WO2023225048A1 - Systèmes et procédés pour plateformes et modules pouvant venir en prise pour le traitement de cellules - Google Patents

Systèmes et procédés pour plateformes et modules pouvant venir en prise pour le traitement de cellules Download PDF

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Publication number
WO2023225048A1
WO2023225048A1 PCT/US2023/022484 US2023022484W WO2023225048A1 WO 2023225048 A1 WO2023225048 A1 WO 2023225048A1 US 2023022484 W US2023022484 W US 2023022484W WO 2023225048 A1 WO2023225048 A1 WO 2023225048A1
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WIPO (PCT)
Prior art keywords
processing module
liquid
chamber
board
control board
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PCT/US2023/022484
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English (en)
Inventor
Morteza MIANSARIGAVZAN
S. Sammy DATWANI
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Synthego Corporation
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Publication of WO2023225048A1 publication Critical patent/WO2023225048A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/48—Automatic or computerized control
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps

Definitions

  • genetically modified cells are used in various different industries.
  • genetically modified cells e.g., T-cells
  • genetically modified cells e.g., Chinese hamster ovary “CHO” cells
  • therapeutic proteins e.g., monoclonal antibodies
  • Some embodiments of the disclosure provide a system for processing cells.
  • the system can include a control board, a gas source fluidly coupled to the control board, a process board that is engageable with the control board to fluidly couple the process board to the control board, and a processing module that is engageable with the process board to fluidly couple the processing module to the process board.
  • the gas source can be configured to drive gas into or out of the control board to move liquid including cells suspended therein through the processing module.
  • the processing module can be configured to perform a process on the cells as the liquid including the cells pass through the cell processing module.
  • the system can include a control board, a gas source fluidly coupled to the control board, and a process board fluidly coupled to the control board.
  • the process board can be removably coupled to the control board.
  • the system can include a processing module fluidly coupled to the process board.
  • the processing module can be removably coupled to the process board and the processing module can be configured to implement one or more processes on cells that pass through the cell processing module.
  • the system can include a computing device in communication with the control board and the gas source.
  • the computing device can be configured to receive, from another computing device, a signal, and in response to the signal, cause the gas source to drive gas into or out of the control board to move liquid including cells suspended therein through the processing module to implement the one or more processes on the cells.
  • the control board can include a substrate, and a plurality of gas connectors coupled to the substrate. Each of the plurality of gas connectors can be configured to engage with a respective gas connector of the process board. When the process board engages with the control board and each of the plurality of gas connectors engages with the respective gas connector of the process board, each of the plurality of gas connectors can be configured to be fluidly coupled to a respective liquid connector of the process board.
  • a gas source can be configured to be fluidly coupled to the plurality of gas connectors of the control board. The gas source can drive gas through or pull gas from the plurality of gas connectors of the control board thereby driving gas through or pulling gas from the plurality of gas connectors of the process board to drive liquid through the process board.
  • Some embodiments of the disclosure provide a process board.
  • the process board can include a substrate, and a plurality of gas connectors coupled to the substrate. Each of the plurality of gas connectors can be configured to engage with a respective gas connector of a control board.
  • the process board can include a plurality of liquid connectors coupled to the substrate. Each of the plurality of liquid connectors can be an aseptic connector and can be configured to engage with a respective liquid connector of one or more processing modules.
  • Some embodiments of the disclosure provide a processing module.
  • the processing module can include a housing, and a chamber within the housing isolated from the ambient environment. The chamber can be configured to contain cells dispersed within cell media.
  • the processing module can include a membrane that can be gas permeable and can be liquid impermeable.
  • the membrane can at least partially define the chamber.
  • the processing module can include a plurality of liquid connectors coupled to the housing. Each of the plurality of liquid connectors can be configured to engage with a respective liquid connector of a process board.
  • FIG. 1 shows a schematic illustration of a cell processing system.
  • FIG. 2 shows a schematic illustration of the cell processing system of FIG. 1.
  • FIG. 3 shows an illustration of a cell processing unit.
  • FIG. 4 shows different views of the cell processing unit of FIG. 3.
  • FIG. 5 shows an isometric view of the cell processing unit with the top of the enclosure removed for visualization of the components positioned within the interior volume of the enclosure.
  • FIG. 6 shows a top isometric view of the cell processing unit of FIG. 5 with the enclosure removed for visualization of the components positioned therein.
  • FIG. 7 shows an isometric view of the cell processing unit of FIG. 5 with the enclosure transparent for visualization of the components positioned therein.
  • FIG. 8 shows an enlarged view of the cell processing unit of FIG. 5 without the enclosure 302 for visualization of the components positioned therein.
  • FIG. 9 shows an isometric view of the control board of the cell processing unit of FIG 5
  • FIG. 10 shows a side view of the control board.
  • FIG. 11 shows a top view of the control board of FIG. 10.
  • FIG. 12 shows a top view of the process board.
  • FIG. 13 shows a side isometric view of the process board of FIG. 12 positioned above and aligned with the control board of FIG. 10.
  • FIG. 14 shows a front isometric view of the process board of FIG. 12 and a plurality of different processing modules positioned above the process board.
  • FIG. 15 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 16 shows the processing module of FIG. 15.
  • FIG. 17 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 18 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 19 shows the configuration with at least two liquid permeable membranes extending across a portion of the angled wall of the housing of the processing module of FIG. 19.
  • FIG. 20 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 21 shows a top view and a cross-sectional view of a processing module.
  • FIG. 22A shows a process of cell culturing and cell expansion using the processing module of FIG. 21.
  • FIG. 22B shows a process of cell culturing and cell expansion using the processing module of FIG. 21 and the processing module of FIG. 17.
  • FIG. 23 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 24 shows a process of cell concentrating using the processing module of FIG. 23.
  • FIG. 25 shows an illustration of a processing module.
  • FIG. 26 shows a process of collecting cells using the processing module of FIG. 25.
  • FIG. 27A shows an illustration of a processing module.
  • FTG. 27B shows a process of concentrating cells using a plunger and an actuator driving the plunger, or a process of adjusting the gap between electrodes using the plunger and the actuator.
  • FIG. 28 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 29 shows an isometric view, a top view, and cross-sectional views of a processing module.
  • FIG. 30 shows a side view of a processing module.
  • FIG. 31 shows a side view of the processing module of FIG. 30 with a plurality of vacuum tubes positioned within a chamber.
  • FIG. 32 shows an isometric view of a processing module.
  • FIG. 33 shows an isometric view of a processing module.
  • FIG. 34 shows a top view and a cross-sectional view of a processing module.
  • FIG. 35 shows an isometric view of a control board, a process board coupled to the control board, processing modules coupled to the process board, and a liquid handling device coupled to the process board.
  • FIG. 36 shows a top view of the configuration of FIG. 35.
  • FIG. 37 shows atop view of the configuration of FIG. 35, with a processing module removed.
  • FIG. 38 shows a top view of the configuration of FIG. 37.
  • FIG. 39 shows a rear isometric view of the configuration of FIG. 35.
  • FIG. 40 shows a front isometric view of the configuration of FIG. 35.
  • FIG. 41 shows a rear isometric view of the configuration of FIG. 35.
  • FIG. 42 shows a front isometric view of the configuration of FIG. 35.
  • FIG. 43 shows a top view of the configuration of FIG. 35.
  • FIG. 44 shows a top view of the control board, the process board, and processing modules coupled to the process board.
  • FIG. 45 shows an isometric view of the control board, the process board, and the processing modules coupled to the process board.
  • FIG. 46 shows an isometric view of the control board, the process board, and processing modules coupled to the process board.
  • FTG. 47 shows an isometric view of the control board, the process board, the processing module coupled to the process board, and the liquid handling device coupled to the processing module.
  • FIG. 48 shows an isometric view of the control board, the process board, and the processing modules coupled to the process board.
  • FIG. 49 shows an isometric view of the control board, the process board, and the processing modules coupled to the process board.
  • FIG. 50 shows an isometric view of the control board, the process board, and the processing modules coupled to the process board.
  • FIG. 51 shows an isometric view of the control board, the process board, and a processing module coupled to the process board.
  • FIG. 52 shows an isometric view of the control board, the process board, and a processing module coupled to the process board.
  • FIG. 53 shows an isometric view of the control board, the process board, the processing modules coupled to the process board, and an optical connector coupled to the optical connector of the process board.
  • FIG. 54 shows an isometric view of the control board, the process board, the processing modules coupled to the process board, and vacuum tubes.
  • FIG. 55 shows an isometric view of the control board, the process board including liquid connectors, the processing module coupled to the process board, and a processing module coupled to the process board.
  • FIG. 56 shows an isometric view of the control board, the process board, a processing module coupled to the process board, and a processing module (or a processing module) coupled to the process board.
  • FIG. 57 shows an isometric view of the processing module engaged with the process board.
  • FIG. 58 shows an isometric view of the processing module engaged with the process board, with one chamber including a plurality of vacuum tubes (or vials).
  • FIG. 59 shows an isometric view of the process board coupled to the control board, and with one or more UV lights being configured to emit light at one or more liquid connectors of the process board to decontaminate the liquid connectors.
  • FIGS. 60-82 show examples of different prototypes, tests, and results of different cell processing systems described herein:
  • FIG. 60 shows a flowchart of an automated cell therapy manufacturing process.
  • FIG. 61 shows a simplified model (e.g., a prototype) that integrates the control board, the process board, and two cell processing modules.
  • FIG. 62 shows the filling of the cell processing module (“CPM”) via a top port, followed by transferring the liquid (water) from one CPM to another CPM by pressurizing the one CPM (e.g., by adding gas to the one CPM).
  • CPM cell processing module
  • FIG. 63 shows a prototype of a double layer CPM using a modified filtration flask integrating a gas-permeable membrane and liquid- (but not cell-) permeable membrane.
  • FIG. 64 shows testing of a CPM prototype using a pneumatic system.
  • FIG. 64 shows the inflation of the gas-permeable membrane while pushing out the liquid from the bottom cell chamber.
  • FIG. 65 shows the results of a liquid leak test by inflating the gas-permeable membrane of the CPM prototype.
  • FIG. 66 shows a second CPM prototype built using a filtration flask. About a liter of liquid was removed through a port from the top media chamber of the second CPM prototype.
  • FIG. 67 shows a third CPM prototype fabricated using a layer-by-layer method that integrates a gas-permeable membrane and a liquid- (but not cell-) permeable membrane.
  • FIG. 68 shows the results from the third CPM prototype set up for a leak test. Less than 1 mL of liquid remained after removing the liquid from the cell chamber.
  • FIG. 69 shows the prototypes for the microbeads tests.
  • FIG. 70 shows the additional prototypes for the microbeads tests.
  • FIG. 71 shows the fluorescent images of the original liquid, the supernatant liquid, and the washed samples.
  • FIG. 72 shows images of the prototypes after completion of the microbeads tests showing that beads were retained in the cell chamber between the 2 membranes.
  • FIG. 73 show the first prototype of the CPM with a spacer that is liquid permeable and is impermeable to cells passing through.
  • FTG. 74 shows a first prototype of an electroporation processing module (e g , an electroporation cuvette) that integrates liquid level sensing using embedded electrodes.
  • an electroporation processing module e g , an electroporation cuvette
  • FIG. 75 shows a second prototype of an electroporation processing module (e.g., an electroporation cuvette) that integrates liquid level sensing using embedded electrodes.
  • an electroporation processing module e.g., an electroporation cuvette
  • FIG. 76 shows a prototype of a cell processing module that is a cell electroporation processing module and a cell growing processing module.
  • FIG. 77 shows a prototype of a quality control (“QC”) sampling processing module.
  • FIG. 78 shows a top view and isometric views of a prototype that is that is configured to create a formulation and integrated to electroporate cells.
  • QC quality control
  • FIG. 79 shows a testing setup for evaluating liquid leaks and gas leaks between needleless connectors.
  • biological therapeutics typically only those that treat diseases that negatively impact large swaths of the population (e.g., diseases with a large prevalence) are manufactured because of the large economic burden of large-scale biopharmaceutical manufacturing.
  • companies that manufacture biological therapeutics typically only manufacture those that can treat large segments of the population because costs to manufacture the biological therapeutics can be high (e.g., equipment, training, quality control practices including good manufacturing practices, etc.).
  • high costs can be a barrier that prevent the manufacturing of biological therapeutics that treat more scarcely prevalent diseases, such as orphan diseases.
  • a biological fluid e.g., blood
  • desired cells to be genetically modified can be harvested from an individual (e.g., by storing the biological fluid within a blood collection bag). Then, the biological fluid is transported to a lab facility for genetic engineering and other modifications. Once successfully transported to the lab facility, the desired cells can be extracted from the biological fluid, can be genetically engineered, modified, etc., and can be grown. After, the genetically modified cells can be collected (e.g., repackaged into a container, vial, cryopreserved, etc.) and the genetically modified cells can be transported to a medical facility (e.g., a hospital) for delivery of the genetically modified cells into the specific patient.
  • a medical facility e.g., a hospital
  • some embodiments of the disclosure provide advantages to these issues (and others) by providing improved systems and methods for engageable platforms and integratable modules for cell processing.
  • a cell processing unit that can include a plurality of control boards, a plurality of process boards, and a plurality of processing modules.
  • Each control board is configured to be coupled with a respective process board, and each process board is configured to engage with one or more processing modules (e.g., cell processing modules) each of which is configured to implement a process on cells (or implement a process associated with cells, such as creating a formulation for genetically modifying cells).
  • processing modules e.g., cell processing modules
  • the cell processing unit can create different biological products (e.g., for different patients) within the same enclosure of the cell processing unit.
  • different biological products can be created simultaneously at the same facility (e.g., a hospital) that patients are located, which can greatly improve biological product workflows and increase engineered cell throughput.
  • the relatively small size (and modular nature) of the control board, the process board, and the processing modules can tailor biological products for specific patients, even those that have more rare diseases, thereby improving patient care.
  • FIG. 1 shows a schematic illustration of a cell processing system 100.
  • the cell processing system 100 can include a control board 102, a process board 104, processing modules 106, 108, 110, a gas source(s) 112, a sensor(s) 114, an imaging device(s) 116, a disinfection system 118, an actuator(s) 120, a magnet(s) 122, a power source 124, and a computing device 126.
  • some or all of the components of the system 100 e.g., including the gas source 112 can be coupled to a substrate 128 of the control board 102 (e.g., as appropriate), integrated within the substrate 128, or aligned with the substrate 128.
  • the gas source 112 can be a pump or compressor that is fluidly coupled to the control board 102 (e.g., to drive gas through the control board 102), and/or can include a pressurized reservoir (e.g., a cylinder) of a gas (e.g., compressed air or a medical gas including nitrogen, oxygen, etc ).
  • the control board 102 can include gas connectors 130, 132, 134, 136, 138, 140, and the gas source 112 can drive gas through the control board 102 and through one or more of the gas connectors 130, 132, 134, 136, 138, 140.
  • each gas connector 130, 132, 134, 136, 138, 140 can be coupled to a first side of the substrate 128 and can extend away from the first side of the substrate 128 (e.g., towards the process board 104).
  • each gas connector 130, 132, 134, 136, 138, 140 can be an aseptic connector (e.g., a needle-based connector, a needleless connector, etc.).
  • the process board 104 can include a substrate 142, gas connectors 141, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164 coupled to the substrate 142, and liquid connectors 168, 170, 170, 172, 174, 176 coupled to the substrate 142.
  • the gas connectors 154, 156, 158, 160, 162, 164 can be coupled to and can extend away from a first side of the substrate 142, while the gas connectors 141, 144, 146, 148, 150, 152 can be coupled to and can extend away from a second side of the substrate 142 that is opposite the first side.
  • each gas connector of the process board 104 and each liquid connector of the process board 104 can be an aseptic connector.
  • different connectors can be fluidly coupled to other connectors of the process board 104.
  • each gas connector 141, 144, 146, 148, 150, 152 can be fluidly coupled to a respective gas connector 154, 156, 158, 160, 162, 164. In some cases, and as shown in FIG.
