottom of the bottle to the body of the bottle 326. The bottom interface 388 has a hexagonal shape when viewed from the underside. This allows a corresponding hexagonal protrusion to fit into the bottom recess and be rotatably locked. The vial 321 similarly has a vial bottom interface 390, which is the same as the bottom interface 388 of the bottle 326. These bottom interfaces 388, 390 allow the bottle 326 or vial 321 to be rotatably held from below. This allows the desorption machine 344 to be configured to be attached from the underside, or the bottle to be restrained from rotating by a plate protrusion, so that the decapping operation of the bottle or vial lid does not lead to the rotation of the bottle or vial itself.

[0114] The lower interface can also be used to prevent the bottles 326 and vials 321 from tipping or falling as they are moved through the system 99 by resting them on a tray with specific ridges for alignment. This also allows the bottles 326 and vials 321 to be properly positioned on a tray or plate for various robotic handling devices to interact with them.

[0115] If necessary, a combination of upper and lower interfaces can be used. The interfaces provided on the upper and lower sides do not have to be the same. However, the identity of the interfaces can be useful for unified operations. Vials 321 and bottles 326 can have interfaces of the same shape, so that they can be handled by the same gripper on the same picking or decapping robot 344.

[0116] Further modifications can be made to the capping interface 382, ​​386, such as an undercut interface 390 where the recess in the lid 380, 384 has a narrower mouth than the depth of the cap. This allows for an interface with additional vertical locking, such as a protrusion that expands at the distal end when the lid 380, 384 is removed from the bottle 326 or vial 321. This can reduce the risk of the lid 380, 384 being dropped by the gripper of the picking or decapping robot 344.

[0117] The top or bottom interfaces 382, ​​386, 388, 390 are chamfered or beveled to align with the gripper of the decapper or picker as it approaches the interface. This allows for some tolerance in positioning the vial 321 or bottle 326, such as the tray or plate, or the tray or plate in the plate slot 110 itself. This also helps with machine or robotic tolerances. These features also allow for more reliable automation as labware 300 that does not have the correct interface cannot be used with the machine, rejecting third party or poorly tolerated labware 300.

[0118] FIG. 1 illustrates a storage module 100 according to one embodiment of the present invention. The storage module 100 has an outer shell or housing 102 that forms a box having four sides 104. These sides 104 may all be the same length to form a storage module 100 with a square footprint. Due to the nature of the module and the internal carousel function (described in more detail below), equal length sides 104 are preferred, however, in some embodiments the sides 104 may vary in length resulting in a rectangular or other polygonal shaped module 100. It is even possible to have more than four sides 104.

[0119] The length 106 of each side 104 can be between 70 cm and 80 cm. In particular, the length 106 of each side 104 of each storage module 100 should be no greater than 80 cm in at least two dimensions. This allows the overall system 99 of modules 100 to be compact, which is advantageous because these systems are often installed in laboratories or clean rooms where floor space is at a premium, and this allows the modules 100 to fit through doors. This also reduces the difficulty and cost of shipping the storage modules 100.

[0120] Inside the outer shell 102 is a carousel 108, which is a circular plate that occupies the footprint of the storage module 100. The carousel 108 has tray or plate slots 110 arranged along its radii (i.e. radially). The center of the carousel 108 is open, with a center well 112. The plate slots 110 are arranged such that their edges all face the center well 112. In the illustration, the center well 112 has eight tray edges 114, and is therefore octagonal in shape. In some embodiments, the center well 112 has flat tray edges 114 such that it is a polygon with a number of sides equal to the number of plate slots 110. However, in some embodiments, a center well 112 with a circular edge may be used, with the tray edges 114 forming a perimeter of the circular center well 112.

[0121] Plate slots 110 are locations designated to hold plates, trays, or labware. The plates or trays can be process plates, cell culture plates, microtiter or microplates, plates that hold other labware or containers, or labware itself. More details about plate slots and plates are provided below.

[0122] The carousel 108 may be placed on the floor of the module 100 or may be elevated off the floor.

[0123] The module 100 has a height such that the shell 102 forms a cube (i.e., a cuboid shape). The height of the storage module 100 need not be equal to the length 106. However, the height preferably does not exceed the height of the access door, and ideally should be less than the access door for ease of transportation and assembly.

[0124] In a vertical configuration (see Figures 9A and 9B, described in more detail below), the plate slots 110 are stacked vertically so that process plates or other labware can be stacked vertically in a rack 210. Thus, each plate slot 110 has a plate slot above it, forming a rack 210 of plate slots 110. The design of the plate slots 110 can vary from being directly on the carousel 108 to being higher (or lower) above the carousel 108, as will be described in more detail below.

[0125] The racks 210 can extend through the height 204 of the storage module 100, or even below that height when the carousel 108 is elevated. The space within the shell or housing 102 can have clean air inside and is constructed by assembling multiple modules 100 that can be locked together, depending on the requirements of each module 100. Thus, there is no need to install the storage modules 100 in additional expensive shrouds or large, expensive clean air cabinets, since the interior is hermetically sealed.

[0126] 2 shows several storage modules 100 in a modular arrangement to form a modular system 99. In particular, an incubator module 124 is shown on the far left, a process module 120 in the middle, and a plasticware storage module 122 on the far right. These modules are indicative and not limiting, however, as shown, each module 100 uses the same format, e.g., each has a carousel 108 with respective plate slots 110 formed therein or thereon.

[0127] Other modules 100 such as a freezer (126; Fig. 3A) can be envisaged. Many experiments, and the media required for culture, contain reagents such as growth factors, which need to be frozen if they are to be stored for more than one or two days. This results in a system 99 that prepares the medium every day or every two days by mixing the reagents into a basal medium, where some of the reagents are stored frozen within the system. Thus, a freezer module 126 can be provided, which allows the system 99 to store frozen reagents and to retrieve and thaw them as required. Another module 100 of the system is a refrigerator (128; Fig. 3A). Many reagents, especially cell culture media, are stored in the refrigerator, and relying only on the freezer module would make repeated freezing and thawing of the reagents cumbersome and even harmful.

[0128] As shown in FIG. 2, in this example of a modular system 99 used for cell culture, a process module 120 and a series of storages are provided, namely an incubator 124 for cell culture and a plasticware storage 122, such as the module on the right. As mentioned above, other modules can include a refrigerator for storing media, a freezer for storing, for example, growth factors, samples, etc., and a room temperature reagent storage. A slot 110 is provided that is configured to receive a set of labware 300 designed to fit into the slot with a microplate footprint. The set 300 can include trays, adapter racks for bottles or vials, boxes, bottles or dishes. This will be described in more detail below with reference to FIGS. 13A and 13B. In the plate slot 110, a plate 116 (e.g., a cell culture plate, an adapter rack, or labware) can be placed. The plate 116 can carry vials or containers that can hold reagents or cell cultures. Plates 116 may be transferred between modules 100, for example, such as when a plate 116 is passed from an incubator 124 to a process module 120. The transfer occurs at a specific interface 134 of the module 100.

