WO2007139747A1 - Interface of a cultureware module in a cell culture system and installation method thereof - Google Patents
Interface of a cultureware module in a cell culture system and installation method thereof Download PDFInfo
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- WO2007139747A1 WO2007139747A1 PCT/US2007/012052 US2007012052W WO2007139747A1 WO 2007139747 A1 WO2007139747 A1 WO 2007139747A1 US 2007012052 W US2007012052 W US 2007012052W WO 2007139747 A1 WO2007139747 A1 WO 2007139747A1
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- 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
- C12M41/40—Means for regulation, monitoring, measurement or control, e.g. flow regulation of pressure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- C12M23/28—Constructional details, e.g. recesses, hinges disposable or single use
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- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/44—Multiple separable units; Modules
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- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/58—Reaction vessels connected in series or in parallel
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- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
- C12M25/10—Hollow fibers or tubes
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- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/10—Perfusion
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- C12M29/18—External loop; Means for reintroduction of fermented biomass or liquid percolate
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- C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
- C12M33/14—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus with filters, sieves or membranes
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- C12M41/18—Heat exchange systems, e.g. heat jackets or outer envelopes
- C12M41/20—Heat exchange systems, e.g. heat jackets or outer envelopes the heat transfer medium being a gas
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/26—Means for regulation, monitoring, measurement or control, e.g. flow regulation of pH
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
- C12M41/34—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of gas
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
- C12M41/38—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of metabolites or enzymes in the cells
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- C12M41/48—Automatic or computerized control
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- C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
- C12M47/02—Separating microorganisms from the culture medium; Concentration of biomass
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- C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
- C12M47/04—Cell isolation or sorting
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- C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
- C12M47/10—Separation or concentration of fermentation products
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- C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
- C12M47/20—Heating or cooling
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q3/00—Condition responsive control processes
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/0009—Special features
- F04B43/0054—Special features particularities of the flexible members
- F04B43/0072—Special features particularities of the flexible members of tubular flexible members
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/08—Machines, pumps, or pumping installations having flexible working members having tubular flexible members
- F04B43/09—Pumps having electric drive
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
- F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
- F04B43/00—Machines, pumps, or pumping installations having flexible working members
- F04B43/12—Machines, pumps, or pumping installations having flexible working members having peristaltic action
- F04B43/1253—Machines, pumps, or pumping installations having flexible working members having peristaltic action by using two or more rollers as squeezing elements, the rollers moving on an arc of a circle during squeezing
- F04B43/1292—Pumps specially adapted for several tubular flexible members
Definitions
- the present invention relates to the interface features of a disposable cultureware module and a reusable compact instrumentation base device that is capable of expanding cells including primary cells and cell lines as well as patient-specific cells or cells lines, and more particularly, to an installation method that enables a single motion installation of the cultureware module on the instrumentation base device.
- T-fiasks, roller bottles, stirred bottles or cell bags are manual methods using incubators or warm-rooms to provide environments for cell growth and production. These methods are very labor intensive, subject to mistakes and difficult for large scale production.
- Another method ascites production, uses a host animal (usually a mouse) where the peritoneum is injected with the cells that express the product and are parasitically grown and maintained. The animals are sacrificed and the peritoneal fluid with the product is collected. This method is also labor intensive, difficult for large scale production and objectionable because of the use of animals.
- Yet another method is to inoculate and grow the cells in a small stirred tank or bioreactor or bag-type chamber.
- the tank provides the environmental and metabolic needs and the cell secretions are allowed to accumulate.
- This method is costly in terms of facility support in order to do a large number of unique cells and produces product at low concentration.
- Another method is to use a bioreactor (hollow fiber, ceramic matrix, fluidizer bed, etc) in lieu of the stirred tank. This can bring facilities costs down and increases product concentration.
- Biovest International of Coon Rapids, MN has or had instruments using these technologies - hollow fiber, ceramic matrix, fluidized bed and stirred tanks.
- a hollow fiber culture device includes a plurality of hollow fiber membranes.
- Medium containing oxygen, nutrients, and other chemical stimuli is transported through the lumen of the hollow fiber membranes or capillaries and diffuses through the walls thereof into an extracapillary (EC) space between the membranes and the shell of the cartridge containing the hollow fibers.
- the cells that are to be maintained collect in the extracapillary space. Metabolic wastes are removed from the bioreactor.
- the cells or cell products can be harvested from the device.
- Preparing the system to start the cell culture is also very labor intensive.
- the cultureware must be assembled and sterilized or probes must be prepared, sterilized and aseptically inserted into the pre-sterilized portion of the cultureware.
- the cultureware assembly is then loaded onto the instrument. A series of manual operations are needed to check the integrity of the assembly, introduce fluid into the cultureware flow path, flush the toxic residuals (e.g. surfactants) from the cultureware, start the cultureware in a pre- inoculation mode, introduce factors into the flow path getting it ready for the cells, inoculating the cells into the bioreactor and starting the run (growth of the cell mass and eventual harvest of product).
- toxic residuals e.g. surfactants
- Two methods are generally used for sterilization.
- One method places an electrode in a holder, wherein steam sterilizes the assembly (probe) and then aseptically inserts the probe into the pre-sterilized cultureware.
- the second method involves placing a non-sterile probe into a holder and then using steam to sterilize the electrode in place, referred to as steam in place. Both methods are labor intensive, prone to failure and the procedures need to be validated.
- Cold sterilants can be used to sterilize the holder and electrode before aseptic insertion.
- a permeable membrane can be used to isolate the non-sterile probe from the sterile fluid being sensed.
- a holder with the membrane is placed in the fluid path, either before sterilization or after if the holder and membrane is sterilized separately, and then the sensor is placed against or close to the membrane and the fluid on both sides of the membrane is assumed to be equilibrated.
- Each unique cell or cell line must be cultured, cell products harvested and purified separately. In order to do a large number of unique cells or cell lines, a considerable number of instruments would be needed. If application of the cells or products for therapeutic purposes is contemplated, strict segregation of each cell production process would be required. Consequently compactness of the design and the amount of ancillary support resources needed will become an important facilities issue. Moreover, the systems currently available are general purpose in nature and require considerable time from trained operators to setup, load, flush, inoculate, run, harvest and unload. Each step usually requires manual documentation.
- One aspect of the present invention is to provide a compact, sealed, sterilizable cultureware module removably attached to the instrumentation base device that will enable the cost effective manufacture of cells, cell lines, patient specific cells and cell products on an industrial scale.
- Another aspect of the present invention is to provide a method and system that incorporates disposable cultureware, which eliminates the need for cleaning and reuse.
- Yet another aspect of the present invention is a cultureware module that has the plurality of interface methods integrated therein to enable an easy and reliable installation.
- the system of the present invention incorporates features that greatly reduce the operator's time needed to support the operations (e.g. integrated pump cassette, pre- sterilized cultureware with pH sensors, quick-load cultureware) and designed automated procedures and apparatus which allow the system to sequence through the operations (e.g. automated fluid clamps, control software).
- integrated pump cassette pre- sterilized cultureware with pH sensors, quick-load cultureware
- automated procedures and apparatus which allow the system to sequence through the operations
- the system is capable of integrating the cell culture product production and purification process.
- the design of the cultureware and instrument simplifies and reduces labor needed to produce product. This reduces sources of error in the process.
- the present invention provides an automated cell culture system and method which creates a self-contained culture environment.
- the apparatus incorporates perfusion culture with sealed, pre-sterilized disposable cultureware, such as hollow fiber or other bioreactors , programmable process control, automated fluid valving, pH feedback control, lactic acid feedback control, temperature control, nutrient delivery control, waste removal, gas exchange mechanism, reservoirs, tubing, pumps and harvest vessels.
- the present cell culture apparatus (referred to as AutovaxED Cell Culture ModuleTM) is capable of expanding cells in a highly controlled, contaminant-free manner.
- Cells to which this approach are applicable include transformed or non-transformed cell lines, primary cells including somatic cells such as lymphocytes or other immune cells, chondrocytes, myocytes or myoblasts, epithelial cells and patient specific cells, primary or otherwise. Included also are cells or cell lines that have been genetically modified, such as both adult and embryonic stem cells.
- the automated cell culture apparatus allows for production and harvest of cells or cell-secreted protein in a manner that minimizes the need for operator intervention and minimizes the need for segregated clean rooms for the growth and manipulation of the cells.
- the system provides a culture environment that is completely self- contained and disposable. This eliminates the need for individual clean rooms typically required in a regulated, multi-use facility. Control of fluid dynamics within the bioreactor allows for growth conditions to be adjusted, e.g. changing growth factor concentrations, to facilitate application of unique culture protocols or expansion of unique cells or cell lines. As a result, there is less variation and less labor required for consistent, reproducible production of cells for applications to expansion of autologous cells and their use in personalized medicine applications.
- a cell culture system for the production of cells and cell derived products including a reusable instrumentation base device incorporating mechanical and electrical hardware to support cell culture growth and at least one disposable cell cultureware module removably attachable to the instrumentation base device.
- the cultureware module includes a plurality of mechanical and electrical interfaces, such that when the cultureware module is positioned on the instrumentation base device the plurality of mechanical and electrical interfaces of the cultureware module mate with the mechanical and electrical hardware of the instrumentation base device.
- a method of removably positioning a cultureware module on an instrumentation device of a cell culture system including the steps of providing a disposable cultureware module, the module including a plurality of mechanical and electrical interfaces, providing a reusable instrumentation base device incorporating electrical and mechanical hardware to support cell culture growth, and removably attaching the cultureware module to the instrumentation base device, such that when the cultureware module is positioned on the instrumentation base device the plurality of mechanical and electrical interfaces of the module mate with respective mechanical and electrical hardware of the instrumentation base device.
- FIG. 1 is a perspective view of the system for producing cells and/or cell derived products according to the present invention.
- FIG. 2 is another perspective view of the system of the present invention.
- Fig. 3 is a perspective view of the instrumentation base device of the present invention.
- Fig. 4 a rear view of the instrument base device of Fig. 3 with covers removed.
- FIG. 5 is a perspective view of the disposable culture medium module of the present invention.
- Fig. 6 is an interior view of the module of Fig. 5.
- Fig. 7 is a perspective interior view of the back of the module of Fig. 5.
- Fig. 8 illustrates the installation method of the cell culture module and the device of the present invention.
- the present invention provides a fully integrated system 10 for producing cells and cell derived products in a closed, self-sufficient environment. More specifically, the system allows for cell expansion and harvest of cells and their products with minimal need for technician interaction.
- the system incorporates cell culture technology, for example, hollow fiber or similar bioreactor perfusion technology, with all tubing components, media feed, harvest tubing and tubes threaded through the pump cassette, encased in a single- use, disposable incubator 12. Following bioreactor inoculation with cells, the system follows pre-programmed processes to deliver media, maintain pH, maintain lactate levels, control temperature and harvest cells or cell-secreted protein. Standard or unique cell culture growth parameters can be programmed, such that, various cell types can be expanded and such that cells or cell products can be harvested in an efficient, reproducible manner with minimal chance of human error.