  • each gas connector 141, 144, 146, 148, 150, 152 can be aligned with the respective gas connector 154, 156, 158, 160, 162, 164, which can be more economical from a manufacturing perspective (e.g., requiring less complicated internal channels through the substrate 142).
  • pairs of liquid connectors can be fluidly coupled to each other (e.g., via one or more channels of the process board 104, such as through the substrate 142 of the process board 104).
  • the liquid connectors 166, 168 can be fluidly coupled to each other
  • the liquid connectors 170, 172 can be fluidly coupled to each other
  • the liquid connectors 174, 176 can be fluidly coupled to each other.
  • liquid connectors 166, 168, 170, 172, 174, 176 can be fluidly coupled to each other, via a channel 178 through the substrate 142 (e g., or a channel 178 coupled to the substrate 142).
  • each of the gas connectors 141, 144, 146, 148, 150, 152 of the process board 104 can be complementary with and can engage with the respective gas connector 130, 132, 134, 136, 138, 140 of the control board 102.
  • the gas source 112 e.g., a pump
  • each processing module 106, 108, 110 can be configured to implement a process (e g., a cell process) on the cells as they flow through the particular processing module 106, 108, 110.
  • a process for a processing module can include growing cells, culturing cells, concentrating cells, performing cell media exchange for cells, separating cells, electroporating cells, mechanoporating cells, magnetoporation cells, isolating cells, debeading cells, storing cells, collecting cells, washing cells, collecting cells, isolating cells, etc.
  • each processing module 106, 108, 110 can be configured to implement multiple processes (e.g., sequentially) on the cells as they flow through the particular processing module.
  • each processing module 106, 108, 110 can be a cell processing module.
  • each processing module 106, 108, 110 can be configured to implement a process for cells, which can include preparing a formulation for cells (e.g., a reagent formulation, such as for genetically modifying cells).
  • each processing module 106, 108, 110 can include a respective housing 180, 182, 184, a plurality of gas connectors and a plurality of liquid connectors.
  • the processing module 106 can include gas connectors 186, 188 coupled to the housing 180, and liquid connectors 190, 192 coupled to the housing 180.
  • the processing module 108 can include gas connectors 194, 196 coupled to the housing 182, and liquid connectors 198, 200, while the processing module 110 can include gas connectors 202, 204, and liquid connectors 206, 208.
  • some of the connectors of each processing module 106, 108, 110 can engage with corresponding connectors of the process board 104.
  • each connector 186, 188, 190, 192 of the processing module 106 can be complementary with and can be configured to engage with a respective connector 154, 156, 166, 168 of the process board 104
  • each connector 194, 196, 198, 200 can be complementary with and can be configured to engage with a respective connector 158, 160, 170, 172 of the process board 104
  • each connector 202, 204, 206, 208 can be complementary with and can be configured to engage with a respective connector 162, 164, 174, 176 of the process board 104.
  • each connector of each processing module 106, 108, 110 can be coupled to a first side of the respective processing module 106, 108, 110.
  • each processing module 106, 108, 110 can include other connectors.
  • each processing module 106, 108, 110 can include one or more liquid connectors coupled to a second side of the respective processing module 106, 108, 110 (e.g., opposite the first side).
  • each connector of each processing module 106, 108, 110 can be an aseptic connector.
  • each connector of each processing module 106, 108, 110 can be fluidly coupled to one or more inner chambers of the respective processing module 106, 108, 110 that is isolated from the ambient environment.
  • each processing module 106, 108, 110 can ensure that the one or more inner chambers are isolated from the ambient environment (and thus the contaminants therein) to ensure that the one or more inner chambers are fluidly coupled to the process board 104 only when the respective connectors are engaged.
  • the process board 104 can be electrically connected to the control board 102, and each processing module 106, 108, 110 can be electrically connected to the process board 104 (e.g., and thus to the control board 102).
  • the process board 104 can be selectively electrically connected to the control board 102, and each processing module 106, 108, 110 can be selectively electrically connected to the process board 104 (e.g., and thus to the control board 102).
  • control board 102 can include one or more electrical connectors 210 coupled to the substrate 128 (e.g., coupled to the first side of the substrate 128)
  • the process board 104 can include one or more electrical connectors 212 coupled to the substrate 142 (e.g., coupled to a second side of the substrate 142)
  • each processing module 106, 108, 110 can include one or more electrical connectors (not shown).
  • the process board 104 can be electrically connected to (and disconnected from) the control board 102 when the one or more electrical connectors 210 and the one or more electrical connectors 212 are coupled together.
  • one or more other electrical connectors of the process board 104 can be coupled to the one or more electrical connectors of the processing module 106, 108, 110 to electrically connect each processing module 106, 108, 110 to the process board 104.
  • more expensive electrical components e.g., electronics for electroporation, a power source, such as an electrical power source, a gas source, etc.
  • a power source such as an electrical power source, a gas source, etc.
  • these more expensive components can advantageously be kept, being used for another process board and other processing modules, and less expensive components including the process board 104, and the processing module 106, 108, 110 can simply be disposed of after completion of the one or more processes on the cells.
  • the process board 104 can be patient specific.
  • the process board 104 can be for use for a specific patient (e.g., a single patient).
  • the process board 104 can be specific to a particular type of biological product to be created.
  • the particular type of biological product can be a particular type of genetically modified cell (e.g., a T-cell), a particular type of biological therapeutic protein, etc.
  • the process board 104 can include a symbol 214 that can be associated with the specific patient or can be associated with the particular biological product to be created.
  • the symbol 214 can include information encoded by the symbol 214 (e.g., a string) that can be extracted by, for example, scanning the symbol 214 with a symbol scanner (e.g., a barcode scanner).
  • the information encoded by the symbol 214 can be associated with a specific patient (e.g., a patient identifier), or can be associated with a specific type of biological product to be created (e.g., a biological product identifier to be created).
  • the computing device 126 can receive the information encoded by the symbol 214 to control the components of the system 100 accordingly (e.g., the gas source 112).
  • each processing module 106, 108, 110 can be a specific type of processing module, and each specific type of processing module can be configured to implement one or more processes on cells (or associated with the cells).
  • each processing module 106, 108, 110 can include a respective symbol 216, 218, 220 that can identify the specific type of processing module.
  • each symbol 216, 218, 220 can have information encoded therein (e.g., a barcode string) to identify the specific type of processing module.
  • the computing device 126 can ensure that the particular processing module is positioned correctly on the process board 104, and that the number and type of desired processing modules for the process board 104 are utilized.
  • the information encoded by the symbol 214 of the process board 104 can be associated with a list (e g., a bill of materials) of a number and particular types of cell processing modules. In this way, the correct number and type of processing modules as required according to the information encoded by the symbol 214 can be ensured by comparing each scanned symbol of each cell processing module to the list.
  • a list e g., a bill of materials
  • FIG. 2 shows a schematic illustration of the cell processing system 100 engaged together.
  • the process board 104 which can be removably coupled to the control board 102 and can be coupled to the control board 102.
  • each processing module 106, 108, 110 which can be removably coupled to the process board 104, can be coupled to the process board 104.
  • FIG. 2 shows a schematic illustration of the cell processing system 100 engaged together.
  • the process board 104 which can be removably coupled to the control board 102 and can be coupled to the control board 102.
  • each processing module 106, 108, 110 which can be removably coupled to the process board 104, can be coupled to the process board 104.
  • FIG. 1 shows a schematic illustration of the cell processing system 100 engaged together.
  • the process board 104 when the process board 104 is coupled to the control board 102 (e.g., via the engagement between one or more connectors of the process board 104 with one or more connectors of the control board 102), the process board 104 fluidly couples to the control board 102 (e.g., prior to engagement one or more channels of the process board 104 can be isolated from the ambient environment, and one or more chambers of a processing module can be isolated from the ambient environment).
  • each processing module 106, 108, 110 when each processing module 106, 108, 110 is coupled to the process board 104 (e.g., via the engagement between one or more connectors of the respective processing module with one or more connectors of the process board 104) each processing module 106 fluidly couples to the control board 102.
  • each of the connectors of the control board 102, the process board 104, and the processing modules 106, 108, 110 being aseptic can be advantageous at least because the connectors and the components fluidly coupled to the connectors are isolated from the ambient environment prior to engagement with each other. In this way, the connectors can maintain an aseptic environment, which can be advantageous for cell health and growth.
  • the gas source 112 can include one or more pumps (and in some cases a gas manifold including one or more valves) to deliver gas to the gas connectors of the control board 102.
  • the gas source 112 can drive gas through the control board 102, through the connector 130, through the connector 141, through the process board 104, through the connector 154, through the connector 186 and through the inner chamber of the processing module 106.
  • the gas can drive liquid through the inner chamber of the processing module. In some cases, the liquid can be driven out of a liquid connector of the processing module 106, and into the process board 104.
  • the liquid can be driven through the process board 104 and through a liquid connector of the processing module 108 and into the inner chamber of the processing module 108.
  • the gas source 112 can drive gas into different connectors of the control board 102 and thus drive gas into different connectors of the process board 104 to drive gas and thus liquid through different processing modules and different portions of the process board 104.
  • the gas source 112 rather than driving gas into the process board 104 and thus the processing modules 106, 108, 110, can pull gas out of the process board 104 as described herein and thus the processing modules 106, 108, 110 to alternatively move liquid through one or more of the processing modules 106, 108, 110 and through the process board 104 (e.g., to one of the other processing modules 106, 108, 110).
  • the gas source 112 can be configured to sequentially drive liquid including cells through each of the processing modules 106, 108, 110 to implement one or more respective processes on the cells.
  • the gas source 1 12 can be configured to drive liquid through the processing module 106 to implement one or more first processes on the cells dispersed in the liquid. Then, after the one or more first processes have been completed, the gas source 112 can drive liquid and the cells dispersed therein (e.g., having been processed according to the one or more first processes), from the processing module 106 (e g., an internal chamber of the processing module 106), through the process board 104, and into the processing module 108 (e.g., an internal chamber of the processing module 108).
  • the gas source 112 can then be configured to drive the liquid through the processing module 108 to implement one or more second processes on the cells dispersed in the liquid. Subsequently, after the one or more second processes have been completed, the gas source 112 can drive liquid and the cells dispersed therein (e.g., having been processed according to the one or more second processes), from the processing module 108 (e.g., the internal chamber of the processing module 108), through the process board 104, and into the processing module 110 (e g., an internal chamber of the processing module 110). Then, the gas source 112 can be configured to drive the liquid through the processing module 108 to implement one or more third processes on the cells dispersed in the liquid.
  • the processing module 108 e.g., the internal chamber of the processing module 108
  • the processing module 110 e.g., an internal chamber of the processing module 110
  • the processing module 110 can be configured to generate a reagent formulation (e.g., a reagent formulation for genetically modifying cells).
  • the gas source 1 12 can be configured to drive liquid through the processing module 1 10 to create the reagent formulation and can drive the reagent formulation from the processing module 110 to the processing module 108 (e.g., to genetically modify cells therein using the reagent formulation).
  • control board 102 can be isolated from any liquid that flows through the process board 104, or the processing modules 106, 108, 110, which can advantageously maintain an aseptic environment of the control board 102, such that the control board 102 can be advantageously reused with other process boards after the processing has been completed for the process board 104.
  • control board 102 e.g., via the gas source 112 only provides gas to (or pulls gas from) the process board 104 and the processing modules 106, 108, 110, liquid is avoided from passing through the control board 102, including being passed through any of the gas connectors of the control board 102.
  • each gas connector of the control board 102 can include a barrier (e.g., a membrane) fluidly coupled to the respective gas connector, which can be gas permeable but liquid impermeable. In this way, liquid that could contain contaminants is ensured not to pass through the gas connectors into the control board 102, which could compromise the aseptic environment of the control board 102.
  • a barrier e.g., a membrane
  • each gas connector of the process board 104 can also include a barrier fluidly coupled to the respective gas connector, which can be gas permeable but liquid impermeable to provide a redundancy to ensure that liquids that could contain contaminants does not undesirably enter a designated gas channel of the process board 104. Still yet, each gas connector of each processing module 106, 108, 110 can also include a barrier that can be gas permeable but liquid impermeable to provide even further redundancy to ensure liquids of the processing module do not undesirably enter gas designated channels of the processing module (and other components fluidly coupled to the gas designated channels).
  • each gas connector of the control board 102 can be fluidly coupled to a respective one-way valve that can allow gas flow out of the gas connector and can block gas flow into the gas connector. In this way, if liquid including contaminated laden aerosols are positioned in the environment surrounding the control board 102, the liquid is avoided from passing into the control board 102 (e.g., which could later contaminate a different process board).
  • the sensor(s) 114 can be configured to sense one or more parameters of the cells as they travel through the process board 104 and the one or more of the processing modules 106, 108, 110.
  • the sensor 114 can include a pH sensor that can be coupled to the control board 102 and can be optically coupled to the process board 104 (e.g., when the process board 104 is coupled to the control board 102) and a processing module.
  • the pH sensor can be configured to optically sense a pH of a liquid (e.g., including cells) in the process board 104, in a processing module 106, 108, 110, etc., which can be used to control liquid through the cell processing system 100.
  • the sensor 114 can include an oxygen sensor that can be coupled to the control board 102 and can be optically coupled to the process board 104 (e.g., when the process board 104 is coupled to the control board 102), and a processing module.
  • the oxygen sensor can be configured to optically sense an oxygen concentration of a liquid (e.g., including cells) in the process board 104, in a processing module 106, 108, 110, etc., which can be used to control liquid through the cell processing system 100.
  • the sensor 114 can include a carbon dioxide sensor that can be coupled to the control board 102 and can be optically coupled to the process board 104 (e.g., when the process board 104 is coupled to the control board 102), and a processing module.
  • the carbon dioxide sensor can be configured to optically sense a carbon dioxide concentration of a liquid (e g., including cells) in the process board 104, in a processing module 106, 108, 110, etc., which can be used to control liquid through the cell processing system 100.
  • the sensor 114 can include a temperature sensor that can be coupled to the control board 102 and can be optically coupled (or thermally coupled) to the process board 104 (e.g., when the process board 104 is coupled to the control board 102), and a processing module.
  • the temperature sensor can be configured to optically sense a temperature of a liquid (e.g., including cells) in the process board 104, in a processing module 106, 108, 110, etc., which can be used to control heating (or cooling) of the components of the cell processing system 100, and can be used to control liquid through the cell processing system 100.
  • a liquid e.g., including cells
  • each sensor 114 can be isolated from the liquid that the respective sensor 114 is sensing.
  • each sensor 114 can sense a parameter without being in contact with a liquid, which can be advantageous in that the specific sensor 114 can be reused for other process boards and does not need to be replaced after the process board 104 has been used.
  • each sensor 114 can be fluidly coupled to the liquid that the sensor 114 is sensing to sense the parameter from the liquid.
  • the sensor 114 can be an electrochemical sensor.
  • the sensor 114 can be an optical density (OD) sensor, which can sense the optical density of a sample optically coupled to the optical density sensor.
  • the optical density sensor can be a cell density sensor.
  • the imaging device 116 can be coupled to the control board 102 or can be aligned with the process board 104 (e.g., the imaging device 116 being aligned with a window through the substrate 128 of the control board 102).
  • the imaging device 116 can be a camera, a microscope, etc.
  • the imaging device 116 can include an infrared (“IR”) camera that can be configured to monitor the cells and media within a processing module.
  • IR infrared
  • the imaging device 116 can include a microscope that can be configured to acquire one or more images of cells (e.g., that flow through a hemocytometer grid of the process board 104) to determine the quality of cells and a concentration of cells in the liquid of a processing module (e.g., including determining or estimating a total number of cells in the liquid processing module).
  • the imaging device 116 can include an image sensor (e.g., a CCD array, a CMOS array, etc.).
  • the imaging device 116 can determine an optical density (“OD”) from, for example, acquiring an image of the cells.
  • the OD readings can be used to detect contamination in a cell culture, for example by detecting increases in OD (e.g. increases in OD600 readings) due to scattering by contaminants such as bacteria.
