Cell Expansion Systems (CESs) are used to expand and differentiate cells. Cell expansion systems may be used to expand, e.g., grow, stem cells, such as mesenchymal stem cells, human mesenchymal stem cells, etc. Cell expansion systems may also expand other types of cells, such as bone marrow cells, for example. Stem cells which are expanded from donor cells may be used to repair or replace damaged or defective tissues and have broad clinical applications for a wide range of diseases. Cells, of both adherent and non-adherent type, may be grown in a bioreactor in a cell expansion system.
Embodiments of the present disclosure generally relate to using the passive replacement of media in a cell expansion system to conserve media and provide an environment conducive to encouraging cell growth. The expansion of cells, such as human mesenchymal stem cells, for example, uses external chemical signaling between the cells to initiate cell expansion by inhibiting lag phase signaling pathways internal to the cells. The expansion of other types of cells, such as Chinese hamster ovary (CHO) cells, for example, may be particularly sensitive to chemical signaling between the cells, according to embodiments. For example, CHO cells secrete cholecystokinin (CCK), a regulatory hormone responsible in part for cell culture maintenance and proliferation via chemical signaling. In embodiments, CCK may be small enough to pass through the microporous membrane of a hollow fiber bioreactor. Due to such ability to pass through the membrane, dilution of chemical signaling may occur regardless of inlet media addition to the intracapillary or extracapillary loop of a cell expansion system. To reduce or prevent the dilution of external chemical signaling in a closed, automated cell expansion system and, thus, reduce the lag phase of the cells, aspects of particular embodiments provide for passively replacing media by interrupting protocol procedures being executed and replacing a waste or outlet bag(s) used with the cell expansion system with a media bag(s). In embodiments, a bag containing base media may be attached to a waste line of the cell expansion system, in which such configuration allows base media to be added to the system at the rate of evaporation during conditions of no active inlet fluid flow. In embodiments, other types of replacement fluids are used in the media bag(s), such as, for example, complete media or cytokines or other cell-signaling protein molecules. In other embodiments, fluid may be passively replaced by interrupting protocol procedures being executed and allowing any fluid in the waste or outlet bag (assuming no constituents toxic to cell growth are present in the waste or outlet bag) to be passively added to the system at the rate of evaporation during conditions of no active inlet fluid flow. The passive addition of fluid avoids adding an excess amount of fluid, in which an excess amount of fluid may dilute the chemical signaling used to initiate cell expansion. Further, media constituents themselves may ultimately be conserved, resulting in increased system efficiencies and a savings of resources.
Embodiments of the present disclosure further relate to enhancing chemical signaling by adding a molecule(s), e.g. cell-signaling protein molecules, such as cytokines, according to embodiments, to the expanding cell population in a bioreactor. In an embodiment, cytokines, or other type of cell-signaling protein molecules, may be added to the bioreactor by, for example, welding a tubing line or other material connected to a cytokine source, or pre-filled with cytokines or other desired constituents, to a sampling coil or sample coil of the cell expansion system. The cytokines may thus be added to the bioreactor at the sample coil. Such direct addition results in a significant savings of cytokines, which may be costly, because a much higher amount of cytokines would need to be added to a media bag to compensate for dilution of the cytokines by the media than are needed when only the cytokine source itself replenishes the bioreactor. Further, cytokines tend to degrade quickly over time or with exposure to ultra-violet (UV) light, in which such degradation may be minimized by adding cytokines closer to the expanding cell population, e.g., at the sample coil of the bioreactor itself which is isolated from UV light sources. In such embodiments, the cytokines in the bioreactor may thus be maintained at a certain level while conserving resources.
As used herein, “at least one,” “one or more,” and “and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C,” “at least one of A, B, or C,” “one or more of A, B, and C,” “one or more of A, B, or C” and “A, B, and/or C” may mean A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.
This Summary is included to provide a selection of concepts in a simplified form, in which such concepts are further described below in the Detailed Description. This Summary is not intended to be used in any way to limit the claimed subject matter's scope. Features, including equivalents and variations thereof, may be included in addition to those provided herein.
Embodiments of the present disclosure may be described by referencing the accompanying figures. In the figures, like numerals refer to like items.
The following Detailed Description provides a discussion of illustrative embodiments with reference to the accompanying drawings. The inclusion of specific embodiments herein should not be construed as limiting or restricting the present disclosure. Further, while language specific to features, acts, and/or structures, for example, may be used in describing embodiments herein, the claims are not limited to the features, acts, and/or structures described. A person of skill in the art will appreciate that other embodiments, including improvements, are within the spirit and scope of the present disclosure.
Embodiments of the present disclosure are generally directed to systems and methods for passively replacing media in a cell expansion system. Passive replacement of media may be accomplished by interrupting one or more protocol procedures being executed with respect to the system, e.g., cell loading, cell feeding, etc., and replacing a waste or outlet bag(s) used with the system with a media bag(s). By interrupting, or stopping, mechanisms of the cell expansion system from operating according to the protocol being executed, active inlet fluid flow to the system may be halted to reduce or prevent the dilution of chemical signaling used to inhibit the internal signaling pathways that keep a cell population in the lag phase in a bioreactor of the closed system. Reducing or preventing such dilution may thus reduce the lag phase of cell growth. More efficient and increased cell expansion may therefore occur, in which a greater number of cells may be expanded in a shorter amount of time, according to embodiments of the present disclosure.
Dilution of chemical signaling may occur where an inlet fluid flow into a cell expansion system overcompensates for the evaporation of fluid from the system. For example, an oxygenator or gas transfer module may be used in a closed cell expansion system to maintain the media in fibers in the bioreactor with a desired gas concentration, e.g., 5% CO2, 20% O2, 75% N2. As an example, evaporation in the gas transfer module may occur at 14 mL/day. Without any inlet flow, such evaporation could result in either a build-up of air in the system or a back-flow of fluid from the waste or outlet line in embodiments where the waste line is the only source of fluid for the system which is not occluded by a pump, for example. Using an inlet flow, however, to account for such evaporation may result in overcompensating for the actual amount of fluid lost due to evaporation. For example, in an embodiment, the inlet flow rate into the cell expansion system may have a minimum flow rate. As an example, the inlet flow rate may be set at a minimum rate of 0.1 mL/min or 144 mL/day. Where evaporation in the gas transfer module occurs at 14 mL/day, the fluid lost due to evaporation may be overcompensated for by a rate of 130 mL/day in such embodiment. Such excess 130 mL/day dilutes chemical signaling for initiating cell expansion. For example, such dilution may occur in embodiments where chemical signaling molecules are able to cross, or pass through, a hollow fiber membrane from an intracapillary to an extracapillary side. As a result, adding replacement fluid to either the intracapillary or extracapillary side may result in dilution of the chemical signaling molecules by preventing or reducing them from building up by continuously adding fluid into the system. Where such dilution occurs, communication between the chemical signaling cells may be significantly impacted such that the cells may be unable to expand or even survive. Such dilution may have a particularly significant impact with respect to some cell types as compared to others. For example, reducing or preventing the dilution of chemical signaling molecules may have a significant impact on the expansion of Chinese hamster ovary (CHO) cells, according to embodiments.
In embodiments, instead of using an active inlet fluid flow which may unduly overcompensate for the evaporation of fluid from the system, the active inlet fluid flow to the system may be halted to prevent or minimize the dilution of chemical signaling used to inhibit the signaling pathways that maintain the cell population in a bioreactor in the lag phase. Such active inlet fluid flow may be halted, for example, by interrupting, or stopping, system mechanisms from operating according to the protocol(s) being executed. Instead of using an overcompensating active inlet fluid flow, such active inlet fluid flow may therefore be stopped while using a passive replacement of media and, therefore, not result in a build-up of air or back-flow of waste. To accomplish such passive media replacement, fluid, e.g., base media, may be added to the system at a rate equal to the rate of evaporation from the system, e.g., such as the rate of evaporation from a gas transfer module, through the use of one or more media bags used to replace one or more waste or outlet bags normally used with the system. The active inlet fluid flow may therefore be stopped while media from the replacement, or substitute, media bag replaces any fluid lost from the system due to evaporation. Such passive addition of fluid avoids adding an excess amount of fluid, in which an excess amount of fluid may dilute the chemical signaling used to initiate cell expansion. As a result, lost fluid may be replaced by adding media at about the rate of evaporation and without diluting chemical signaling used to inhibit signaling pathways that keep the cell population in the lag phase. The lag phase of cell growth may therefore be significantly reduced. Further, media constituents themselves may ultimately be conserved, resulting in increased system efficiencies and a savings of resources.
In other embodiments, fluid may be passively replaced by interrupting protocol procedures being executed and allowing any fluid in the waste or outlet bag (assuming no constituents toxic to cell growth are present in the waste or outlet bag) to be passively added to the system at the rate of evaporation during conditions of no active inlet fluid flow.
The dilution of chemical signaling may be particularly costly where the cell media includes expensive additives. For example, cell-signaling proteins, e.g., cytokines, may be used in the bioreactor to spur cell growth. Diluting cytokines may thus result in significant costs. Accordingly, saving the excess media, e.g., 130 mL/day, may provide significant cost savings over other cell expansion processes. Instead of using an overcompensating active inlet fluid flow, the passive replacement of media may thus be used, according to embodiments of the present disclosure, to maintain media constituent concentrations and conserve media in general. Further, in embodiments, other types of replacement fluids are used in the media bag(s), such as, for example, a media bag comprising cytokines or other cell-signaling protein molecules.
In embodiments, molecules, such as cell-signaling protein molecules, may be added to the bioreactor from a source of such molecules. For example, tubing or other material connected to a molecule source, such as a cytokine source, may be sterile-welded to a sample coil in the cell expansion system, and cytokines in the bioreactor may be replenished by such direct source of cytokines. In an embodiment, such tubing or other material comprises an additional volume added to the sampling coil. In another embodiment, such tubing or other material comprises a segment of tubing or other material used to replace a corresponding segment, or portion, of the sampling coil. In embodiments, such tubing or other material may be pre-filled with the desired constituents, e.g., cytokines. In another embodiment, such tubing or material may be connected to a container or bag comprising such desired constituents. A source of cytokines conserves the amount of cytokines used because the cytokines are not added to an IC media bag, for example, which could dilute the cytokines and use a larger amount of cytokines to achieve the same replenishment concentrations. Further, the cytokines may be added closer to the expanding cell population to minimize degradation of the cytokines. Degradation of the cytokines increases with exposure time to the media bags and UV light where they may be stored. Where cytokines are added closer to the expanding cell population, such degradation may be reduced because the cytokines reach the expanding cell population in a shorter amount of time in an environment protected from any sources of UV light. Such cytokines may be passively or actively added to the bioreactor, according to embodiments, to enhance chemical signaling capabilities. For example, such passive addition of cytokines may occur where the cytokines are added to the system from a media bag used to replace a waste bag, according to an embodiment, at the rate of evaporation during conditions of no active inlet fluid flow.