- a bioreactor 20 has a plurality of semi-permeable hollow fibers or other type of semi-permeable membrane or substrate potted in a housing to create a space inside the fiber or one side of the membrane (referred to as intracapillary or IC space) separate from that outside the fibers or on the other side of the membrane (referred to as extracapillary or EC space). Fluid distribution between the IC and EC space occurs through the fiber pores which can range in size from IOMW (Kd) to 0.2 ⁇ m.
- Cells are placed on one side of the fiber or membrane, usually in the EC space, in a complete cell culture medium, which, is usually the same medium used to expand cells prior to bioreactor inoculation (serum containing, serum-free, or protein-free medium). Cells are usually placed in the EC space when secreted protein is the desired product. In some instances, when cells are the desired product, it may be beneficial to place cells in the IC space.
- Medium is perfused through bioreactor 20 by circulating through the IC space at a fast rate. This serves to deliver nutrients to the cell space and conversely, removes or prevents a toxic build-up of metabolic waste.
- medium is passed through an oxygenator or gas exchange cartridge 24 which serves to provide pH control and oxygen for the cells and conversely, remove carbon dioxide from the culture.
- the oxygenator or gas exchange cartridge is used to provide CO 2 and subsequently control pH of the culture environment. As cell number increases, the oxygenator is used to remove CO 2 which serves to enhance acid neutralization and control the pH of the culture.
- Other bioreactor configurations, in addition to hollow fibers, that are designed and optimized for the growth and production of cells and production of cell-derived products are also included.
- the system 10 provides significant efficiencies and cost reduction through its disposable component and enclosed operation. As such, cell lines are contained in a closed system and continuously cultured without the need for specialized, segregated clean rooms. This fully integrated apparatus eliminates the need for cleaning and sterilization validations, as well as the need for hard plumbing associated with conventional cell culture facilities.
- the system consists of two individual parts: an instrumentation base device 14 that is reusable and an enclosed cultureware module 12 that is used for a single production run and is disposable.
- the instrument provides the hardware to support cell culture growth and production in a compact package.
- an easy-load multiple channel peristaltic pump drive 16 located in instrumentation base device 14 along with a pump cassette 70 move fresh basal media into the cultureware, remove spent media, add growth factors or other supplements, and remove product harvest.
- An integrated cool storage area 18 maintains the factor and harvest at a low temperature (approximately 4°C).
- An integrated heating mechanism 22 (Fig. 4) maintains the cell environment to promote growth and production.
- Gas exchange cartridge 24, in conjunction with a cultureware pH sensor 26 controls the pH of the cell culture medium.
- Two automated tube valving drives 90 (Figs. 3 and 4) are used to control the cultureware flow path configuration to accomplish the
- Valves 90 and sensors 32 (Figs. 3, 4) in the instrument control the fluid cycling in the cultureware module 12.
- An attached barcode reader, not shown, facilitates operator and lot tracing.
- a communication port ties the instrument to a data management system (such as an MES).
- a flat panel display 36 (Fig. 1) with touch screen is available for user interaction.
- the one-time use cultureware module 12 is provided pre-sterilized. It is designed for quick loading onto the instrument ("quick-load"), as will be described further herein.
- the loading of the cultureware body makes connections to the instrument.
- a pump cassette 70 (Fig. 2), which is physically attached to the tubing, allows the user to quickly load the pump segments. The design and layout minimizes loading errors.
- the cultureware enclosure 12 provides an area that is heated to maintain cell fluid temperature.
- Fluid cycling unit 40 (Figs. 5-7) maintains fluid volumes and cycling and is included in the cultureware. Sensors for fluid circulation rate, pH and a thermal well for the instrument's temperature sensor are also provided.
- the blended gas from the instrument is routed to gas exchange cartridge 24 that provides oxygen and adds or removes carbon dioxide to the circulated fluid to support cell metabolism.
- a magnetically coupled pump 164 (Fig. 7) circulates fluid thru the bioreactor 20 and gas exchange cartridge 24.
- the bioreactor 20 that provides the cell space and media component exchange is also in the cultureware.
- Disposable containers for harvest collection are provided. Prior to the beginning of the culture the operator attaches a media source, factor bag and spent media container to the cultureware before running. At the conclusion of the run the harvest containers are removed or drained, media and spent media container is disconnected, pump cassette is unloaded, harvest bag disconnected, cultureware body is unloaded and the used cultureware is placed in a biohazard container for disposal. Another disposable cultureware module can then be positioned on the instrumentation base device and the process started again.
- the system of the present invention has application in a regulated cell culture environment. It is anticipated that autologous whole cell therapies or patient-specific proteins (vaccines) therapies, would by their nature, require the simultaneous culture of numerous cell lines in a single facility. In addition to the segregation created through this closed culture approach, the apparatus is designed to support a standard information management system (such as a LIMS or MES) protocol. This capability contributes to the creation of thorough batch records and verification of culture conditions to ensure standardization, tracking and safety of each product. This capability facilitates the multi-product concept that is pivotal to facilities involved with autologous or patient-specific products.
- a standard information management system such as a LIMS or MES
- disposable cell culture module 12 is removably attachable to device 14.
- the module requires multiple mechanical and electrical interfaces to the control instrumentation of device 14.
- Module 12 has interface features integrated into the module that mate with instrument interface features in the device to allow for a single motion installation as shown in Fig. 8.
- instrumentation base device 14 includes circulation pump 34, actuator valves 90 and cycling sensor 32.
- a temperature probe 44 and a flow sensor 46 interface with the components of module 12.
- Device 14 also includes an electrical connection 48 for pH sensor 26 disposed within module 12.
- Device 14 includes gas ports 52 that communicate with gas exchanger 24.
- One port 52 communicates with the input to exchanger 24 and the other port 52 communicates with the output of the exchanger.
- Gas ports 54 control pressure to the cycling fixture 40.
- One port 54 communicates with the IC chamber and the other port 54 communicates with the EC pressure bag.
- the left port 52 is the exchanger output
- the right port 52 is the exchanger input.
- the top port 54 is the IC reservoir pressurization port
- the lower port 54 is the EC reservoir pressurization port.
- module 12 is heated to maintain cell fluid temperature.
- Heating mechanism 22 (Fig. 4) maintains the cell environment to promote growth and production.
- the cell culture, disposable module 12 requiring elevated temperatures are warmed by fully encapsulating the module and attaching the module to instrument base device 14, such that air ports are aligned and warmed air is forced into the module from the instrument at one location and allowed to escaped at another.
- Instrument device 14 has a heated air outlet 58 and a return heated air inlet 56.
- Module 12 includes a plurality of mechanical and electrical interfaces formed integrally in a back panel 148 of module 12.
- the mechanical and electrical interfaces of the module simultaneously mate with the hardware of device 14.
- the module installation and mating of the hardware and module interfaces can be accomplished in a single motion.
- module 12 includes air inlet 88 (Fig. 7) that aligns with the air outlet 58 of the instrument device. Heating mechanism 22 forces warmed air through outlet 58 and into the warmed air inlet 88 and into disposable module 12. The warmed air elevates the temperature of the components inside of the module. The exhaust air exits through air outlet 86 formed in back pane! 148 and into air inlet 56 of instrument device 14 where it is circulated through recirculated.
- module 12 is aligned with the connections of the device 14 and the module is placed into the operating position as shown in Fig. 8.
- AU mating interface features are functional.
- certain features of the module 12 interface with device 14.
- module air outlet 86 aligns with device air inlet 56
- module air inlet 88 aligns with device air outlet 58 to circulate heated air through the module.
- Module back panel 148 include gas connectors 152 and 154 that engage device gas ports 52 and 54, respectively, to allow gas to enter and exit module 12.
- Valve housings 156 are formed integrally with the back panel and are constructed and arranged to receive actuator valves 90.
- Hub 158 formed in back panel 148 interfaces with pH sensor 26 and aligns with electrical connector 48 of device 14.
- Module 12 is. connected to circulation pump drive 34 via module pump 164. Cycling unit 40 also communicates with cycling sensor 32 when the module is installed.
- the flow sensor 46 of device 12 mates with flow sensor connection 166.
- the temperature sensor 44 of device 14 mates with a non-invasive receptacle 150 in module 12 that is in contact with the IC media to provide control feed back to the control mechanism to regulate the thermal output of heater 22.
- the above mating interfaces or connections facilitate the one-motion installation of the module 12 on the device 14.
- the system of the present invention fully integrates the concept of disposable cultureware into automated process control for maintaining and expanding specialized (autologous or other) cell lines for a duration of any time needed.
- the system of the present invention was designed for EC space fluid flow that enhances cell growth in high density perfusion culture, yet remains completely closed and disposable.
- the integrated pre-assembled cultureware which consists of all tubing, bioreactor, oxygenator, pH probe, is enclosed in a single unit that easily snaps into the apparatus.
- the entire cultureware unit enclosed by the casing becomes the cell culture incubator with temperature control regulated through automated process control of the instrument.
- Each unique cell line must be cultured, cell secretions harvested and purified separately.
- a considerable number of instruments would be needed.
- Compactness of the design and the amount of ancillary support resources needed become an important facilities issue.
- Small stirred tank systems require a means of steam generation and distribution (for steam-in-place sterilization) or autoclaves to sterilize the vessels and supporting plumbing.
- To support a large number of units becomes a logistics problem for the facility.
- the system of the present invention has no such requirement. Larger scale cell culture is historically done in segregated steps that often require separate types of equipment. Manual handling, storage and tracking is needed for all these steps as the culture expands and product is harvested.
- the method of the present invention integrates these steps into a continuous, fully integrated sequential process. This eliminates the handling risk and facilitates the data gathering required for thorough documentation of the entire process.
Abstract
A cell culture system for the production of cells and cell derived products and an interface system and method for removably connecting a disposable cell cultureware module to a reusable instrumentation base device incorporating mechanical and electrical hardware to support cell culture growth. The cultureware module includes a plurality of mechanical and electrical interfaces, such that when the cultureware module is positioned on the instrumentation base device the plurality of mechanical and electrical interfaces of the cultureware module mate with the mechanical and electrical hardware of the instrumentation base device.
Description
INTERFACE OF A CULTUREWARE MODULE IN A CELL CULTURE SYSTEM AND INSTALLATION METHOD THEREOF
BACKGROUND OF THE INVENTION
1. Field of the Invention:
[0001 ] The present invention relates to the interface features of a disposable cultureware module and a reusable compact instrumentation base device that is capable of expanding cells including primary cells and cell lines as well as patient-specific cells or cells lines, and more particularly, to an installation method that enables a single motion installation of the cultureware module on the instrumentation base device.
2. Description of the Related Art:
[0002] The anticipated growth of personalized medicine will require new paradigms for the manufacture of therapies tailored to the needs of individual patients. The greatest challenge is expected to come in the area of cell based therapies, especially when such therapies are autologous in nature, hi such cases each .cell or cell based product will need to be manufactured from scratch for each patient. Manual methods for mammalian cell culture, by their nature, are prone to technician error or inconsistency leading to differences between supposed identical cultures. This becomes especially evident as more and more autologous cells are expanded for personalized therapies. Patient-specific cells, or proteins, are subject to variation, especially when scaled beyond levels that can be managed efficiently with manual methods.