  • the disinfection system 118 can be configured to disinfect one or more surfaces of the process board 104, and one or more surfaces of each of the processing modules 106, 108, 110.
  • the disinfection system 118 can be configured to disinfect each connector (e g., a liquid connector) of the process board 104, and each of the processing modules 106, 108, 110.
  • the disinfection system 118 can be implemented in different ways.
  • the disinfection system 118 can include a reservoir containing a chemical disinfectant (e.g., hydrogen peroxide, an alcohol such as ethanol, etc.) and a nozzle fluidly coupled to the reservoir.
  • a chemical disinfectant e.g., hydrogen peroxide, an alcohol such as ethanol, etc.
  • the nozzle can be configured to receive the chemical disinfectant from the reservoir and spray the chemical disinfectant over one or more surfaces of the cell processing system 100 to disinfect the one or more surfaces.
  • the disinfection system 118 can include one or more UV lights (e.g., a UVC light) that can be configured to emit UV light (e g., within a wavelength range of 200 to 280 nm) at one or more surfaces of the cell processing system 100 to disinfect the one or more surfaces.
  • the process board 104 can include one or more holes to receive the disinfection system 118, such that a portion of the disinfection system 118 can be positioned on the first side of the process board 104 (e.g., for better access to the desired surfaces to disinfect of the process board 104 and the processing modules 106, 108, 110).
  • the actuators 120 can be coupled to the control board 102 or can be configured to extend through the control board 102.
  • the actuators 120 can be implemented in different ways.
  • the actuator 120 can be a rotational actuator (e.g., a motor), a linear actuator, etc.
  • the actuators 120 can include an actuator that can be configured to extend through the process board 104 to disengage the processing module 106 from the process board 104 (e.g., thereby fluidly decoupling the processing module 106 from the process board 104), which can occur after the processing module 106 (and the processing modules 108, 110) have been used.
  • the actuators 120 can include an actuator that can be configured to extend to disengage the process board 104 from the control board 102 (e.g., after the process board 104 has been used, to, for example, accommodate a different process board).
  • the magnet(s) 122 can be configured to implement a magnetoporation process (or a mechanoporation process) or an isolation process (a debeading process) on cells within the process board 104 or one of the processing modules 106, 108, 110.
  • the magnets 122 can each be coupled to the control board 102 (e.g., the substrate 128 of the control board 102) and can extend on the first side of the substrate 128 of the control board 102.
  • each magnet 122 can extend through a respective hole in the substrate 142 of the process board 104 when, for example, the process board 104 is coupled to the control board 102.
  • each magnet 122 can be advantageously brought closer to the processing module 106 (or a different processing module) to thereby impart a larger magnitude magnetic field on the cells of the processing module 106.
  • each magnet 122 can be a permanent magnet or can be an electromagnet.
  • the power source 124 can provide power to some or all of the components of the cell processing system 100.
  • the power source 124 can be an electrical power source (e.g., a battery, a power cord, etc.) and can provide power to the gas source(s) 112, the sensor(s) 114, the imaging device(s) 116, the disinfection system 118, the actuator(s) 120, the actuator(s) 120, the magnet(s) 122, the power source 124, and the computing device 126.
  • the computing device 126 can be in communication (e.g., bidirectional communication) with some or all the components of the cell processing system 100.
  • the computing device 126 can be in communication with the gas source(s) 112, the sensor(s) 114, the imaging device(s) 116, the disinfection system 118, the actuator(s) 120, the magnet(s) 122, the power source 124, etc., to transmit instructions to (or receive data from) a respective component of the cell processing system 100.
  • this can include the computing device 126 controlling the gas source 112 to move liquid through one or more of the processing modules 106, 108, 1 10, the process board 104, the computing device 126 causing the cells to be electroporated, etc.
  • the computing device 126 can be implemented in a variety of ways.
  • the computing device 126 can be implemented as one or more processor devices (e.g., a hardware processor) of known types (e.g., microcontrollers, field-programmable gate arrays, programmable logic controllers, logic gates, etc.), including as general or special purpose computers.
  • the computing device 126 can also include other computing components, such as memory, inputs, other output devices, etc. (not shown).
  • the computing device 126 can be configured to implement some or all the steps of the processes described herein, as appropriate, which can be retrieved from memory.
  • the computing device 126 can control one or more of the components of the cell processing system 100, based on (e.g., in response to) a signal (e.g., an electrical signal) from another computing device.
  • a signal e.g., an electrical signal
  • the computing device 126 can include multiple control devices (or modules) that can be integrated into a single component or arranged as multiple separate components.
  • each processing module 106, 108, 1 10 can be disengaged from the process board 104.
  • the process board 104 can be disengaged from the control board 102.
  • the processing modules 106, 108, 110, and the process board 104 can be disposed (e.g., in a biological waste container, which can be destined for autoclaving before disposal).
  • control board 102 can be advantageously used for many different biological products, including different types of genetically modified cells, different types of biological therapeutic products, etc. Accordingly, this modular ability of the cell processing system 100 can not only ensure that multiple different types of biological products can be created each for different patients, but that the same control board 102 can be used to ensure that the multiple different type of biological products are isolated from each other. In this way, and advantageously, smaller batches of biological products can be created that can be patient specific, which can considerably increase access to different types of biological products to patients who would otherwise not have access to them.
  • some components of the cell processing system 100 can be integrated with, coupled to, fluidly coupled to, electrically connected to, etc., the control board 102, as appropriate.
  • the gas source(s) 112 can be fluidly coupled to the control board 102
  • the sensor(s) 114 can be electrically connected to (and coupled to) the control board 102
  • the imaging device(s) 116 can be optically coupled to (and coupled to) the control board 102
  • the disinfection system 118 can be optically or fluidly coupled to the control board 102 (e.g., and can extend through the control board 102 and the process board 104)
  • the actuator(s) 120 can be coupled to the control board 102 (e.g., and can extend through the process board 104, can extend through the control board 102)
  • the power source 124 can be electrically connected to (and coupled to) the control board 102
  • the computing device 126 can be electrically connected to (and coupled to) the control board 102.
  • the cell processing system 100 can include other numbers of processing modules (e.g., one, two, four, five, six, seven, eight, nine, ten, etc.).
  • the control board 102, the process board 104, and the processing modules 106, 108, 110 have been illustrated as having certain numbers of gas connectors and liquid connectors, each of these components can have other numbers of gas connectors and liquid connectors (e.g., one, two, three, four, five, six, seven, eight, nine, ten, etc.), as appropriate.
  • control board 102 (and the process board 104) has been described as a board, which can include having one or more substantially (i.e., deviating by less than 10 percent from) planar surfaces (e.g., opposing planar surfaces), the control board 102 (and the process board 104) can have other shapes (e.g., two dimensional shapes, three dimensional shapes, etc.).
  • the control board 102 (and the process board 104) can be curved, can be a block of material, etc.
  • the control board 102 is configured to engage a single process board at a time (e.g., the process board 104).
  • each control board can be designated to a single respective process board, which can ensure that each control board and respective process board are isolated from other pairs of a control board and a respective process board (e.g., to ensure that biological products from one pair are not inadvertently introduced into another pair, and vice versa).
  • the cell processing system 100 can include an agitator that can be configured to agitate a processing module.
  • the agitator can be implemented in different ways.
  • the agitator can be an actuator (e.g., a linear actuator), a transducer (e.g., a piezoelectric transducer, a thermal transducer, etc.), an eccentric rotating mass vibration motor (ERM), etc.
  • the transducer can be configured to transform one from of energy (e.g., electrical energy, thermal energy, etc.) to mechanical energy.
  • the transducer can be powered by the power source 124.
  • the actuator can extend through a hole in the process board 104 to contact a processing module.
  • the actuator can extend and retract (e.g., sequentially) while in contact with the processing module to agitate the processing module.
  • each connector e.g., a gas connector, a liquid connector, etc.
  • each gas connector can define a gas port that directs gas through the gas port
  • each liquid connector can define a liquid port that directs liquid through the liquid port.
  • a port of a connector can be a specific type of port, in which the port is fluidly coupled.
  • a liquid port of a liquid connector of a processing module can be a cell port, a sampling port, etc.
  • FIG. 3 shows an illustration of a cell processing unit 300, which can include some or all the components of the cell processing system 100 (and vice versa as appropriate).
  • the cell processing unit 300 can be a miniaturized cell therapy manufacturing unit, which can be configured to create a plurality of different biological products (e.g., different genetically modified cells) including each for different patients.
  • the cell processing unit 300 can be positioned within a health care facility (e.g., a hospital, an outpatient clinic, etc ), a different facility, a different building, etc., which can allow for on-site manufacturing of biological products for one or more different patients. In this way, the cell processing unit 300 can mitigate logistical hurdles with previous patient-specific cell engineering workflows (and other biological therapeutic workflows).
  • the cell processing unit 300 can include an enclosure 302 defining an internal volume 304 that can be configured to enclose some or all of the components of the cell processing unit 300. In this way, the components enclosed by the enclosure 302 (e.g., positioned within the internal volume 304) can be isolated from the ambient environment to ensure that the internal volume 304 remains an aseptic environment. In some cases, the internal volume 304 can be maintained at or within a range of particular parameters or conditions.
  • the cell processing unit 300 can include a computing device that can control an HVAC system to maintain a specific temperature (e.g., 37 degrees Celsius) of air within the internal volume 304 (e.g., to maintain an environment that is favorable for cell growth).
  • the computing device can control one more gas sources (e.g., a medical gas source of oxygen, a pump to vacate air out of the internal volume 304, etc.) to maintain a specific concentration of carbon dioxide within the internal volume 304.
  • the computing device can remove gas from within the internal volume 304 (e.g., by activating a pump), or can introduce gas into the internal volume 304 (e.g., by opening a valve fluidly coupled to the medical gas source) to decrease the concentration of carbon dioxide within the internal volume 304.
  • maintaining a desired temperature and carbon dioxide concentration within the internal volume 304 of the enclosure 302 can advantageously obviate the need for an incubator.
  • each process board or processing module does not have to be physically moved into and out of the incubator (e.g., preventing physically moving components can be less complicated, can be less prone to introduce contaminants, etc.).
  • the cell processing unit 300 can include one or more filters (e.g., HEPA filters) fluidly coupled to the internal volume 304 of the enclosure 302. In this way, the computing device can cause a pump to drive fluid within the internal volume 304 to filter (and thus clean) the fluid within the internal volume 304 to maintain an aseptic environment within the enclosure 302.
  • the cell processing unit 300 can include pass-through cabinets 306, 308, 310. Each of the pass-through cabinets 306, 308, 310 can provide access to the internal volume 304 of the enclosure 302, while ensuring that the aseptic environment of the internal volume 304 is not compromised.
  • each pass-through cabinet 306, 308, 310 can include at least two doors that are separately openable (and closeable), with two doors being spaced apart from each other to define an intermediate volume that is selectively fluidly coupled to the internal volume 304 of the enclosure 302. In this way, materials, components, etc., can be brought into (and out of) the internal volume 304 of the enclosure 302 to maintain the aseptic environment of the internal volume 304 of the enclosure 302.
  • the pass-through cabinet 306 can be dimensioned to facilitate the passage of biological samples into and out of the internal volume 304
  • the cabinet 308 can be dimensioned to facilitate the passage of one or more reagents into (and out of) the internal volume 304
  • the cabinet 310 can be dimensioned to facilitate the passage of a person into and out of the internal volume 304.
  • the enclosure 302 can be coupled to a structure that supports one or more components of the cell processing unit 300.
  • the cell processing unit 300 can include a platform 312 that can support one or more components of the cell processing unit 300 (e.g., with the platform 312 at least partially defining the internal volume 304 of the enclosure 302).
  • the cell processing unit 300 can include shelves 314, 316 that can be positioned outside of the internal volume 304 of the enclosure 302, and can support, secure, etc., one or more components of the cell processing unit 300.
  • each of the shelves 314, 316 can support one or more pumps, a power source, a computing device, one or more other components of the cell processing unit 300 (e.g., including one or more components of the cell processing system 100).
  • the cell processing unit 300 can include other components to provide access to the internal volume 304 while maintaining the aseptic environment of the internal volume 304.
  • the cell processing unit 300 can include one or more entry port gloves coupled to the enclosure 302, or one or more entry ports coupled to the enclosure 302 that are resealable (e.g., an iris port). In this way, a user can access the internal volume 304 of the enclosure 302 via the one or more entry port gloves or the one or more entry ports.
  • FIG. 4 shows different views of the cell processing unit 300, with the enclosure 302 opaque for some views and transparent for others.
  • FIG. 5 shows an isometric view of the cell processing unit 300 with the top of the enclosure 302 removed for visualization of the components positioned within the internal volume 304 of the enclosure 302.
  • the cell processing unit 300 can include a freezer 318, a cabinet 320 that can contain one or more processing modules (e.g., any of the processing modules herein), an incubator 322, a centrifuge 324, a tray 328, a robot arm 330, and a liquid handling device 332, each of which can be positioned within the internal volume 304 of the enclosure 302.
  • the cell processing unit 300 can include control boards 334, 336 (e.g., similar to the control board 102), each of which is configured to engage with a respective process board 338, 340. While there are six control boards with three positioned on one side of the robot arm 330, and the other three positioned on the other side of the robot arm 330, the cell processing unit 300 can include other numbers of control boards (and other numbers of control boards positioned on opposing sides of the robot arm 330). In some cases, each control board and a respective process board (e.g., the control board 334 and the process board 338) can be defined as a cell processing station that can be configured to create a different biological product (e.g., that can be for a particular patient). Thus, each cell processing station (e.g., with a control board and a respective process board) can be positioned at a different location within the enclosure 302.
  • control boards 334, 336 e.g., similar to the control board 102
  • the cell processing unit 300 can contain a plurality of processing modules, which can include a plurality of a first type of processing module, a plurality of a second type of processing module, and so on.
  • the cabinet 320 can store the plurality of processing modules
  • the tray 328 can store the plurality of processing modules (e.g., or a plurality of other processing modules).
  • the tray 328 can include a plurality of sections, each of which can include a plurality of recesses (or slots) for receiving a processing module.
  • each recess of a respective section of the tray 328 can receive the same type of processing module, and each station can receive a different type of processing module.
  • a processing module can be placed in one or more of the instruments within the enclosure 302 to perform a respective process on the cells contained therein.
  • a processing module can be placed into the freezer 318 to freeze the cells contained therein, the processing module can be placed into the incubator 322 to mix, provide a better environment, etc., for the cells contained therein, the processing module can be placed into the centrifuge 324 to concentrate the cells contained therein, etc.
  • a different container e.g., a vial or a tube
  • the processing module can be placed into the one or more of the instruments within the enclosure 302 to perform the respective process on the biological product contained therein.
  • the robot arm 330 can be positioned between at least two control boards, which can provide better access to the at least two control boards.
  • the robot arm 330 positioned between control boards can require less complicated movement, can require smaller linkages, etc., than, for example, if one row of control boards were positioned behind another row of control boards.
  • the robot arm 330 e.g., the end effector
  • the robot arm 330 can move to a stack of process boards (e.g., supported by the platform 312 of the enclosure 302), can grasp a process board (e.g., the top process board of the stack of process boards), move the process board to the control board, and move the process board towards the control board to engage the control board.
  • the robot arm 330 can engage each processing module to the respective process board and can disengage each processing module from the respective process board.
  • the robot arm 330 can move to the tray 328, can grasp a processing module, move the processing module to the control board, and move the processing module to the control board to engage the process board.
  • the cell processing unit can include other mechanical devices to engage and disengage components (and move components including the process board, the processing modules, etc.).
  • the cell processing unit can include a conveyor (e.g., a conveyor belt) that can move one or more process boards into the enclosure, and a rotatable platform to rotate each process board (e.g., until the process board reaches the desired orientation with respect to a control board).
  • the cell processing unit can include a first actuator that can be configured to move the process board off the conveyor (e g., a horizontal actuator), and a second actuator that can be configured to move the process board to couple the process board to the control board (e.g., a vertical actuator).