In an embodiment, chemical signaling may thus be controlled by the addition of cytokines at the sample coil. In another embodiment, chemical signaling may be controlled through such addition of cytokines at the sample coil coupled with the replacement of a waste bag(s) with a media bag(s). By replacing a waste bag(s) with a media bag(s), dilution in the bioreactor may be significantly reduced, as discussed above. Such dilution may be particularly costly where cytokines are used in the cell population expansion in the bioreactor. Preventing or reducing such dilution through the use of the media bag replacement thus may result in significant savings, according to embodiments.
In embodiments, a method provides for controlling chemical signaling in a bioreactor of a closed cell expansion system that includes a disposable tubing set(s). In such embodiments, the method may include the steps of coating the bioreactor and loading cells from a cell inlet bag into the bioreactor. For example, steps for loading cells with circulating distribution may be performed, according to an embodiment. In another embodiment, steps involving the loading of cells with uniform suspension, for example, may be performed. The cells may then be distributed across a membrane of the bioreactor by activating an intracapillary circulation pump, for example. In embodiments, after the loading and the distributing, a waste bag attached to the cell expansion system may be replaced with a media bag. After the waste bag is replaced, one or more pumps, e.g., an intracapillary circulation pump, extracapillary inlet pump, and intracapillary inlet pump, may be turned “OFF” or otherwise deactivated, according to an embodiment. In another embodiment, one or more pumps may be turned “OFF” or otherwise deactivated before replacing the outlet or waste bag. For example, in an embodiment expanding adherent cells, the intracapillary circulation pump may be deactivated after replacing a waste or outlet bag with a media bag. In another embodiment expanding adherent cells, for example, the intracapillary circulation pump may be deactivated before replacing the waste or outlet bag with a media bag. In yet other embodiments expanding non-adherent cells, for example, the intracapillary circulation pump may stay activated while one or more other pumps are deactivated.
In at least one embodiment, the media from the media bag flows through an extracapillary waste valve to the extracapillary circulation loop to replenish fluid evaporated from a gas transfer module in the extracapillary circulation loop. In embodiments, after replacement of the waste bag with the media bag, the method further includes deactivating an intracapillary inlet pump, deactivating an extracapillary inlet pump, maintaining an extracapillary circulation pump in an activated state, and maintaining the extracapillary waste valve in an open position.
In some embodiments, the cells include adherent cells, and the method may include the additional steps of enabling the adherent cells to attach to the bioreactor membrane and maintaining flow on an extracapillary circulation loop by maintaining an extracapillary circulation pump in an activated state. In some embodiments, the adherent cells are allowed to attach to the bioreactor membrane for a period of time, e.g., a first period of time, of about eighteen (18) hours to about twenty-four (24) hours. In other embodiments, the cells include non-adherent or suspension cells, such as, for example, CHO cells.
The method, in some embodiments, may further include feeding the cells in the bioreactor of the closed cell expansion system while maintaining the media bag in replacement of the waste bag and while reducing an intracapillary inlet rate. In these embodiments, feeding may include activating the intracapillary circulation pump. In embodiments, the feeding of the cells may be stopped after a second period of time of about forty-five (45) hours to about fifty (50) hours of feeding. In yet other embodiments, the feeding may be stopped after a second period of time of about forty-eight (48) hours of feeding.
The method, in embodiments, further involves measuring a concentration of lactate generated from the cells and stopping the feeding of the cells when the concentration of lactate is equal to or greater than about 6 mmol/L. In some embodiments, the method includes removing the media bag, inserting the waste bag, activating the intracapillary inlet pump, activating the intracapillary circulation pump, and maintaining an extracapillary circulation pump in an activated state. The intracapillary inlet pump may operate at an intracapillary inlet rate of about 0.1 mL/min, in some embodiments. The intracapillary circulation pump may operate at an intracapillary circulation rate of about 20 mL/min, in some embodiments. The extracapillary circulation pump may operate at an extracapillary circulation rate of about 30 mL/min, according to embodiments. In an embodiment, the method may additionally involve doubling, or otherwise increasing, according to other embodiments, the intracapillary inlet rate until a desired number of the cells are available for harvest. When the desired number of cells is available for harvest, embodiments include the additional steps of: releasing the cells from the membrane of the bioreactor, suspending the cells in the intracapillary circulation loop, and transferring the cells in suspension to a harvest bag.
Steps performed, including, for example, coating the bioreactor, loading cells, and distributing the cells, may be performed automatically in some embodiments, such as by a processor executing pre-programmed tasks stored in memory. Replacing a waste bag with a media bag may be performed manually in some embodiments and automatically in others. The automatic replacement of the waste bag may include, in embodiments, receiving, by a processor, a command to execute a task for replacing the waste bag, the task being stored in a memory. In an embodiment, for example, upon receiving such a command for the bag replacement, a processor may send a signal to close a valve(s), for example, for the waste bag and open another valve(s) for an attached media bag. In another embodiment, a single valve, or other type of mechanism, may control the flow of fluid from the waste bag or attached media bag.
The media bag may store base media and, in some embodiments, stores about 500 mL of base media, for example. The base media may include a number of different components, including, for example, glucose to provide an energy source for cells to grow, according to an embodiment. The media bag may comprise other fluids and/or constituents in accordance with embodiments of the present disclosure.
Other embodiments of the method provide for additional steps, some of which include loading cell-signaling protein molecules into a sample coil of an intracapillary circulation loop and activating the intracapillary circulation pump to transfer the cell-signaling protein molecules to the bioreactor. In some embodiments, the sample coil and the intracapillary circulation loop are part of a disposable tubing set.
In embodiments, the method may further include, prior to loading cells into the bioreactor, replacing fluid on an intracapillary circulation loop and on an extracapillary circulation loop with media from an intracapillary media bag, and allowing the media from the intracapillary media bag to reach equilibrium with a gas supply.
Some embodiments are directed to a cell expansion system, as noted above. In embodiments, such cell expansion system is closed, in which a closed cell expansion system comprises contents that are not directly exposed to the atmosphere. Such cell expansion system may be automated. In embodiments, cells, of both adherent and non-adherent type, may be grown in a bioreactor in the cell expansion system. According to embodiments, the cell expansion system may include base media. Methods for replenishment of media are provided for cell growth occurring in a bioreactor of the closed cell expansion system. In embodiments, the bioreactor used with such systems may be a hollow fiber bioreactor. Many types of bioreactors may be used in accordance with embodiments of the present disclosure.
The system may include, in embodiments, a bioreactor that further includes a first fluid flow path having at least opposing ends, a first opposing end of the first fluid flow path fluidly associated with a first port of a hollow fiber membrane and a second end of the first fluid flow path fluidly associated with a second port of the hollow fiber membrane, wherein the first fluid flow path comprises an intracapillary portion of the hollow fiber membrane. The system may further include a fluid inlet path fluidly associated with the first fluid flow path, wherein the plurality of cells are introduced into the first fluid flow path through a first fluid inlet path. A first pump for circulating fluid in the first fluid flow path of the bioreactor may also be included. In embodiments, the system includes a controller, e.g., first controller, for controlling operation of the first pump. In an embodiment, the controller may be a computing system, including a processor, for example. The controller may be configured, in embodiments, to control the pump to circulate a fluid at a first rate within the first fluid flow path, and, when a waste bag in the cell expansion system is replaced with a media bag, the controller stops the circulation of the fluid within the first fluid flow path after the plurality of the cells are loaded into the bioreactor. In some embodiments, a second pump for transferring intracapillary inlet fluid from an intracapillary media bag to the first fluid flow path and a controller, e.g., second controller, for controlling operation of the second pump are included. The second controller in embodiments controls the second pump to transfer cells from a cell inlet bag to the first fluid flow path, and when a waste bag in the cell expansion system is replaced with a media bag, stop the transfer of the cells from the cell inlet bag after the plurality of the cells are loaded into the bioreactor. Additional controllers, e.g., third controller, fourth controller, fifth controller, sixth controller, etc., may be used in accordance with embodiments. Further, additional pumps, e.g., third pump, fourth pump, fifth pump, sixth pump, etc., may be used in accordance with embodiments of the present disclosure. In addition, while the present disclosure may refer to a media bag, a waste bag, a cell inlet bag, etc., multiple bags, e.g., a first media bag, a second media bag, a third media bag, a first waste bag, a second waste bag, a third waste bag, a first cell inlet bag, a second cell inlet bag, a third cell inlet bag, etc., or other types of containers, may be used in embodiments. In other embodiments, a single media bag, a single waste bag, a single cell inlet bag, etc., may be used.
In embodiments, the system may be controlled by, for example: a processor coupled to the cell expansion system; a display device, in communication with the processor, and operable to display data; and a memory, in communication with and readable by the processor, and containing a series of instructions. In embodiments, when the instructions are executed by the processor, the processor receives an instruction to coat the bioreactor, for example. In response to the instruction to coat the bioreactor, the processor may execute a series of steps to coat the bioreactor and may next receive an instruction to load cells into the bioreactor, for example. In response to the instruction to load cells, the processor may execute a series of steps to load the cells from a cell inlet bag into the bioreactor. After loading the cells into the bioreactor, the processor may receive an instruction to stop an intracapillary inlet pump, an intracapillary circulation pump, and an extracapillary inlet pump, for example. The cell expansion system may be operated to allow media to flow from a media bag through an extracapillary waste valve, wherein the extracapillary waste valve is in an open position. The processor may receive an instruction to pump the media in the extracapillary circulation loop to replace fluid evaporated from a gas transfer module located in the extracapillary circulation loop.
Referring to
According to embodiments of the present disclosure, fluid in a first circulation path enters cell growth chamber 100 through IC inlet port 108 at a first longitudinal end 112 of the cell growth chamber 100, passes into and through the intracapillary side (referred to in various embodiments as the intracapillary (“IC”) side or “IC space” of a hollow fiber membrane) of a plurality of hollow fibers 116, and out of cell growth chamber 100 through IC outlet port 120 located at a second longitudinal end 124 of the cell growth chamber 100. The fluid path between the IC inlet port 108 and the IC outlet port 120 defines the IC portion 126 of the cell growth chamber 100. Fluid in a second circulation path flows in the cell growth chamber 100 through EC inlet port 128, comes in contact with the extracapillary side or outside (referred to as the “EC side” or “EC space” of the membrane) of the hollow fibers 116, and exits cell growth chamber 100 via EC outlet port 132. The fluid path between the EC inlet port 128 and the EC outlet port 132 comprises the EC portion 136 of the cell growth chamber 100. Fluid entering cell growth chamber 100 via the EC inlet port 128 may be in contact with the outside of the hollow fibers 116. Small molecules (e.g., ions, water, oxygen, lactate, etc.) may diffuse through the hollow fibers 116 from the interior or IC space of the hollow fiber to the exterior or EC space, or from the EC space to the IC space. Large molecular weight molecules, such as growth factors, are typically too large to pass through the hollow fiber membrane, and remain in the IC space of the hollow fibers 116. The media may be replaced as needed, in embodiments. Media may also be circulated through an oxygenator or gas transfer module to exchange gasses as needed. Cells may be contained within a first circulation path and/or a second circulation path, as described below, and may be on either the IC side and/or EC side of the membrane, according to embodiments.