[0003] In addition to being labor intensive, the stringent requirements for segregation of each patient's materials from that of every other patient will mean that manufacturing facilities will be large and complex, containing a multitude of isolation suites each with its own equipment (incubators, tissue culture hoods, centrifuges) that can be used for only one patient at a time. Because each patient's therapy is a new and unique product, patient specific manufacturing will also be labor intensive, requiring not just direct manufacturing personnel but also disproportionately increased manpower for quality assurance and quality control functions.
[0004] Conventional approaches and tools for manufacturing cells or cell based products typically involve numerous manual manipulations that are subject to variations, even when conducted by skilled technicians. When used at the scale needed to manufacture hundreds or thousands of different cells, cell lines and patient specific cell based therapies,
the variability, error or contamination rate may become unacceptable for commercial processes.
[0005] Small quantities of secreted product are produced in a number of different ways. T-fiasks, roller bottles, stirred bottles or cell bags are manual methods using incubators or warm-rooms to provide environments for cell growth and production. These methods are very labor intensive, subject to mistakes and difficult for large scale production.
[0006] Another method, ascites production, uses a host animal (usually a mouse) where the peritoneum is injected with the cells that express the product and are parasitically grown and maintained. The animals are sacrificed and the peritoneal fluid with the product is collected. This method is also labor intensive, difficult for large scale production and objectionable because of the use of animals.
[0007] Yet another method is to inoculate and grow the cells in a small stirred tank or bioreactor or bag-type chamber. The tank provides the environmental and metabolic needs and the cell secretions are allowed to accumulate. This method is costly in terms of facility support in order to do a large number of unique cells and produces product at low concentration.
[0008] Another method is to use a bioreactor (hollow fiber, ceramic matrix, fluidizer bed, etc) in lieu of the stirred tank. This can bring facilities costs down and increases product concentration. Biovest International of Coon Rapids, MN, has or had instruments using these technologies - hollow fiber, ceramic matrix, fluidized bed and stirred tanks.
[0009] Cell culturing devices or cultureware for culturing cells in vitro are known. As disclosed in U.S. Patent No. 4,804,628, the entirety of which is hereby incorporated by reference, a hollow fiber culture device includes a plurality of hollow fiber membranes. Medium containing oxygen, nutrients, and other chemical stimuli is transported through the lumen of the hollow fiber membranes or capillaries and diffuses through the walls thereof into an extracapillary (EC) space between the membranes and the shell of the cartridge containing the hollow fibers. The cells that are to be maintained collect in the extracapillary space. Metabolic wastes are removed from the bioreactor. The cells or cell products can be harvested from the device.
[0010] These methodologies rely on costly, labor intensive off-line sampling and analysis or additional equipment to interface with the instrument or require the addition of a lactate or pH probe and electronics to the culture.
[0011] Preparing the system to start the cell culture is also very labor intensive. The cultureware must be assembled and sterilized or probes must be prepared, sterilized and
aseptically inserted into the pre-sterilized portion of the cultureware. The cultureware assembly is then loaded onto the instrument. A series of manual operations are needed to check the integrity of the assembly, introduce fluid into the cultureware flow path, flush the toxic residuals (e.g. surfactants) from the cultureware, start the cultureware in a pre- inoculation mode, introduce factors into the flow path getting it ready for the cells, inoculating the cells into the bioreactor and starting the run (growth of the cell mass and eventual harvest of product).
[0012] Two methods are generally used for sterilization. One method places an electrode in a holder, wherein steam sterilizes the assembly (probe) and then aseptically inserts the probe into the pre-sterilized cultureware. The second method involves placing a non-sterile probe into a holder and then using steam to sterilize the electrode in place, referred to as steam in place. Both methods are labor intensive, prone to failure and the procedures need to be validated.
[0013] Other methods exist which are less common. Cold sterilants can be used to sterilize the holder and electrode before aseptic insertion. A permeable membrane can be used to isolate the non-sterile probe from the sterile fluid being sensed. A holder with the membrane is placed in the fluid path, either before sterilization or after if the holder and membrane is sterilized separately, and then the sensor is placed against or close to the membrane and the fluid on both sides of the membrane is assumed to be equilibrated.
[0014] Each unique cell or cell line must be cultured, cell products harvested and purified separately. In order to do a large number of unique cells or cell lines, a considerable number of instruments would be needed. If application of the cells or products for therapeutic purposes is contemplated, strict segregation of each cell production process would be required. Consequently compactness of the design and the amount of ancillary support resources needed will become an important facilities issue. Moreover, the systems currently available are general purpose in nature and require considerable time from trained operators to setup, load, flush, inoculate, run, harvest and unload. Each step usually requires manual documentation.
[0015] Known systems typically locate the disposable near the instrument and require that the interface features, such as the connectors, tubing and probes, be individually connected or mated with the corresponding feature. Bio vest, assignee of the present invention, has utilized this concept in its prior Xcell, Maximizer, miniMax and CP2500 instruments. This is a time intensive activity that increases the chance of loading errors.
[0016] Accordingly, there is a need for a system and method wherehy the disposable cultureware module includes the device interface features integrated therein to allow a quick and reliable installation.
SUMMARY OF THE INVENTION
[0017] One aspect of the present invention is to provide a compact, sealed, sterilizable cultureware module removably attached to the instrumentation base device that will enable the cost effective manufacture of cells, cell lines, patient specific cells and cell products on an industrial scale.
[0018] Another aspect of the present invention is to provide a method and system that incorporates disposable cultureware, which eliminates the need for cleaning and reuse.
[0019] Yet another aspect of the present invention is a cultureware module that has the plurality of interface methods integrated therein to enable an easy and reliable installation.
[0020] The system of the present invention incorporates features that greatly reduce the operator's time needed to support the operations (e.g. integrated pump cassette, pre- sterilized cultureware with pH sensors, quick-load cultureware) and designed automated procedures and apparatus which allow the system to sequence through the operations (e.g. automated fluid clamps, control software).
[0021] The system is capable of integrating the cell culture product production and purification process. The design of the cultureware and instrument simplifies and reduces labor needed to produce product. This reduces sources of error in the process.
[0022] The present invention provides an automated cell culture system and method which creates a self-contained culture environment. The apparatus incorporates perfusion culture with sealed, pre-sterilized disposable cultureware, such as hollow fiber or other bioreactors , programmable process control, automated fluid valving, pH feedback control, lactic acid feedback control, temperature control, nutrient delivery control, waste removal, gas exchange mechanism, reservoirs, tubing, pumps and harvest vessels. Accordingly, the present cell culture apparatus (referred to as AutovaxED Cell Culture Module™) is capable of expanding cells in a highly controlled, contaminant-free manner. Cells to which this approach are applicable include transformed or non-transformed cell lines, primary cells including somatic cells such as lymphocytes or other immune cells, chondrocytes, myocytes or myoblasts, epithelial cells and patient specific cells, primary or otherwise. Included also are cells or cell lines that have been genetically modified, such as both adult and embryonic stem cells. Specifically, the automated cell culture apparatus allows for production and harvest of
cells or cell-secreted protein in a manner that minimizes the need for operator intervention and minimizes the need for segregated clean rooms for the growth and manipulation of the cells.
[0023] Further, the system provides a culture environment that is completely self- contained and disposable. This eliminates the need for individual clean rooms typically required in a regulated, multi-use facility. Control of fluid dynamics within the bioreactor allows for growth conditions to be adjusted, e.g. changing growth factor concentrations, to facilitate application of unique culture protocols or expansion of unique cells or cell lines. As a result, there is less variation and less labor required for consistent, reproducible production of cells for applications to expansion of autologous cells and their use in personalized medicine applications.
[0024] According to these and other aspects of the present invention, there is provided a cell culture system for the production of cells and cell derived products including a reusable instrumentation base device incorporating mechanical and electrical hardware to support cell culture growth and at least one disposable cell cultureware module removably attachable to the instrumentation base device. The cultureware module includes a plurality of mechanical and electrical interfaces, such that when the cultureware module is positioned on the instrumentation base device the plurality of mechanical and electrical interfaces of the cultureware module mate with the mechanical and electrical hardware of the instrumentation base device.
[0025] According to these and other aspects of the present invention, there is also provided a method of removably positioning a cultureware module on an instrumentation device of a cell culture system, the method including the steps of providing a disposable cultureware module, the module including a plurality of mechanical and electrical interfaces, providing a reusable instrumentation base device incorporating electrical and mechanical hardware to support cell culture growth, and removably attaching the cultureware module to the instrumentation base device, such that when the cultureware module is positioned on the instrumentation base device the plurality of mechanical and electrical interfaces of the module mate with respective mechanical and electrical hardware of the instrumentation base device.
[0026] These and other features, aspects, and advantages of the present invention will become more apparent from the following detailed description of the preferred embodiment relative to the accompanied drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Fig. 1 is a perspective view of the system for producing cells and/or cell derived products according to the present invention.
[0028] Fig. 2 is another perspective view of the system of the present invention.
[0029] Fig. 3 is a perspective view of the instrumentation base device of the present invention.
[0030] Fig. 4 a rear view of the instrument base device of Fig. 3 with covers removed.
[0031] Fig. 5 is a perspective view of the disposable culture medium module of the present invention.
[0032] Fig. 6 is an interior view of the module of Fig. 5.
[0033] Fig. 7 is a perspective interior view of the back of the module of Fig. 5.
[0034] Fig. 8 illustrates the installation method of the cell culture module and the device of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0035] Referring to Fig. 1, the present invention provides a fully integrated system 10 for producing cells and cell derived products in a closed, self-sufficient environment. More specifically, the system allows for cell expansion and harvest of cells and their products with minimal need for technician interaction. The system incorporates cell culture technology, for example, hollow fiber or similar bioreactor perfusion technology, with all tubing components, media feed, harvest tubing and tubes threaded through the pump cassette, encased in a single- use, disposable incubator 12. Following bioreactor inoculation with cells, the system follows pre-programmed processes to deliver media, maintain pH, maintain lactate levels, control temperature and harvest cells or cell-secreted protein. Standard or unique cell culture growth parameters can be programmed, such that, various cell types can be expanded and such that cells or cell products can be harvested in an efficient, reproducible manner with minimal chance of human error.
[0036] The system is based on cell growth chamber technology. For example, a bioreactor 20 has a plurality of semi-permeable hollow fibers or other type of semi-permeable membrane or substrate potted in a housing to create a space inside the fiber or one side of the membrane (referred to as intracapillary or IC space) separate from that outside the fibers or on the other side of the membrane (referred to as extracapillary or EC space). Fluid distribution between the IC and EC space occurs through the fiber pores which can range in
size from IOMW (Kd) to 0.2μm. Cells are placed on one side of the fiber or membrane, usually in the EC space, in a complete cell culture medium, which, is usually the same medium used to expand cells prior to bioreactor inoculation (serum containing, serum-free, or protein-free medium). Cells are usually placed in the EC space when secreted protein is the desired product. In some instances, when cells are the desired product, it may be beneficial to place cells in the IC space.