[0129] The storage module 100 has an interface 134 through which the module 100 can present or receive a plate 116 (or other plasticware). The interface 134 aligns with an interface 134 on an adjacent module 100 to allow the plate 116 to be transferred from one module to another. This allows, for example, a plate 116 holding vials to be transferred from an incubator 124 to a process module 120. The interface 134 can have doors 130 to close access to the module 100. These doors can open vertically or horizontally, can be sliding doors, can have multiple panels or be a single door 130. The doors may vary depending on the requirements of the module 100. For example, some doors are pressure-resistant or thermally insulated. These interfaces 134 can be in the same plane (e.g., in a horizontal plane to greatly simplify robotic handling). Alternatively, some interfaces can be vertical or variations thereof. The storage modules 100 can be stacked vertically to save floor space. This allows the construction of a system 99 by stacking modules 100 together without the need for gaps or spaces between the modules and therefore without the need for further processing capabilities to transfer trays 116 or other items between. It also allows the system 99 to be upgraded to add more functionality or more capacity by stacking more modules 100. The vertically stacked modules are described in detail with reference to FIG. 9A. They are connected using sealing elements 311 that form the gripper passages.

[0130] As mentioned above, the modules 100 are joined together at interfaces 134, and in some embodiments, these interfaces are hermetically sealed by sealing elements 311 and / or doors. Thereby, by "connecting" the modules 100, a complete system 99 including clean air can be built, without the need for expensive and bulky housings including clean air spaces. Thus, the interfaces 134 only provide access to adjacent modules 100, instead of passing the plates 116 to the external space outside the outer shell 102 or housing. To ensure this, the doors 130, if any, are also hermetically sealed to each other. This also has the advantage of simplifying handling.

[0131] 2 also shows a robotic device 160. The robotic device 160 is located in the center well 112 of the module 100. The robotic device has a grabber 162 capable of holding a plate 116 from a plate slot 110. The robotic device 160 also has a robotic arm 164 connected to the grabber 162 to allow actuation of the grabber 162 to extend and retract. The robotic arm 164 is telescopic. The grabber 162 can reach a plate 116 holding a plate slot 110 (or a rack 210 of the slot 110) and restrain the plate 116 so that the plate is pulled out of the slot 110 or rack 210 and placed in the slot 110 or rack 210. The robotic device 160 is also used to pass or transport the plate 116 through the interface 134 so that the plate can be passed to an adjacent module 100 by actuation of the robotic device 160. 2 shows two modules 100 (e.g., incubator 124 and plasticware storage 122) with similar robotic devices 160 with grabbers 162 and doors 130 in the same locations. Not all modules 100 need to have robotic devices 160, and some modules 100 may rely on robotic devices 160 from adjacent modules to pass or transfer plates 116. Notably, process module 120 is shown without a robotic device 160.

[0132] A robotic device 160 in the center well 112 of a module 100 can hand off a plate 116 to a plate slot 110 in another module 100 without intermediate devices such as a robotic arm or conveyor belt. This provides a simpler system 99 by eliminating the intermediate devices. Eliminating the space required for intermediate devices also makes the system 99 more compact, reduces alignment and tolerance stack-up issues, reduces double handling, and facilitates the construction of compact systems that do not require additional external shrouds or clean air housings.

[0133] The robotic device 160 in the center well 112 can have very limited degrees of freedom of movement. It can have only two degrees of freedom: vertically in the well 112 and horizontally through the door 130 or interface 134 or into the slot 110. The carousel 108 can be configured to rotate so that the robotic device 160 can access all of the racks 210. Thus, the robotic device 160 is restricted to moving horizontally (and linearly) toward the interface 134 and vertically. Alternatively, in some embodiments, the robotic device 160 can be rotated and the carousel 108 can be constrained. Or there is a combination of both. The robotic device 100 can be further restricted, such as running in rails or having a grabber 162 that runs in rails instead of extending the robotic arm 164. This reduces the chances that the robotic device 160 will lose alignment. The modular system 99 also allows for modular software with code that is reused. This is achieved in part by making the storage module 100 a "self-contained vending machine," in the sense that instead of having an incubator 124 with an automatic door 130 and a carousel 108 reached by, for example, a 3D robotic arm, it autonomously provides plates 116 (and other objects) to other modules 100.

[0134] 3A and B show a plan view of a further system 99 including several modules 100. The multiple modules 100 are arranged horizontally to provide an example complete system 99 built from an incubator 124, a refrigerator 128, a freezer 126, and a plasticware storage 122 that interface with a central process module 120. Since each module, except the process module, is equipped with a robotic device 160 in the center well 112, no "external" untethered 3D robotic arm is required. All modules 100 interface to allow the plate 116 to pass through an adjacent door 130 or interface 134. The process module 120 is centrally located to allow access to each side of the multiple modules 100 (the incubator 124, the refrigerator 128, the freezer 126, and the plasticware storage 122). When the extending robotic arm 164 is fixed (so that it cannot rotate), it is directed towards the door of the process module 120 to allow the plate 116 to enter and exit the process module 120. A service module 138 may be added to provide additional functionality, such as a processor unit, a power means, or a machine unit for operating the robotic device 160.

[0135] In some embodiments, there may be a dedicated "load lock" where the module 100 has a door that is externally accessible and not connected to another module 100. This load lock is routinely accessible to humans. This allows users to interact with the plate slots 110 or racks 210 to exchange consumables, plates containing cells or samples, etc. within the system 99. The load lock may be a plate slot 110 that only opens to the outside or inside of the module 100 at any time to avoid contamination or changes in environmental conditions inside the module 100. This allows the system 99 to continue to operate without risk of injury, since access to rotating or manipulating machinery is prevented when a user accesses the load lock. In some embodiments, the load lock may be rotatable to access additional accessible doors or to allow a robotic handler to access contents placed within the load lock.

[0136] Figure 3B shows a system with the same modules 100 as in Figure 3A, namely an incubator 124, a refrigerator 128, a freezer 126 and a plasticware storage 122. However, the freezer 126 is connected to a refrigerator module 128 which is connected to the process module 120. This means that the freezer 126 is accessed via the refrigerator 128, reducing frosting and temperature cycling within the freezer 126. A refrigerator module has been described. However, further environmental changes between the modules 100 are envisaged, such as changes in humidity, temperature or gas concentrations. Automated or user controlled control means are provided to control the environment of each module 100.

[0137] The process module 120 may optionally not include a robotic device 160 for transferring the plate 116. However, other robotic operations may be implemented within the process module 120 for the automated cell culture system 99. The process module 120 may include a liquid handler with a rotating work deck, or "turntable work deck" 108, that interfaces with at least one carousel. Slots on the work deck may accommodate the microplate 116 or compatible labware by simple (horizontal linear) transfer from an appropriately positioned carousel 108 and rotation of the turntable work deck and carousel 108. The process module 120 may also include a microscope, other handling modules (vial decapper, vial picker, plate de-lidder), or other functions, as described below with reference to Figures 15A and 15B.

[0138] Plates 116 are microtiter plates or microplates, or other labware with a similar footprint. These plates conform to the Society for Laboratory Automation and Screening (SLAS) standard, which requires microplates to be 85.48 mm wide and 127.76 mm long, although variations and modifications to this are possible.

[0139] An additional tube picking robotic device may be provided in the refrigerator 128 or freezer 126, for example, to pick frozen tubes from the rack 210 while minimizing temperature cycling of other tubes in the rack 210. The picking robot may be integrated into wasted space within the rack 210 of the refrigerator 128 or freezer 126.