The material used to make the hollow fiber membrane may be any biocompatible polymeric material which is capable of being made into hollow fibers. One material which may be used is a synthetic polysulfone-based material, according to an embodiment of the present disclosure. In order for the cells to adhere to the surface of the hollow fibers, the surface may be modified in some way, either by coating at least the cell growth surface with a protein such as fibronectin or collagen, or by exposing the surface to radiation. Gamma treating the membrane surface allows for attachment of adherent cells without additionally coating the membrane with fibronectin or the like. Bioreactors made of gamma treated membranes may be reused. Other coatings and/or treatments for cell attachment may be used in accordance with embodiments of the present disclosure.
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In accordance with embodiments, a shaft or rocker control 258 for rotating the bioreactor 100 is shown. Shaft fitting 260 associated with the shaft or rocker control 258 allows for proper alignment of a shaft access aperture, see e.g., 424 (
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According to embodiments, the premounted fluid conveyance assembly 400 includes tubing 408A, 408B, 408C, 408D, 408E, etc., and various tubing fittings to provide the fluid paths shown in
With regard to the IC loop 502, samples of media may be obtained from sample port 516 or sample coil 518 during operation. Pressure/temperature gauge 520 disposed in first fluid circulation path 502 allows detection of media pressure and temperature during operation. Media then returns to IC inlet port 501A to complete fluid circulation path 502. Cells grown/expanded in cell growth chamber 501 may be flushed out of cell growth chamber 501 into harvest bag 599 through valve 598 or redistributed within the hollow fibers for further growth. This will be described in more detail below.
Fluid in second fluid circulation path 504 enters cell growth chamber 501 via EC inlet port 501C, and leaves cell growth chamber 501 via EC outlet port 501D. Media in the EC loop 504 may be in contact with the outside of the hollow fibers in the cell growth chamber 501, thereby allowing diffusion of small molecules into and out of the hollow fibers.
Pressure/temperature gauge 524 disposed in the second fluid circulation path 504 allows the pressure and temperature of media to be measured before the media enters the EC space of the cell growth chamber 501. Pressure gauge 526 allows the pressure of media in the second fluid circulation path 504 to be measured after it leaves the cell growth chamber 501. With regard to the EC loop, samples of media may be obtained from sample port 530 or a sample coil during operation.
In embodiments, after leaving EC outlet port 501D of cell growth chamber 501, fluid in second fluid circulation path 504 passes through EC circulation pump 528 to oxygenator or gas transfer module 532. EC circulation pump 528 may also pump the fluid in opposing directions. Second fluid flow path 522 may be fluidly associated with oxygenator or gas transfer module 532 via oxygenator inlet port 534 and oxygenator outlet port 536. In operation, fluid media flows into oxygenator or gas transfer module 532 via oxygenator inlet port 534, and exits oxygenator or gas transfer module 532 via oxygenator outlet port 536. Oxygenator or gas transfer module 532 adds oxygen to and removes bubbles from media in the CES 500. In various embodiments, media in second fluid circulation path 504 may be in equilibrium with gas entering oxygenator or gas transfer module 532. The oxygenator or gas transfer module 532 may be any appropriately sized oxygenator or gas transfer device. Air or gas flows into oxygenator or gas transfer module 532 via filter 538 and out of oxygenator or gas transfer device 532 through filter 540. Filters 538 and 540 reduce or prevent contamination of oxygenator or gas transfer module 532 and associated media. Air or gas purged from the CES 500 during portions of a priming sequence may vent to the atmosphere via the oxygenator or gas transfer module 532.
In the configuration depicted for CES 500, fluid media in first fluid circulation path 502 and second fluid circulation path 504 flows through cell growth chamber 501 in the same direction (a co-current configuration). The CES 500 may also be configured to flow in a counter-current conformation.
In accordance with at least one embodiment, media, including cells (from bag 562), and fluid media from bag 546 may be introduced to first fluid circulation path 502 via first fluid flow path 506. Fluid container 562 (e.g., Cell Inlet Bag or Saline Priming Fluid for priming air out of the system) may be fluidly associated with the first fluid flow path 506 and the first fluid circulation path 502 via valve 564.
Fluid containers, or media bags, 544 (e.g., Reagent) and 546 (e.g., IC Media) may be fluidly associated with either first fluid inlet path 542 via valves 548 and 550, respectively, or second fluid inlet path 574 via valves 570 and 576. First and second sterile sealable input priming paths 508 and 509 are also provided. An air removal chamber (ARC) 556 may be fluidly associated with first circulation path 502. The air removal chamber 556 may include one or more ultrasonic sensors including an upper sensor and lower sensor to detect air, a lack of fluid, and/or a gas/fluid interface, e.g., an air/fluid interface, at certain measuring positions within the air removal chamber 556. For example, ultrasonic sensors may be used near the bottom and/or near the top of the air removal chamber 556 to detect air, fluid, and/or an air/fluid interface at these locations. Embodiments provide for the use of numerous other types of sensors without departing from the spirit and scope of the present disclosure. For example, optical sensors may be used in accordance with embodiments of the present disclosure. Air or gas purged from the CES 500 during portions of the priming sequence or other protocols may vent to the atmosphere out air valve 560 via line 558 that may be fluidly associated with air removal chamber 556.
EC media (from bag 568) or wash solution (from bag 566) may be added to either the first or second fluid flow paths. Fluid container 566 may be fluidly associated with valve 570 that may be fluidly associated with first fluid circulation path 502 via distribution valve 572 and first fluid inlet path 542. Alternatively, fluid container 566 may be fluidly associated with second fluid circulation path 504 via second fluid inlet path 574 and EC inlet path 584 by opening valve 570 and closing distribution valve 572. Likewise, fluid container 568 may be fluidly associated with valve 576 that may be fluidly associated with first fluid circulation path 502 via first fluid inlet path 542 and distribution valve 572. Alternatively, fluid container 568 may be fluidly associated with second fluid inlet path 574 by opening valve 576 and closing valve distribution 572.
An optional heat exchanger 552 may be provided for media reagent or wash solution introduction.
In the IC loop, fluid may be initially advanced by the IC inlet pump 554. In the EC loop, fluid may be initially advanced by the EC inlet pump 578. An air detector 580, such as an ultrasonic sensor, may also be associated with the EC inlet path 584.
In at least one embodiment, first and second fluid circulation paths 502 and 504 are connected to waste line 588. When valve 590 is opened, IC media may flow through waste line 588 and to waste or outlet bag 586. Likewise, when valve 582 is opened, EC media may flow through waste line 588 to waste or outlet bag 586.
In embodiments, cells may be harvested via cell harvest path 596. Here, cells from cell growth chamber 501 may be harvested by pumping the IC media containing the cells through cell harvest path 596 and valve 598 to cell harvest bag 599.
Various components of the CES 500 may be contained or housed within a machine or housing, such as cell expansion machine 202 (
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With regard to the IC loop, samples of media may be obtained from sample coil 618 during operation. Media then returns to IC inlet port 601A to complete fluid circulation path 602. Cells grown/expanded in cell growth chamber 601 may be flushed out of cell growth chamber 601 into harvest bag 699 through valve 698 and line 697. Alternatively, when valve 698 is closed, the cells may be redistributed within chamber 601 for further growth.
Fluid in second fluid circulation path 604 enters cell growth chamber 601 via EC inlet port 601C and leaves cell growth chamber 601 via EC outlet port 601D. Media in the EC loop may be in contact with the outside of the hollow fibers in the cell growth chamber 601, thereby allowing diffusion of small molecules into and out of the hollow fibers that may be within chamber 601, according to an embodiment.
Pressure/temperature sensor 624 disposed in the second fluid circulation path 604 allows the pressure and temperature of media to be measured before the media enters the EC space of the cell growth chamber 601. Sensor 626 allows the pressure and/or temperature of media in the second fluid circulation path 604 to be measured after it leaves the cell growth chamber 601. With regard to the EC loop, samples of media may be obtained from sample port 630 or a sample coil during operation.
After leaving EC outlet port 601D of cell growth chamber 601, fluid in second fluid circulation path 604 passes through EC circulation pump 628 to oxygenator or gas transfer module 632. EC circulation pump 628 may also pump the fluid in opposing directions, according to embodiments. Second fluid flow path 622 may be fluidly associated with oxygenator or gas transfer module 632 via an inlet port 632A and an outlet port 632B of oxygenator or gas transfer module 632. In operation, fluid media flows into oxygenator or gas transfer module 632 via inlet port 632A, and exits oxygenator or gas transfer module 632 via outlet port 632B. Oxygenator or gas transfer module 632 adds oxygen to and removes bubbles from media in the CES 600. In various embodiments, media in second fluid circulation path 604 may be in equilibrium with gas entering oxygenator or gas transfer module 632. The oxygenator or gas transfer module 632 may be any appropriately sized device useful for oxygenation or gas transfer. Air or gas flows into oxygenator or gas transfer module 632 via filter 638 and out of oxygenator or gas transfer device 632 through filter 640. Filters 638 and 640 reduce or prevent contamination of oxygenator or gas transfer module 632 and associated media. Air or gas purged from the CES 600 during portions of a priming sequence may vent to the atmosphere via the oxygenator or gas transfer module 632.
In the configuration depicted for CES 600, fluid media in first fluid circulation path 602 and second fluid circulation path 604 flows through cell growth chamber 601 in the same direction (a co-current configuration). The CES 600 may also be configured to flow in a counter-current conformation, according to embodiments.
In accordance with at least one embodiment, media, including cells (from a source such as a cell container, e.g. a bag) may be attached at attachment point 662, and fluid media from a media source may be attached at attachment point 646. The cells and media may be introduced into first fluid circulation path 602 via first fluid flow path 606. Attachment point 662 may be fluidly associated with the first fluid flow path 606 via valve 664, and attachment point 646 may be fluidly associated with the first fluid flow path 606 via valve 650. A reagent source may be fluidly connected to point 644 and be associated with fluid inlet path 642 via valve 648, or second fluid inlet path 674 via valves 648 and 672.