[0037] Medium is perfused through bioreactor 20 by circulating through the IC space at a fast rate. This serves to deliver nutrients to the cell space and conversely, removes or prevents a toxic build-up of metabolic waste. During this circulation, medium is passed through an oxygenator or gas exchange cartridge 24 which serves to provide pH control and oxygen for the cells and conversely, remove carbon dioxide from the culture. When the bioreactor 20 contains a smaller number of cells, just after inoculation, the oxygenator or gas exchange cartridge is used to provide CO2 and subsequently control pH of the culture environment. As cell number increases, the oxygenator is used to remove CO2 which serves to enhance acid neutralization and control the pH of the culture. Other bioreactor configurations, in addition to hollow fibers, that are designed and optimized for the growth and production of cells and production of cell-derived products are also included.
[0038] The system 10 provides significant efficiencies and cost reduction through its disposable component and enclosed operation. As such, cell lines are contained in a closed system and continuously cultured without the need for specialized, segregated clean rooms. This fully integrated apparatus eliminates the need for cleaning and sterilization validations, as well as the need for hard plumbing associated with conventional cell culture facilities.
[0039] As shown in Fig. 1, the system consists of two individual parts: an instrumentation base device 14 that is reusable and an enclosed cultureware module 12 that is used for a single production run and is disposable. The instrument provides the hardware to support cell culture growth and production in a compact package. As shown in Fig. 2, an easy-load multiple channel peristaltic pump drive 16 located in instrumentation base device 14 along with a pump cassette 70 move fresh basal media into the cultureware, remove spent media, add growth factors or other supplements, and remove product harvest. An integrated cool storage area 18 maintains the factor and harvest at a low temperature (approximately 4°C). An integrated heating mechanism 22 (Fig. 4) maintains the cell environment to promote growth and production. Gas exchange cartridge 24, in conjunction with a cultureware pH sensor 26 controls the pH of the cell culture medium. Two automated tube valving drives 90 (Figs. 3 and 4) are used to control the cultureware flow path configuration to accomplish the
- 1 -
fluidic switching functions needed to initiate and do a successful run. Valves 90 and sensors 32 (Figs. 3, 4) in the instrument control the fluid cycling in the cultureware module 12. An attached barcode reader, not shown, facilitates operator and lot tracing. A communication port ties the instrument to a data management system (such as an MES). A flat panel display 36 (Fig. 1) with touch screen is available for user interaction.
[0040] The one-time use cultureware module 12 is provided pre-sterilized. It is designed for quick loading onto the instrument ("quick-load"), as will be described further herein. The loading of the cultureware body makes connections to the instrument. A pump cassette 70 (Fig. 2), which is physically attached to the tubing, allows the user to quickly load the pump segments. The design and layout minimizes loading errors. The cultureware enclosure 12 provides an area that is heated to maintain cell fluid temperature. Fluid cycling unit 40 (Figs. 5-7) maintains fluid volumes and cycling and is included in the cultureware. Sensors for fluid circulation rate, pH and a thermal well for the instrument's temperature sensor are also provided. The blended gas from the instrument is routed to gas exchange cartridge 24 that provides oxygen and adds or removes carbon dioxide to the circulated fluid to support cell metabolism. A magnetically coupled pump 164 (Fig. 7) circulates fluid thru the bioreactor 20 and gas exchange cartridge 24. The bioreactor 20 that provides the cell space and media component exchange is also in the cultureware. Disposable containers for harvest collection are provided. Prior to the beginning of the culture the operator attaches a media source, factor bag and spent media container to the cultureware before running. At the conclusion of the run the harvest containers are removed or drained, media and spent media container is disconnected, pump cassette is unloaded, harvest bag disconnected, cultureware body is unloaded and the used cultureware is placed in a biohazard container for disposal. Another disposable cultureware module can then be positioned on the instrumentation base device and the process started again.
[0041] Cell expansion and subsequent process tracking mandates generation of a batch record for each culture. Historically this is done with a paper-based system that relies on operator input of the information. This is labor intensive and subject to errors. The fully integrated device incorporates a barcode reader and data gathering software which, when used with an information management system (such as a MES), allows for automatic generation of the batch record.
[0042] The system of the present invention has application in a regulated cell culture environment. It is anticipated that autologous whole cell therapies or patient-specific proteins (vaccines) therapies, would by their nature, require the simultaneous culture of numerous cell
lines in a single facility. In addition to the segregation created through this closed culture approach, the apparatus is designed to support a standard information management system (such as a LIMS or MES) protocol. This capability contributes to the creation of thorough batch records and verification of culture conditions to ensure standardization, tracking and safety of each product. This capability facilitates the multi-product concept that is pivotal to facilities involved with autologous or patient-specific products.
[0043] Referring to Figs. 1 and 8, disposable cell culture module 12 is removably attachable to device 14. The module requires multiple mechanical and electrical interfaces to the control instrumentation of device 14. Module 12 has interface features integrated into the module that mate with instrument interface features in the device to allow for a single motion installation as shown in Fig. 8.
[0044] As shown in Fig. 3, the mechanical and electrical hardware of instrumentation base device 14 include circulation pump 34, actuator valves 90 and cycling sensor 32. In addition, a temperature probe 44 and a flow sensor 46 interface with the components of module 12. Device 14 also includes an electrical connection 48 for pH sensor 26 disposed within module 12.
[0045] Device 14 includes gas ports 52 that communicate with gas exchanger 24. One port 52 communicates with the input to exchanger 24 and the other port 52 communicates with the output of the exchanger. Gas ports 54 control pressure to the cycling fixture 40. One port 54 communicates with the IC chamber and the other port 54 communicates with the EC pressure bag. As viewed from the front, the left port 52 is the exchanger output, and the right port 52 is the exchanger input. The top port 54 is the IC reservoir pressurization port, and the lower port 54 is the EC reservoir pressurization port.
[0046] As described above, module 12 is heated to maintain cell fluid temperature. Heating mechanism 22 (Fig. 4) maintains the cell environment to promote growth and production. The cell culture, disposable module 12 requiring elevated temperatures are warmed by fully encapsulating the module and attaching the module to instrument base device 14, such that air ports are aligned and warmed air is forced into the module from the instrument at one location and allowed to escaped at another. Instrument device 14 has a heated air outlet 58 and a return heated air inlet 56.
[0047] Module 12 includes a plurality of mechanical and electrical interfaces formed integrally in a back panel 148 of module 12. When disposable module 12 is installed onto the controlling instrument device 14 the mechanical and electrical interfaces of the module
simultaneously mate with the hardware of device 14. Thus, the module installation and mating of the hardware and module interfaces can be accomplished in a single motion.
[0048] Referring to Figs. 3 and 7, module 12 includes air inlet 88 (Fig. 7) that aligns with the air outlet 58 of the instrument device. Heating mechanism 22 forces warmed air through outlet 58 and into the warmed air inlet 88 and into disposable module 12. The warmed air elevates the temperature of the components inside of the module. The exhaust air exits through air outlet 86 formed in back pane! 148 and into air inlet 56 of instrument device 14 where it is circulated through recirculated.
[0049] During installation, module 12 is aligned with the connections of the device 14 and the module is placed into the operating position as shown in Fig. 8. AU mating interface features are functional. When installed, certain features of the module 12 interface with device 14. As described above, module air outlet 86 aligns with device air inlet 56 and module air inlet 88 aligns with device air outlet 58 to circulate heated air through the module.
[0050] Module back panel 148 include gas connectors 152 and 154 that engage device gas ports 52 and 54, respectively, to allow gas to enter and exit module 12. Valve housings 156 are formed integrally with the back panel and are constructed and arranged to receive actuator valves 90. Hub 158 formed in back panel 148 interfaces with pH sensor 26 and aligns with electrical connector 48 of device 14.
[0051] Module 12 is. connected to circulation pump drive 34 via module pump 164. Cycling unit 40 also communicates with cycling sensor 32 when the module is installed. The flow sensor 46 of device 12 mates with flow sensor connection 166. The temperature sensor 44 of device 14 mates with a non-invasive receptacle 150 in module 12 that is in contact with the IC media to provide control feed back to the control mechanism to regulate the thermal output of heater 22. The above mating interfaces or connections facilitate the one-motion installation of the module 12 on the device 14.
[0052] At present, the system of the present invention fully integrates the concept of disposable cultureware into automated process control for maintaining and expanding specialized (autologous or other) cell lines for a duration of any time needed. To accomplish this, the system of the present invention was designed for EC space fluid flow that enhances cell growth in high density perfusion culture, yet remains completely closed and disposable. The integrated pre-assembled cultureware, which consists of all tubing, bioreactor, oxygenator, pH probe, is enclosed in a single unit that easily snaps into the apparatus. In addition to this error-proof, quick-load design, the entire cultureware unit enclosed by the casing becomes the cell culture incubator with temperature control regulated through
automated process control of the instrument. Pumps and fluid control valves facilitate disposability and error-proof installation, eliminating the possibility of technician mistakes. Finally, during the course of any culture, the closed system has restricted access except for trained and authorized personnel. Manipulations or sampling, outside of program parameters, require password and bar code access before they can be implemented.
[0053] Each unique cell line must be cultured, cell secretions harvested and purified separately. In order to manage a large number of unique cell lines, as for example might be required for the production of large numbers of autologous cell therapeutic products or large numbers of unique monoclonal antibodies, a considerable number of instruments would be needed. Compactness of the design and the amount of ancillary support resources needed become an important facilities issue. Small stirred tank systems require a means of steam generation and distribution (for steam-in-place sterilization) or autoclaves to sterilize the vessels and supporting plumbing. To support a large number of units becomes a logistics problem for the facility. The system of the present invention has no such requirement. Larger scale cell culture is historically done in segregated steps that often require separate types of equipment. Manual handling, storage and tracking is needed for all these steps as the culture expands and product is harvested. The method of the present invention integrates these steps into a continuous, fully integrated sequential process. This eliminates the handling risk and facilitates the data gathering required for thorough documentation of the entire process.
[0054] Although the present invention has been described in relation to particular embodiments thereof, many other variations and modifications and other uses will become apparent to those skilled in the art. It is preferred therefore, that the present invention be limited not by the specific disclosure herein, but only by the appended claims.
Claims
1. A cell culture system for the production of cells and cell derived products comprising: a reusable instrumentation base device incorporating mechanical and electrical hardware to support cell culture growth; and at least one disposable cell cultureware module removably attachable to the instrumentation base device, the module having a plurality of mechanical and electrical interfaces, such that when the cultureware module is positioned on the instrumentation base device said plurality of mechanical and electrical interfaces of the cultureware module mate with said mechanical and electrical hardware of the instrumentation base device.
2. The cell culture system of claim 1, wherein said plurality of mechanical and electrical interfaces are constructed and arranged in the cultureware module so as to simultaneously mate with respective mechanical and electrical hardware of the instrumentation base device.