[0140] In operation, one or more source storage plates 116 are removed, for example from a shelf or rack 210 of the freezer 126, and the desired tubes are removed from the plate 116 to the target plate 116. The source plate 116 is returned to the storage shelf 210, and the target plate 116 with the picked tubes is transferred to the incubator 124 where it is thawed and / or warmed. Once sufficient time has elapsed to reach the target temperature, the plate 116 with the tubes is transferred to the work deck. The process is reversed, with tubes with unused reagents being returned to the freezer storage 126. Bottles or vials can be thawed or pre-warmed by transferring them to the incubator 124. Additionally, to save space on the work deck, a de-lidder can be incorporated into the slots 110 in the rack 210 of the incubator 124.

[0141] A high efficiency particulate air (HEPA) filter can be provided for the incubator 124, and the air within the incubator 124 is recirculated through the filter to reduce particulate matter within the incubator 124. Although not a HEPA air filter, an air filter can also be provided that removes 99.97% of particles 0.3 μm or larger (from the air passing through).

[0142] 4A and 4B, a plan view of an interface 134 between two rotating carousels 108 of adjacent modules 100 is shown. FIG. 4B shows a 6-well tissue culture plate 116 passing through the interface. An interface 134 is provided between the modules 100. Both modules 100 have a rotating carousel 108. Only a portion of each rotating carousel 108 (i.e., one slot for a plate 116) is shown. One module 100 can be an incubator 124 with a carousel 108 that includes racks 210 (also called a plate hotel). The main operation performed at the interface is to move plates 116 between the two modules 100. In some embodiments, these plates generally conform to SLAS size standards, such as cell culture plates 116 (e.g., a 6-well cell culture plate 116 is shown), or other compatible labware. An automatic door 130 (not shown) is provided between the modules. Some modules do not require a door 130 at the interface 134. However, for example, if the environment between the modules 100 is different, a door 130 is provided. The two modules 100 are secured or locked at the interface 134 by a connecting means or fastener (bolt) 132. The fastener 132 is near the interface 134 to minimize tolerance stack-up. The fastener 132 ensures that the modules 100 are aligned and held or locked in place to ensure that the plate 116 can pass between the modules 100 without collision between the outer shells or housings 102 of the modules 100. Additional fasteners 132 can also be provided so that the modules 100 can be coupled to each other or to other features or modules 100. Thus, interface 134 provides a controlled location where the position of plate 116 is constrained for delivery of plate 116. Connection means or fasteners 132 are proximate the location where plate 116 is to be delivered. In some embodiments, the fasteners 132 are no more than half the width of the interface 134 from the edge of the interface 134. This reduces "tolerance stack-up" that can affect the alignment of parts that are important to align due to fasteners, manufacturing variations, or movement during operation. In particular, because the fasteners 132 are located at or near the interface 134, there is reduced variation in alignment between modules. The connection means 132 can be bolts or any other means that restrain or compress the housings of two adjacent modules 100 to hold them firmly together. In some embodiments, interlocking lips or other indexing means are provided to align the modules so that the connection means 132 can be aligned. The carousel 108 is indexed relative to the interface 134, for example, by means of pins 140 and slots 142. The pins 140 are provided in the walls of the module 100. The alignment slots 142 are provided in the carousel 108 where the carousel 108 can receive or hold the plate 116. The plate slots 110 on the carousel 108 can be aligned with each other by indexing the carousel 108 relative to the interface 134, such that the transfer of a plate 116 (or other compatible labware) between two plate slots 110 on the carousel 108 can be accomplished by a simple linear movement from one plate slot 110 to an adjacent plate slot 110 on the other carousel 108. The pins 140 can be moved such that the alignment slots 142 are always unconstrained. Alternatively, the carousel 108 may be aligned when moved to the transfer position and may rotate freely at other times. Although a pin 140 and slot 142 are shown, other alignment means, electronic or mechanical, may be provided. For example, the slot and pin may be swapped so that the pin 140 is located within the carousel 108. Alternatively, the motor of the carousel 108 may be indexed and stopped at a predetermined index position. In FIG. 4B, a plate 116 is shown passing between modules 100 as it passes through interface 134 from one plate slot 110 to another plate slot 110. The plate 116 may pass in an orientation dictated by the robotic device 160.

[0143] This movement is driven by the robotic device 160. The carousel 108 rotates and the robotic device 160 moves vertically, and then the robotic device 160 transfers the plate 116 from any position in the carousel rack 210 to the interface 134 by a combination of highly constrained movements along two constrained axes: vertical movement to the appropriate level in the rack, horizontal movement to remove the plate 160, vertical movement to the height of the working deck (i.e., plate slot 110) of the carousel 108, and horizontal movement to place the plate 116 in the plate slot 110 on the carousel 108. More specifically, the robotic device 160 moves horizontally in a direction along a line connecting the two central axes of the center wells 114 of adjacent modules 100. The interfaces / doors 130, 134 between adjacent modules are located on the side walls of each module such that the line connecting the two central axes of the center wells 114 of adjacent modules 100 is centered in the width direction. The robotic device 160 has enough horizontal movement to move the plate 116 directly into the slot 110 of the other carousel 108. Not all robotic devices 160 require this amount of horizontal movement, as there may be a robotic device 160 in an adjacent module 100. In such a situation, the robotic device 160 can hand off to the robotic device 160 in the adjacent module 100.

[0144] FIG. 4A shows an additional alignment feature 144 to ensure that the plate 116 is accurately aligned during transfer. A chamfer 144 at the end of the plate slot 110 of the carousel 108 opposite the interface 134 serves to capture and align the incoming labware 116 even if it is misaligned by a few millimeters. This occurs when the plate 116 hits the chamfer 144, which tilts toward the plate slot 110, thus causing the plate 116 to slide and align toward the plate slot 110. Alternatively, the alignment feature 146 can be in the interface 134 itself, for example in the opening or door 130. In such a case, the door 130 or the interface 134 between the modules can be provided with a chamfer 146, which is shaped to slope toward the plate slot 110 of either module 100. This is shown in FIG. 4B. In such an arrangement, any plate 116 that falls out of alignment during transport will collide with the chamfer 146 and be oriented back into alignment with the plate slot 110 .

[0145] 8 shows an alternative embodiment of the interface in which a chamfer 146 is located on the surface of the interface 134 facing the interior of the module 100. The chamfer thus narrows the width of the mouth of the interface 134 as the distance from the center of the module 100 increases. This allows for alignment of the plate 116 and / or grabber 164 entering the mouth of the interface 134. Although not shown, in some embodiments, the plate 116 may have a chamfer that allows for alignment of the plate 116 as it enters the plate slot 110, the interface 134, the grabber 164, or any other feature that may interact with the plate 116. Such alignment features of the plate 116 further allow for alignment of plastic instruments passing through the module 100 or the system 99. A combination of these chamfer locations may be provided on the module 100.