Air removal chamber (ARC) 656 may be fluidly associated with first circulation path 602. The air removal chamber 656 may include one or more sensors including an upper sensor and lower sensor to detect air, a lack of fluid, and/or a gas/fluid interface, e.g., an air/fluid interface, at certain measuring positions within the air removal chamber 656. For example, ultrasonic sensors may be used near the bottom and/or near the top of the air removal chamber 656 to detect air, fluid, and/or an air/fluid interface at these locations. Embodiments provide for the use of numerous other types of sensors without departing from the spirit and scope of the present disclosure. For example, optical sensors may be used in accordance with embodiments of the present disclosure. Air or gas purged from the CES 600 during portions of a priming sequence or other protocol(s) may vent to the atmosphere out air valve 660 via line 658 that may be fluidly associated with air removal chamber 656.
An EC media source may be attached to EC media attachment point 668 and a wash solution source may be attached to wash solution attachment point 666, to add EC media and/or wash solution to either the first or second fluid flow path. Attachment point 666 may be fluidly associated with valve 670 that may be fluidly associated with first fluid circulation path 602 via valve 672 and first fluid inlet path 642. Alternatively, attachment point 666 may be fluidly associated with second fluid circulation path 604 via second fluid inlet path 674 and second fluid flow path 684 by opening valve 670 and closing valve 672. Likewise, attachment point 668 may be fluidly associated with valve 676 that may be fluidly associated with first fluid circulation path 602 via first fluid inlet path 642 and valve 672. Alternatively, fluid container 668 may be fluidly associated with second fluid inlet path 674 by opening valve 676 and closing valve distribution 672.
In the IC loop, fluid may be initially advanced by the IC inlet pump 654. In the EC loop, fluid may be initially advanced by the EC inlet pump 678. An air detector 680, such as an ultrasonic sensor, may also be associated with the EC inlet path 684.
In at least one embodiment, first and second fluid circulation paths 602 and 604 are connected to waste line 688. When valve 690 is opened, IC media may flow through waste line 688 and to waste or outlet bag 686. Likewise, when valve 692 is opened, EC media may flow to waste or outlet bag 686.
After cells have been grown in cell growth chamber 601, they may be harvested via cell harvest path 697. Here, cells from cell growth chamber 601 may be harvested by pumping the IC media containing the cells through cell harvest path 697, with valve 698 open, into cell harvest bag 699.
Various components of the CES 600 may be contained or housed within a machine or housing, such as cell expansion machine 202 (
While
In some embodiments, the media bag (e.g., 700) may be positioned at a physically higher level than at least a portion of the EC loop 604 to allow gravity to assist in draining fluid from the media bag into the EC loop 604. In some embodiments, the waste bag 686 (
Turning to
In some embodiments, when the waste bag 586 is replaced by the media bag 800, the substitute or replacement media bag may be positioned physically higher than the original position of the waste bag 586 to allow gravity to assist in draining media into the EC loop 504.
The replacement of the waste bag with a media bag allows passive replacement of fluid lost due to evaporation. Such passive replacement of fluid may provide a significant conservation of fluid in cell expansion processes. In processes involving active media replacement, media may be added and circulated in the IC loop during attachment of cells to replace fluid lost due to evaporation. As described above, if media is added at 0.1 ml/min, which may occur in some processes, according to embodiments, this may result in an excess amount (over the amount that has evaporated) of fluid of up to 130 mL/day in the system, for example. Passive addition of fluid with the replacement of the waste bag with a media bag avoids the addition of an excess amount. As can be appreciated, the media may include expensive additives. Saving about 130 mL/day, for example, may provide significant cost savings over other cell expansion processes.
While
While various example embodiments of a cell expansion system and methods for passively replacing media in conjunction therewith have been described,
Process 1000 next proceeds to loading cells into the bioreactor from a cell inlet bag with circulating distribution 1014. In an embodiment, cells are loaded into the bioreactor from the cell inlet bag until the bag is empty. Cells are then chased from the air removal chamber to the bioreactor. Larger chase volumes spread the cells and move the cells toward the IC outlet. The distribution of cells is promoted across the membrane via IC circulation, such as through the IC circulation pump, with no IC inlet, for example.
After completion of the load cells with circulating distribution task 1014, the waste or outlet bag is replaced with a media bag 1016. In an embodiment, the media bag comprises about 500 mL of base media. The media bag may comprise other fluids and/or constituents, according to embodiments. In embodiments, the replacement of the outlet or waste bag with a media bag 1016 may be optional, in which fluid may be passively replaced by interrupting protocol procedures being executed and allowing any fluid in the outlet or waste bag (assuming no constituents toxic to cell growth are present in the outlet or waste bag) to be passively added to the system at the rate of evaporation during conditions of no active inlet fluid flow. Such passive addition of fluid avoids adding an excess amount of fluid and, thus, avoids diluting chemical signaling molecules.
Returning to
After the attaching of any adherent cells for about eighteen (18) to about twenty-four (24) hours, according to an embodiment, a continued cell attachment phase 1022 continues for up to about forty-eight (48) hours. During operation 1022, the IC circulation pump may be activated or turned “ON” to provide even the furthest fibers of the bioreactor membrane with media. For example, the IC circulation pump may be activated to adjust the IC circulation rate to about 20 mL/min, according to an embodiment of the present disclosure. However, during this period of modified feeding through activation of the IC circulation pump 1022, the IC inlet rate remains at 0 mL/min. Rather, the substitute media bag (in replacement of the waste bag) continues to provide any necessary fluid replacement to the system while not diluting the membranes or inhibiting chemical signaling. Operation 1022 with modified feeding of the cells thus allows for cell attachment to continue without disruption of chemical signaling occurring in the bioreactor. This continued cell attachment phase continues, according to embodiments, for up to about forty-eight (48) additional hours and/or, in embodiments, until the lactate generation of the cells is greater than or equal to about 6 mmol/L. In an embodiment, the concentration of lactate is measured. In another embodiment, the lactate generation rate, for example, is measured. In an embodiment, the lactate generation is thus checked at operation 1024 to determine if the concentration of lactate is equal to or exceeds 6 mmol/L. In other embodiments, the lactate generation is checked at operation 1024 to determine the concentration of lactate in relation to another predetermined amount.
Process 1000 next proceeds to query 1026, in which it is determined whether more than forty-eight hours has passed since the IC circulation pump was activated or whether the concentration of lactate is equal to or greater than about 6 mmol/L. If less than forty-eight (48) hours has passed or if the concentration of lactate is not equal to or in excess of about 6 mmol/L, process 1000 proceeds NO to check lactate generation operation 1024 and then to query 1026 again. It is noted that the present disclosure is not limited to determining whether forty-eight (48) hours have passed or whether there is a lactate concentration equal to or in excess of 6 mmol/L. In other embodiments, process 1000 may involve a different predetermined period of time. For example, at query 1026, a determination may be made whether about 12 hours, about 24 hours, about 36 hours, or about 40 hours have passed. In other embodiments, the predetermined period of time may be about 50 hours or about 60 hours. In embodiments, a determination may be made whether more than about 12 hours, more than about 24 hours, more than about 36 hours, or more than about 40 hours have passed. In other embodiments, a determination may be made whether less than about 60 hours or less than about 50 hours have passed. In yet other embodiments, process 1000 may involve determining whether the concentration of lactate is equal to or greater than another predetermined amount, such as about 3 mmol/L, about 4 mmol/L, about 5 mmol/L, about 7 mmol/L, or about 8 mmol/L. In embodiments, a determination may be made whether the concentration of lactate is more than about 3 mmol/L, more than about 4 mmol/L, or more than about 5 mmol/L. In other embodiments, a determination may be made whether the concentration of lactate is less than about 8 mmol/L or less than about 7 mmol/L.
If at query 1026 it is determined that more than about forty-eight (48) hours has passed since the IC circulation pump was activated or that the concentration of lactate is equal to or greater than 6 mmol/L, process 1000 proceeds YES to feed cells operation 1028, in which the IC inlet pump is activated or turned “ON” to maintain an IC Inlet Rate of 0.1 mL/min. Next, process 1000 proceeds to measure the glucose consumption 1030. In an embodiment, the concentration of glucose is measured. In another embodiment, the glucose consumption rate, for example, is measured. At query 1032, it is determined whether the measured glucose consumption is less than about 70 mg/L, in an embodiment. If the glucose consumption is less than about 70 mg/L (or another predetermined amount, according to other embodiments), process 1000 proceeds YES to double the IC Inlet Rate 1034. Process 1000 then proceeds to operation 1030 to continue measuring the glucose consumption of the cells and back to query 1032.
The present disclosure is not limited to determining whether the glucose consumption is less than about 70 mg/L. In other embodiments, process 1000 may involve a different predetermined amount. For example, in embodiments, process 1000 may involve determining whether the glucose consumption is less than another predetermined amount, such as about 65 mg/L, about 60 mg/L, or about 55 mg/L, for example. In other embodiments, the process 1000 may involve determining whether the glucose consumption is less than another predetermined amount, such as about 85 mg/L, about 80 mg/L, or about 75 mg/L, for example. In embodiments, a determination may be made whether the glucose consumption is more than about 55 mg/L, more than about 60 mg/L, or more than about 65 mg/L. In other embodiments, a determination may be made whether the glucose consumption is less than about 85 mg/L, less than about 80 mg/L, or less than about 75 mg/L.
If, at query 1032, the glucose consumption is determined to be greater than 70 mg/L, process 1000 proceeds NO to release the cells operation 1036, in which the cells are released from the membrane of the bioreactor and are suspended in the IC loop. In embodiments, an IC/EC Washout task in preparation for adding a reagent is performed. For example, IC/EC media may be replaced with a phosphate buffered saline (PBS) to remove protein, calcium (Ca2+), and magnesium (Mg2+) in preparation for adding trypsin, or another chemical-releasing agent, to release any adherent cells. A reagent may be loaded into the system until the reagent bag is empty. The reagent may be chased into the IC loop, and the reagent may be mixed within the IC loop. Following the release of any adherent cells, harvest operation 1038 transfers the cells in suspension from the IC circulation loop, including any cells remaining in the bioreactor, to the harvest bag. Process 1000 then terminates at END operation 1040.
Next,
After priming the set, process 1100 proceeds to coat the bioreactor 1108, in which the bioreactor may be coated with a reagent. For example, in embodiments, a reagent is loaded into the IC loop until a reagent container is empty. The reagent may be chased from the air removal chamber into the IC loop, and the reagent may then be circulated in the IC loop. Once the bioreactor is coated, the IC/EC Washout task may be executed 1110, in which fluid on the IC circulation loop and on the EC circulation loop may be replaced, according to an embodiment. In an embodiment, the replacement volume is determined by the number of IC Volumes and EC Volumes exchanged.
Next, to maintain the proper or desired gas concentration across fibers in the bioreactor membrane, the condition media task 1112 is executed to allow the media to reach equilibrium with the provided gas supply before cells are loaded into the bioreactor. For example, rapid contact between the media and the gas supply provided by the gas transfer module or oxygenator is provided by using a high EC circulation rate. In an embodiment, the system may then be maintained in a proper or desired state until an operator or user is ready to load cells into the bioreactor. In embodiments, such loading of cells is performed automatically.