  • this process can be also used for moving and engaging a processing module to a process board.
  • the cabinet 308 can include a plurality of sub-compartments that include a respective reservoir that is fluidly coupled to the liquid handling device 332.
  • the cabinet 308 can include a first reservoir containing cell media positioned within a first sub-compartment, a second reservoir containing a buffer reagent (e.g., to be included for genetically modifying cells) positioned within a second sub-compartment, and a third reservoir containing waste (or to contain waste) positioned within a third sub-compartment.
  • each sub -compartment can be sealed from the other sub-compartments, and each reservoir can be positioned behind a wall of the sub-compartment of the cabinet 308.
  • each sub-compartment can be isolated from the internal volume 304 of the enclosure 302, but each reservoir (e.g., the first reservoir, the second reservoir, and the third reservoir) can be fluidly coupled to the liquid handling device 332 (e.g., via a tube that extends through the wall of the sub-compartment).
  • the liquid handling device 322 can have a reservoir, which can prevent the need for a tube to extend from the cabinet 308 to the liquid handling device 322.
  • the liquid handling device 322 can go to a pass- through cabinet, or a robot arm (e.g., the robot arm 330) can grasp the used reservoir, disengage the reservoir from the liquid handling device 322, and move the disengaged reservoir onto a shuttle (or a track), which can move the reservoir to the cabinet 306.
  • the robot arm can move the disengaged reservoir and place the disengaged reservoir into the cabinet 308 (or other pass-through door, cabinet, etc.).
  • the robot arm can grasp another reservoir (e.g., a full reservoir), move the other reservoir to the liquid handling device 322, and engage the other reservoir to the liquid handling device 322 (e.g., at a receptacle of the liquid handling device 322).
  • another reservoir e.g., a full reservoir
  • the other reservoir e.g., a full reservoir
  • engage the other reservoir to the liquid handling device 322 e.g., at a receptacle of the liquid handling device 322).
  • FIG. 6 shows a top isometric view of the cell processing unit 300 with the enclosure
  • the robot arm 330 can include one or more grippers 344 (e.g., at the end effector of the robot arm 330) to selectively grasp a process board, a processing module, etc.
  • the robot arm 330 can include a symbol scanner (e.g., a barcode scanner) that is configured to scan a symbol of a component (e.g., a process board, a processing module, etc.) to identify the component prior to grasping (and moving) the component.
  • the robot arm 330 (e.g., at the end effector of the robot arm 330) can have an actuator coupled thereto (e.g., piston-like mechanism), which can extend to push (e.g., vertically push) the process board into engagement with the control board, and one or more processing modules with the process board, which can ensure that the components are properly engaged with each other.
  • an actuator coupled thereto e.g., piston-like mechanism
  • the liquid handling device 332 can include a housing 346, an articulatable arm 348 coupled to the housing 346, liquid connectors 350, 352, 354 coupled to the articulatable arm 348 (e.g., at a distal end of the articulatable arm 348 to, for example, define an end effector of the articulatable arm 348), and pumps 356, 358, 360 each of which is fluidly coupled to a respective liquid connector 350, 352, 354 (e.g., which can each be an aseptic connector).
  • the liquid handling device 332 can direct liquid into a processing module or can pull liquid out of the processing module (or another processing module).
  • the articulatable arm 348 can fluidly couple each liquid connector 350, 352, 354 to a respective liquid connector of the processing module. Then, each pump 356, 358, 360 can direct liquid (e g., from a respective reservoir) through a respective liquid connector 350, 352, 354 into the processing module, or can pull liquid from the respective liquid connector 350, 352, 354 out of the processing module.
  • the liquid handling device 322 can be defined as a dispenser.
  • the articulatable arm 348 (and the robot arm 330) can have a plurality of degrees of freedom (e.g., one, two, three, four, five, six, etc.), and the articulatable arm 348 can be a robot arm.
  • the robot arm 330 and the liquid handling device 332 can be slidably coupled to a track 362 that is coupled to the platform 312. In this way, the robot arm 330 and the liquid handling device 332 can each slide along the track 362 to translate the respective device to change the position of the robot arm 330 and the liquid handling device 332 with respect to a desired control board.
  • FIG. 7 shows an isometric view of the cell processing unit 300 with the enclosure 302 transparent for visualization of the components positioned therein.
  • the cell processing unit 300 can include one or more sensors for testing a byproduct of liquid containing cells that can be indicative of the health of the cells.
  • the cell processing unit 300 can include a glucose sensor and a lactate sensor, each of which can be in communication with a computing device.
  • the robot arm 330 (or a different robot arm) can collect a sample from one of the process boards (or processing modules coupled to the process board) and can fluidly couple the sample (e.g., including a liquid) to the glucose sensor and the lactate sensor.
  • the glucose sensor can sense a glucose concentration of the sample
  • the lactate sensor can sense a lactate concentration of the sample.
  • the computing device can, based on the glucose concentration, the lactate concentration, or both, cause the gas source (or the liquid handling device 332) to implement a process on cells including performing exchange of cell media (e.g., at least because the current glucose or lactate concentration indicates that the cell byproducts are too high) of a processing module.
  • the glucose concentration, lactate concentration, etc. can indicate that the number of cells, or the cell concentration, has reached a sufficient level (e.g., for harvesting).
  • FIG. 8 shows an enlarged view of the cell processing unit 300 without the enclosure 302 for visualization of the components positioned therein.
  • FIG. 9 shows an isometric view of the control board 334.
  • the control board 334 can include a substrate 364, a plurality of gas connectors 366 coupled to the substrate 364, holes 368, 370, 372, 374, 376, 378, one or more engagement features 380, 382, an actuator 384, a plate 386 moveably coupled to the actuator 384 and including a plurality of protrusions 388, and an electrical board 390 including a plurality of electrical connectors 392.
  • Each of the holes 368, 370, 372, 374, 376, 378 can facilitate the passage of a component through the control board 334 (e.g., to the process board 338), or to allow visual access of the process board or a processing module coupled to the process board.
  • a UV light can be aligned with the hole 368
  • a magnet e.g., a south side of the magnet
  • a magnet e.g., a north side of the magnet
  • an actuator can extend through the hole 374 to disengage a processing module from the process board 338 (e.g., that is coupled to the control board 334)
  • an imaging device e.g., a microscope
  • an imaging device e.g., an infrared camera
  • each hole 376, 378 can be lined with a transparent (or translucent) substrate to define a respective well or a chamber.
  • Each of these wells can be used to create a vacuum (or facilitate fluidly receiving a vacuum source) to pull out a specific cell sample volume out of a processing module, when a processing module engages with the process board 104 that has a membrane or diaphragm at its bottom surface (e.g., where the cell counting grid and CO2, O2, pH, OD sensors are located).
  • the control board 334 can include one or more engagement features that are configured to align with a respective one or more engagement features of the process board 338.
  • the engagement feature 380 can include a wall that can block the process board 338 from moving out of engagement with the control board 334, and the engagement feature 382 can include a magnet that can magnetically couple to a respective magnet of the process board 338.
  • the control board 334 can include a plurality of peripheral magnets (e.g., four), each of which is configured to magnetically coupled with a respective magnet of the process board 338.
  • the plate 386 can be pivotally coupled to the actuator 384.
  • the actuator 384 can rotate the plate 386 towards the substrate 364 to cause each protrusion 388 to contact and fluidly couple a respective cartridge to a processing module.
  • the actuator 384 can rotate the plate 386 away from the substrate 364.
  • a processing module can include one or more liquid level sensors.
  • Each liquid level sensor which can be an electrode, can be electrically connected to a respective electrical connector 392 of the electrical board 390, which is electrically connected to a computing device.
  • the computing device can receive an indication that two liquid level sensors are electrically connected (e.g., via an electrically conductive liquid) or that a resistance (or impedance) is indicative of two liquid level sensors being electrically connected to determine that a liquid level has been (or has not been reached) in a processing module.
  • FIG. 10 shows a side view of the control board 334, while FIG. 1 1 shows a top view of the control board 334. As shown in FIGS.
  • the UV light sources can be aligned with one or more respective holes in the substrate 364, the microscope objective can be aligned with a hole in the substrate, and an IR camera can be aligned with a hole in the substrate.
  • the control board can be configured to never come in contact with liquid including cells (e.g., aside from aerosols).
  • a gas source that directs gas into (or out of) the gas connectors, which drives liquid through the process board 338 and one or more process modules, does not flow into or out of the control board 334. In this way, the control board 334 can remain hygienic and can thus be reused for different process boards.
  • FIG. 12 shows a top view of the process board 338.
  • the process board 338 can include a substrate 394, a plurality of gas connectors 396 coupled to the substrate 394, a plurality of liquid connectors 398 coupled to the substrate 394, holes 400, 402, 404, 406, 408, an optical connector 412, and one or more engagement features 414.
  • Elements 406 and 412 each may include a membrane or diaphragm over the opening which aligns with holes 378 and 376, respectively, on the control board 334.
  • each gas connector 396 can be configured to engage with a corresponding gas connector 366 of the control board 334.
  • each liquid connector 398 can be configured to engage with a corresponding liquid connector of a processing module.
  • the substrate 394 can include a number of identifiers (e.g., indicated “S”) to identify a number of different sections of the substrate 394. For example, five different sections are illustrated in FIG. 12, however, different numbers of sections could be used.
  • Each section of the substrate 394 is configured to engage with a respective (different) processing module.
  • each hole 400, 402, 404, 406, 408 can be configured to allow for a component to pass through the respective hole, or to allow for the component to align with the hole (e.g., for visualization of the control board 338 or a processing module).
  • the hole 400 can align with a magnet (e.g., a south end of the magnet) and can allow the magnet to pass through the substrate 394 at the hole 400
  • the hole 402 can align with a magnet (e.g., a north end of the magnet) and can allow the magnet to pass through the substrate 394 at the hole 402
  • the hole 404 can align with an imaging device (e g., an IR camera)
  • the hole 406 can align with an imaging device (e g., a microscope)
  • the hole 408 can align with (and can allow passage through) of a UV light source
  • the hole 410 can receive an actuator that can be configured to disengage a processing module (e.g., that is engaged with the process board 338 at the section “S5” of the process board 338).
  • the process board 338 can include an optical connector 412 that can be coupled to the substrate 394 of the process board 338.
  • the optical connector 412 can be configured to be selectively optically coupled to the control board 334, which is optically coupled to one or more of a carbon dioxide sensor, a pH sensor, an OD sensor, or an oxygen sensor, each of which can be an optical sensor.
  • the optical connector 412 optically couples to the one or more sensors of the control board 334.
  • each of these sensors can be optically coupled to a processing module that couples with the process board 338 at the section “S2” of the substrate 394 of the control board 334 (e.g., so that each of the sensors can then sense a parameter of the fluid within the processing module).
  • each of these sensors can be optically coupled to a chamber that is fluidly coupled to a processing module. In this way, liquid including cells dispersed therein can be drawn into the chamber to sense parameters of a smaller amount of liquid in the chamber (e.g., as compared to the volume of an inner chamber of a processing module).
  • the process board 338 can include one or more engagement features 414 that are each configured to align with a respective one or more engagement features 382 of the control board 334.
  • the process board 338 can include a plurality of peripheral magnets each of which is configured to magnetically coupled to a respective peripheral magnet of the control board 334 to align the process board 338 with the control board 334.
  • FIG. 13 shows a side isometric view of the process board 338 positioned above and aligned with the control board 334.
  • FIG. 14 shows a front isometric view of the process board 338 and a plurality of different processing modules positioned above the process board 338.
  • the cell processing unit 300 can include processing modules 416, 418, 420, 422, 424, 426, each of which can be positioned above the process board 338 can be a specific implementation of other processing modules described herein (and vice versa), as appropriate.
  • Each processing module 416, 418, 420, 422, 424, 426 can be configured to implement one or more cell processes (or processes associated with cells).
  • the processing module 416 can be configured to collect a sample of liquid including cells and can be configured to collect a final biological product for cryopreservation.
  • each processing module 418, 420 can be configured to concentrate cells within the respective processing module, and the processing module 422 can be configured to grow and proliferate cells therein.
  • the processing module 424 is configured to electroporate cells therein, and the processing module 426 is configured to create a reagent (or reagent formulation) for genetically modifying cells (e.g., the reagent including a ribonucleoprotein “RNP”).
  • a reagent or reagent formulation for genetically modifying cells
  • RNP ribonucleoprotein
  • Some or all the processing modules 416, 418, 420, 422, 424, 426 can be configured to simultaneously engage the process board 338 to fluidly couple the respective processing module 416, 418, 420, 422, 424, 426 to the process board 338.
  • FIG. 15 shows an isometric, a top view, and cross-sectional views of a processing module 450, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 450 can be a cell concentrating processing module, or a cell growing processing module.
  • the processing module 450 can include a housing 452, inner chambers 454, 456, a plurality of gas connectors 458 coupled to the housing 452, a plurality of liquid connectors 460 coupled to the housing 452, and membranes 462, 464 positioned within the housing 452.
  • the membrane 462 and the housing 452 can define the inner chamber 454 (e.g., which can be a cell media chamber), while the membranes 462, 464 and the housing 452 can define the inner chamber 456 (e.g., which can be a cell chamber, such as for growing cells).
  • the membrane 462 can be liquid permeable, but impermeable to the passage of cells therethrough.
  • the membrane 462 can include a plurality of pores sized to allow nutrients, byproducts, etc., therethrough, but sized to block cells from passing through the pores to the inner chamber 454.
  • the membrane 464 can be liquid impermeable, but can be gas permeable. In this way, gasses including carbon dioxide and oxygen can pass through the membrane 464 in both directions to equilibrate the gases (e.g., dissolved within the liquid contained in the processing module 450).
  • the processing module 450 can include a tube 466 positioned within the housing 452 and extending from a bottom end of the chamber 454 to an upper end of the chamber 454.
  • the tube 466 can be a chimney.
  • the tube 466 can be fluidly coupled to the chamber 454 at (only) an upper region of the chamber 454. In this way, gas can be pulled out of the chamber 454 or directed into the chamber 454 (e.g., via the tube 466, which can be fluidly coupled to a gas connector of the processing module 450) to force liquid out of the inner chamber 456 to concentrate cells within the inner chamber 456.
  • a membrane e.g., the membrane 464 that is gas permeable and liquid impermeable can have a plurality of pores each having an average pore diameter less than (or less than or equal to) 1 nm.
  • a membrane e.g., the membrane 462 that is liquid permeable and impermeable to the passage of cells therethrough can have a plurality of pores each having an average pore diameter less than (or less than or equal to) 5 micrometers, 4 micrometers, 3 micrometers, 2 micrometers, 1 micrometer, 0.5 micrometers, etc. and greater than (or greater than or equal to) 0.5 micrometers, 1 micrometer, 2 micrometers, 3 micrometers, etc.
  • each membrane described herein can be a barrier. In this way, the barrier can provide the same permeability, but can be more rigid than, for example, a membrane.
  • FIG. 16 shows the processing module 450 with cell media positioned within the inner chambers 454, 456 of the processing module 450 to show how cells can be concentrated within the inner chamber 456.
  • gas can be introduced into a gas connector of the processing module, which drives liquid from the chamber 456 to the chamber 454 to the chamber 454 and out of the chamber 454 through a liquid connector. In this way, because the cells are blocked from passing through the membrane 462, the cells can advantageously concentrate within the chamber 456.
  • FIG. 17 shows an isometric, a top view, and cross-sectional views of a processing module 500, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 500 can be a cell concentrating processing module, or a cell growing processing module.
  • the processing module 500 can include a housing 502, an inner chamber 504, a plurality of gas connectors 506 coupled to the housing 502, a plurality of liquid connectors 508 coupled to the housing 502, and a membrane 510 positioned within the housing 502.
  • the membrane 510 and the housing 502 can define the inner chamber 504 (e.g., which can be a cell chamber, such as for growing cells).