[0146] 4C, instead of or in addition to providing a chamfer 144 on one or more edges of the plate slot 110, a recess 148 can be provided in the wall of the interface 134. The recess 148 has a shape that extends from the side of the interface 134 toward the center of the interface 134. The recess can be shaped so that the space or opening 150 for the plate 116 (the space defined by the interface 134 between the modules 100) is close to that of the width of the plate 116. This ensures that the side of the plate 116 is flush with the wall of the interface 134 as it passes through. Such recesses can be present on both modules 100, so that there is an extension area where the plate 116 is forced to align within the recess 148. The recess is shaped such that an unaligned plate 116 slides across the face of the recess 148 until it is aligned to pass through the interface 134. In some cases, the grabber 164 that manipulates the plate 116 may be wider than the width of the plate 116. In such cases, any alignment means such as recesses 148 are configured to accommodate the grabbers 164 and thus be equal to or slightly larger than the outer width of the grabbers 164. In other cases, rails or slots may be provided to guide or support the movement of the grabbers 164. In some instances, a slot may be constructed by making the interface 134 narrower than the width of the plate 116 and grabbers 164 and providing a slot in the interface through which the grabbers 164 extend. A combination of carousel chamfers 144, interface chamfers 146, and interface recesses 148 may be provided, all of which function to dynamically align the moving plastic instruments with the plate 116 and / or grabbers 164.

[0147] Although spaces are shown in the figures to provide clear boundaries between the different modules 100, the interfaces 134 can be adjacent so that they are flush with each other. Furthermore, as described above, in some embodiments, the interfaces 134 are hermetically sealed. At least some of the modules 100 in the automated cell culture system 99 have clean air that is HEPA filtered. Sealing the interfaces 134 prevents the ingress of unfiltered air. Sealing can be accomplished by ensuring there are no gaps between the modules 100 and / or by placing seals around the interfaces 134 or doors 130. Seals can also be provided between the edges of the modules 100.

[0148] The openings 150 (in the interface 134 between modules 100) and the plate slots 110 in the carousel 108 can be closely positioned and closely fitted to the plates 116 (e.g., microplates) such that together the openings 150 and the plate slots 110 form a substantially continuous "race" or "channel" along which the plates 116 and / or grabbers 164 of the robotic device 160 slide or run, thereby greatly reducing the chance of labware being dropped, lost, or misaligned since the position of the labware is always constrained.

[0149] 5, there is shown a plate slot 110 having slot sides 152 extending from a bottom surface 154 of the plate slot 110. A plate 116 is positioned between the slot sides 152 on the bottom surface 154 of the plate slot 110. The slot sides limit the lateral movement of the plate 116. The end of the plate slot 110 opposite the end of the plate slot 110 in the direction of movement of the plate 116 can further be closed, for example, by a backplate or endstop extending partially or completely between the slot sides 152 to prevent rearward movement of the plate 116. In the slot sides 152 there is a gripper groove 166. This is a groove 166 that extends along the length of the slot sides 152. The gripper groove 166 is shaped such that a gripper finger 168 of a grabber 162 can move along the gripper groove 166 when the plate 116 is present. A microplate 116 is shown where grabbers 164 or gripper fingers 168 grab the plate 116 by surrounding either side of the plate 116. This allows the robotic device 160 to pick up and move the plate 116 as needed. In some embodiments, the gripper grooves 166 extend only partially along the length of the slot side 152. A corresponding groove 166 can extend from the opposite edge, allowing the gripper fingers 168 to grab the plate from either side. Other examples of grabbing mechanisms can be provided. For example, grooves can be provided so that the gripper fingers 168 fit into the plate itself 116 instead of the bottom surface 154 of the plate slot 110, or grooves can be provided in the plate 116 itself so that the gripper fingers 168 enter the plate body.

[0150] 5 has a bottom that is wider than its sides. To accommodate this shape, the slot sides 152 of the plate slot 110 can have different widths above and below the gripper grooves 166.

[0151] FIG. 6 shows a side cross-sectional view of the interface 134, and the bottom view shows an exemplary plate 116 passing through the interface 134. As described above, the plate slot 110 of the carousel 108 has a recess formed by the slot side 152, so that the plate 116 or other labware and / or grabber 164 of the robotic device 160 rides in a channel 156 or trough or race or rail. In this manner, the plate 116 and grabber 164 are highly confined and the transfer is very reliable. This substantially continuous channel 156 formed in the interface 134 between modules 100 with slots 110 in the carousel 108 or between two carousels 108 uses the bottom 154 of the plate slot 110 as the floor of the channel 156. The plate 116 or other labware and / or grabber 164 slides in this channel 156. By physically restraining plate 116 / labware and grabber 164, channel 156 greatly reduces the chance of labware being dropped or lost, making the system simpler, more reliable, and easier to program.

[0152] 7A and 7B show a plate 116 in a plate slot 110 of a carousel 108 ready to be moved to an adjacent plate slot 110 via an interface 134. A robotic device 160 having a grabber 164 with gripper fingers 168 is shown transferring the plate 116 through the interface 134. A robotic arm 162 is actuated to move the grabber 164. The width of the interface 134 is approximated to the width of the gripper fingers 168 to ensure that the plate and grabber 164 can fit and be physically constrained to align.

[0153] 8 shows an alternative embodiment of the interface 134 that is not carousel based, where the plate slot 110 on the module 100 is a conveyor belt 170. This conveyor 170 can pass plates through or towards the interface 134. A robotic device 160 can still be present to deliver or retrieve plates 116 to the conveyor 170. As mentioned above, chamfer 146 is also shown, but is located on the surface of the interface 134 that faces the interior of the module 100.

[0154] The modules 100 can be arranged vertically for added flexibility. Figures 9A and 9B show a system 99 with the modules 100 so arranged. This arrangement facilitates arrangement of the system 99 by allowing more freedom as to where the modules 100 can be placed in the system 99. For example, it is easy to add more capacity to the system 99 by stacking the plastic labware storage 122 or incubators 124 higher. Stacking the modules 100 vertically allows the system 99 to occupy less floor space.

[0155] As described above, two modules 100 are provided to be arranged vertically stacked. Between the modules there is a vertical interface 234, which is very similar to the interface 134 between horizontally arranged modules 100 shown in Figures 4A-4C. The vertical interface 234 optionally has a door 230 or opening 231 through which the robotic device 160 can move vertically. The modules 100 have connection means or fastening points 232 around the door 230 or opening 231 to ensure that the vertically stacked modules 100 are restrained to each other. The fastening points 232 are located near the opening 231 or door 230 to reduce tolerance stack-up, as described with reference to the connection means 132 in Figures 4A-4C. An airtight seal means 311 can be located between the interfaces 134, 234 of two adjacent modules.

[0156] 9A and 9B show a plate rack 210 in which multiple vertically stacked plate slots 110 are arranged. Thus, the plate slots 110 are arranged in layers to form the racks 210. Although two racks 210 are shown in FIG. 9A, the racks 210 are arranged on the plate slots 110 around the carousel 108 shown in FIG. 1. For simplicity, the carousel 108 is not shown in FIG. 9A or 9B. However, the plate racks 210 rotate about the axis of rotation of the carousel 108 so that the robotic device 160 can access each row of the racks 210. The robotic device 160 is rotatably fixed so that it can only move horizontally and vertically. Thus, to access a plate slot 110 behind the robotic device 160, the racks 210 (and therefore the carousel 108) are rotated so that the required plate slot 110 faces the robotic device. Then, vertical and horizontal movements of the robotic device can be performed to access the plate slots 110. In some alternative configurations, the racks 210 can rotate in subgroups such that a layer of plate slots 110 rotates independently from the plate slots 110 below it. Alternatively, the robotic device 160 can rotate and the racks 210 are held stationary.