Process 1100 next proceeds to loading cells into the bioreactor from a cell inlet bag with circulating distribution 1114. In an embodiment, cells are loaded into the bioreactor from a cell inlet bag until the bag is empty. Cells are then chased from the air removal chamber to the bioreactor. In embodiments that utilize larger chase volumes, cells are spread and move toward the IC outlet. The distribution of cells may be promoted across the membrane via IC circulation, such as through the IC circulation pump, with no IC inlet flow, for example.
After completion of the load cells with circulating distribution task 1114, the waste bag is replaced with a media bag 1116. In an embodiment, the media bag comprises about 500 mL of base media. In another embodiment, the media bag comprises any type of replacement fluid. In a further embodiment, step 1116 is optional, in which the outlet or waste bag stays connected and is not replaced with another bag. In yet a further embodiment, step 1116 is optional, in which the outlet or waste bag stays connected and desired constituents or other fluid(s) are added to the outlet or waste bag for passively adding such constituents/other fluid to the system.
In embodiments, one or more pumps, e.g., the IC Inlet Pump, the IC Circulation Pump, and the EC Inlet Pump, may then be turned “OFF” or may otherwise be indicated to stop or deactivate 1118. Any adherent cells in the bioreactor are then allowed to attach to the bioreactor membrane 1120 for a period of time, such as for about eighteen (18) to about twenty-four (24) hours, according to an embodiment of the present disclosure. During this timeframe, flow may continue on the EC circulation loop, in which the EC circulation rate may be maintained at about 30 mL/min, according to an embodiment. A non-zero EC circulation rate helps to maintain the proper or desired gas concentration across the fibers of the bioreactor membrane by continuing to pump fluid in the EC loop through the gas transfer module or oxygenator. While the proper or desired gas concentration is maintained through the use of the gas transfer module, evaporation of fluid also occurs at the gas transfer module. By keeping the EC Waste Valve open, however, media from the substitute media bag (replacing the waste bag) may back-flow into the system and be pumped by the EC Circulation Pump through the EC loop. The media may thus replace fluid lost due to evaporation from the gas transfer module at the rate of evaporation. Thus, membrane fibers in the bioreactor will not be diluted with excess fluid, and the transition of cell growth out of the lag phase will not be inhibited.
After the attaching of any adherent cells, an add molecule phase 1122 is performed. The molecule may be a protein molecule that is added to promote expansion of the cells. For example, the molecule may be a signaling molecule, such as one or more cytokines or growth factors that are involved in intercellular communications. The molecule may signal the cells to expand. In other embodiments, the molecule may not be directly involved in signaling but may help create an environment that is conducive to cell growth, in which examples of such molecules include carrier proteins, buffers, pH modifiers, etc. In embodiments, the molecule is added to the space where the cells are being grown, e.g., the IC or EC space. In embodiments, the molecules are added directly to the IC loop from a direct source of such molecules. Such direct addition may occur at a sampling coil or at a sample port, for example, according to embodiments. Cytokines, or other type of cell-signaling protein molecules, may be added to the bioreactor by, for example, welding a tubing line or other material connected to a cytokine source to a sampling coil or sample coil of the cell expansion system. The cytokines may thus be added to the bioreactor at the sample coil. Such direct addition results in a significant savings of cytokines, which may be costly, because a much higher amount of cytokines would need to be added to a media bag to compensate for dilution of the cytokines by the media than are needed when only the cytokine source itself replenishes the bioreactor, according to an embodiment. Further, cytokines tend to degrade quickly, in which such degradation may be minimized by adding cytokines closer to the expanding cell population, e.g., at the sample coil of the bioreactor itself. In such embodiments, the cytokines in the bioreactor may thus be maintained at a certain level while conserving resources. Through such a source, i.e., direct source, cytokines may be added to the IC loop without diluting such proteins, in which such dilution may occur where the cytokines are added instead at the IC Media bag, for example.
As noted above, the add molecule phase 1122 may be performed after the waste bag is replaced with a media bag 1116, according to an embodiment. In some embodiments, the molecule that is added at operation 1122 may be relatively expensive, and it is desirable to use the minimum amount required to promote growth of the cells. Performing operation 1116 first allows media from the media bag (replacing the waste bag) to back-flow into the system and be pumped by the EC Circulation Pump through the EC loop. According to an embodiment, only the media that is lost due to evaporation from the gas transfer module is replaced and at the rate of evaporation. Thus, the molecule may not be diluted with excess fluid. Accordingly, in an embodiment, only an amount of the molecule that may be effective at promoting growth may be added at operation 1122 since dilution by excess fluid may not be occurring.
After operation 1122, cells are grown at operation 1124. It is noted that, in embodiments, operation 1124 may involve a number of sub-operations. In some embodiments, the sub-operations include operations performed in process 1000 (
Operation 1124 may further involve a sub-operation of activating the IC inlet pump to maintain a predetermined IC inlet rate, e.g., 0.1 mL/min. This sub-operation may be triggered based on a predetermined period of time having elapsed or on a measurement, such as lactate concentration, for example.
In some embodiments, operation 1124 may involve a number of sub-operations to determine when to stop growing cells and begin releasing and harvesting cells. In one embodiment, this may include measuring a parameter, such as glucose consumption. In some embodiments, a predetermined glucose concentration, e.g., greater than 70 mg/L, may trigger subsequent operations, e.g., 1126 and 1128. In other embodiments, other parameters or the passage of a predetermined period of time may trigger subsequent operations.
At operation 1126, any adherent cells are released from the membrane of the bioreactor and are suspended, e.g., in the IC loop. In embodiments, an IC/EC washout task in preparation for adding a reagent to release the cells may be performed as part of operation 1126. For example, IC/EC media may be replaced with PBS to remove protein, calcium (Ca2+), and magnesium (Mg2+) in preparation for adding trypsin, or other chemical-releasing agent, to release any adherent cells. A reagent may be loaded into the system until the reagent bag is empty. The reagent may be chased into the IC loop, and the reagent may be mixed within the IC loop. Following the release of any adherent cells, harvest operation 1128 transfers the cells in suspension from the IC circulation loop, including any cells remaining in the bioreactor, to a harvest bag(s). Process 1100 then terminates at END operation 1130.
Turning to
Process 1200 next proceeds to loading cells with uniform suspension 1212. In an embodiment, cells may be loaded from a cell inlet bag. IC circulation may be used to distribute the cells. In an embodiment, cells are loaded into the bioreactor from a cell inlet bag. Cells are then chased from the air removal chamber to the IC loop. The distribution of cells is promoted across the membrane via IC circulation with no IC inlet, for example, and thus no ultrafiltration, according to embodiments.
Next, process 1200 proceeds to the optional (shown in a dashed-line format) step of replacing an outlet or waste bag with a media bag (e.g., a substitute media bag) 1214. In an embodiment, the substitute media bag comprises about 0.2 L of media without protein. Other volumes and types of replacement fluid in the substitute media bag may be used in accordance with embodiments of the present disclosure. Process 1200 next proceeds to turning “OFF” or otherwise deactivating one or more pumps 1216. In an embodiment, the IC inlet pump and the EC inlet pump are turned “OFF” or otherwise indicated to stop or deactivate 1216. Such pump deactivation allows chemical signals, such as CCK, to increase in concentration by turning the inlet media flow rate “OFF” to the IC circulation loop and the EC circulation loop. In such embodiments, fluid from the substitute bag may be passively added to the system at the rate of evaporation during conditions of no active inlet fluid flow. In embodiments where the outlet or waste bag is not replaced, fluid may be passively replaced in the system by interrupting protocol procedures being executed and allowing any fluid in the outlet or waste bag (assuming no constituents toxic to cell growth are present in the outlet or waste bag) to be passively added to the system at the rate of evaporation during conditions of no active inlet fluid flow. Such passive addition of fluid avoids adding an excess amount of fluid and, thus, avoids diluting chemical signaling. In an embodiment, the EC circulation pump may remain “ON.” In further embodiments, both the IC circulation pump and the EC circulation pump remain activated or “ON.”
Next, process 1200 proceeds to feeding the cells 1218. In an embodiment, the cell culture may be sampled for cell counts as well by excising a length of tubing to provide a representative cell concentration sample of the IC loop. In other embodiments, cells may be counted by withdrawing a sample from the sampling coil or sample port, for example.
Process 1200 next proceeds to measuring the glucose and/or lactate concentration(s) 1220. At query 1222, it is determined whether the cell culture conditions have reached a minimum tolerance glucose concentration or a maximum tolerance lactate concentration. Such tolerance concentrations may occur earlier or later than day 4, according to embodiments. If the tolerance concentration(s) have not been reached, process 1200 proceeds NO to continue to measure the glucose/lactate concentration(s) 1220. If the tolerance concentration(s) have been reached, process 1200 proceeds YES to the optional (shown in a dashed-line format) step of replacing the substitute media bag (from optional step 1214) with the waste or outlet bag 1224. In an embodiment, the original waste or outlet bag removed at optional step 1214 is used to replace the substitute media bag at optional step 1224. In another embodiment, a different waste or media bag is used to replace the substitute media bag at optional step 1224.
Following optional step 1224, process 1200 proceeds to feed the cells by adding a controlled flow rate to the IC circulation loop and/or the EC circulation loop 1226 once the cell culture conditions have reached a minimum tolerance glucose concentration or a maximum tolerance lactate concentration, for example. In an embodiment, a low flow rate is continuously added to the IC circulation loop and/or the EC circulation loop. Such feeding with the continuous addition of a low flow rate, for example, may occur earlier or later than day 4, according to embodiments.
Harvest operation 1228 next transfers cells in suspension from the IC circulation loop, including cells in the bioreactor, to a harvest bag. Process 1200 then terminates at END operation 1230.
With respect to the processes illustrated in
Finally,
The computing system 1300 may include a user interface 1302, a processing system 1304, and/or storage 1306. The user interface 1302 may include output device(s) 1308, and/or input device(s) 1310 as understood by a person of skill in the art. Output device(s) 1308 may include one or more touch screens, in which the touch screen may comprise a display area for providing one or more application windows. The touch screen may also be an input device 1310 that may receive and/or capture physical touch events from a user or operator, for example. The touch screen may comprise a liquid crystal display (LCD) having a capacitance structure that allows the processing system 1304 to deduce the location(s) of touch event(s), as understood by those of skill in the art. The processing system 1304 may then map the location of touch events to user interface (UI) elements rendered in predetermined locations of an application window. The touch screen may also receive touch events through one or more other electronic structures, according to embodiments. Other output devices 1308 may include a printer, speaker, etc. Other input devices 1310 may include a keyboard, other touch input devices, mouse, voice input device, etc., as understood by a person of skill in the art.