3. The cell culture system of claim 1, wherein said plurality of mechanical and electrical interfaces are integrally formed in a back panel of the cultureware module.
4. The cell culture system of claim 1, wherein said mechanical and electrical hardware of the instrumentation base device includes a pump for circulating cell culture medium through the cultureware module.
5. The cell culture system of claim 4, wherein said plurality of mechanical and electrical interfaces includes a pump connection disposed in the cultureware module, such that when the cultureware module is positioned on the instrumentation base device the pump and pump connection align and connect.
6. The cell culture system of claim 1, wherein the instrumentation base device includes a plurality of rotary selection valves to control flow of cell culture medium through the cultureware module.
7. The cell culture system of claim 6, wherein the cultureware module has a plurality of valve bodies, such that when the cultureware module is positioned on the instrumentation base device the rotary selection valves are positioned within the valve housings.
8. The cell culture system of claim 1 , wherein the cultureware module forms a cell growth chamber.
9. The cell culture system of claim 8, wherein the instrumentation base device includes a heating mechanism for heating the cell growth chamber to promote growth and production and an air inlet and air outlet in communication with the heating mechanism.
10. The cell culture system of claim 9, wherein the cultureware module includes an inlet and outlet port, such that when the cultureware module is positioned on the instrumentation base device said inlet and outlets of the cultureware module align with the air inlet and outlet ports of the instrument base device so that the heat exchange mechanism forces heated air into the module from the instrument base device.
11. The cell culture system of claim 1, further comprising a pH sensor disposed in the cultureware module to control the pH of cell culture medium in the module.
12. The cell culture system of claim 11 , wherein the cultureware module includes a hub formed therein that interfaces with the pH sensor, such that when the cultureware module is positioned on the instrumentation base device said hub aligns with an electrical connector of instrument base device.
13. The cell culture system of claim 8, wherein the cultureware module includes a fluid cycling unit disposed therein to cycle and maintain fluid volumes within the cell growth chamber.
14. The cell culture system of claim 13, wherein the instrumentation base device includes a cycling sensor to sense fluid flow within the fluid cycling unit, such that when the cultureware module is positioned on the instrumentation base device the fluid cycling unit of the cultureware module communicates with the cycling sensor of the instrumentation base device.
15. The cell culture system of claim 1, wherein the instrumentation device includes sensors for sensing fluid circulation rate and temperature of cell culture medium in the cultureware module.
16. The cell culture system of claim 15, wherein the cultureware module includes a flow sensor connection and a temperature sensor connection, such that when the cultureware module is positioned on the instrumentation base device the flow sensor connection mates with the fluid circulation sensor and the temperature sensor connection mates with the temperature sensor.
17. The cell culture system of claim I3 wherein the cultureware module includes a gas exchange unit that provides oxygen and adds or removes carbon dioxide to cell culture medium to support cell metabolism.
18. The cell culture system of claim 17, wherein cultureware module includes gas connectors in fluid communication with the gas exchange unit, such that when the cultureware module is positioned on the instrumentation base device the gas connectors are in fluid communication with gas ports located in the instrumentation base device to allow gas to enter and exit the cultureware module.
19. The cell culture system of claim 1, wherein said cultureware module is pre-sterilized.
20. An interface system for connection of a cultureware module to an instrumentation base device of a cell culture apparatus, the interface system comprising:
mechanical and electrical hardware incorporated in a reusable instrumentation base device to support cell culture growth in a cell chamber having a cell culture medium; and
a plurality of mechanical and electrical interfaces disposed on the cultureware module,
such that when the cultureware module is positioned on the instrumentation base device said plurality of mechanical and electrical interfaces of the module mate with mechanical and electrical hardware of the instrumentation base device.
21. The interface system of claim 20, wherein said plurality of mechanical and electrical interfaces are integrally formed in a back panel of the cultureware module.
22. The interface system of claim 20, wherein said mechanical and electrical hardware of the instrumentation base device includes a pump for circulating cell culture medium through the cultureware module.
23. The interface system of claim 22, wherein said plurality of mechanical and electrical interfaces includes a pump connection disposed in the cultureware module, such that when the cultureware module is positioned on the instrumentation base device the pump and pump connection align and connect.
24. The interface system of claim 20, wherein said mechanical and electrical hardware of the instrumentation device includes a plurality of rotary selection valves to control flow of cell culture medium through the cultureware module.
25. The interface system of claim 24, wherein said plurality of mechanical and electrical interfaces includes a plurality of valve bodies, such that when the cultureware module is positioned on the instrumentation base device the rotary selection valves are positioned within the valve housings.
26. The interface system of claim 20, wherein said mechanical and electrical hardware of the instrumentation base device includes a heating mechanism for heating the cell growth chamber to promote growth and production and an air inlet and air outlet in communication with the heating mechanism.
27. The interface system of claim 26, wherein said plurality of mechanical and electrical interfaces of the cultureware module includes an inlet and outlet port, such that when the cultureware module is positioned on the instrumentation base device said inlet and outlets of the cultureware module align with the air inlet and outlet ports of the instrument device so that the heat exchange mechanism forces heated air into the cultureware module.
28. The interface system of claim 20, wherein the cultureware module includes a pH sensor disposed therein to control the pH of cell culture medium and wherein said plurality of mechanical and electrical interfaces of the cultureware module includes a hub formed therein that interfaces with the pH sensor, such that when the cultureware module is positioned on the instrumentation base device said hub aligns with an electrical connector of the instrumentation base device.
29. The interface system of claim 20, wherein the cultureware module includes a fluid cycling unit disposed therein to cycle and maintain fluid volumes within the cell growth chamber and said mechanical and electrical hardware of the instrumentation device includes a cycling sensor to sense fluid flow within the fluid cycling unit, such that when the cultureware module is positioned on the instrumentation base device the fluid cycling unit of the cultureware module communicates with the cycling sensor of the instrumentation base device.
30. The interface system of claim 20, wherein said mechanical and electrical hardware of the instrumentation device includes sensors for sensing fluid circulation rate and temperature of the cell culture medium.
31. The interface system of claim 30, wherein said plurality of mechanical and electrical interfaces of the cultureware module includes a flow sensor connection and a temperature sensor connection, such that when the cultureware module is positioned on the instrumentation base device the flow sensor connection mates with the fluid circulation sensor and the temperature sensor connection mates with the temperature sensor.
32. The interface system of claim 20, wherein the cultureware module includes a gas exchange unit that provides oxygen and adds or removes carbon dioxide to the cell culture medium to support cell metabolism and said plurality of mechanical and electrical interfaces of the cultureware module includes gas connectors in fluid communication with the gas exchange unit, such that when the cultureware module is positioned on the instrumentation base device the gas connectors are in fluid communication with gas ports located in the instrumentation base device to allow gas to enter and exit the module.
33. A cultureware module for connection to an instrumentation base device of a cell culture system; the module comprising:
a plurality of mechanical and electrical interfaces, wherein when the module is positioned on the instrumentation base device said plurality of mechanical and electrical interfaces of the module mate with mechanical and electrical hardware of the instrumentation base device.
34. The module of claim 33, wherein said plurality of mechanical and electrical interfaces are integrally formed in a back panel of the cultureware module.
35. The module of claim 33, wherein said plurality of mechanical and electrical interfaces includes a pump connection disposed in the cultureware module, such that when the cultureware module is positioned on the instrumentation base device the pump connection aligns and connects with a pump disposed in the instrumentation base device.
36. The module of claim 33, wherein said plurality of mechanical and electrical interfaces includes a plurality of valve bodies, such that when the cultureware module is positioned on the instrumentation base device a plurality of rotary selection valves located in the instrumentation base device are positioned within the valve housings.
37. The module of claim 33, wherein said plurality of mechanical and electrical interfaces of the cultureware module includes an inlet and outlet port, such that when the cultureware module is positioned on the instrumentation base device said inlet and outlets of the cultureware module align with air inlet and outlet ports of the instrument device so that a heat exchange mechanism located within the instrumentation base device forces heated air into the module.
38. The module of claim 33, further comprising a pH sensor for controlling a pH of the cell culture medium and wherein said plurality of mechanical and electrical interfaces of the cultureware module includes a hub formed therein that interfaces with the pH sensor, such that when the cultureware module is positioned on the instrumentation base device said hub aligns with an electrical connector of the instrumentation base device.
39. The module of claim 33, further comprising a fluid cycling unit to cycle and maintain fluid volumes within the cell growth chamber and wherein said mechanical and electrical hardware of the instrumentation device include a cycling sensor to sense fluid flow within the fluid cycling unit, such that when the cultureware module is positioned on the instrumentation base device the fluid cycling unit of the cultureware module communicates with the cycling sensor of the instrumentation base device.
40. The module of claim 33, wherein said plurality of mechanical and electrical interfaces of the cultureware module includes a flow sensor connection and a temperature sensor connection, such that when the cultureware module is positioned on the instrumentation base device the flow sensor connection mates with a fluid circulation sensor of the instrumentation base device and the temperature sensor connection mates with a temperature sensor of the instrumentation base device.
41. The module of claim 33, further comprising a gas exchange unit that provides oxygen and adds or removes carbon dioxide to the medium to support cell metabolism and said plurality of mechanical and electrical interfaces includes gas connectors in fluid communication with the gas exchange unit, such that when the cultureware module is positioned on the instrumentation base device the gas connectors are in fluid communication with gas ports located in the instrumentation base device to allow gas to enter and exit the module.
42. A method of removably positioning a cultureware module on an instrumentation device of a cell culture system, the method comprising the steps of: providing a disposable cultureware module, the module including a plurality of mechanical and electrical interfaces; providing a reusable instrumentation base device incorporating electrical and mechanical hardware to support cell culture growth, the instrumentation base device; and removably attaching the cultureware module to the instrumentation base device, such that when the cultureware module is positioned on the instrumentation base device said plurality of mechanical and electrical interfaces of the module mate with respective mechanical and electrical hardware of the instrumentation base device.
43. The method of claim 42, wherein said mechanical and electrical hardware of the instrumentation base device include a pump for circulating cell culture medium through the cultureware module and said plurality of mechanical and electrical interfaces include a pump connection disposed in the cultureware module, wherein the step of removably attaching the cultureware module to the instrumentation base device comprises aligning and connecting the pump and pump connection.
44. The method of claim 42, wherein the instrumentation base device includes a plurality of rotary selection valves to control the medium flow through the cultureware module and the cultureware modules has a plurality of valve housings, wherein the step of removably attaching the cultureware module to the instrumentation base device comprises positioning the rotary selection valves within the valve housings.
45. The method of claim 42, wherein the instrumentation base device includes a heating mechanism for heating a cell growth chamber of the cultureware module to promote growth and production, an air inlet and air outlet in communication with the heating mechanism, and an inlet and outlet port located in the cultureware module, wherein the step of removably attaching the cultureware module to the instrumentation base device comprises aligning the inlet and outlets of the cultureware module with the air inlet and outlet ports of the instrument base device so that the heat exchange mechanism forces heated air into the module.