  • the membrane 510 can be liquid impermeable, but can be gas permeable. In this way, gasses including carbon dioxide and oxygen can pass through the membrane 510 in both directions to equilibrate the gases.
  • the processing module 500 can include a tube 512 positioned within the housing 502 and extending from a bottom end of the chamber 504 to an upper end of the chamber 504.
  • the tube 512 can be fluidly coupled to the chamber 504 at (only) an upper region of the chamber 504. In this way, gas can be pulled out of the chamber 504 or directed into the chamber 504 (e.g., via the tube 512, which can be fluidly coupled to a gas connector of the processing module 500) to force liquid out of the inner chamber 504 to concentrate cells within the inner chamber 504.
  • the processing module 500 can concentrate cells within the inner chamber 504.
  • gas can be introduced into a gas connector of the processing module, which drives liquid from the inner chamber 504 out of the inner chamber 504 through a liquid connector.
  • the cells can advantageously concentrate within the chamber 504.
  • FIG. 18 shows an isometric, a top view, and cross-sectional views of a processing module 550, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 550 can be a cell concentrating processing module, or a centrifugation processing module.
  • the processing module 550 can include a housing 552, an inner chamber 554, a plurality of gas connectors 556 coupled to the housing 552, a plurality of liquid connectors 558 coupled to the housing 552.
  • the inner chamber 554 can decrease in cross-section along a dimension (e.g., an axial axis of the housing 552 that is parallel to a gravity vector) until the inner chamber 554 ends.
  • the inner chamber 554 at an end can have the smallest cross-sectional area, which can facilitate the formation of a cell pellet therein.
  • a membrane 560 can extend across the inner chamber 554 (e g., at the smallest cross-sectional area of the chamber 554) and can be impermeable to cells passing through.
  • the housing 502 can include one or more angled walls 562 that can define the inner chamber 554.
  • the processing module 550 can include a tube 564 positioned within the housing 552 and extending from a bottom end of the chamber 554 to an upper end of the chamber 554.
  • the tube 564 can be fluidly coupled to the chamber 554 at (only) an upper region of the chamber 554.
  • gas can be pulled out of the chamber 554 or directed into the chamber 554 (e.g., via the tube 564, which can be fluidly coupled to a gas connector of the processing module 550) to force liquid out of the inner chamber 554 to concentrate cells and form a cell pellet within the inner chamber 554.
  • the processing module 550 can include one or more liquid permeable (but cell impermeable) membranes that extend along at least a portion of an angled wall 562 of the housing 552.
  • each liquid permeable membrane can be fluidly coupled to a liquid connector.
  • cell media can be introduced through the liquid connector to pass through the liquid permeable membrane to force the cells off the liquid permeable membrane thereby resuspending the cells in the cell media (or one or more liquid buffers, one or more liquid cryopreservation agents, etc.).
  • FIG. 19 shows the configuration with at least one liquid permeable membrane (e g., a ring membrane) extending across a portion of the angled wall of the housing of the processing module.
  • FIG. 20 shows an isometric, a top view, and cross-sectional views of a processing module 600, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 600 can be a cell growing processing module, or a electroporation processing module.
  • the processing module 600 can include a housing 602, inner chambers 604, 606, 608, a plurality of gas connectors 610 coupled to the housing 602, and electrodes 609, 611 positioned within the inner chamber 606.
  • the processing module 600 can include a plurality of tubes, each of which can be positioned within a respective chamber 604, 606, 608 and can extend and can be fluidly coupled to the respective chamber 604, 606, 608 at a top region of the respective chamber 604, 606, 608.
  • each tube can be fluidly coupled to a respective gas connector 610. Tn this way, gas can be introduced into a respective chamber (e.g. via the tube and the respective gas connector 610) to move liquid (including cells positioned therein) between chambers and into (and out of) the processing module 600.
  • the processing module 600 can include a plurality of liquid connectors each of which can be fluidly coupled to one or more of the inner chambers of the processing module 600.
  • one or more reagents e.g., an electroporation buffer, an RNP, etc.
  • cells can be driven into the inner chamber 604 (e.g., via a liquid connector).
  • the one or more reagents and the cells can be driven into the chamber 606 (e g., via a gas connector and a tube, generating a pressure differential), and the one or more reagents and the cells can be electroporated by the electrodes 609, 611.
  • the electroporated cells and the remaining liquid
  • can be driven into the chamber 608 e.g., via a gas connector and a tube for loading into a different processing module (e.g., for growing cells).
  • the processing module 600 can include electrodes 612, 614, 616 positioned within the chamber 604. These electrodes 612, 614, 616 can provide information for a liquid level of the chamber 604. For example, when the liquid from the chamber 604 is driven into the chamber 606, the liquid level is above the electrode 616, but has not reached the electrode 614. Thus, the resistance (or impedance) between the electrodes 614, 616 (e g., which can be received by a computing device) is large (e.g., due to the high resistance air gap) indicating that the liquid level is below the electrode 614.
  • the resistance between the electrodes 614, 616 is small (e.g., due to the electrically conductive liquid), which indicates that the liquid level is at least at the electrode 614.
  • the resistance between the electrodes 612, 616 is large, indicating that the liquid level is between the electrodes 612, 614.
  • the resistance between the electrodes 612, 614 is small, thus indicating that the liquid level in the chamber 606 is at or above the electrode 612.
  • these electrodes 612, 614, 616 can each be electrically connected to an electrical terminal of the control board.
  • the processing module 650 can be a cell concentrating processing module, a cell growing processing module, a cell electroporation module, or combinations thereof.
  • the processing module 650 can include a housing 652, inner chambers 654, 656, a plurality of gas connectors 658 coupled to the housing 652, a plurality of liquid connectors 660 coupled to the housing 652, membranes 662, 664 positioned within the housing 652, and electrodes 668, 670 positioned within the housing 652.
  • each electrode 668, 670 can be positioned within the chamber 656, while in other cases, the electrodes 668, 670 can be positioned outside of the chamber 656.
  • each electrode 668, 670 can include a plurality of holes positioned therethrough (e.g., slots, elongated slots), so as to ensure that each electrode is in contact with the electrically conductive liquid within the chamber 656 (e.g., to electroporate the cells).
  • each electrode 668, 670 can be a mesh (e.g., a metal mesh screen).
  • each electrode 668, 670 can perform a function of a respective membrane.
  • the electrode 668 can be liquid permeable, but impermeable to the passage of cells therethrough, while the electrode 670 can be liquid impermeable, but gas permeable.
  • the processing module 650 does not include one or more of the membranes 662, 664.
  • each electrode 668, 670 can include the respective membrane 662, 664 coupled thereto.
  • FIG. 22A shows a process of cell culturing, cell concentration, and cell electroporation using the processing module 650.
  • FIG. 22B shows a process of cell culturing and cell expansion, cell concentration, and cell cry opreservation using the processing module 650 and the processing module 500.
  • FIG. 23 shows an isometric, a top view, and cross-sectional views of a processing module 700, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 700 can be similar to the processing module 650.
  • the processing module 700 can include spacers 702, 704 positioned between respective electrodes, respective membranes, or both.
  • Each spacer 702, 704 can be liquid permeable, but impermeable to the passage of cells therethrough. In this way, when liquid is evacuated from the chamber containing cells, liquid can advantageously be removed from the sides of the chamber that are between the membranes, electrodes, etc., which could otherwise be a location for pooling of liquid.
  • FIG. 24 shows a process of cell concentrating using the processing module 700.
  • FIG. 25 shows an illustration of a processing module 750, which can be similar to the processing module 700.
  • the processing module 750 can include a septum (e.g., that is pierceable) that is fluidly coupled to a liquid connector of the processing module and the inner chamber of the processing module.
  • a needle can pierce the septum to collect a sample of the liquid containing cells (e.g., to count the cells and thus provide a cell concentration).
  • FIG. 26 shows a process of collecting cells using the processing module 700.
  • FIG. 27A shows an illustration of a processing module 800, which can be similar to the processing module 700.
  • the processing module 800 can include a plunger 802 that can be slidably coupled to the housing of the processing module 800.
  • the plunger 802 can move (e.g., by an actuator) to force an electrode closer to another electrode.
  • the gap between the electrodes can be adjusted, which can be helpful to accommodate different volumes of liquids including cells. For example, less cells require less liquid and less reagents.
  • the processing module 800 can electroporate smaller amounts of liquid including cells suspended therein.
  • FIG. 27B shows a process of concentrating cells using a plunger and an actuator driving the plunger, or a process of adjusting the gap between electrodes using the plunger and the actuator.
  • FIG. 28 shows an isometric, a top view, and cross-sectional views of a processing module 850, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 850 can be a formulation processing module that is configured to create one or more reagents to genetically modify cells (e.g., RNP).
  • the processing module 850 can include a housing 852, a plurality of chambers 854 directed into the housing 852, a plurality of needles 856, a plurality of cartridges 858, and a plurality of gas connectors 860 coupled to the housing 852.
  • the plurality of needles 856 can include at least two needles 862, 864 directed through each chamber 854.
  • the needles 862, 864 can be coaxial to each other, and the needle 862 can be longer than the needle 864 (e.g., with the needle 862 extending further towards an open end of a respective chamber than the needle 864).
  • each gas connector 860 can be fluidly coupled to a respective needle 864, and each needle 864 can be fluidly coupled to one or more other needles 864 of the processing module 850 (e.g., via one or more channels in the housing 852 of the processing module 850).
  • gas can be driven into (or out of) the gas connectors 860 to move liquid between cartridges (e.g., to mix liquid from cartridges to create a formulation for genetically modifying cells).
  • FIG. 29 shows an isometric, a top view, and cross-sectional views of a processing module 900, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 900 can be a formulation processing module that is configured to create one or more reagents to genetically modify cells (e.g., RNP).
  • the processing module 900 can be similar to the processing module 850.
  • the processing module 900 can include a plurality of chambers, with each chamber including a septum (or a barrier) to seal the respective chamber from the ambient environment. Each chamber can be prefilled with a different reagent, and each chamber can be fluidly coupled to each other.
  • the septum of a chamber can be pierced (e g., from a top septum, through the needles, and through the plate 386) to drive gas into or out of the chamber thereby driving liquid from the chamber to other chambers (e.g., to mix liquids from at least two chambers).
  • FIG. 30 shows a side view of a processing module 950, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module can include a housing defining two chambers, a plurality of gas connectors coupled to the housing, and a plurality of liquid connectors.
  • One liquid connector can be fluidly coupled to a container (e g., a bag) that can be positioned within a first chamber for cry opreservation, and another liquid connector fluidly coupled to a pouch that can be positioned within a second chamber and that contains a plurality of individual quality control (“QC”) samples.
  • QC individual quality control
  • the processing module 950 can include a plurality of vacuum tubes that can be positioned within the second chamber. Each of the vacuum tubes can be selectively fluidly coupled to the liquid connector (e.g., when the vacuum tube is punctured, the vacuum tube fluidly couples to the liquid connector).
  • FIG. 31 shows this configuration.
  • FIG. 32 shows an isometric view of a processing module 1000, which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 1000 can include a housing, a plurality of gas connectors coupled to the housing, a plurality of holes directed into the housing, and a plurality of vacuum tubes each of which is configured to be received in a respective hole of the housing.
  • Each of the vacuum tubes can include a septum (e g., that is pierceable), and the process board can include a plurality of needles (e.g., that are aseptic, such as the needles including a sleeve protecting the needle from the ambient environment).
  • each vacuum tube can be advanced (e.g., by an actuator, by a robot arm, etc.) towards a respective needle of the process board to pierce the septum of the vacuum tube to draw an amount of liquid from the needle (e.g., originating from the processing module) to the vacuum tube.
  • the processing module 1000 can include chambers rather than holes.
  • FIG. 33 shows an isometric view of a processing module 1050.
  • the processing module 1050 can include a housing, and a plurality of chambers each including a needle positioned therein. In this way, each vacuum tube can be received within a chamber and the septum of each vacuum tube can be pierced to fluidly couple each needle to the vacuum tube.
  • Each needle can be fluidly coupled to a liquid connector of the processing module 1050.
  • This liquid connector can include a septum that can be pierceable, and the process board can include a needle (e.g., that is aseptic) to pierce the septum of the liquid connector (e.g., to fluidly couple each needle to the liquid connector to distribute a sample to each vacuum tube from the liquid connector).
  • the processing module 1000 does not include any gas connectors and/or any liquid connectors.
  • the processing module 1050 can include only a single liquid connector. In this case, for example, the processing module 1050 does not include any gas connectors.
  • FIG. 34 shows a top view and a cross-sectional view of a processing module 1 101 , which can pertain to the other processing modules described herein (and vice versa).
  • the processing module 1101 can be a cell concentrating processing module, an isolating processing module, a separating processing module, a labeling processing module, a monitoring processing module, a sensing processing module, etc.
  • the processing module 1101 can include a housing 1103, a plurality of liquid connectors 1105, and a microfluidic circuit 1107 fluidly coupled to the plurality of liquid connectors.
  • the liquid connectors 1105 can include a waste liquid connector, a product liquid connector, a sample liquid connector, and a buffer liquid connector.
  • the microfluidic circuit 1107 can be a microfluidic circuit, a microfluidic chip, etc., that is sold, for example, by BendBio.
  • the microfluidic circuit 1107 can be configured to concentrate the cells (e.g., centrifuge the cells) at the sample connector, which can include creating a cell pellet at the sample connector.
  • FIG. 35 shows an isometric view of a control board 1102, a process board 1104 coupled to the control board 1102, processing modules 1106, 1108, 1110 coupled to the process board 1104, and a liquid handling device 1112 coupled to the process board 1104.
  • each gas connector of the control board 1102 is fluidly coupled to the a respective gas connector of a first plurality of gas connectors the process board 1104, each gas connector of a second plurality of second gas connectors of the process board 1104 can be fluidly coupled to a respective gas connector of a respective processing module 1 106, 1108, 1 110, and each liquid connector of a processing module 1106, 1108, 1110 can be fluidly coupled to a respective liquid connector the process board 1104.
  • each liquid connector of the liquid handling device 1112 can be fluidly coupled to a respective liquid connector of the processing modules 1106, 1108, 1110 or the process board 1104.
  • FIG. 36 shows a top view of the configuration of FIG. 35.
  • target cells can be labeled with magnetic beads and can pass through a serpentine channel in the process board that is positioned between two magnets. In this way, the target cells can be trapped within the serpentine channel by the properties of the serpentine channel and by the magnets to isolate the target cells.
  • the non-target cells can flow to the processing module 1110 (e.g., for waste), while the target cells can be trapped within the serpentine channel.
  • the target cells can flow to the processing module 1108 (e.g., together with fresh media from the processing module 1106). In some cases, this process can be reversed, if, for example, the non-target cells are labeled with magnetic beads.
  • FIG. 37 shows a top view of the configuration of FIG. 35, with the processing module 1106 removed. As shown in FIG. 37, the target cells can be trapped and then directed into the processing module 1108, with the non-target cells freely passing through the serpentine channel and the magnets.
  • FIG. 38 shows a top view of the configuration of FIG. 37.
  • the target cells can be directed out of the serpentine channel to the processing module 1108 (e.g., for harvesting, cell growth, cell proliferation, cell cryopreservation, etc.).
  • FIG. 39 shows a rear isometric view of the configuration of FIG. 35.
  • the liquid handling device 1112 can fill each of the processing modules 1106, 1108, 1110 with cell media (e.g., sequentially, simultaneously, etc.).
  • a pump e.g., a peristaltic pump
  • the cell media can include one or more cytokines.
  • FIG. 40 shows a front isometric view of the configuration of FIG. 35.
  • a liquid connector of the liquid handling device 1112 can be fluidly coupled to a liquid connector of the cell processing module 1106 to drive liquid (e.g., cell media) from a reservoir fluidly coupled to the liquid handling device 1112 and to the processing module 1106.
  • the processing modules 1108, 1110 can also be fdled by the liquid handling device 1112 in a similar manner.
  • FIG. 41 shows a rear isometric view of the configuration of FIG. 35.