Processing system 1304 may include a processing unit 1312 and/or a memory 1314, according to embodiments of the present disclosure. The processing unit 1312 may be a general purpose processor operable to execute instructions stored in memory 1314. Processing unit 1312 may include a single processor or multiple processors, according to embodiments. Further, in embodiments, each processor may be a multi-core processor having one or more cores to read and execute separate instructions. The processors may include general purpose processors, application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), other integrated circuits, etc., as understood by a person of skill in the art.
The memory 1314 may include any short-term or long-term storage for data and/or processor executable instructions, according to embodiments. The memory 1314 may include, for example, Random Access Memory (RAM), Read-Only Memory (ROM), or Electrically Erasable Programmable Read-Only Memory (EEPROM), as understood by a person of skill in the art. Other storage media may include, for example, CD-ROM, tape, digital versatile disks (DVD) or other optical storage, tape, magnetic disk storage, magnetic tape, other magnetic storage devices, etc., as understood by a person of skill in the art.
Storage 1306 may be any long-term data storage device or component. Storage 1306 may include one or more of the systems described in conjunction with the memory 1314, according to embodiments. The storage 1306 may be permanent or removable. In embodiments, storage 1306 stores data generated or provided by the processing system 1304.
Below are examples of protocols that may be used with a cell expansion system, such as CES 500 (
This part of the example protocol coats a bioreactor with a reagent. The bioreactor may include a hollow fiber membrane.
Before starting this task, the following preconditions may be satisfied:
Table 1 describes the bags of solution that are attached to each line when performing the Coat Bioreactor portion of the protocol. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for each setting for step 1 may be used as shown in Table 2.
Values for each setting for step 2 shown in Table 3 may be used.
Values for each setting for step 3 shown in Table 4 may be used.
This part of the example protocol is performed to replace the fluid on both the IC circulation loop and the EC circulation loop. The replacement volume may be specified by the number of IC Volumes and EC Volumes exchanged.
Table 5 describes the bags of solution that are attached to each line when performing IC EC Washout of this example protocol. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for IC EC Washout shown in Table 6 may be used.
This part of the example protocol is performed to allow the media to reach equilibrium with the provided gas supply before loading the cells. This task may include two separate steps:
Table 7 describes the bags of solution that are attached to each line when performing Condition Media. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 8 may be used.
The values for step 2 shown in Table 9 may be used.
This part of the example protocol is performed to loads cells into the bioreactor from a cell inlet bag. IC circulation may be used to distribute the cells and may not attempt to chase the cells from the line into the bioreactor. This task may include three separate steps.
Before starting this task, the following preconditions may be satisfied:
Table 10 describes the bags of solution attached to each line when performing Load Cells with Circulating Distribution. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 11 may be used.
The values for step 2 shown in Table 12 may be used.
The values for step 3 shown in Table 13 may be used.
This part of the example protocol is performed to enable adherent cells to attach to the bioreactor membrane while allowing flow on the EC circulation loop. The pump flow rate to the IC loop is set to approximately zero.
Table 14 describes the bags of solution attached to each line when performing Attach Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for Attach Cells shown in Table 15 may be used.
This part of the example protocol is performed to continuously add a low flow rate to the IC circulation loop and/or the EC circulation loop. There are several outlet settings that may used to remove the fluid added to the system.
Table 16 describes the bags of solution attached to each line when performing Feed Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 17 may be used.
The IC Inlet rate may be increased as needed. As one example, the IC inlet rate may be increased as follows: Day 1-Day 2: 0.0 mL/min; Day 2-Day 3: 0.1 mL/min; Day 3-Day 4: 0.2 mL/min; Day 4-Day 5: 0.4 mL/min; and Day 5-Day 6: 0.8 mL/min.
This part of the example protocol is performed to release cells from the membrane, leaving the cells in the IC loop.
Before starting this task, the following preconditions may be satisfied:
Table 18 describes the bags of solution attached to each line when performing Release Adherent Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 19 may be used.
The values for step 2 shown in Table 20 may be used.
The values for step 3 shown in Table 21 may be used.
The values for step 4 shown in Table 22 may be used.
Samples may be taken from a sample coil and/or a sample port for a trypsin assay.
This part of the example protocol is performed to transfer cells in suspension from the IC circulation loop, including cells in the bioreactor, to the harvest bag.
Table 23 describes the bags of solution attached to each line when performing Harvest Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for Harvest Cells shown in Table 24 may be used.
Cholecystokinin (CCK) is a regulatory hormone secreted by cells and, in many cases, may in part be responsible for cell culture maintenance and proliferation via chemical signaling. If CCK concentration in the culture media does not reach a threshold, the cell population can be compromised. Example 2 provides an example of a cell-secreted chemical signal used to maintain and proliferate a population of cells in vitro; in this case, CHO cells. According to an embodiment, the molecular weight of CCK of approximately 4,000 Daltons makes it small enough to readily pass through the microporous membrane of a hollow-fiber bioreactor. In an embodiment, regardless of inlet media addition to the IC circulation loop or EC circulation loop, dilution of the chemical signal may occur due to the freedom to pass through the membrane. However, through the passive replacement of media, according to embodiments, such dilution of chemical signaling can be minimized or eliminated altogether. The following protocol provides for the passive replacement of media during the cell expansion of non-adherent or suspension cells, such as CHO cells, for example, according to embodiments.
This part of the example protocol is performed to replace the fluid on both the IC circulation loop and the EC circulation loop in preparation for cell culturing. The replacement volume may be specified by the number of IC Volumes and EC Volumes exchanged.
Table 25 describes the bags of solution that are attached to each line when performing IC EC Washout of this example protocol. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for IC EC Washout shown in Table 26 may be used.
This part of the example protocol is performed to allow the media to reach equilibrium with the provided gas supply before loading the cells. This task may include two separate steps:
Table 27 describes the bags of solution that are attached to each line when performing Condition Media. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 28 may be used.
The values for step 2 shown in Table 29 may be used.
This part of the example protocol is performed to load cells into the bioreactor from a cell inlet bag. For example, in an embodiment, such cells comprise CHO cells. IC circulation may be used to distribute the cells and may not attempt to chase the cells from the line into the bioreactor. This task may include three separate steps.
Before starting this task, the following preconditions may be satisfied:
Table 30 describes the bags of solution attached to each line when performing Load Cells with Uniform Suspension. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 31 may be used.
The values for step 2 shown in Table 32 may be used.
The values for step 3 shown in Table 33 may be used.
This part of the example protocol is performed to allow chemical signals, such as CCK, to increase in concentration by turning the inlet media flow rate “OFF” to the IC circulation loop and the EC circulation loop. IC or EC Outlet can be used in this configuration.
Table 34 describes the bags of solution attached to each line when performing Feed Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 35 may be used.
In an embodiment, each day, the cell culture is sampled for cell counts using the following settings:
In an embodiment, immediately following the stop condition, a length of tubing of about six (6) inches long (1 mL) is excised. The volume in this sample provides a representative cell concentration sample of the entire IC loop. This allows the user(s) to monitor the cells throughout the duration of culturing.
This part of the example protocol is performed to continuously add a low flow rate to the IC circulation loop and/or the EC circulation loop once the cell culture conditions have reached a minimum tolerance glucose concentration or maximum tolerance lactate concentration. This may occur earlier or later than day 4, in embodiments. There are several outlet settings that may used to remove the fluid added to the system.
Table 37 describes the bags of solution attached to each line when performing Feed Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for step 1 shown in Table 38 may be used.
In an embodiment, each day, the cell culture is sampled for cell counts (see Table 36, for example).
This part of the example protocol is performed to transfer cells in suspension from the IC circulation loop, including cells in the bioreactor, to the harvest bag.
Table 39 describes the bags of solution attached to each line when performing Harvest Cells. These solutions and corresponding volumes are provided as one example of default settings that may be used.
The values for Harvest Cells shown in Table 40 may be used.
It will be apparent to those skilled in the art that various modifications and variations may be made to the apparatus, systems, structure, and methods described herein. Thus, it should be understood that the embodiments are not limited to the subject matter discussed in the present disclosure. Rather, the present disclosure is intended to cover modifications, variations, and/or equivalents. The acts, features, structures, and/or media are disclosed as illustrative embodiments for implementation of the claims.
This application is a divisional application of, and claims priority to, U.S. patent application Ser. No. 14/668,659, entitled, “Passive Replacement of Media,” filed on Mar. 25, 2015, which claims the benefit of U.S. Provisional Application Ser. No. 61/970,274, filed on Mar. 25, 2014, and entitled, “Passive Replacement of Media.” The disclosures of the above-identified applications are hereby incorporated by reference in their entireties as if set forth herein in full for all that they teach and for all purposes.