46. The method of claim 42, wherein the cultureware module includes a pH sensor to control the pH of the cell culture medium and a hub formed therein that interfaces with the pH sensor, wherein the step of removably attaching the cultureware module to the instrumentation base device comprises aligning the hub and pH sensor with an electrical connector of the instrument base device.
47. The method of claim 42, wherein the cultureware module includes a fluid cycling unit disposed therein to cycle and maintain fluid volumes within the cell growth chamber and the instrumentation base device includes a cycling sensor to sense fluid flow within the fluid cycling unit, wherein the step of removably attaching the cultureware module to the instrumentation base device comprises interfacing the fluid cycling unit of the cultureware module and the cycling sensor of the instrumentation base device.
48. The method of claim 42, wherein the instrumentation base device includes sensors for sensing fluid circulation rate and temperature of the medium and the cultureware module includes a flow sensor connection and a temperature sensor connection, wherein the step of removably attaching the cultureware module to the instrumentation base device comprises connecting the flow sensor connection of the cultureware module with the fluid circulation sensor of the instrumentation base device and the temperature sensor connection of the cultureware module with the temperature sensor of the instrumentation base device.
49. The method of claim 42, wherein the cultureware module includes a gas exchange unit that provides oxygen and adds or removes carbon dioxide to the medium to support cell metabolism and gas connectors in fluid communication with the gas exchange unit, and wherein the step of removably attaching the cultureware module to the instrumentation base device comprises fluidly connecting the gas connectors with gas ports located in the instrumentation base device to allow gas to enter and exit the cultureware module.
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Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8309347B2 (en) | 2007-03-05 | 2012-11-13 | Terumo Bct, Inc. | Cell expansion system and methods of use |
US8383397B2 (en) | 2006-05-22 | 2013-02-26 | Biovest International, Inc. | Method and system for the production of cells and cell products and applications thereof |
US8691565B2 (en) | 2008-03-05 | 2014-04-08 | Terumo Bct, Inc. | Method of reseeding adherent cells grown in a hollow fiber bioreactor system |
US8895291B2 (en) | 2010-10-08 | 2014-11-25 | Terumo Bct, Inc. | Methods and systems of growing and harvesting cells in a hollow fiber bioreactor system with control conditions |
US8999046B2 (en) | 2008-10-27 | 2015-04-07 | Terumo Bct, Inc. | Air removal chamber for a cell expansion system and method of use associated therewith |
US9057045B2 (en) | 2009-12-29 | 2015-06-16 | Terumo Bct, Inc. | Method of loading and distributing cells in a bioreactor of a cell expansion system |
US9284523B2 (en) | 2008-10-27 | 2016-03-15 | Terumo Bct, Inc. | Premounted fluid conveyance assembly for cell expansion system and method of use associated therewith |
US9617506B2 (en) | 2013-11-16 | 2017-04-11 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
US9725768B2 (en) | 2012-08-31 | 2017-08-08 | Biovest International, Inc. | Methods for producing high-fidelity autologous idiotype vaccines |
US9732313B2 (en) | 2011-06-10 | 2017-08-15 | Biovest International, Inc. | Method and apparatus for virus and vaccine production |
US9902928B2 (en) | 2012-08-28 | 2018-02-27 | Biovest International, Inc. | Biomanufacturing suite and methods for large-scale production of cells, viruses, and biomolecules |
US10077421B2 (en) | 2014-04-24 | 2018-09-18 | Terumo Bct, Inc. | Measuring flow rate |
US10093956B2 (en) | 2011-06-10 | 2018-10-09 | Biovest International, Inc. | Method and apparatus for antibody production and purification |
US10577576B2 (en) | 2012-08-20 | 2020-03-03 | Terumo Bct, Inc. | System for expanding cells |
US11008547B2 (en) | 2014-03-25 | 2021-05-18 | Terumo Bct, Inc. | Passive replacement of media |
US11104874B2 (en) | 2016-06-07 | 2021-08-31 | Terumo Bct, Inc. | Coating a bioreactor |
US11608486B2 (en) | 2015-07-02 | 2023-03-21 | Terumo Bct, Inc. | Cell growth with mechanical stimuli |
US11624046B2 (en) | 2017-03-31 | 2023-04-11 | Terumo Bct, Inc. | Cell expansion |
US11629332B2 (en) | 2017-03-31 | 2023-04-18 | Terumo Bct, Inc. | Cell expansion |
US11667881B2 (en) | 2014-09-26 | 2023-06-06 | Terumo Bct, Inc. | Scheduled feed |
US11685883B2 (en) | 2016-06-07 | 2023-06-27 | Terumo Bct, Inc. | Methods and systems for coating a cell growth surface |
US11965175B2 (en) | 2017-05-25 | 2024-04-23 | Terumo Bct, Inc. | Cell expansion |
Families Citing this family (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8409846B2 (en) | 1997-09-23 | 2013-04-02 | The United States Of America As Represented By The Department Of Veteran Affairs | Compositions, methods and devices for maintaining an organ |
CA3178010A1 (en) | 2004-10-07 | 2006-04-20 | Transmedics, Inc. | Systems and methods for ex-vivo organ care |
US8304181B2 (en) | 2004-10-07 | 2012-11-06 | Transmedics, Inc. | Method for ex-vivo organ care and for using lactate as an indication of donor organ status |
US9301519B2 (en) | 2004-10-07 | 2016-04-05 | Transmedics, Inc. | Systems and methods for ex-vivo organ care |
US9078428B2 (en) | 2005-06-28 | 2015-07-14 | Transmedics, Inc. | Systems, methods, compositions and solutions for perfusing an organ |
US7754148B2 (en) | 2006-12-27 | 2010-07-13 | Progentech Limited | Instrument for cassette for sample preparation |
US7727473B2 (en) | 2005-10-19 | 2010-06-01 | Progentech Limited | Cassette for sample preparation |
CA2881613C (en) | 2006-04-19 | 2017-11-14 | Stanley Kyi | Systems and methods for ex vivo organ care |
US9457179B2 (en) | 2007-03-20 | 2016-10-04 | Transmedics, Inc. | Systems for monitoring and applying electrical currents in an organ perfusion system |
US8420380B2 (en) * | 2008-01-31 | 2013-04-16 | Transmedics, Inc. | Systems and methods for ex vivo lung care |
GB0808373D0 (en) * | 2008-05-09 | 2008-06-18 | Synexa Life Sciences Pty Ltd | Scalable cell culture bioreactor and cell culture process |
AU2009282271B2 (en) | 2008-08-12 | 2015-05-28 | Terumo Bct, Inc. | A predictor of when to harvest cells grown in a bioreactor |
AU2009308354A1 (en) * | 2008-10-22 | 2010-04-29 | Biovest International, Inc. | Perfusion bioreactors, cell culture systems, and methods for production of cells and cell-derived products |
US8211692B2 (en) * | 2008-10-24 | 2012-07-03 | Coskata, Inc. | Bioconversion process using liquid phase having to enhance gas phase conversion |
FR2941385B1 (en) | 2009-01-23 | 2011-04-01 | Millipore Corp | METHOD FOR PROVIDING A CIRCUIT FOR BIOLOGICAL LIQUID AND CIRCUIT OBTAINED |
DE102009019868B4 (en) * | 2009-05-06 | 2015-10-22 | Hosokawa Alpine Ag | Process engineering plant for laboratory use |
US9247729B2 (en) * | 2009-05-29 | 2016-02-02 | Institut Georges Lopez | Systems and methods for preserving a human organ for transplantation |
US9206383B2 (en) * | 2009-12-07 | 2015-12-08 | The Trustees Of Columbia University In The City Of New York | Bioreactor, devices, systems and methods |
WO2011072039A1 (en) * | 2009-12-08 | 2011-06-16 | The Trustees Of Columbia University In The City Of New York | Peristaltic pump devices, methods, and systems |
EP2516682B1 (en) * | 2009-12-22 | 2020-02-26 | GE Healthcare Bio-Sciences AB | A method for controlling culture parameters in a bioreactor |
FR2955119B1 (en) | 2010-01-13 | 2012-12-28 | Millipore Corp | CIRCUIT FOR BIOLOGICAL LIQUID |
CA2977845C (en) | 2010-02-23 | 2020-08-04 | Luminex Corporation | Apparatus and methods for integrated sample preparation, reaction and detection |
US20110265897A1 (en) * | 2010-04-30 | 2011-11-03 | Developmental Technologies, Llc | Fertigation Efficacy Enhancement System And Associated Methods |
FR2960796B1 (en) | 2010-06-08 | 2014-01-24 | Millipore Corp | DEVICE FOR A PLANT FOR TREATING BIOLOGICAL LIQUID |
FR2960794B1 (en) | 2010-06-08 | 2012-07-27 | Millipore Corp | DEVICE FOR A PLANT FOR TREATING BIOLOGICAL LIQUID |
FR2960795B1 (en) | 2010-06-08 | 2012-07-27 | Millipore Corp | DEVICE FOR A PLANT FOR TREATING BIOLOGICAL LIQUID |
FR2961713B1 (en) | 2010-06-23 | 2012-08-10 | Millipore Corp | POCKET FOR CIRCUIT OF A BIOLOGICAL LIQUID TREATMENT FACILITY |
FR2961711B1 (en) | 2010-06-23 | 2012-08-17 | Millipore Corp | POCKET FOR CIRCUIT OF A BIOLOGICAL LIQUID TREATMENT FACILITY |
FR2963573B1 (en) * | 2010-08-03 | 2012-08-31 | Millipore Corp | PUMPING TROLLEY FOR A BIOLOGICAL LIQUID TREATMENT FACILITY |
FR2973396B1 (en) | 2011-03-28 | 2013-05-10 | Millipore Corp | FACILITY FOR TREATING BIOLOGICAL LIQUID |
WO2012141055A1 (en) * | 2011-04-13 | 2012-10-18 | 株式会社日立製作所 | Cell culture device and transport device |
EP2704560B1 (en) | 2011-04-14 | 2022-04-06 | Transmedics, Inc. | Organ care solution for ex-vivo machine perfusion of donor lungs |
WO2012151473A2 (en) | 2011-05-04 | 2012-11-08 | Luminex Corporation | Apparatus and methods for integrated sample preparation, reaction and detection |
US10989362B2 (en) | 2011-10-07 | 2021-04-27 | Pall Technology Uk Limited | Fluid processing control system and related methods |
WO2013086502A1 (en) * | 2011-12-09 | 2013-06-13 | President And Fellows Of Harvard College | Organ chips and uses thereof |
US9683207B2 (en) * | 2012-05-01 | 2017-06-20 | FiberCell Production Solutions LLC | Method for growing cells in hollow fibers |