[0157] As will be appreciated from the previous discussion, a horizontal interface 134 exists on the module 100. This horizontal interface 134 is formed at a height in the rack 210 that is the same height as the plate slots 110 of the current module 100 and the required plate slots 110 of the adjacent module 100. Those plate slots 110 located at the height and rotational position of the horizontal interface 134 are transfer slots. The transfer slots are rotatable on the carousel 108 so that they can align with the interfaces 134 of the module 100. A corresponding transfer slot exists on the adjacent module 100. In some embodiments, any plate slot 110 on the rack 210 that is horizontally aligned with the interface 134 can function as a transfer slot, which can include plate slots 110 that are vertically aligned on the rack 210.

[0158] In use, to transfer a plate from the storage module 100 (incubator 124, refrigerator 128, freezer 126, plasticware storage 122, load lock, etc.), the carousel 108 rotates to index the door of the interface 134 in the horizontal direction, aligning the "transfer slot" of the rack 210 with the location of the interface 134 of the module 100. The transfer slot may be empty or may contain the plate 116 to be transferred. The receiving module 100 is then indexed to the interface 134, the receiving transfer slot is aligned with the handover transfer slot and the interface 134, and the door, if present, is opened, thus forming a continuous space or channel consisting of the transfer slot, the door or interface 134, and the receiving transfer slot. If the transfer slot contains a plate 116, the grabber 164 moves horizontally into the transfer slot, engages the plate 116, and then moves further along the same axis through the door or interface (134 in FIG. 7) until the plate 116 is located in the receiving transfer slot. The grabber 164 then releases the plate 116 and retracts into its own center well 112. In some embodiments, any slot in the horizontal row can be used as a transfer slot. In some embodiments, a slot in that horizontal row can be used as a buffer (described below).

[0159] In some embodiments, the interface 134 has a height sufficient to pass through a cell culture plate 116, such as a microplate. However, in other embodiments, the height of the interface 134 is greater to allow taller labware 300 to be transferred to and from the module 100. The height can be specified by the door 300 opening to the required height depending on the plate 116. In such a case, the interface 134 can extend vertically greater than the height of a microplate. More specifically, in some embodiments, the door 130 can be taller in a particular module 100. For example, a refrigerator can have a taller door 130 to accommodate bottles. The height of the door 130 or interface 134 would be 4 cm to allow for the transfer of deep well plates, 8 cm to allow for the transfer of bottles, and 10 cm to allow for the transfer of pipette boxes.

[0160] The robotic device 160 is disposed in the center well 112 and can transfer plates 116 or other labware to or from plate slots 110 on racks 210 in another vertically disposed module 100. A vertical rail 172 is provided that appropriately extends the height of the rack 210 to allow the robotic handling device 160 to move fully vertically to access all plate slots 110 on the rack 210. A grabber 162 of the robotic device 160 is connected to the rail 172 by an engagement device 174. The engagement device 174 is attached to the rail 172 by runners 176. The runners 176 are disposed vertically at either end of the engagement device 174. The engagement device 174 moves the robotic device 160 vertically along the vertical rail 172 by actuating the runners 176. The actuation means can be a motor. The grabber 162 is attached to the engagement device 174 and moves vertically along the engagement device 174. This allows the grabber 162 to reach all plate slots 110 throughout the height of the rack 210 and is not limited by the height of the engagement device 174. Vertical movement of the grabber 162 can be achieved via a motor or servo mechanism located within the engagement device 174.

[0161] When transitioning from one module 100 to another, it is necessary to transition to the rails 172 of the other module 100. To accomplish this, the runners 176 disengage from the rails of the module 100 to which the robotic device 160 is transitioning, so that the robotic device is held by the runners 176 on the opposite vertical side of the engagement device 174. The disengaged runners 176 then engage the rails 172 of the module 100 to which the robotic device 160 is transitioning, as shown in FIG. 9B, with continued vertical movement from the runners 176 with which the robotic device 160 is still engaged. Continuing the vertical movement releases the other runners 176 to re-engage with the rails 172 of the other module 100. Thus, the robotic device 160 is always held and constrained within at least one module 100 with at least one runner 176 engaged with the rails 172.

[0162] Each module 100 may have its own robotic device 160, or alternatively, a single robotic device may be provided that performs operations on both modules 100. If multiple robotic devices 160 are provided, they are constrained to not collide with each other. In some embodiments, the robotic devices 160 move in different horizontal planes. Additionally or alternatively, they operate on different rails 172 or other transport means. If a shared rail 172 is used for multiple robotic devices 160, plates 116 must be handed between the devices to allow access to all plate slots 110 of the modules 100.

[0163] While a particular configuration has been described, other means of transitioning the robotic device 160 are possible. For example, multiple runners 176 could be used, or a single runner that has a height that spans the interface 234 between modules 100 to ensure that the modules 100 are always engaged with the rail. By providing multiple rails, the robotic device 160 can be restrained at multiple points to ensure better alignment and less sagging due to the weight of the plate 116. Alternatively, the rails 172 could be omitted, and instead a vertically extending robotic arm could be used that is fixed at a single point and is not guided by rails or other means to transport the device vertically.

[0164] Thus, the robotic device 160 can engage with alignment and / or indexing features (e.g., rails 172, shelf chamfers, slot and pin features, indexing motors) in other modules 100. The transfer can be in a downward or upward direction, but not necessarily both.

[0165] As previously mentioned, the racks 210 are positioned on the carousel 108 so that they rotate, and the robotic device is constrained to horizontal movement in one plane, so that vertical movement in one plane and horizontal movement in one plane allows the robotic device to access all of the plates 116 in the racks 210.

[0166] FIG. 10 shows a schematic diagram of a system in which multiple modules 100 are provided in a vertically and horizontally stacked arrangement. In this configuration, the system 99 is provided with a freezer module 126. The freezer module 126 has a robotic device 160 capable of grabbing plates 116. The robotic device 160 can be any of the robotic devices described herein. A vial picker can also be provided (described in more detail with reference to FIG. 15B). The freezer module 126 is horizontally connected on its horizontal side to a refrigerator module 128 and a plasticware storage 122. The robotic device 160 can transfer plates 116 (or other plasticware) between these vertically connected modules. The refrigerator module 128 also has a robotic device 160. The robotic device 160 can be any of the robotic devices described herein. The incubator module 124 is vertically stacked on top of the refrigerator module 128. The incubator module 124 and refrigerator module 128 have an interface that allows plates 116 (or other plasticware) to be transferred between them by vertical movement of a robotic device 160. The incubator 124 also has a robotic device 160 for gripping plates. The robotic device 160 can be any of the robotic devices described herein. The incubator 124 can optionally be equipped with a plate de-lidder. The process module 120 is positioned horizontally relative to the incubator module 124. Thus, the process module 120 is stacked vertically on the freezer module 126. However, there is no interface between the process module 120 and the freezer module 126. The process module 120 may have a microscope, a vial decapper, and a liquid handler. It also has a turntable / carousel 108. However, in this example, the process module 120 is not provided with a robotic device 160 for handling the plate 116. Instead, the plate 116 is placed on the carousel 108 and other devices in the module perform the operations. The incubator 124 and the process module 120 interface such that the robotic device 160 of the incubator can pass the plate 116 from the incubator onto the carousel 108 of the process module 120. The process module is connected and interfaced horizontally to the plasticware storage 122. The plasticware storage 122 can also contain reagents at room temperature. Since the freezer 126 and the process module 120 are both connected horizontally to the plasticware storage 122, the plasticware storage 122 is a double-height module compared to the other modules 100 in the system 99. For example, the module is a cube of about 70 cm3. However, the height of the double-height module is about 1.4 m. Two modules of the same specifications, i.e. two plasticware storages 122, can be stacked vertically to achieve the same effect. However, such an arrangement can reduce the cost of robotics and sealing interfaces, which are unlikely to be large enough for the required functions in a single module 100. The plasticware storage 122 in FIG. 10 has a robotic device 160 that grips plates and can transfer plates 116 (or other plasticware) to both the process module 120 and the freezer 126.