  • the liquid handling device 1112 can remove cell media from each of the processing modules 1 106, 1108, 1 110 (e.g., sequentially, simultaneously, etc ).
  • the pump e.g., a peristaltic pump
  • a reservoir e.g., a waste reservoir
  • the pump can direct cell media from each of the processing modules, through the liquid connector of the process board 1104, and into the reservoir to simultaneously remove cell media from each of the processing modules 1106, 1108, 1100 (e.g., for cell media exchange).
  • FIG. 42 shows a front isometric view of the configuration of FIG. 35.
  • a liquid connector of the liquid handling device 1112 can be fluidly coupled to a liquid connector of the cell processing module 1106 to remove liquid (e.g., waste cell media) from the processing module 1106 to a reservoir fluidly coupled to the liquid handling device 1112.
  • liquid including cell media waste can also be removed from the processing modules 1108, 1110 by the liquid handling device 1112 in a similar manner.
  • FIG. 43 shows a top view of the configuration of FIG. 35.
  • waste cell media in the processing module 1108 can be directed into the processing module 1110, and subsequently, cell media (e.g., fresh cell media) can be directed from the processing module 1106 into the processing module 1108 (e.g., to resuspend cells). In this way, a media exchange can be performed in the processing module 1108.
  • cell media e.g., fresh cell media
  • FIG. 44 shows a top view of the control board 1102, the process board 1104, and processing modules 1114, 1116 coupled to the process board 1104.
  • the processing module 1114 can be a centrifugation processing module that is configured to create a cell pellet.
  • liquid can be directed into the processing module 1114 to the cell pellet to resuspend the cells in the processing module 1114.
  • the resuspended cells can be directed from the processing module 1114, through the process board 1104, and into the processing module 1116.
  • FIG. 45 shows an isometric view of the control board 1102, the process board 1104, and the processing modules 1106, 1108 coupled to the process board 1104.
  • the processing module 1106 can be a cell concentration processing module that is configured to concentrate cells. For example, after the processing module 1106 concentrates cells, liquid can be directed into the processing module 1106 to resuspend the concentrated cells. Then, the resuspended cells can be directed from the processing module 1106, through the process board 1104, and into the processing module 1108.
  • FIG. 46 shows an isometric view of the control board 1102, the process board 1104, and processing modules 1106, 1108, 1118 coupled to the process board 1104.
  • the processing module 1118 can be a centrifugation processing module that is configured to create a cell pellet.
  • waste liquid can be directed from the processing module 1118, through a liquid connector of the processing module 1118, through a liquid connector of the process board 1104, through the process board 1104 and into the processing module 1108 (e.g., via a pair of liquid connectors).
  • liquid e.g., fresh media
  • liquid can be directed into the processing module 1118 at the cell pellet to force the liquid and the cell pellet through a liquid connector of the processing module 1118, through a liquid connector of the process board 1104, through the process board 1104 and into the processing module 1106 (e.g., via a pair of liquid connectors) to resuspend the cells in the processing module 1106.
  • the processing module 1118 can sort or concentrate cells in a continuous-flow manner. That is, cells can be continuously separated from the liquid (e.g., media) during a continuous flow of the liquid. Therefore, the cell-enriched media can be collected in module 1106, while the excess media can continuously be directed to the processing module 1 108.
  • FIG. 47 shows an isometric view of the control board 1102, the process board 1104, the processing module 1106 coupled to the process board 1104, and the liquid handling device 1112 coupled to the processing module 1106.
  • the liquid handling device 1112 can pull liquid (e.g., waste liquid, waste buffer, etc.) out of the processing module 1106 via a first liquid connector of the liquid handling device 1112 and by using a first pump of the liquid handling device 1112.
  • the liquid handling device 1112 can direct liquid (e.g., fresh media, fresh buffer, etc.) into the processing module 1106 via a second liquid connector of the liquid handling device 1112 and by using a second pump of the liquid handling device 1112.
  • FIG. 48 shows an isometric view of the control board 1 102, the process board 1104, and the processing modules 1106, 1108, 1110 coupled to the process board 1104.
  • FIG. 48 shows that liquid (e.g., waste liquid, waste buffer, etc.) can be driven out of the processing module 1106 and into the processing module 1110.
  • liquid e.g., fresh media, fresh buffer, etc.
  • FIG. 48 shows an isometric view of the control board 1 102, the process board 1104, and the processing modules 1106, 1108, 1110 coupled to the process board 1104.
  • liquid e.g., waste liquid, waste buffer, etc.
  • liquid e.g., fresh media, fresh buffer, etc.
  • FIG. 49 shows an isometric view of the control board 1102, the process board 1104, and the processing modules 1106 coupled to the process board 1104.
  • gas can be directed into (or pulled out of) the processing module 1106 to move a membrane (e g., the liquid impermeable membrane) to agitate the liquid contained by the membrane.
  • a membrane e g., the liquid impermeable membrane
  • gas can be pulled into and out of the gas connector to agitate the membrane at a frequency thereby agitating the liquid including cells contained by the membrane.
  • the liquid e.g., including cells suspended therein
  • FIG. 50 shows an isometric view of the control board 1102, the process board 1104, and the processing modules 1106 coupled to the process board 1104.
  • liquid e.g., a small amount of liquid, such as 1 mL, 10 mL, etc.
  • This process can be repeated a number of times (e.g., one, two, three, etc.) to mix the liquid within the processing module 1106 (e.g., in a pipette-like manner).
  • FIG. 51 shows an isometric view of the control board 1102, the process board 1104, and a processing module 1120 coupled to the process board 1104.
  • the processing module 1120 can be a formulation processing module (as described above) and can be configured to create a formulation of one or more reagents (e.g., RNP) for genetically modifying cells.
  • FIG. 52 shows an isometric view of the control board 1102, the process board 1104, and a processing module 1122 coupled to the process board 1104.
  • the processing module 1 122 can be an electroporation processing module (as described above) and can be configured to electroporate cells.
  • FIG. 53 shows an isometric view of the control board 1102, the process board 1104, the processing modules 1108, 1110 coupled to the process board 1104, and an optical connector 1124 coupled to the optical connector of the process board 1104.
  • the optical connector 1124 can be optically coupled to one or more sensors. In this way, the optical connectors can be coupled together to optically couple the one or more sensors to the process board 1104.
  • FIG. 54 shows an isometric view of the control board 1102, the process board 1104, the processing modules 1108, 1110 coupled to the process board 1104, and vacuum tubes 1126, 1128.
  • each vacuum tube 1126, 1128 can include a liquid connector to fluidly couple each vacuum tube 1126, 1128 to the process board 1104.
  • the liquid connector of the vacuum tube 1126 can be coupled to a liquid connector of the process board 1104, which drives liquid from the processing module 1108, through the liquid connector of the processing module 1108, through a first liquid connector of the process board 1104, through a second liquid connector of the process board 1104, and through the liquid connector of the vacuum tube 1126 to drive the liquid into the vacuum tube 1126.
  • the vacuum tube 1 126 can sample liquid and cells contained therein during processing of cells (e g., the vacuum tube 1126 can collect an in-process sample).
  • the vacuum tube 1128 can be engaged in a similar manner to draw liquid from the processing module 1110 to the vacuum tube 1128.
  • FIG. 55 shows an isometric view of the control board 1102, the process board 1104 including liquid connectors 1132, 1134, the processing module 1108 coupled to the process board 1104, and a processing module 1130 coupled to the process board 1104.
  • the processing module 1130 can be a sampling processing module and can include one or more vacuum tubes each of which can be fluidly coupled to a liquid connector 1132 of the processing module 1130. In this way, when the processing module 1130 is coupled to the process board 1104, the liquid connectors 1132, 1136 couple together, and when the processing module 1108 is coupled to the process board 1104, the liquid connector 1138 of the processing module 1108 couples to the liquid connector 1134 of the process board 1104.
  • liquid is drawn from the processing module 1108, through the liquid connectors 1134, 1138 through the process board 1104, through the liquid connectors 1132, 1136 and through the processing module 1108 into each vacuum tube with a precisely aliquoted volume.
  • FIG. 56 shows an isometric view of the control board 1102, the process board 1104, a processing module 1140 coupled to the process board 1104, and a processing module 1142 (or a processing module 1144) coupled to the process board 1104.
  • the processing module 1142 can be a centrifugation processing module
  • the processing module 1144 can be a cell concentrating processing module. As shown in FIG.
  • the cell pellet can be directed from the processing module 1142 to the processing module 1140 (e.g., using liquid, such as a buffer, one or more cryopreservation reagents, etc., and in some cases using the process board 1104), or the concentrated cells in the processing module 1144 can be directed into the processing module 1140 (e.g., via the process board 1104).
  • liquid such as a buffer, one or more cryopreservation reagents, etc., and in some cases using the process board 1104
  • the concentrated cells in the processing module 1144 can be directed into the processing module 1140 (e.g., via the process board 1104).
  • FIG. 57 shows an isometric view of the processing module 1140 engaged with the process board 1104.
  • FIG. 57 also shows how cryopreserved cells can be transferred to (small) QC sampling bags, pouches, etc., from the main larger cryopreservation bag at the end of the process.
  • FIG. 58 shows an isometric view of the processing module 1140 engaged with the process board, with one chamber including a plurality of vacuum tubes (or vials). Each of the plurality of vials or vacuum tubes are configured to receive a sample of cells.
  • FIG. 59 shows an isometric view of the process board 1104 coupled to the control board 1104, and with one or more UV lights being configured to emit light at one or more liquid connectors of the processing modules through the holes in the process board 1104 to decontaminate the liquid connectors.
  • the systems herein can provide the following important features or capabilities: 1. Initial Fresh cell & media transfer & Cytokine addition, 2. Cell isolation, 3. Cell activation, 4. Media exchange, 5. Connections’ decontamination, 6. Pipetting- like On-Chip cell Mixing, 7. RNP micro-Formulation, 8. New metered flow-through Electroporation, 9. Tn-Process QC sampling & Monitoring, 10 Cell concentration and washing, 11. Cryopreservation, and 12. Final QC sampling.
  • the systems can include no tubing and the valving can be fully aseptic.
  • the systems can provide miniaturized, modular, and scalable modules, which can be customized.
  • the systems can be reusable (e.g., the cell processing unit including one or more instruments, which can make the system more affordable.
  • the system does not require an incubator instrument or a centrifuge instrument aside from a processing module (e.g., in this way a processing module or cells do not need to be transferred to an incubator or a centrifuge).
  • the system can be compatible with microfluidic platforms and other technologies (e g., microfluidic chips).
  • each processing module there can be a single step reliable, independent alignment of each processing module with a process board (e.g., each processing module does not include any mechanical moving parts, aside from a membrane that moves).
  • the on-demand media exchange, cell wash and mixing without cell loss can be provided using the systems herein (e.g., a processing module).
  • simultaneous metered transfer to (or from) multiple processing modules e.g., cell processing modules (“CPMs”)
  • multiple processing modules e.g., cell processing modules (“CPMs”)
  • a type of processing module can provide cell culturing, cell concentration, cell washing, and cell electroporation. In this way, a processing module dedicated solely to cell centrifugation (or cell concentration) can be eliminated. Accordingly, the total number and type of processing modules for creating a biologically product can be advantageously reduced thereby decreasing processing time (e.g., from transfer).
  • Some embodiments of the disclosure provide system for processing cells, the system comprising as components: (a) a control board for receiving a signal and delivering an input including but not limited to pneumatic, mechanical, electrical, acoustic, thermal, optical, and magnetic inputs in response to a desired signal; (b) a process board that is engageable with the control board for receiving an input including but not limited to the pneumatic, mechanical, electrical, acoustic, thermal, optical, and magnetic inputs from the control board; and (c) one or more processing modules that are engageable with the process board for receiving an input including but not limited to the pneumatic, mechanical, electrical, acoustic, thermal, optical, and magnetic inputs and performing a process in response to the inputs.
  • a control board can include one or more of the following: a board made of plastic, metal or composite materials; aseptic or needleless connectors as well as channels to provide pneumatic sources as well as vent and close to the process board; alignment tools such as a magnet or features to guide pins to properly engage with process board; permanent and or variable magnetic sources that are used for separation of magnetic particles and/or labeled cells required for de-beading, isolation, and activation of cells; an electrical board to receive signals from the processing modules e.g., for sensing the liquid levels in the modules; optical readout sensors including but not limited to temperature, pH, O2, CO2, OD, microscope objectives and cameras; UVC source and or ethanol spray, hydrogen peroxide for decontamination of connectors, etc.; a mechanical, hydraulic, or electromagnetic retraction mechanism used to retract the processing modules from the process board once a process is completed; a micro formulator station where the formulation module or an integrated micro formulator and electroporation module is placed and actuated either mechanical
  • the process board can include one or more of the following: a board made of plastic, metal or composite materials; alignment tools like a magnet or alignment features to guide pins to properly engage with the control board; aseptic or needleless connectors for either gas or liquid transfers from control board or to processing modules; micro to millimeter length scale channels to transfer cells or liquids within process board and between processing modules; channels with different 2D and 3D geometries including but not limited to straight, spiral, serpentine, herringbone and zigzag channels with different types of active and or passive mixing features/mechanisms along the channel s/flui die conduit; several stations depending on the workflows and applications including but not limited to formulation, media exchange, cell concentration and wash, cell isolation and activation, de-beading, mixing, cell electroporation, cell magnetoporation, cell mechanoporation, in process and final QC sampling, cell/sample monitoring, cell counting, microscopy, and sensing (e.g., pH, temperature, O2, CO2,
  • a processing module can be a cell processing module.
  • the processing module can include one or more of the following: one or more membranes; if one membrane is used (e.g., a single membrane), the membrane can be gas-permeable but not liquid- or cell-permeable; if more than one membrane is used in a multilayered structure, then the bottom membrane can be a gas-permeable membrane, and the top membrane can be liquid/nutrient-permeable but not cell-permeable; a cell chamber that can be the volume between the gas-permeable and liquid- (but not cell-) permeable membranes where cells are cultured and processed e.g., concentration, washing, or electroporation processes; the cell chamber can be formed by a bottom gas-permeable and top liquid/nutrient- (but not cell-) permeable membrane separated by a liquid- (but not cell-) permeable spacer including but not limited to a liquid- (but not cell-) permeable membrane
  • a processing module can be cell processing module.
  • the processing module can be configured to centrifugate cells to create a cell pellet, or the processing module can be configured to concentrate cells.
  • the processing module can include one or more of the following: a double membrane to remove the excess media and concentrate the cells for downstream processes, which can be implemented by first, removing the cell media in top media chamber through either the top or bottom ports fluidly coupled to the media chamber, then removing the media left in the bottom cell chamber by inflating the bottom gas- permeable membrane or pressurizing the processing module, which in turn can force out the liquid but not the cells from the cell chamber through the liquid- (but not cell-) permeable spacer (or membrane) while leaving the loose cells in an acceptable low volume media or buffer behind in the cell chamber; inflation of the bottom gas-permeable can be implemented by pushing the membrane up by using an adjustable perforated piston replacing the support layer under the membrane, in which the level of the piston can be adjusted mechanically, hydrodynamically, or electromagnetically, thereof; the piston can have different
  • one side of the processing module comes off the connectors that are on the process board, which gives the processing module a slope toward the outlet ports in both cell and media chambers.
  • the asymmetric support can be used on top of the top liquid/nutrient- (but not cell-) permeable membrane, hence forming a slight slope toward the outlet of the top media chamber.
  • gutters at one or more edges (e.g., four edges) of the top media chambers can have a slope toward the outlet port, which can be used to enhance the excess liquid/media collection and removal.
  • a conical chamber and at least four aseptic ports/connectors can be used to centrifuge (spin down) cells in a centrifugation device.
  • Two top ports can be used to pull out the supernatant or pump in media or buffers, one port providing pneumatic, vent, or close to the processing module, and one port at the bottom center of the module through which the cell pellet can be pull/push out.
  • the positions of the two top ports from the bottom of the cone can be adjusted to accommodate different cell pellet size depending on the number of cells at different process stages.