ES2435092B1 (en) | 2012-06-14 | 2014-09-09 | Aglaris Cell S.L. | Method and cell culture system |
FR2993572B1 (en) | 2012-07-23 | 2016-04-15 | Emd Millipore Corp | CIRCUIT FOR BIOLOGICAL LIQUID COMPRISING A PINCH VALVE |
WO2014038024A1 (en) | 2012-09-05 | 2014-03-13 | 株式会社日立製作所 | Valve mechanism, cell cultivation apparatus using same, and cell cultivation method |
USD727327S1 (en) * | 2013-11-22 | 2015-04-21 | Compliance Software, Inc. | Compact stand with mobile scanner |
KR102296181B1 (en) * | 2013-12-06 | 2021-08-31 | 인제대학교 산학협력단 | Cell culture system using complex stimulus |
USD735883S1 (en) * | 2013-12-30 | 2015-08-04 | Illumina, Inc. | Sample preparation instrument |
WO2015118146A1 (en) | 2014-02-10 | 2015-08-13 | Univercells Nv | System, apparatus and method for biomolecules production |
WO2015165700A1 (en) | 2014-04-28 | 2015-11-05 | Vivabiocell Spa | Automated cell culturing and harvesting device |
DK3151663T3 (en) | 2014-06-02 | 2020-11-30 | Transmedics Inc | EX VIVO ORGAN CARE SYSTEM |
AU364136S (en) * | 2015-02-05 | 2015-09-14 | Gen Electric | Compact bioreactor for cell cultivation |
AU364138S (en) * | 2015-02-05 | 2015-09-14 | Gen Electric | Stackable bioreactor for cell cultivation |
US10611991B2 (en) | 2015-04-07 | 2020-04-07 | University Of South Carolina | Pulsatile perfusion bioreactor for mimicking, controlling, and optimizing blood vessel mechanics |
DE102015112343A1 (en) * | 2015-07-29 | 2017-02-02 | Westfälische Wilhelms-Universität Münster | Apparatus and method for processing body fluids |
USD776825S1 (en) * | 2015-08-25 | 2017-01-17 | General Electric Company | Bioreactor housing |
CN107949419B (en) | 2015-09-09 | 2021-03-05 | 特兰斯迈迪茨公司 | Aorta cannula for isolated organ care system |
WO2017070304A1 (en) | 2015-10-20 | 2017-04-27 | Sean Farmer | Apparatus, systems and methods for growing miroorganisms |
KR102116338B1 (en) * | 2016-02-03 | 2020-06-05 | 밀워키 일렉트릭 툴 코포레이션 | Systems and methods for constructing reciprocating saws |
USD810084S1 (en) | 2016-03-23 | 2018-02-13 | Formfox, Inc. | Mobile scanner |
FR3053051B1 (en) * | 2016-06-24 | 2022-11-11 | Cellprothera | CELL CULTURE CASSETTE AND AUTOMATA |
CN106119110A (en) * | 2016-08-22 | 2016-11-16 | 诸葛洁婧 | A kind of culture carrier structure |
CN106190839B (en) * | 2016-08-22 | 2018-08-24 | 杭州荣泽生物科技有限公司 | A kind of cell culture apparatus can be used for Comparability test |
CN106047703B (en) * | 2016-08-22 | 2018-08-10 | 青岛爱博生物科技有限公司 | A kind of test sample culture apparatus |
CN106222089B (en) * | 2016-08-22 | 2018-09-21 | 王铁苗 | A kind of experiment auxiliary culture apparatus |
CN106190843B (en) * | 2016-08-22 | 2018-06-15 | 刘力伟 | A kind of multisample culture apparatus |
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EP3504315A4 (en) | 2016-08-27 | 2020-04-15 | 3D Biotek, LLC | Bioreactor |
JP6480093B2 (en) * | 2017-02-27 | 2019-03-06 | 剛士 田邊 | Somatic cell manufacturing system |
US11518972B2 (en) * | 2017-05-25 | 2022-12-06 | Lun-Kuang Liu | Movable cell incubator |
US10987636B2 (en) | 2017-08-31 | 2021-04-27 | Massachusetts Institute Of Technology | Filtration systems and methods for manufacturing biologically-produced products |
US10247724B1 (en) | 2017-09-28 | 2019-04-02 | Autobiologic Inc. | Optically clear sealable petri dish bioreactor |
GB201717652D0 (en) | 2017-10-26 | 2017-12-13 | Ge Healthcare Bio Sciences Ab | Bioprocess System |
CN107904170A (en) * | 2017-12-18 | 2018-04-13 | 上海白泽医疗器械有限公司 | Media to cell culture modules and cell culture system |
WO2019191685A1 (en) * | 2018-03-30 | 2019-10-03 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Workstation for automated control of an in vitro system |
IL258738B (en) * | 2018-04-16 | 2020-04-30 | Pluristem Ltd | Methods and compositions for formulating and dispensing pharmaceutical formulations |
WO2019215344A2 (en) * | 2018-05-11 | 2019-11-14 | Univercells Nv | System and method for clarifying a cell culture harvest solution |
US20190352589A1 (en) * | 2018-05-18 | 2019-11-21 | Huacells Corporation | Automated Cell Culturing |
EP3584305B1 (en) * | 2018-06-19 | 2021-07-28 | Lun-Kuang Liu | Movable cell incubator |
IL293492A (en) * | 2019-12-02 | 2022-08-01 | Avant Meats Company Ltd | Methods of meat production by in vitro cell cultivation |
EP4103201A4 (en) * | 2020-02-14 | 2024-04-03 | Xcell Biosciences Inc | Gas and liquid flow regulation system for cell culture |
USD937266S1 (en) * | 2020-02-25 | 2021-11-30 | Amazon Technologies, Inc. | Pedestal scanner |
EP4107247A2 (en) | 2020-03-10 | 2022-12-28 | Cellares Corporation | Systems, devices, and methods for cell processing |
USD962239S1 (en) * | 2020-08-20 | 2022-08-30 | Amazon Technologies, Inc. | Pedestal scanner |
US20220135921A1 (en) * | 2020-10-29 | 2022-05-05 | Applied Materials, Inc. | Methods and apparatus for cell development |
CN112553072B (en) * | 2020-12-10 | 2022-04-08 | 上海艾众生物科技有限公司 | Micro-channel power equipment for external circulation of bioreactor tank |
JP2024511915A (en) * | 2021-03-26 | 2024-03-18 | テルモ株式会社 | cell culture system |
EP4301841A1 (en) * | 2021-03-26 | 2024-01-10 | TERUMO Kabushiki Kaisha | Cell culturing system |
GB202105923D0 (en) | 2021-04-26 | 2021-06-09 | Cytiva Sweden Ab | Reconfigurable bioprocessing systems |
WO2023288314A1 (en) * | 2021-07-15 | 2023-01-19 | Georgia Tech Research Corporation | Methods of determining viable cell count and impedance-based biosensors for the same |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4282902A (en) * | 1979-05-04 | 1981-08-11 | Becton Dickinson & Company | Valve apparatus for simultaneous control of a plurality of fluid paths |
WO2003087292A2 (en) * | 2002-04-08 | 2003-10-23 | Millenium Biologix Inc. | Automated tissue engineering system |
WO2005116186A1 (en) * | 2004-05-26 | 2005-12-08 | Millenium Biologix Inc. | Advanced tissue engineering system |
Family Cites Families (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3148624A (en) * | 1961-06-21 | 1964-09-15 | Alan W Baldwin | Hydraulic pump |
US4047844A (en) | 1975-12-08 | 1977-09-13 | Searle Cardio-Pulmonary Systems Inc. | Blood pumping system |
US4167046A (en) * | 1977-12-12 | 1979-09-11 | Andros, Inc. | Blood pumping device |
US4417861A (en) * | 1981-08-10 | 1983-11-29 | Monsanto Company | Cell culture pumping system |
DE3572381D1 (en) * | 1984-05-25 | 1989-09-21 | Isco Inc | Peristaltic pump |
US4804628A (en) * | 1984-10-09 | 1989-02-14 | Endotronics, Inc. | Hollow fiber cell culture device and method of operation |
US4604038A (en) * | 1985-03-08 | 1986-08-05 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Remotely operable peristaltic pump |
WO1987006610A1 (en) | 1986-04-28 | 1987-11-05 | Endotronics, Inc. | Method of culturing leukocytes |
US4973558A (en) | 1988-04-28 | 1990-11-27 | Endotronics, Inc. | Method of culturing cells using highly gas saturated media |
US5416022A (en) | 1988-08-10 | 1995-05-16 | Cellex Biosciences, Inc. | Cell culture apparatus |
WO1991002049A1 (en) | 1989-08-04 | 1991-02-21 | Peter Grandics | An integrated cell culture-protein purification system for the automated production and purification of cell culture products |
AR244863A1 (en) * | 1989-09-07 | 1993-11-30 | Marcelo Alberto Hoegner | A multi-valve and the sterilising equipment that contains it. |
US5656421A (en) | 1990-02-15 | 1997-08-12 | Unisyn Technologies, Inc. | Multi-bioreactor hollow fiber cell propagation system and method |
US5098261A (en) * | 1990-05-04 | 1992-03-24 | Brandel Corporation | Peristaltic pump and method for adjustable flow regulation |
US5330915A (en) | 1991-10-18 | 1994-07-19 | Endotronics, Inc. | Pressure control system for a bioreactor |
US5622857A (en) * | 1995-08-08 | 1997-04-22 | Genespan Corporation | High performance cell culture bioreactor and method |
US5882918A (en) * | 1995-08-08 | 1999-03-16 | Genespan Corporation | Cell culture incubator |
US6066497A (en) * | 1994-08-16 | 2000-05-23 | Powell Biological Machines Limited | Cell culture apparatus |
US5554123A (en) * | 1994-10-31 | 1996-09-10 | Glenn Herskowitz | Portable infusion pump |
US5688687A (en) * | 1995-06-07 | 1997-11-18 | Aastrom Biosciences, Inc. | Bioreactor for mammalian cell growth and maintenance |
US5998184A (en) | 1997-10-08 | 1999-12-07 | Unisyn Technologies, Inc. | Basket-type bioreactor |
US6001585A (en) | 1997-11-14 | 1999-12-14 | Cellex Biosciences, Inc. | Micro hollow fiber bioreactor |
US6780617B2 (en) * | 2000-12-29 | 2004-08-24 | Chen & Chen, Llc | Sample processing device and method |
JP3461725B2 (en) * | 1998-06-26 | 2003-10-27 | 東京エレクトロン株式会社 | Treatment liquid supply device and treatment liquid supply method |
NO20002828D0 (en) | 2000-06-02 | 2000-06-02 | Statens Inst For Folkehelse | Proteinaceous vaccine against Neisseria meningtidis serogroup and method of preparation thereof |
WO2002087662A1 (en) * | 2001-04-27 | 2002-11-07 | Nexell Therapeutics Inc. | Cell processing and fluid transfer apparatus and method of use |
US6673595B2 (en) * | 2001-08-27 | 2004-01-06 | Biocrystal, Ltd | Automated cell management system for growth and manipulation of cultured cells |
US6733252B2 (en) * | 2002-05-10 | 2004-05-11 | Fqubed | Fluid-handling systems and components comprising a bladder pump, a methods therefor |
US20030217957A1 (en) * | 2002-05-24 | 2003-11-27 | Bowman Joseph H. | Heat seal interface for a disposable medical fluid unit |
DE10244090A1 (en) * | 2002-09-23 | 2004-04-01 | Ismatec S.A. | Hose cassette for a peristaltic pump |
US7377686B2 (en) * | 2003-09-04 | 2008-05-27 | Millipore Corporation | Disposable mixing system |