[0167] As is evident from the above description, the modules 100 have compatible interface formats to allow stacking of the modules. This is particularly true when the modules are cubic in structure and the larger modules are integral multiples of the cube. In particular, the capacity of the plasticware storage 122 can be increased by stacking on top of another storage 122. The capacity of the plasticware storage 122 may be limited in some cases. This arrangement therefore allows the system 99 to operate autonomously for extended periods of time without restocking, for example on weekends or holidays, while still maintaining modularity. In some embodiments, the system 99 has the capacity to culture at least 150-200 cell culture plates.

[0168] This would require a refrigerator 128 with a capacity of approximately 100 plates to store enough media and other liquids to operate unattended. Specifically, if each plate requires an average of 10 ml of media every two days, 200 plates would require 1,000 ml of media per day. A deep-well plate holds approximately 192 ml of liquid, so a three-day supply of media would require 16 plates (i.e., 3 x 1,000 ml / 192 ml), and the deep-well plate would need to be at least twice as tall as the cell culture plate. Thus, the media alone would require the equivalent of 32 plate slots. PBS, trypsin, etc. would require another 40 or more slots. The plasticware storage 122 may require the equivalent of approximately 400 cell culture plates, depending on whether it accommodates pipette tip boxes.

[0169] Processing such a large number of plates therefore places a significant strain on the robotics of the system 99. The liquid handler 340 (described in more detail below) may be operated close to its capacity. This may require minimizing cycle times and therefore plate transfer times (in and out of the process module 120). The robotics 160 may operate sequentially with the liquid handling robot 340 since the liquid handler 340 may not be able to operate while the process module 120 is being loaded or unloaded. For example, if the robotics 160 was transferring items between the plasticware storage 122 and the process module 120, this could become a bottleneck reducing effective system performance.

[0170] Furthermore, plate transfer can be a cumbersome problem. Specifically, the robotic device 160 that moves plates 116 to and from the process module 120 has two-way traffic in the sense that plates "pass" the robotic device 160 in two different directions, one into the process module and one out of the process module. Such two-way traffic can be difficult to handle efficiently, especially for a highly utilized robotic device 160, and the robotic device 160 can become a bottleneck. Therefore, in some embodiments, the system 99 uses "buffering" - that is, a plate slot 110 that is temporarily used to move labware to and from an adjacent module 100. This plate slot 110 is called a buffer. Moreover, the movement of plates from the buffer to the process module is fast, with short movements. Moreover, the traffic is very simple in nature.

[0171] On the level of the rack 210, i.e., on the transfer slots, that are horizontally at the same level as the interface 134, the module 100 has at least one transfer slot or space that functions as a "pass-through" slot, in which case the robotic device 160 can pass the plate 116 through the pass-through slot, through the interface 134, and onto another module 100. If all the transfer slots on the same level as the interface 134 are pass-through slots, they can be used as buffers to provide buffering.

[0172] 11A and 11B, the step is to load half of the turntable of the process module 120. Plates or other labware can be placed in buffer slots 1-3 (see 211, 212, 213 in FIG. 11A) of the module 100 (e.g., incubator 124) that interfaces with the process module 120. The robotic device 160 of the module 100 can pick up a plate 116 from any slot 110 of the module 100 and place it in the appropriate buffer slot 211, 212, 213 (as mentioned above, in some embodiments, this is done via a combination of vertical and radial movement in a single plane of the robotic device 160 and rotation of the carousel 108). Referring to FIG. 11B, the plates 116 can be placed in an order that results in the plates being placed in the desired position on the turntable / carousel 108 of the process module. This buffering can be done while the process module 120 is operating (e.g., performing liquid handling).

[0173] Considering the step of loading the process module 120, the carousel 108 of the storage module 100 rotates to align, for example, buffer / transfer slot 1 211 with the interface 134 to the process module 120. The carousel 108 of the process module 120 rotates to align the transfer slot with the interface 134. The robotic device 160 of the storage module 100 then pushes the first plate 116 from the transfer slot through the interface 134, which may have a door 130 that is opened as needed, into the transfer slot of the carousel 108 of the process module 120. The robotic device 160 then retracts to the center well 112 of the carousel 108 of the storage module 100. The carousel 108 of the module 100 then rotates to align the next transfer slot, buffer slot 2 212, which is carrying the next labware to be transferred, with the interface 134. At the same time, the carousel 108 of the process module 120 rotates to align the next transfer slot with the interface 134. The robotic device 160 then pushes the second plate from the transfer slot, through the interface 134, into the transfer slot of the carousel 108 of the process module, and then backs away to the center well 112 of the carousel 108 of the module 100. This operation is repeated once more to transfer the remaining plates. In this example, the carousel 108 of each of the process module 120 and the storage module 100 rotates to the next plate slot 110 on the carousel 108 so that the next operation can begin. Thus, for a carousel 108 with eight plate slots 110 on a horizontal plane, the carousel 108 only needs to rotate 1 / 8 of a full rotation. This reduces the travel time and, therefore, the time between transfer operations.

[0174] Although the above examples describe a single module 100 supplying plates to the process module 120, more modules can simultaneously supply the process module 120. In some embodiments, the modules are generally on opposite sides of the process module 120. This allows each half of the carousel 108 of the process module 120 to be filled (or emptied) at the same time, allowing for the most efficient transfer to the process module 120.

[0175] In the embodiment shown in Figures 12A-12F, the two modules 100 are the incubator 124 and the plasticware storage 122. These two modules 100 send the most items to the process module 120. Figure 12A shows the flow of plates 116 with arrows for indication. Furthermore, the unloading and loading of the process module 120 is typically done continuously without pauses. Typically, each module 100 loads about four plates into its buffer, or transfer slot, ready to be transferred to the process module 120. Figure 12B shows the starting position where the module 100 is buffered and the process module 120 is full of plates 116. For example, as shown, if the carousel 108 of the process module 120 holds eight plates and the carousel 108 of the module 100 has eight buffer positions, the combined capacity of the two modules 100 can buffer up to eight plates 116 in the transfer slots. FIG. 12C shows the first transfer of plates 116. In use, one module 100 can buffer more than half of this total number, while the other module 100 can buffer the remainder of the total number depending on the requirements of the system 99. Similarly, each module 100 typically keeps four transfer slots of its buffer empty and ready to receive items from the process module 120. As above, plates 116 can be organized on the transfer slot tiers as required in adjacent slots, so that only a series of 1 / 8 rotations are required, which is shown in FIG. 12D where all carousels 108 rotate one slot. The overall unloading of the process module 120 is shown in FIG. 12E, where the module 100 contains a mix of plates unloaded from the process module 120 and plates to be loaded. FIG. 12F then shows the first step of loading the process module 120.