Number | Name | Date | Kind |
---|---|---|---|
2997077 | Rodrigues | Aug 1961 | A |
3013435 | Rodrigues | Dec 1961 | A |
3067915 | Shapiro et al. | Dec 1962 | A |
3191807 | Rodrigues | Jun 1965 | A |
3283727 | Rodrigues | Nov 1966 | A |
3701717 | Ingvorsen | Oct 1972 | A |
3821087 | Knazek et al. | Jun 1974 | A |
3896061 | Tanzawa et al. | Jul 1975 | A |
4173415 | Wyatt | Nov 1979 | A |
4301010 | Eddleman et al. | Nov 1981 | A |
4301118 | Eddleman et al. | Nov 1981 | A |
4391912 | Yoshida et al. | Jul 1983 | A |
4412990 | Lundblad et al. | Nov 1983 | A |
4418691 | Yannas et al. | Dec 1983 | A |
4439322 | Sonoda et al. | Mar 1984 | A |
4439901 | Eddleman | Apr 1984 | A |
4478829 | Landaburu et al. | Oct 1984 | A |
4486188 | Altshuler et al. | Dec 1984 | A |
4509695 | Bessman | Apr 1985 | A |
4585654 | Landaburu et al. | Apr 1986 | A |
4618586 | Walker et al. | Oct 1986 | A |
4629686 | Gruenberg | Dec 1986 | A |
4647539 | Bach | Mar 1987 | A |
4650766 | Harm et al. | Mar 1987 | A |
4670544 | Schwinn et al. | Jun 1987 | A |
4722902 | Harm et al. | Feb 1988 | A |
4727059 | Binder et al. | Feb 1988 | A |
4804628 | Cracauer et al. | Feb 1989 | A |
4828706 | Eddleman | May 1989 | A |
4885087 | Kopf | Dec 1989 | A |
4889812 | Guinn et al. | Dec 1989 | A |
4894342 | Guinn et al. | Jan 1990 | A |
4897358 | Carrasco | Jan 1990 | A |
4918019 | Guinn | Apr 1990 | A |
4960521 | Keller | Oct 1990 | A |
4973558 | Wilson et al. | Nov 1990 | A |
4988623 | Schwarz et al. | Jan 1991 | A |
5015585 | Robinson | May 1991 | A |
5019054 | Clement et al. | May 1991 | A |
5079168 | Amiot | Jan 1992 | A |
5126238 | Gebhard et al. | Jun 1992 | A |
5130141 | Law et al. | Jul 1992 | A |
5149544 | Gentile et al. | Sep 1992 | A |
5162225 | Sager et al. | Nov 1992 | A |
5169930 | Ruoslahti et al. | Dec 1992 | A |
5192553 | Boyse et al. | Mar 1993 | A |
5197985 | Caplan et al. | Mar 1993 | A |
5202254 | Amiot | Apr 1993 | A |
5225346 | Matsumiya et al. | Jul 1993 | A |
5226914 | Caplan et al. | Jul 1993 | A |
5240614 | Ofsthun et al. | Aug 1993 | A |
5240861 | Bieri | Aug 1993 | A |
5283058 | Faustman | Feb 1994 | A |
5310676 | Johansson et al. | May 1994 | A |
5324428 | Flaherty | Jun 1994 | A |
5330915 | Wilson et al. | Jul 1994 | A |
5342752 | Platz et al. | Aug 1994 | A |
5399493 | Emerson et al. | Mar 1995 | A |
5416022 | Amiot | May 1995 | A |
5422197 | Zito | Jun 1995 | A |
5436151 | McGlave et al. | Jul 1995 | A |
5437994 | Emerson et al. | Aug 1995 | A |
5439757 | Zito | Aug 1995 | A |
5459069 | Palsson et al. | Oct 1995 | A |
5460964 | McGlave et al. | Oct 1995 | A |
H1509 | Eran et al. | Dec 1995 | H |
5478739 | Slivka et al. | Dec 1995 | A |
5486359 | Caplan et al. | Jan 1996 | A |
5496659 | Zito | Mar 1996 | A |
5507949 | Ho | Apr 1996 | A |
5510257 | Sirkar et al. | Apr 1996 | A |
5512180 | Ho | Apr 1996 | A |
5527467 | Ofsthun et al. | Jun 1996 | A |
5541105 | Melink et al. | Jul 1996 | A |
5543316 | Zawadzka et al. | Aug 1996 | A |
5545492 | Zito | Aug 1996 | A |
5549674 | Humes et al. | Aug 1996 | A |
5571720 | Grandics et al. | Nov 1996 | A |
5591625 | Gerson et al. | Jan 1997 | A |
5593580 | Kopf | Jan 1997 | A |
5595909 | Hu et al. | Jan 1997 | A |
5599703 | Davis et al. | Feb 1997 | A |
5605822 | Emerson et al. | Feb 1997 | A |
5605829 | McGlave et al. | Feb 1997 | A |
5605835 | Hu et al. | Feb 1997 | A |
5622857 | Goffe | Apr 1997 | A |
5626731 | Cooley et al. | May 1997 | A |
5627070 | Gruenberg | May 1997 | A |
5631006 | Melink et al. | May 1997 | A |
5635386 | Palsson et al. | Jun 1997 | A |
5635387 | Fei et al. | Jun 1997 | A |
5643736 | Bruder et al. | Jul 1997 | A |
5646043 | Emerson et al. | Jul 1997 | A |
5654186 | Cerami et al. | Aug 1997 | A |
5656421 | Gebhard et al. | Aug 1997 | A |
5658995 | Kohn et al. | Aug 1997 | A |
5667985 | O'Leary et al. | Sep 1997 | A |
5670147 | Emerson et al. | Sep 1997 | A |
5670351 | Emerson et al. | Sep 1997 | A |
5674750 | Kraus et al. | Oct 1997 | A |
5684712 | Goffe et al. | Nov 1997 | A |
5686289 | Humes et al. | Nov 1997 | A |
5688687 | Palsson et al. | Nov 1997 | A |
5695989 | Kalamasz | Dec 1997 | A |
5700289 | Breitbart et al. | Dec 1997 | A |
5705534 | D'Agostino et al. | Jan 1998 | A |
5707859 | Miller et al. | Jan 1998 | A |
5712163 | Parenteau et al. | Jan 1998 | A |
5728581 | Schwartz et al. | Mar 1998 | A |
5733541 | Taichman et al. | Mar 1998 | A |
5733542 | Haynesworth et al. | Mar 1998 | A |
5736396 | Bruder et al. | Apr 1998 | A |
5744347 | Wagner et al. | Apr 1998 | A |
5750651 | Oppermann et al. | May 1998 | A |
5753506 | Johe | May 1998 | A |
5763194 | Slowiaczek et al. | Jun 1998 | A |
5763197 | Tsukamoto et al. | Jun 1998 | A |
5763261 | Gruenberg | Jun 1998 | A |
5763266 | Palsson et al. | Jun 1998 | A |
5766944 | Ruiz | Jun 1998 | A |
5772994 | Ildstad et al. | Jun 1998 | A |
5783075 | Eddleman et al. | Jul 1998 | A |
5783216 | Faustman | Jul 1998 | A |
5785912 | Cooley et al. | Jul 1998 | A |
5804446 | Cerami et al. | Sep 1998 | A |
5806529 | Reisner et al. | Sep 1998 | A |
5807686 | Wagner et al. | Sep 1998 | A |
5811094 | Caplan et al. | Sep 1998 | A |
5811397 | Francavilla et al. | Sep 1998 | A |
5817773 | Wilson et al. | Oct 1998 | A |
5821218 | Toback et al. | Oct 1998 | A |
5827735 | Young et al. | Oct 1998 | A |
5827740 | Pittenger | Oct 1998 | A |
5830921 | Cooley et al. | Nov 1998 | A |
5833979 | Schinstine et al. | Nov 1998 | A |
5837258 | Grotendorst | Nov 1998 | A |
5837539 | Caplan et al. | Nov 1998 | A |
5840502 | Van Vlasselaer | Nov 1998 | A |
5840576 | Schinstine et al. | Nov 1998 | A |
5840580 | Terstappen et al. | Nov 1998 | A |
5842477 | Naughton et al. | Dec 1998 | A |
5843633 | Yin et al. | Dec 1998 | A |
5846796 | Cerami et al. | Dec 1998 | A |
5853247 | Shroyer | Dec 1998 | A |
5853717 | Schinstine et al. | Dec 1998 | A |
5855608 | Brekke et al. | Jan 1999 | A |
5855613 | Antanavich et al. | Jan 1999 | A |
5855619 | Caplan et al. | Jan 1999 | A |
5858747 | Schinstine et al. | Jan 1999 | A |
5858782 | Long et al. | Jan 1999 | A |
5861315 | Nakahata | Jan 1999 | A |
5866115 | Kanz et al. | Feb 1999 | A |
5866420 | Talbot et al. | Feb 1999 | A |
5868930 | Kopf | Feb 1999 | A |
5882295 | Kope | Mar 1999 | A |
5882918 | Goffe | Mar 1999 | A |
5882929 | Fofonoff et al. | Mar 1999 | A |
5888807 | Palsson et al. | Mar 1999 | A |
5902741 | Purchio et al. | May 1999 | A |
5906827 | Khouri et al. | May 1999 | A |
5906934 | Grande et al. | May 1999 | A |
5908782 | Marshak et al. | Jun 1999 | A |
5908784 | Johnstone et al. | Jun 1999 | A |
5912177 | Turner et al. | Jun 1999 | A |
5914108 | Tsukamoto et al. | Jun 1999 | A |
5922597 | Verfaillie et al. | Jul 1999 | A |
5922847 | Broudy et al. | Jul 1999 | A |
5925567 | Kraus et al. | Jul 1999 | A |
5928945 | Seliktar et al. | Jul 1999 | A |
5935849 | Schinstine et al. | Aug 1999 | A |
5938929 | Shimagaki et al. | Aug 1999 | A |
5939323 | Valentini et al. | Aug 1999 | A |
5942225 | Bruder et al. | Aug 1999 | A |
5955353 | Amiot | Sep 1999 | A |
5958763 | Goffe | Sep 1999 | A |
5965436 | Thiede et al. | Oct 1999 | A |
5972703 | Long et al. | Oct 1999 | A |
5980795 | Klotzer et al. | Nov 1999 | A |
5981211 | Hu et al. | Nov 1999 | A |
5981708 | Lawman et al. | Nov 1999 | A |
5985653 | Armstrong et al. | Nov 1999 | A |
5994129 | Armstrong et al. | Nov 1999 | A |
5998184 | Shi | Dec 1999 | A |
6001585 | Gramer | Dec 1999 | A |
6001643 | Spaulding | Dec 1999 | A |
6001647 | Peck et al. | Dec 1999 | A |
6004743 | Kenyon et al. | Dec 1999 | A |
6010696 | Caplan et al. | Jan 2000 | A |
6015554 | Galy | Jan 2000 | A |
6022540 | Bruder et al. | Feb 2000 | A |
6022742 | Kopf | Feb 2000 | A |
6022743 | Naughton et al. | Feb 2000 | A |
6027743 | Khouri et al. | Feb 2000 | A |
6030836 | Thiede et al. | Feb 2000 | A |
6040180 | Johe | Mar 2000 | A |
6045818 | Cima et al. | Apr 2000 | A |
6048721 | Armstrong et al. | Apr 2000 | A |
6048727 | Kopf | Apr 2000 | A |
6049026 | Muschler | Apr 2000 | A |
6054121 | Cerami et al. | Apr 2000 | A |
6060270 | Humes | May 2000 | A |
6066317 | Yang et al. | May 2000 | A |
6071691 | Hoekstra et al. | Jun 2000 | A |
6074366 | Rogers et al. | Jun 2000 | A |