  • more than half of the cone surface area can be liquid- (but not cell-) permeable membrane.
  • spinning down the cells in a centrifuge can be eliminated. Instead, liquid/media is pushed out or pulled out by pressurizing the chamber or by the dispenser, respectively, leaving behind loose, concentrated cells in the conical region.
  • the conical chamber with liquid permeable membrane configuration can also be used for continuous and dynamic removal of liquid/media from the chamber while spinning down the cells in a centrifuge.
  • a processing module can be cell processing module.
  • the processing module can be configured to electroporate cells.
  • the processing module can include three chambers: a first chamber to receive and combine the RNP formulation, cells and electroporation buffer, a middle chamber that can act as the electroporation cuvette where cells are electroporated, and the third chamber to collect the treated cells.
  • each chamber can be fluidly coupled to a pneumatic source.
  • a cells-buffer mixture and RNP formulation can be transferred to the middle chamber from two different modules and can get mixed right before entering the chamber/cuvette by passing through a mixing and debeading channel/fluidic conduit.
  • the middle chamber/cuvette can include three electrodes embedded into processing module side wall.
  • each electrode can be positioned outside the processing module can electrically connected to an electrical board which can communicate with a flow/pneumatic source, and the other ends can be positioned inside the middle chamber/cuvette where they can contact the liquid sample during the cuvette filling and draining.
  • the signal can be the change in the resistance between any two electrodes.
  • the formulation module e.g., the micro formulation module
  • an electroporation module (“EPM”) can be integrated together as a single processing module that can perform the formulation as well as the electroporation.
  • the integrated module can be placed at station “0” (SO) on the process board to accomplish the two processes.
  • any type of processing module can be used for electroporation, as appropriate.
  • any type of processing module described above can be also used for the electroporation.
  • the two plastic perforated flat supporting sheets that are placed under the bottom gas-permeable and under the top liquid/nutrient- but (not cell-) permeable membranes can be replaced by two conductive, flat, inert to chemical reactions (e.g., Gold, Platinum) electrodes including but not limited to metal sheets/scrips, metal mesh screen, and perforated metal sheets.
  • a processing module When a processing module is used for electroporation, it can be defined as an electroporation cell processing module (“ECPM”).
  • ECPM electroporation cell processing module
  • the piston can add another capability to a ECPM which is a tunable gap size between the two electrodes, hence tunable electric field and energy density can be achievable, which can then be transferred to EP buffer and cells.
  • viral/nonviral, chemi cal/phy si cal mechanisms such as magnetoporation, mechanoporation, sonoporation, hydroporation, or nanoneedle type poration devices can be integrated into a processing module.
  • a processing module can be a formulation processing module.
  • the processing module can be configured to create a formulation, a reagent, etc., to genetically modify cells.
  • the processing module can include one or more of the following: at least two main layers including the chambers layer/block and the channel/fluidic conduit layer; the chambers can have a perforated guide channel/cannula with a needle at the center of cannula which pierce the septum on the vials/cartridge containing reagents and is connected to pneumatic source through the channel/fluidic conduit layer; the bottom of chambers’ layer/block has extra ports/channels that are connected to the fluidic conduit layer through which the liquids are transferred between chambers; or channel/fluidic layer contains micro to millimeter length scale channels that are connected to pneumatic sources, and also connect chambers to each other for liquid transfer.
  • chambers do not include any cannula or needle (e.g., at their centers) to provide pneumatic sources to the chambers.
  • the pneumatic sources can be provided through control board to the chambers via needles piercing the septum placed on the top surface of the chambers.
  • chambers are prefilled with reagents, hence no vials/cartridges can be used.
  • the final formulation can be pumped out from the last chamber to the process board through the aseptic port at the bottom surface of the module.
  • Metered liquid pumping can include but not limited to diaphragm/membrane, peristaltic, and acoustic pumping can be integrated with either process board or micro formulator module.
  • a processing module can be a cell processing module.
  • the processing module can be configured to collect one or more samples (e.g., one for cryopreservation, one for QC sampling, etc ).
  • the processing module can include a cry opreservation chamber, and a QC sampling chamber.
  • the processing module can include two chambers, one for a large bag to collect all treated cells in a cryopreserved buffer, and the other for QC sampling small bags/pouches. In some cases, both chambers are connected to pneumatic sources through the aseptic ports/connectors underneath the module.
  • the QC sampling pouches can be replaced by an array of sampling vacuum tubes which pull in the desired volumes once engaged with needles inside the QC sampling chamber in CQCM. All needles are connected to a liquid channel network inside QC chamber in CQCM which is connected to a port underneath the module.
  • a processing module can be a sampling processing module.
  • the processing module can be configured to collect one or more samples (e g., each in a separate container).
  • the processing module can include an array of vacuum tubes assembled in a module (PQCM) comes in to contact with an array of inter-connected needles on the process board.
  • the channel/fluidic conduit network in the process board, which connects the needles, can be connected to a port/connector underneath a CPM via a fluidic conduit in the process board. Once the needles pierce the septum located on the CPM port/connector, a desired volume of the sample get transferred into the tubes.
  • the needles and channel/fluidic conduit network can be integrated in a PQCM. In this case, only one needle on the process board will be sufficient to transfer samples from a CPM or other processing modules to sampling vacuum tubes. In some cases, either of above QC sampling approaches can also be used to pull out desired numbers of QC samples from the final cryopreserved large cell bag.
  • the systems herein can include one or more external technologies that can include one or more of the following: microfluidic devices including inertial microfluidic-based technologies that are used for but not limited to cell separation, concentration, isolation, activation, debeading, mixing, cryopreservation, fractionation, centrifugation, sensing, monitoring, counting, can be modified in a way that their inputs and outputs can be attached or plugged in to the connectors on the process board to perform the intended processes.
  • microfluidic devices including inertial microfluidic-based technologies that are used for but not limited to cell separation, concentration, isolation, activation, debeading, mixing, cryopreservation, fractionation, centrifugation, sensing, monitoring, counting, can be modified in a way that their inputs and outputs can be attached or plugged in to the connectors on the process board to perform the intended processes.
  • a system for processing cells can include a miniaturized workcell where all the processes take place.
  • the whole miniaturized enclosure/workcell can be kept at 37°C and 5% CO2.
  • no incubator will be required, hence numerous transfers into and from the incubator can advantageously be eliminated.
  • a robotic arm that has a barcode reader, which read the barcodes on all processing modules, and move the processing modules around the miniaturized workcell.
  • a dispenser which can be equipped with one or more peristaltic pumps to transfer metered liquids to and/or from storage pass-through window where all the fresh media, buffers, cells, wastes, reagents, thereof are stored.
  • the aseptic tips/connectors of the dispenser can be equipped with built-in UVC and/or ethanol spray, and /or hydrogen peroxide to decontaminate the tips/ interfaces after each liquid transfer.
  • a system for processing cells as disclosed herein may include (a) a control board for receiving a signal and delivering an input including but not limited to pneumatic, mechanical, electrical, acoustic, thermal, optical, and magnetic inputs in response to a desired signal; (b) a process board that is engageable with the control board for receiving an input including but not limited to the pneumatic, mechanical, electrical, acoustic, thermal, optical, and magnetic inputs from the control board; and (c) one or more processing modules that are engageable with the process board for receiving an input including but not limited to the pneumatic, mechanical, electrical, acoustic, thermal, optical, and magnetic inputs and performing a process in response to the inputs.
  • the system may further include: a dispenser or liquid handler which may be equipped with one or more peristaltic pumps to transfer metered liquids to and/or from storage pass-through window where all the fresh media, buffers, cells, wastes, reagents, thereof are stored.
  • a dispenser or liquid handler which may be equipped with one or more peristaltic pumps to transfer metered liquids to and/or from storage pass-through window where all the fresh media, buffers, cells, wastes, reagents, thereof are stored.
  • the aseptic tips/connectors of the dispenser may be equipped with built-in UVC and/or ethanol spray, hydrogen peroxide to decontaminate the tips after each liquid transfer.
  • other instruments including the electroporator and pumps may be located outside the enclosure, such that neither the instrument nor the enclosure environment will be affected by the other.
  • control board may be made of plastic, metal, or composite materials.
  • control board may include aseptic and/or needleless connectors as well as channels to provide pneumatic sources as well as vent and close to the process board.
  • control board may include alignment tools such as a magnet or features to guide pins to properly engage with process board.
  • control board may include permanent and or variable magnetic sources that are used for separation of magnetic particles and/or labeled cells required for debeading, isolation, and activation of cells.
  • control board may include an electrical board to receive signals from the processing modules, e.g., for sensing the liquid levels in the modules.
  • control board may include optical readout sensors including but not limited to sensors for temperature, pH, O2, CO2, OD.
  • control board may include microscope objectives and cameras.
  • control board may include a UVC source and or mechanisms to provide ethanol spray/hydrogen peroxide vapor for decontamination of connectors, etc.
  • control board may include a mechanical, hydraulic, or electromagnetic retraction mechanism for retracting the processing modules from the process board once a process is completed.
  • control board may include a micro formulator station where the formulation module and/or an integrated micro formulator and electroporation module is placed and actuated either mechanically and or pneumatically.
  • the control board may include external actuators to stimulate/agitate cells and/or mixtures, including but not limited to acoustic, magnetic, electric, and thermal actuators.
  • the process board may include a board made of plastic, metal or composite materials.
  • the process board may include alignment tools such as a magnet or alignment features to guide pins to properly engage with the control board.
  • the process board may include aseptic and/or needleless connectors for either gas or liquid transfers from control board or to processing modules.
  • the process board may include micro to millimeter length scale channels to transfer cells and/or liquids within process board and between processing modules.
  • the process board may include channels with different 2D and 3D geometries including but not limited to straight, spiral, serpentine, herringbone and zigzag channels with different types of active and/or passive mixing features/mechanisms along the channels/fluidic conduit.
  • the process board may include several stations depending on the workflows and applications including but not limited to formulation, media exchange, cell concentration and wash, cell isolation and activation, debeading, mixing, cell electroporation, cell magnet-poration, in process and final QC sampling, cell/sample monitoring, cell counting, microscopy, and sensing (e.g., pH, temperature, 02, CO2, OD), cryopreservation, cell culturing, and decontamination stations.
  • the process board may include micro, meso- to macrofluidic valving and controlled/metered pumping mechanisms including but limited to diaphragm, membrane, peristaltic, rotary membrane, shape memory allow, and electromagnetic pin-actuator valving and pumping.
  • the process board may include through-hole ports across the process board that are used for processing modules retraction, microscopy, camera/imaging, magnets, sensors, UVC, decontamination sprays, thereof.
  • the process board may include a hemocytometer-like grid used for cell counting.
  • the process board may include pipetting-like sample mixing via pumping out and in a small volume of sample from cell chamber using, but not limited to, metered diaphragm pumping.
  • all channels/fluidic conduits of the process board may be primed before starting any process and each channel/liquid conduit may be flushed by a cleaning reagent after each liquid transfer through that channel/liquid conduit.
  • the system may include one or more of the following processing modules C-l through C-7:
  • C-l Cell Processing Modules
  • CCM Cell Processing Modules
  • one membrane is a gas- (but not liquid/cell-) permeable membrane
  • the bottom membrane is a gas-permeable membrane, and the last/top membrane can be liquid/nutrient- (but not cell-) permeable.
  • Cell chamber defined as the volume between the gas-permeable and liquid- (but not cell-) permeable membranes where cells are cultured and processed e.g., concentration, washing and/or electroporation processes;
  • the cell chamber may be formed by a bottom gas-permeable and top liquid/nutrient- (but not cell-) permeable membranes separated by a liquid (not cell) permeable spacer including but not limited to a liquid (not cell) permeable membrane/filter thereof. Therefore, excess liquid can be removed from the cell chamber by pressurizing the media/cell chamber through the liquid (not cell) permeable spacer;
  • the non-permeable membrane can be a semi-permeable membrane
  • the cell chamber which has a septum attached to the center of the bottom gas permeable membrane at the center of PCM, where a needle with perforated tip can pierce to pull out or push in samples;
  • the septum may have a flexible back support underneath like but not limited to a spring, which allows the center of the gas permeable membrane moves downward slightly, forming a conical-like center where concentrated cells can be collected and pulled out.
  • At least seven aseptic ports/connectors (two are accessible from top and five from the bottom surface of CPM): one port providing pneumatic, vent, or close to the CPM, two (one top and one bottom) connected to the top media chamber, three (one top and two bottom) connected to the bottom cell chamber, one at the bottom center, which is normally open to environment to provide air to cells through bottom gas permeable membrane, is used to either be connected to a pneumatic connector (e.g., used for sample mixing by applying pulsatile pressure), a liquid connector, or a needle may pierce through this connector and septum to transfer sample in or from the bottom cell chamber.
  • a pneumatic connector e.g., used for sample mixing by applying pulsatile pressure
  • a liquid connector e.g., used for sample mixing by applying pulsatile pressure
  • a needle may pierce through this connector and septum to transfer sample in or from the bottom cell chamber.
  • a CPM can also have at least three embedded electrodes (base, min, max) on one of its side walls in order to sense the liquid/media level inside the CPM chamber, which in turn send a signal to the flow source to stop pumping the liquid/media;
  • a CPM can also have a capability for holding a magnet for magnetoporation
  • the liquid level can also be detected using but not limited to acoustic, capacitive, optical, resistive, and/or thermal sensors;
  • a CPM can be modified/customized to include a perfusion cell culture process which involves the constant feeding of fresh media and removal of spent media and product while retaining high numbers of viable cells.
  • a CPM can include a bottom gas- (but not liquid/cell-) permeable membrane, a middle liquid- (but not cell-) permeable membrane, and a top gas- (but not liquid/cell-) permeable membrane.
  • the space between the bottom gas- (but not liquid/cell-) permeable membrane and the middle liquid- (but not cell-) permeable membrane is the cell chamber
  • the space between the middle liquid- (but not cell-) permeable membrane and the top gas- (but not liquid/cell-) permeable membrane is the media chamber.
  • Fresh media and nutrition are continuously provided to the cells through entering and leaving the top media chamber.
  • C-2) Cell Centrifugation (CFM) and Concentration (CPM) Modules may include:
  • a double membrane CPM which can be used to remove the excess media and concentrate the cells for downstream processes.
  • the media in top media chamber is removed through either the top or bottom ports connected to the media chamber, then the media left in the bottom cell chamber is removed either by inflating the bottom gas permeable membrane or pressurizing the CPM which in turn push out the liquid not the cells from the cell chamber through the liquid but not cell permeable spacer while leaving the loose cells in an acceptable low volume media or buffer behind in the cell chamber;
  • the inflation of the bottom gas permeable may also be done via pushing the membrane up by using an adjustable perforated piston replacing the support layer under the membrane.
  • the piston’s level can be adjusted one or more of mechanically, hydrodynamically, or electromagnet! cally;
  • the piston may have different shapes/geometries including but not limited to rectangular, square, circle, ring, or co-axial rings.
  • the piston may be made of one piece or multiple pieces, the latter of which provides more flexibility to shape the bottom, flexible, gas- permeable membrane to a desired form, e.g., a conical shape;
  • the bottom, gas-permeable membrane may be pneumatically inflated asymmetrically, forming a slight slope toward the outlet port that is connected to the cell chamber for cell collection.
  • This asymmetric inflation may be achieved by a gas-permeable membrane support that is perforated asymmetrically, or by a spacer with variable thickness separating the bottom gas permeable membrane and the top liquid/nutrient but not cell permeable membrane. That is, the spacer is thinner toward the outlet port in cell chamber.
  • the tilted gas permeable membrane may be formed if the perforated piston’ s surface under the membrane pushes the membrane up asymmetrically, creating a slope on the membrane surface toward the outlet port in the cell chamber;
  • the whole CPM may be also tilted toward the outlets in both cell and media chambers for better cell or excess media removal once the CPM is engaged with process board. This may be achieved using aseptic connectors with different heights at a specific station on the process board.