[0176] Considering a larger system 99 as shown in FIG. 10, plates 116 can be buffered from other modules 100 to a module 100 that interfaces with a process module 120. For example, media is typically stored in a refrigerator 128, but pre-warmed in an incubator 124. Frozen goods may be buffered in the refrigerator 128, the plasticware storage 122, or the incubator 124, as needed. Thus, the system 99 can transfer plates 116 from one module 100 to another module 100 while the process module 120 is running. For example, the refrigerator 128 can be transferred relative to the incubator 124 while the process module 120 is running to minimize cycle times. In this example (not shown), the refrigerator 128 is connected to the plasticware storage 122, which is connected to the incubator 124 to minimize temperature disturbances during transfer. Similarly, as noted elsewhere herein, it is advantageous for the freezer 126 to interface with the refrigerator 128 and for the system 99 to access the freezer 126 via the refrigerator 128 to minimize temperature disturbances within the freezer 126.

[0177] The plate slot 110 is shown in Figures 11A-12F as having a wider edge facing the center well 112. The orientation of the plate slot 110 can be varied as needed for best efficiency.

[0178] Vertically stacked modules 100 can also have a human-access door on the exterior of the module 100 through which the system 99 can be re-stocked, e.g., with fresh labware at a convenient height. Such an exterior door can be located, for example, in the plasticware storage 122 or refrigerator 128. Alternatively, there can be a dedicated load lock that is the only module 100 with a human-access door on a daily basis, through which users can exchange consumables, cell plates, or samples with the system 99.

[0179] Vertical stacking of modules also allows the incubator 124 doors (interface doors 130, 230 or outer human access doors) to be placed low on the wall, minimizing the escape of warm, moist, CO2 rich air when the doors are opened. It also allows the refrigerators 128 and freezers 126 to be placed low in the system 99, which means that their doors (interface doors 130, 230 or outer human access doors) are placed high on the sides, minimizing the escape of cold air from those compartments 126, 128 when the doors are opened.

[0180] Other possible embodiments illustrating the module and interface innovations are not limited to use with carousels, but can be used with conventional robotic arms, gantry robots, etc., for example.

[0181] Referring to FIG. 28A, the robotic device 160 is located at the center 400 of the four modules 100. The arm 160 rotates about a central axis, the grabber 162 translates to move plates 116 in and out of the module 100, and the robotic device 160 moves vertically along the central axis. One of the modules may be a storage unit 122. The storage unit 122 may optionally have a full-height vertical door 402 to allow the robotic device 160 to access any level within the internal rack 210. The other door may also be a full-height door 402. The carousel 108 of the module 100 rotates to allow access to the required plate slot 110. The rotation of the carousel 108 and the vertical movement of the robotic device 160 allow the robotic device to access any plate slot 110 of the module 100. Therefore, by combining the movements of the robot device 110 (rotation about an axis, movement along an axis, translation in and out of the module 100) with the rotation of the carousel 108 or the rotation of the work deck carousel 108 in the process module 124, the robot device 160 can transport any plate 116 anywhere in the system 99. This has the advantages of simple movements, easy programming, and simple hardware with high reliability.

[0182] The grabber 162 can be mechanically or optically (e.g., using machine vision or optical or magnetic sensors) indexed or aligned to the door 402 or interface 130. The interface 130 can have mechanical alignment features, including features such as chamfers or features such as pin and slot features, as previously described. The grabber 162, or the wrist of the grabber 162, can have some compliance to allow alignment with alignment features such as chamfers. The robotic device 160 can be aligned such that the chamfers (e.g., on the door 402) are not normally contacted as the grabber 162 passes through the door 402, but the grabber 162 only contacts the chamfers if misaligned. Contact with the chamfers can dynamically or mechanically correct misalignment. The chamfers can correct the grabber 162 in the horizontal or vertical plane, or both. Contact with the chamfers can further provide feedback that can be used to correct the alignment of the robotic device 160.

[0183] 28B shows a side view of the robotic device 160 located in a center 400 between modules 100, where vertically stacked modules 100 are provided. The robotic device 160 has vertical movement to reach all modules 100 through doors 402 or interfaces 130. The carousel 108 on which the racks 210 or work decks 330 are located can rotate to allow the robotic device 160 to access the required plate slots 110.

[0184] 30, a close-up view of the robotic device 160 interacting with a rack 210 of a module 100 is shown, where grabber 162 is sized so that it can extend into the module to grab an associated labware 300.

[0185] For example, the system 99 previously described in FIG. 28 can have a standardized interface as already mentioned. The system 99 can have a rotating work deck 330 as already described. The system 99 can have a standardized set of labware 300 and can handle all labware 300 in the same way. The system 99 can use the method already described to enable complex workflows to be performed autonomously by the system 99 using only the complete set of labware 300 described, in the form of SLAS microplates 116. All of these features can be used alone or in combination to enable simple and reliable handling by a single robotic device 160 in the center 400 of the module 100. Using these features in combination, the system can achieve a mean time between failures of more than 30,000, or even more than 60,000 plate transfer or movement events. "Mean time between failures" means the arithmetic average of the number of plate transfers or movements between failures, where one failure is an error that shuts down the system until a human can fix the problem.

[0186] Alternatively, a more flexible robotic arm, such as a 6-axis arm, can be used. Machine vision can be used to enhance the system and make it more reliable. The system 99 can be placed horizontally on one level. The robotic device 160 can run on rails that index to the door 402 or interface 130.

[0187] 29A and 29B, the robotic device 160 may again be located at a center 400 with modules surrounding the robotic device 160. However, the robotic device 160 may be an arm 406 that pops a turntable 404 also located at the center 400. The arm 406 may horizontally transfer plates 116 between the plate slots 110 of the modules 100 and the turntable 404. The arm 406 may also rotate about a central axis to access other modules 100. The arm moves vertically along the central axis. The turntable 404 also moves up and down and rotates. There may be vertical rails 408 to support the robotic device 160, maintain alignment, and to connect or index to doors or interfaces.

[0188] In the embodiment of FIGS. 29A and 29B, the turntable 404 can function as a temporary storage or magazine from which the plates 116 can be transferred to the carousel 108 within the process module 124.

[0189] 31A and 31B, a turntable 404 may be handed over to the process module 124. There may also be two turntables 404, one in the process module 124 where work is being performed and a second one that can be loaded while the first one is working. The turntable 404 can then be swapped.

[0190] FIG. 32 shows a robotic device 160 with a magazine 410 that is a vertical rack. The robotic device 160 collects plates 116 and other labware 300 for the next workflow in the magazine 410 and then transfers them from the magazine 410 to the process module 124. This avoids delays as the robotic device 160 moves between the various modules 100 and the process module 124 with one item at a time. The robotic device 160 can further have two magazines 410. It can load the next item to be loaded into the process module 124 into one magazine 410. Then it unloads from the process module 124 to the second magazine 410, reloads the process module 124 from the first magazine 410, and then unloads from the second magazine 410 to the associated module 100.

[0191] 33, the modules 100 may be arranged in two opposing rows. They may be accessed by a robotic device 160 that moves between them on rails 412 or similar fixed tracks such as a gantry. The robotic device 160 may, for example, be mechanically or optically indexed to a door 402 or interface 130 on a module 100, and the robotic device 160 may move on fixed rails or to the door 402 or interface 130.