EP1668249B1 (en) | 2003-09-26 | 2008-03-19 | Ismatec SA, Laboratoriumstechnik | Peristaltic pump |
WO2005087915A2 (en) | 2004-03-08 | 2005-09-22 | Biovest International, Inc. | Use of ethanolamine for enhancing cell growth in membrane systems |
WO2005090403A2 (en) | 2004-03-12 | 2005-09-29 | Biovest International, Inc. | Method and apparatus for antibody purification |
US7143777B2 (en) * | 2004-07-20 | 2006-12-05 | Ing Tzon Co., Ltd. | Control valve having pressure balance effect |
WO2006119622A1 (en) | 2005-05-09 | 2006-11-16 | Saxonia Biotec Gmbh. | Apparatus for providing media to cell culture modules |
US7875184B2 (en) * | 2005-09-22 | 2011-01-25 | Eastman Chemical Company | Crystallized pellet/liquid separator |
EP2013793A4 (en) * | 2006-02-27 | 2010-01-06 | Fluidnet Corp | Volume measurement using gas laws |
DK2495327T3 (en) | 2006-03-03 | 2017-01-02 | Promis Neurosciences Inc | Methods and compositions for treating and detecting diseases caused by faulty SOD1 |
CA2881613C (en) | 2006-04-19 | 2017-11-14 | Stanley Kyi | Systems and methods for ex vivo organ care |
US10632433B2 (en) | 2006-05-13 | 2020-04-28 | Pall Life Sciences Belgium Bvba | Disposable bioreactor |
WO2007139747A1 (en) | 2006-05-22 | 2007-12-06 | Biovest International Inc. | Interface of a cultureware module in a cell culture system and installation method thereof |
JP4585563B2 (en) * | 2007-12-03 | 2010-11-24 | 株式会社コガネイ | Chemical supply device and pump assembly |
CA2739918A1 (en) | 2008-10-07 | 2010-04-15 | Biovest International, Inc. | Methods for inducing a sustained immune response against a b-cell idiotype using autologous anti-idiotypic vaccines |
AU2009308354A1 (en) | 2008-10-22 | 2010-04-29 | Biovest International, Inc. | Perfusion bioreactors, cell culture systems, and methods for production of cells and cell-derived products |
US9284523B2 (en) | 2008-10-27 | 2016-03-15 | Terumo Bct, Inc. | Premounted fluid conveyance assembly for cell expansion system and method of use associated therewith |
WO2012021840A2 (en) | 2010-08-13 | 2012-02-16 | Biovest International, Inc. | Materials and methods for designing autologous idiotype vaccines and treatment of b-cell malignancies |
EP2625577B1 (en) | 2010-10-08 | 2019-06-26 | Terumo BCT, Inc. | Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
WO2012064760A2 (en) | 2010-11-08 | 2012-05-18 | Biovest International, Inc. | Materials and methods for directing an immune response to an epitope |
WO2012171030A2 (en) | 2011-06-10 | 2012-12-13 | Biovest International, Inc. | Method and apparatus for antibody production and purification |
WO2012171026A2 (en) | 2011-06-10 | 2012-12-13 | Biovest International, Inc. | Methods for high yield virus production |
EP2788025A4 (en) | 2011-12-09 | 2015-07-22 | Biovest Int Inc | Tumor-specifc gm-csf cytokine response as predictor of cancer vaccine effectiveness |
CA2920957A1 (en) | 2012-08-28 | 2014-03-06 | Biovest International, Inc. | Biomanufacturing suite and methods for large-scale production of cells, viruses, and biomolecules |
-
2007
- 2007-05-21 WO PCT/US2007/012052 patent/WO2007139747A1/en active Application Filing
- 2007-05-21 EP EP07777182.2A patent/EP2029722B1/en active Active
- 2007-05-21 ES ES07777182T patent/ES2761938T3/en active Active
- 2007-05-21 WO PCT/US2007/012042 patent/WO2007139742A1/en active Application Filing
- 2007-05-21 AT AT07777189T patent/ATE496987T1/en active
- 2007-05-21 DK DK07777182.2T patent/DK2029722T3/en active
- 2007-05-21 EP EP11173373.9A patent/EP2404991A3/en not_active Withdrawn
- 2007-05-21 EP EP07777189A patent/EP2027247B1/en not_active Not-in-force
- 2007-05-21 WO PCT/US2007/012054 patent/WO2007136821A1/en active Application Filing
- 2007-05-21 DE DE602007012238T patent/DE602007012238D1/en active Active
- 2007-05-21 WO PCT/US2007/012053 patent/WO2007139748A2/en active Application Filing
- 2007-05-21 WO PCT/US2007/012051 patent/WO2007139746A1/en active Application Filing
-
2008
- 2008-11-20 US US12/274,971 patent/US8540499B2/en active Active
- 2008-11-20 US US12/274,993 patent/US8383397B2/en active Active
-
2012
- 2012-10-30 US US13/664,048 patent/US9441195B2/en active Active
-
2013
- 2013-09-23 US US14/033,807 patent/US9534198B2/en active Active
-
2016
- 2016-08-24 US US15/245,601 patent/US10723993B2/en active Active
- 2016-08-24 US US15/245,524 patent/US11345882B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4282902A (en) * | 1979-05-04 | 1981-08-11 | Becton Dickinson & Company | Valve apparatus for simultaneous control of a plurality of fluid paths |
WO2003087292A2 (en) * | 2002-04-08 | 2003-10-23 | Millenium Biologix Inc. | Automated tissue engineering system |
WO2005116186A1 (en) * | 2004-05-26 | 2005-12-08 | Millenium Biologix Inc. | Advanced tissue engineering system |
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---|---|---|---|---|
US9441195B2 (en) | 2006-05-22 | 2016-09-13 | Biovest International, Inc. | Method and system for the production of cells and cell products and applications thereof |
US8383397B2 (en) | 2006-05-22 | 2013-02-26 | Biovest International, Inc. | Method and system for the production of cells and cell products and applications thereof |
US8540499B2 (en) | 2006-05-22 | 2013-09-24 | Biovest International, Inc. | Extra-capillary fluid cycling system and method for a cell culture device |
US11345882B2 (en) | 2006-05-22 | 2022-05-31 | Biovest International, Inc. | Extra-capillary fluid cycling system and method for a cell culture device |
US10723993B2 (en) | 2006-05-22 | 2020-07-28 | Biovest International, Inc. | Method and system for the production of cells and cell products and applications thereof |
US9534198B2 (en) | 2006-05-22 | 2017-01-03 | Biovest International, Inc. | Extra-capillary fluid cycling system and method for a cell culture device |
US8785181B2 (en) | 2007-03-05 | 2014-07-22 | Terumo Bct, Inc. | Cell expansion system and methods of use |
US8309347B2 (en) | 2007-03-05 | 2012-11-13 | Terumo Bct, Inc. | Cell expansion system and methods of use |
US9260698B2 (en) | 2007-03-05 | 2016-02-16 | Terumo Bct, Inc. | Cell expansion system and methods of use |
US10577582B2 (en) | 2008-03-05 | 2020-03-03 | Terumo Bct, Inc. | Method of reseeding adherent cells grown in a hollow fiber bioreactor system |
US9428729B2 (en) | 2008-03-05 | 2016-08-30 | Terumo Bct, Inc. | Method of reseeding adherent cells grown in a hollow fiber bioreactor system |
US8691565B2 (en) | 2008-03-05 | 2014-04-08 | Terumo Bct, Inc. | Method of reseeding adherent cells grown in a hollow fiber bioreactor system |
US9284523B2 (en) | 2008-10-27 | 2016-03-15 | Terumo Bct, Inc. | Premounted fluid conveyance assembly for cell expansion system and method of use associated therewith |
US8999046B2 (en) | 2008-10-27 | 2015-04-07 | Terumo Bct, Inc. | Air removal chamber for a cell expansion system and method of use associated therewith |
US9057045B2 (en) | 2009-12-29 | 2015-06-16 | Terumo Bct, Inc. | Method of loading and distributing cells in a bioreactor of a cell expansion system |
US9670451B2 (en) | 2010-10-08 | 2017-06-06 | Terumo Bct, Inc. | Methods and systems of growing and harvesting cells in a hollow fiber bioreactor system with control conditions |
US11746319B2 (en) | 2010-10-08 | 2023-09-05 | Terumo Bct, Inc. | Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
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US9677042B2 (en) | 2010-10-08 | 2017-06-13 | Terumo Bct, Inc. | Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
US11613727B2 (en) | 2010-10-08 | 2023-03-28 | Terumo Bct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
US10669519B2 (en) | 2010-10-08 | 2020-06-02 | Terumo Bct, Inc. | Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
US11773363B2 (en) | 2010-10-08 | 2023-10-03 | Terumo Bct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
US10870827B2 (en) | 2010-10-08 | 2020-12-22 | Terumo Bct, Inc. | Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system |
US8895291B2 (en) | 2010-10-08 | 2014-11-25 | Terumo Bct, Inc. | Methods and systems of growing and harvesting cells in a hollow fiber bioreactor system with control conditions |
US9732313B2 (en) | 2011-06-10 | 2017-08-15 | Biovest International, Inc. | Method and apparatus for virus and vaccine production |
US10093956B2 (en) | 2011-06-10 | 2018-10-09 | Biovest International, Inc. | Method and apparatus for antibody production and purification |
US10570434B2 (en) | 2011-06-10 | 2020-02-25 | Biovest International, Inc. | Method and apparatus for antibody production and purification |
US10577576B2 (en) | 2012-08-20 | 2020-03-03 | Terumo Bct, Inc. | System for expanding cells |
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US10633625B2 (en) | 2013-11-16 | 2020-04-28 | Terumo Bct, Inc. | Expanding cells in a bioreactor |
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WO2007139742A1 (en) | 2007-12-06 |
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EP2404991A3 (en) | 2013-05-22 |
WO2007139746A1 (en) | 2007-12-06 |
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US20140024012A1 (en) | 2014-01-23 |
US11345882B2 (en) | 2022-05-31 |
US8383397B2 (en) | 2013-02-26 |
US9441195B2 (en) | 2016-09-13 |
US20160362650A1 (en) | 2016-12-15 |
DK2029722T3 (en) | 2020-01-02 |
WO2007139748A2 (en) | 2007-12-06 |
US9534198B2 (en) | 2017-01-03 |
EP2029722A1 (en) | 2009-03-04 |
EP2404991A2 (en) | 2012-01-11 |
US20130058907A1 (en) | 2013-03-07 |
ATE496987T1 (en) | 2011-02-15 |
WO2007136821A1 (en) | 2007-11-29 |
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