  • a tilted CPM can also be achieved by actuating the retraction pin(s) located under the CPM at different time points. That is, first, one side of the CPM comes off the connectors that are on the process board, which gives the CPM a slope toward the outlet ports in both cell and media chambers. Once the excess liquid/media removal is done, the other retraction pin(s) is actuated the other side of the CPM is disengaged from connectors on the process board;
  • an asymmetric support may be used on top of the top liquid/nutrient- (but not cell-) permeable membrane, hence forming a slight slope toward the outlet of the top media chamber;
  • Gutters at four edges of the top media chambers which have a slope toward the outlet port, may be used to enhance the excess liquid/media collection and removal;
  • a conical chamber and at least four aseptic ports/connectors may be used to centrifuge (spin down) cells in a centrifugation device.
  • Two top ports may be used to pull out the supernatant or pump in media or buffers, one port providing pneumatic, vent, or close to the CPM, and one port at the bottom center of the module through which the cell pellet can be pulled or pushed out or used to drive mixing;
  • the positions of the two top ports from the bottom of the cone can be adjusted to accommodate different cell pellet size depending on the number of cells at different process stages;
  • more than half of the bottom cone surface area may be liquid- (but not cell-) permeable membrane.
  • spinning down the cells in a centrifuge can be eliminated. Instead, liquid/media is pushed out or pulled out by pressurizing the chamber or by the dispenser/liquid handler, respectively, leaving behind loose, concentrated cells in the conical region;
  • the conical chamber with a liquid-permeable membrane configuration can also be used for continuous and dynamic removal of liquid/media from the chamber while spinning down the cells in a centrifuge.
  • Electroporation Modules may include:
  • Three chambers a first chamber to receive and combine the RNP formulation, cells and EP buffer, a middle chamber that acts as the electroporation cuvette where cells are electroporated, and a third chamber to collect the treated cells, where each chamber is connected to a pneumatic source;
  • a cell-buffer mixture and RNP formulation may be transferred to the middle chamber/cuvette from two different modules and may be mixed immediately before entering the chamber/cuvette by passing through a mixing and de-beading channel/fluidic conduit;
  • the middle chamber/cuvette has three electrodes embedded into EPM side wall. One end of each electrode that is outside the EPM may be connected to an electrical board which communicates with the flow/pneumatic source, and the other end of each electrode may be inside the middle chamber/cuvette where each may touch the liquid sample during the cuvette fdling and draining, providing an indication of the fluid level.
  • the signal can be measured as the change in the resistance between any two electrodes;
  • the micro formulation module and the electroporation module may be integrated together as a single module which is able to perform the formulation as well as electroporation.
  • the integrated module can be placed at station 0 (SO) on the process board to accomplish the two processes;
  • any types of CPM described above can be also used for the electroporation.
  • the two plastic perforated flat supporting sheets that are placed under the bottom gas permeable and under the top liquid/nutrient but not cell permeable membranes may be replaced by two conductive, flat, inert to chemical reactions (e.g., Gold, Platinum) electrodes including but not limited to metal sheets/strips, metal mesh screen, and perforated metal sheets. It is possible to reduce the voltage required for the electroporation by using metal mesh screen with rough surfaces.
  • ECPM ECPM in this document
  • the top metal mesh screen electrode may act as both electrode and nutrition membrane, hence use of a separate top liquid/nutrition but not cells membrane is eliminated;
  • the adjustable piston/s may add another capability to a ECPM which is tunable gap size between the two electrodes, hence tunable electric field and energy density can be achievable, which can then be transferred to EP buffer and cells;
  • Electroporation may also occur in a stand-alone cuvette which is engaged either horizontally or vertically with process board through aseptic connectors.
  • MicroFormulator Modules may include:
  • At least two main layers including the chambers’ layer/block and the channel/fluidic conduit layer;
  • the chambers may have a perforated guide channel/cannula with a needle at the center of cannula which can pierce the septum on the vials/cartridges containing reagents and is connected to pneumatic source through the channel/fluidic conduit layer;
  • the bottom of chambers’ layer/block has extra ports/ channels that are connected to the fluidic conduit layer through which the liquids are transferred between chambers.
  • Channel/fluidic layer contains micro to millimeter length scale channels that are connected to pneumatic sources, and also connect chambers to each other for liquid transfer;
  • the chambers may not have any cannula and needle at their centers to provide pneumatic sources to the chambers.
  • the pneumatic sources are provided through control board to the chambers via needles piercing the septum placed on the top surface of the chambers.
  • chambers are pre-filled with reagents, hence no vials/cartridges may be used.
  • the final formulation may be pump out from the last chamber to the process board through the aseptic port at the bottom surface of the module;
  • Metered liquid pumping including but not limited to diaphragm/membrane and peristaltic pumping may be integrated with either process board or micro formulator module.
  • C-5) Cryopreservation and final QC sampling Modules may include:
  • the QC sampling pouches may be replaced by an array of sampling vacuum tubes which pull in the desired volumes once engaged with needles inside the QC sampling chamber in CQCM. All needles are connected to a liquid channel network inside QC chamber in CQCM which is connected to a port underneath the module.
  • C-6) In-Process QC sampling Modules may include:
  • An array of vacuum tubes assembled in a module comes in to contact with an array of inter-connected needles on the process board.
  • the channel/fluidic conduit network in the process board which connects the needles, will be connected to a port/connector underneath a CPM via a fluidic conduit in the process board. Once the needles pierce the septum located on the CPM port/connector, a desired volume of the sample get transferred into the tubes or vials;
  • the needles and channel/fluidic conduit network may be integrated in a PQCM.
  • the needles and channel/fluidic conduit network may be integrated in a PQCM.
  • only one needle on the process board will be sufficient to transfer samples from a CPM or other processing modules to sampling vacuum tubes or vials;
  • Either of above QC sampling approaches may also be used to pull out desired numbers of QC samples from the final cryopreserved large cell bag.
  • Microfluidic including inertial microfluidic-based technologies that are used for but not limited to cell separation, concentration, isolation, activation, debeading, mixing, cry opreservation, fractionation, centrifugation, sensing, monitoring, counting, can be modified in a way that their inputs and outputs can be attached or plugged in to the connectors on the process board to perform the intended processes.
  • FIGS. 60-82 show examples of different prototypes, tests, and results of different cell processing systems described herein.
  • FIG. 60 shows a flowchart of an automated cell therapy manufacturing process.
  • FIG. 61 shows a simplified model (e.g., a prototype) that integrates the control board, the process board, and two cell processing modules.
  • FIG. 62 shows the filling of the cell processing module (“CPM”) via a top port, followed by transferring the liquid (water) from one CPM to another CPM by pressurizing the one CPM (e.g., by adding gas to the one CPM).
  • CPM cell processing module
  • FIG. 63 shows a prototype of a double layer CPM using a modified filtration flask integrating a gas permeable membrane and liquid (not cell) permeable membrane.
  • FIG. 64 shows testing of a CPM prototype using a pneumatic system.
  • FIG. 64 shows the inflation of the gas permeable membrane while pushing out the liquid from the bottom cell chamber.
  • FIG. 65 shows the results of a liquid leak test by inflating the gas permeable membrane of the CPM prototype.
  • FIG. 66 shows a second CPM prototype built using a filtration flask. About a liter of liquid was removed through a port from the top media chamber of the second CPM prototype.
  • FIG. 67 shows a third CPM prototype fabricated using a layer-by-layer method that integrates a gas permeable membrane and a liquid (but not cell) permeable membrane.
  • FIG. 68 shows the results from the third CPM prototype set up for a leak test. Less than 1 mL of liquid remained after removing the liquid from the cell chamber.
  • FIGS. 69-72 show the results of the microbeads test. Green 10-micron diameter fluorescent polystyrene beads were loaded in the cell chamber, which was used to test the bead concentration after removing the liquid from the cell chamber as the supernatant. Then, fresh liquid was added to the cell chamber to resuspend and collect the beads from the cell chamber showing that the beads were retained in the cell chamber.
  • FIG. 69 shows the prototypes for the microbeads tests.
  • FIG. 70 shows the additional prototypes for the microbeads tests.
  • FIG. 71 shows the fluorescent images of the original liquid, the supernatant liquid, and the washed or recovered samples.
  • FIG. 72 shows images of the prototypes after completion of the microbeads tests.
  • FIG. 73 show the first prototype of the CPM with a spacer that is liquid permeable but is impermeable to cells passing through. The spacer was positioned between two membranes. The media and the cell chambers were pressurized to push out the liquid through the spacer and into a peripheral channel (e.g., that was narrow). In this configuration, the spacer between the bottom gas permeable membrane and the top liquid permeable membrane (e g., not permeable to cells) is liquid permeable (e.g. but is not permeable to cells).
  • the bottom membrane does not need to be inflated. Rather, the chambers outside of the cell chamber can be pressurized. In this way, the membranes are forced together to push out excess liquid in the cell chamber through the spacer.
  • the peripheral channel can have a sloped (or angled) to force the liquid out of the CPM.
  • FIG. 74 shows a first prototype of an electroporation processing module that integrates liquid level sensing using embedded electrodes.
  • FIG. 75 shows a second prototype of an electroporation processing module (e.g., an electroporation cuvette) that integrates liquid level sensing using embedded electrodes.
  • an electroporation processing module e.g., an electroporation cuvette
  • three electrodes were embedded in the electroporation processing module.
  • the middle chamber can be filled by applying pressure to one of the side chambers. Once the liquid touches the electrodes the resistance between the electrodes changes (e.g., being very high without liquid). This change in resistance can be communicated to a computing device, which can cause the gas source to stop pressurizing the side chambers (e.g., stop further filling of the central chamber with liquid dynamically).
  • a computing device which can cause the gas source to stop pressurizing the side chambers (e.g., stop further filling of the central chamber with liquid dynamically).
  • either side chamber can be pressurized, or the side chamber can be vacuumized (e g., to pull liquid from the central chamber to the side chamber).
  • FIG. 76 shows a prototype of a cell processing module that is a cell electroporation processing module and a cell growing processing module.
  • FIG. 77 shows a prototype of a quality control (“QC”) sampling processing module.
  • FIG. 78 shows a top view and isometric views of a prototype that is configured to create a formulation and is configured to electroporate cells.
  • QC quality control
  • FIG. 79 shows a testing setup for evaluating liquid leaks and gas leaks between needleless connectors.
  • top As used herein, unless otherwise limited or defined, discussion of particular directions is provided by example only, with regard to particular embodiments or relevant illustrations. For example, discussion of “top,” “front,” or “back” features is generally intended as a description only of the orientation of such features relative to a reference frame of a particular example or illustration. Correspondingly, for example, a “top” feature may sometimes be disposed below a “bottom” feature (and so on), in some arrangements or embodiments. Further, references to particular rotational or other movements (e.g., counterclockwise rotation) is generally intended as a description only of movement relative a reference frame of a particular example of illustration.
  • aspects of the disclosure can be implemented as a system, method, apparatus, or article of manufacture using standard programming or engineering techniques to produce software, firmware, hardware, or any combination thereof to control a processor device (e.g., a serial or parallel general purpose or specialized processor chip, a single- or multi-core chip, a microprocessor, a field programmable gate array, any variety of combinations of a control unit, arithmetic logic unit, and processor register, and so on), a computer (e.g., a processor device operatively coupled to a memory), or another electronically operated controller to implement aspects detailed herein.
  • a processor device e.g., a serial or parallel general purpose or specialized processor chip, a single- or multi-core chip, a microprocessor, a field programmable gate array, any variety of combinations of a control unit, arithmetic logic unit, and processor register, and so on
  • a computer e.g., a processor device operatively coupled to a memory
  • another electronically operated controller to implement
  • embodiments of the disclosure can be implemented as a set of instructions, tangibly embodied on a non-transitory computer-readable media, such that a processor device can implement the instructions based upon reading the instructions from the computer-readable media.
  • Some embodiments of the disclosure can include (or utilize) a control device such as an automation device, a special purpose or general purpose computer including various computer hardware, software, firmware, and so on, consistent with the discussion below.
  • a control device can include a processor, a microcontroller, a field-programmable gate array, a programmable logic controller, logic gates etc., and other typical components that are known in the art for implementation of appropriate functionality (e.g., memory, communication systems, power sources, user interfaces and other inputs, etc ).
  • article of manufacture as used herein is intended to encompass a computer program accessible from any computer-readable device, carrier (e.g., non-transitory signals), or media (e.g., non-transitory media).
  • computer-readable media can include but are not limited to magnetic storage devices (e.g., hard disk, floppy disk, magnetic strips, and so on), optical disks (e.g., compact disk (CD), digital versatile disk (DVD), and so on), smart cards, and flash memory devices (e.g., card, stick, and so on).
  • a carrier wave can be employed to carry computer-readable electronic data such as those used in transmitting and receiving electronic mail or in accessing a network such as the Internet or a local area network (LAN).
  • LAN local area network
  • FIGS. Certain operations of methods according to the disclosure, or of systems executing those methods, may be represented schematically in the FIGS, or otherwise discussed herein. Unless otherwise specified or limited, representation in the FIGS, of particular operations in particular spatial order may not necessarily require those operations to be executed in a particular sequence corresponding to the particular spatial order. Correspondingly, certain operations represented in the FIGS., or otherwise disclosed herein, can be executed in different orders than are expressly illustrated or described, as appropriate for particular embodiments of the disclosure. Further, in some embodiments, certain operations can be executed in parallel, including by dedicated parallel processing devices, or separate computing devices configured to interoperate as part of a large system.
  • a component may be, but is not limited to being, a processor device, a process being executed (or executable) by a processor device, an object, an executable, a thread of execution, a computer program, or a computer.
  • a component may be, but is not limited to being, a processor device, a process being executed (or executable) by a processor device, an object, an executable, a thread of execution, a computer program, or a computer.
  • an application running on a computer and the computer can be a component.
  • One or more components may reside within a process or thread of execution, may be localized on one computer, may be distributed between two or more computers or other processor devices, or may be included within another component (or system, module, and so on).
  • devices or systems disclosed herein can be utilized or installed using methods embodying aspects of the disclosure.
  • description herein of particular features, capabilities, or intended purposes of a device or system is generally intended to inherently include disclosure of a method of using such features for the intended purposes, a method of implementing such capabilities, and a method of installing disclosed (or otherwise known) components to support these purposes or capabilities.
  • discussion herein of any method of manufacturing or using a particular device or system, including installing the device or system is intended to inherently include disclosure, as embodiments of the disclosure, of the utilized features and implemented capabilities of such device or system.
  • ordinal numbers are used herein for convenience of reference based generally on the order in which particular components are presented for the relevant part of the disclosure.
  • designations such as “first,” “second,” etc. generally indicate only the order in which the relevant component is introduced for discussion and generally do not indicate or require a particular spatial arrangement, functional or structural primacy or order.
  • phrases “a plurality of A, B, or C” and “two or more of A, B, or C” indicate options of: A and B; B and C; A and C; and A, B, and C.
  • the term “or” as used herein only indicates exclusive alternatives (e.g. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”

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Abstract

L'invention concerne un système de traitement de cellules. Le système peut comprendre un panneau de commande, une source de gaz couplée fluidiquement au panneau de commande, un panneau de traitement pouvant venir en prise avec le panneau de commande pour coupler fluidiquement le panneau de traitement au panneau de commande, et un module de traitement pouvant venir en prise avec le panneau de traitement pour coupler fluidiquement le module de traitement au panneau de traitement. La source de gaz peut être configurée pour entraîner le gaz vers l'intérieur ou l'extérieur du panneau de commande de manière à déplacer un liquide comprenant des cellules en suspension dans celui-ci à travers le module de traitement. Le module de traitement peut être configuré pour effectuer une opération sur les cellules lorsque le liquide contenant les cellules passe à travers le module de traitement de cellules.
PCT/US2023/022484 2022-05-17 2023-05-17 Systèmes et procédés pour plateformes et modules pouvant venir en prise pour le traitement de cellules WO2023225048A1 (fr)

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