[0192] For the robotic device 160 of Figure 33, it may be desirable to avoid one or more of a heavy robotic device 160, a long travel distance and therefore a long rail 412, and / or a fast travel speed, as these may make the system vulnerable to deviations from tolerances. Although robots are inherently very precise, the mechanisms and fixtures used to secure and align the robot to the module may flex, distort, or shift, causing misalignment.

[0193] The module 100 need not be limited to the use of a carousel 108, but instead may use a module 100 with a rectangular arrangement of racks 210, where access to the racks 210 can be by vial rails or a carousel system. A rectangular arrangement of racks is more space efficient and denser than the carousel 108.

[0194] Thus, the described system 99 can use a robotic device 160 located outside of the module 100. This is made practical by the simplified handling previously described (movement along limited axes, horizontal movement, fixed interface, single plastic instrument handling format, etc.). The robotic device 160 can interface to an interface 130 on the module 100, e.g., grabber 162 can index or align to door 402. The robotic device 160 can run on rails 412, which are fixed to the interface 130. The module 100 can have a fixed interface format.

[0195] Referring to FIG. 34, the sequence of operations is shown as viewed from left to right. There is a module 100 with a rack 210 with plate slots 110. Stacked vertically on the module 100 are process modules 124. The robotic device 160 moves between the modules 100 on rails 172 as previously described with reference to FIGS. 9A and 9B. However, the process module 124 does not have a rack 210 since the space of the process module 124 is occupied by liquid handlers, decapping machines, etc. Thus, the process module 124 has a carousel 108 with a working deck 330. The central portion of the working deck 330 is unoccupied, similar to the center well 112 already described, to allow the robotic device 160 to partially pass through in order to deliver labware 300 and plates 116 to the working deck 330. As shown in the sequential views, the robotic handler 160 can pass partially through the process module 124 and deliver the plate 116 to the target plate slot 110 on the work deck 330, thus allowing for vertical delivery of the plate 116 and labware 300. This reduces the space required in the process module 124 for movement of the plate 116, as the rails 172 required for vertical movement may not be present.

[0196] While the above examples show modules implemented as rotating features (such as a carousel with plate hotel), those skilled in the art will appreciate that the features and principles described may also be applied to other types of modules and transports.

[0197] FIG. 35 shows an alternative arrangement similar to that disclosed in FIG.

[0198] The working deck plate slot 110 has windows 111 that open to the top and bottom sides of the working deck 330. The windows 111 are used for the arms of a gripper (not shown) to lift a plate, such as a cell culture plate 116, from the working deck plate slot 110. The gripper can have a tray with protrusions that fit into recesses in the underside of the plate.

[0199] 35 further illustrates a first transfer interface 133 and a second transfer interface 134 arranged at different positions relative to the housing 102 or the rotatable work deck 330. The first transfer interface 133 can be associated with a first storage module (not shown in FIG. 35 but described above). The second transfer interface 134 can be associated with a second storage module (not shown in FIG. 35 but disclosed above). One of the storage modules can store cell culture plates 116 as disclosed above. The other storage module can store labware as described above or liquid media for application to the cell culture plates as described above.

[0200] 36 and 37 show a single well plate 301 having a rectangular bottom 302. The single well plate 301 has the microplate footprint described above (width 85.5±1 mm, length 127.8±1 mm).

[0201] The single well plate 301 has four walls 303 with an upper edge 304. A foil (plastic foil) is sealed to the edge 304 and covers the upper opening of the well 307 surrounded by the walls 303. The connection between the foil 305 and the edge 304 is a heat sealed connection. The plate 301 can be used to transport liquid media from a supplier to a biological laboratory system. The sealed opening of the plate 301 can be covered with a lid 309.

[0202] The foil 305 can be broken by the tip of a pipette of the liquid handler 340 to aspirate the liquid contained within the well 307 .

[0203] 38 and 39 show a sealing element 311 forming a passage for plates moving between one module 100 and another module 120, where one module 100 is a storage module and the other module 120 can be a process module or a storage module 100 as well. The height of the opening 150 formed by the frame 315 and the sealing element 311 located between the frame 315 can be larger than shown. The height of the interface 134 is just enough to move a microplate through the interface 134. The interface 134 can have a uniform height larger than the height of the bottle or the highest instrument stored in the module 100.

[0204] All these features combine to make labware simpler and more reliable to handle, software faster and easier to write and debug, and systems with stable software - in contrast to the current situation where unstable software is one of the major obstacles.

Claims

1. A module (100) for an automated biological laboratory system, comprising: A housing (102); a storage device (108, 330) formed as a carousel (108) rotatably disposed within the housing (102) having a plurality of plate slots (110) for receiving a microplate (116), labware (320, 322, 324) or containers (326, 327) having a footprint identical to that of the microplate (116); a transfer slot (113) among the plurality of plate slots (110), the transfer slot (113) being assigned to the storage device (108, 330) for transferring the microplates (116), the labware (320, 322, 324), or the containers (326, 327) between the inside of the module (100) and the outside of the module (100) using a robotic handling device (160, 162) disposed in a center well (112) of the carousel (108) and vertically movable along a vertical rail (172); and alignment means (140, 142) for easily aligning the transfer slot (113) with a transfer interface (130, 134) comprising an opening in the housing (102); The storage devices (108, 330) each have the plate slots (110) arranged radially with respect to a central axis at different positions in a vertical direction arranged above and below each other, the storage device (108, 330) has a rack (310) arranged as a vertical stand (314) with rack rails (312), the rack rails (312) being arranged to extend into an interior region of the rack (310) between two of the vertical stands (314); the rack (310) can be completely removed from the carousel (108) and replaced with a new rack (310) preloaded with a new set of microplates (116), labware (320, 322, 324), or containers (326, 327); The replacement is performed by means of a user-accessible door on the housing having the same height as the height of the rack (310), the module.

2. The module of claim 1, wherein the robotic handling device (160, 162) transfers the microplate (116), labware (320, 322, 324), or container (326, 327) between the inside of the module (100) and the outside of the module (100) in a vertical motion through an opening in a transport interface (230).

3. 3. The module of claim 1 or 2, wherein the microplate (116), the labware (320, 322, 324), and the containers (326, 327) have the same footprint.

4. The module according to any one of claims 1 to 3, characterized in that the storage device (108, 330) is electrically driven by a drive means controlled by a control device.

5. 1. A method for handling microplates (116), labware (320, 322, 324), or containers (326, 327) stored in a storage module (100) of an automated biological system, the system comprising: a storage device (108), each vertical position of the storage device (108) having at least one plate slot (110) for receiving the microplate (116), the labware (320, 322, 324), or the container (326, 327), and at least a first plate slot is reserved as a buffer slot, the at least first buffer slot being in the same horizontal plane as a transport interface (133, 134, 234); a robotic handling device (160, 162) for vertically moving the microplate (116), the labware (320, 322, 324), or the containers (326, 327) from one position to another; The method further comprising: moving the microplate (116), the labware (320, 322, 324), or the container (326, 327) from the plate slot to a buffer slot by a first robotic handling device (160, 162); temporarily storing the microplate (116), the labware (320, 322, 324), or the container (326, 327) in the buffer slot; and moving the microplate (116), the labware (320, 322, 324), or the container (326, 327) via the transport interface (133, 134, 234) to an adjacent module by a second robotic handling device.

6. The method of claim 5, wherein the robotic handling device (160, 162) and the rotatable storage device (108) are electronically driven and controlled by a microcontroller or computer program.

Images