6082364 | Balian et al. | Jul 2000 | A |
6083747 | Wong et al. | Jul 2000 | A |
6086643 | Clark et al. | Jul 2000 | A |
6087113 | Caplan et al. | Jul 2000 | A |
6096532 | Armstrong et al. | Aug 2000 | A |
6096537 | Chappel | Aug 2000 | A |
6103117 | Shimagaki et al. | Aug 2000 | A |
6103522 | Torok-Storb et al. | Aug 2000 | A |
6110176 | Shapira | Aug 2000 | A |
6110482 | Khouri et al. | Aug 2000 | A |
6114307 | Jaspers et al. | Sep 2000 | A |
6117985 | Thomas et al. | Sep 2000 | A |
6120491 | Kohn et al. | Sep 2000 | A |
6127141 | Kopf | Oct 2000 | A |
6129911 | Faris | Oct 2000 | A |
6143293 | Weiss et al. | Nov 2000 | A |
6146360 | Rogers et al. | Nov 2000 | A |
6146888 | Smith et al. | Nov 2000 | A |
6149902 | Artavanis-Tsakonas et al. | Nov 2000 | A |
6149906 | Mosca | Nov 2000 | A |
6150164 | Humes | Nov 2000 | A |
6152964 | Van Blitterswijk et al. | Nov 2000 | A |
6162643 | Wille, Jr. | Dec 2000 | A |
6165225 | Antanavich et al. | Dec 2000 | A |
6165785 | Ogle et al. | Dec 2000 | A |
6174333 | Kadiyala et al. | Jan 2001 | B1 |
6174526 | Cerami et al. | Jan 2001 | B1 |
6174666 | Pavlakis et al. | Jan 2001 | B1 |
6179871 | Halpern | Jan 2001 | B1 |
6197325 | MacPhee et al. | Mar 2001 | B1 |
6197575 | Griffith et al. | Mar 2001 | B1 |
6200606 | Peterson et al. | Mar 2001 | B1 |
6214369 | Grande et al. | Apr 2001 | B1 |
6214574 | Kopf | Apr 2001 | B1 |
6224860 | Brown | May 2001 | B1 |
6225119 | Qasba et al. | May 2001 | B1 |
6225368 | D'Agostino et al. | May 2001 | B1 |
6228117 | De Bruijn et al. | May 2001 | B1 |
6228607 | Kersten et al. | May 2001 | B1 |
6228635 | Armstrong et al. | May 2001 | B1 |
6238908 | Armstrong et al. | May 2001 | B1 |
6239157 | Mbalaviele | May 2001 | B1 |
6242252 | Reid et al. | Jun 2001 | B1 |
6248319 | Zsebo et al. | Jun 2001 | B1 |
6248587 | Rodgers et al. | Jun 2001 | B1 |
6255112 | Thiede et al. | Jul 2001 | B1 |
6258597 | Bachovchin et al. | Jul 2001 | B1 |
6258778 | Rodgers et al. | Jul 2001 | B1 |
6261549 | Fernandez et al. | Jul 2001 | B1 |
6280718 | Kaufman et al. | Aug 2001 | B1 |
6280724 | Moore | Aug 2001 | B1 |
6281012 | McIntosh et al. | Aug 2001 | B1 |
6281195 | Rueger et al. | Aug 2001 | B1 |
6287864 | Bagnis et al. | Sep 2001 | B1 |
6291249 | Mahant et al. | Sep 2001 | B1 |
6297213 | Oppermann et al. | Oct 2001 | B1 |
6299650 | Van Blitterswijk et al. | Oct 2001 | B1 |
6306424 | Vyakarnam et al. | Oct 2001 | B1 |
6306575 | Thomas et al. | Oct 2001 | B1 |
6322784 | Pittenger et al. | Nov 2001 | B1 |
6322786 | Anderson | Nov 2001 | B1 |
6326198 | Emerson et al. | Dec 2001 | B1 |
6326201 | Fung et al. | Dec 2001 | B1 |
6328765 | Hardwick et al. | Dec 2001 | B1 |
6328960 | McIntosh et al. | Dec 2001 | B1 |
6333029 | Vyakarnam et al. | Dec 2001 | B1 |
6335195 | Rodgers et al. | Jan 2002 | B1 |
6338942 | Kraus et al. | Jan 2002 | B2 |
6340592 | Stringer | Jan 2002 | B1 |
6342370 | Connolly et al. | Jan 2002 | B1 |
6355239 | Bruder et al. | Mar 2002 | B1 |
6358252 | Shapira | Mar 2002 | B1 |
6361997 | Huss | Mar 2002 | B1 |
6365149 | Vyakarnam et al. | Apr 2002 | B2 |
6368636 | McIntosh et al. | Apr 2002 | B1 |
6372210 | Brown | Apr 2002 | B2 |
6372244 | Antanavich et al. | Apr 2002 | B1 |
6372494 | Naughton et al. | Apr 2002 | B1 |
6372892 | Ballinger et al. | Apr 2002 | B1 |
6376742 | Zdrahala et al. | Apr 2002 | B1 |
6379953 | Bruder et al. | Apr 2002 | B1 |
6387367 | Davis-Sproul et al. | May 2002 | B1 |
6387369 | Pittenger et al. | May 2002 | B1 |
6387693 | Rieser et al. | May 2002 | B2 |
6387964 | D'Agostino et al. | May 2002 | B1 |
6392118 | Hammang et al. | May 2002 | B1 |
6394812 | Sullivan et al. | May 2002 | B1 |
6399580 | Elias et al. | Jun 2002 | B1 |
6410320 | Humes | Jun 2002 | B1 |
6414219 | Denhardt et al. | Jul 2002 | B1 |
6416496 | Rogers et al. | Jul 2002 | B1 |
6417205 | Cooke et al. | Jul 2002 | B1 |
6419829 | Ho et al. | Jul 2002 | B2 |
6420138 | Gentz et al. | Jul 2002 | B1 |
6423681 | Barasch et al. | Jul 2002 | B1 |
6426332 | Rueger et al. | Jul 2002 | B1 |
6428802 | Atala | Aug 2002 | B1 |
6429012 | Kraus et al. | Aug 2002 | B1 |
6429013 | Halvorsen et al. | Aug 2002 | B1 |
6432653 | Okarma | Aug 2002 | B1 |
6432711 | Dinsmore et al. | Aug 2002 | B1 |
6440407 | Bauer et al. | Aug 2002 | B1 |
6440734 | Pykett et al. | Aug 2002 | B1 |
6451562 | Ruben et al. | Sep 2002 | B1 |
6454811 | Sherwood et al. | Sep 2002 | B1 |
6455678 | Yin et al. | Sep 2002 | B1 |
6458585 | Vachula et al. | Oct 2002 | B1 |
6458589 | Rambhatla et al. | Oct 2002 | B1 |
6461495 | Morrissey et al. | Oct 2002 | B1 |
6461853 | Zhu | Oct 2002 | B1 |
6464983 | Grotendorst | Oct 2002 | B1 |
6465205 | Hicks, Jr. | Oct 2002 | B2 |
6465247 | Weissman et al. | Oct 2002 | B1 |
6465249 | Reya et al. | Oct 2002 | B2 |
6468794 | Uchida et al. | Oct 2002 | B1 |
6472200 | Mitrani | Oct 2002 | B1 |
6475481 | Talmadge | Nov 2002 | B2 |
6479064 | Atala | Nov 2002 | B1 |
6482231 | Abatangelo et al. | Nov 2002 | B1 |
6482411 | Ahuja et al. | Nov 2002 | B1 |
6482645 | Atala | Nov 2002 | B2 |
6482926 | Thomas et al. | Nov 2002 | B1 |
6488925 | Ruben et al. | Dec 2002 | B2 |
6491918 | Thomas et al. | Dec 2002 | B1 |
6495129 | Li et al. | Dec 2002 | B1 |
6495364 | Hammang et al. | Dec 2002 | B2 |
6497875 | Sorrell et al. | Dec 2002 | B1 |
6498034 | Strobl | Dec 2002 | B1 |
6506574 | Rambhatla et al. | Jan 2003 | B1 |
6511510 | de Bruijn et al. | Jan 2003 | B1 |
6511767 | Calver et al. | Jan 2003 | B1 |
6511958 | Atkinson et al. | Jan 2003 | B1 |
6514514 | Atkinson et al. | Feb 2003 | B1 |
6524452 | Clark et al. | Feb 2003 | B1 |
6528052 | Smith et al. | Mar 2003 | B1 |
6528245 | Sanchez-Ramos et al. | Mar 2003 | B2 |
6531445 | Cohen et al. | Mar 2003 | B1 |
6534084 | Vyakarnam et al. | Mar 2003 | B1 |
6537807 | Smith et al. | Mar 2003 | B1 |
6541024 | Kadiyala et al. | Apr 2003 | B1 |
6541249 | Wager et al. | Apr 2003 | B2 |
6544506 | Reisner | Apr 2003 | B2 |
6548734 | Glimcher et al. | Apr 2003 | B1 |
6555324 | Olweus et al. | Apr 2003 | B1 |
6555374 | Gimble et al. | Apr 2003 | B1 |
6559119 | Burgess et al. | May 2003 | B1 |
6562616 | Toner et al. | May 2003 | B1 |
6565843 | Cohen et al. | May 2003 | B1 |
6566126 | Cadwell | May 2003 | B2 |
6569421 | Hodges | May 2003 | B2 |
6569427 | Boyse et al. | May 2003 | B1 |
6569428 | Isner et al. | May 2003 | B1 |
6569654 | Shastri et al. | May 2003 | B2 |
6576188 | Rose et al. | Jun 2003 | B1 |
6576428 | Assenmacher et al. | Jun 2003 | B1 |
6576464 | Gold et al. | Jun 2003 | B2 |
6576465 | Long | Jun 2003 | B1 |
6582471 | Bittmann et al. | Jun 2003 | B1 |
6582955 | Martinez et al. | Jun 2003 | B2 |
6586192 | Peschle et al. | Jul 2003 | B1 |
6589728 | Csete et al. | Jul 2003 | B2 |
6589786 | Mangano et al. | Jul 2003 | B1 |
6596274 | Abatangelo et al. | Jul 2003 | B1 |
6599300 | Vibe-Hansen et al. | Jul 2003 | B2 |
6599520 | Scarborough et al. | Jul 2003 | B2 |
6610535 | Lu et al. | Aug 2003 | B1 |
6613798 | Porter et al. | Sep 2003 | B1 |
6616912 | Eddleman et al. | Sep 2003 | B2 |
6617070 | Morrissey et al. | Sep 2003 | B1 |
6617152 | Bryhan et al. | Sep 2003 | B2 |
6617159 | Cancedda et al. | Sep 2003 | B1 |
6623749 | Williams et al. | Sep 2003 | B2 |
6623942 | Ruben et al. | Sep 2003 | B2 |
6624108 | Clark et al. | Sep 2003 | B1 |
6626950 | Brown et al. | Sep 2003 | B2 |
6627191 | Bartelmez et al. | Sep 2003 | B1 |
6632425 | Li et al. | Oct 2003 | B1 |
6632620 | Makarovskiy | Oct 2003 | B1 |
6632934 | Moreadith et al. | Oct 2003 | B1 |
6638765 | Rosenberg | Oct 2003 | B1 |
6642019 | Anderson et al. | Nov 2003 | B1 |
6642048 | Xu et al. | Nov 2003 | B2 |
6642049 | Chute et al. | Nov 2003 | B1 |
6642201 | Khavinson et al. | Nov 2003 | B1 |
6645489 | Pykett et al. | Nov 2003 | B2 |
6645727 | Thomas et al. | Nov 2003 | B2 |
6645763 | Kobayashi et al. | Nov 2003 | B2 |
6649189 | Talmadge et al. | Nov 2003 | B2 |
6649595 | Clackson et al. | Nov 2003 | B2 |
6649631 | Orme et al. | Nov 2003 | B1 |
6653105 | Triglia et al. | Nov 2003 | B2 |
6653134 | Prockop et al. | Nov 2003 | B2 |
6660523 | Blom et al. | Dec 2003 | B2 |
6662805 | Frondoza et al. | Dec 2003 | B2 |
6667034 | Palsson et al. | Dec 2003 | B2 |
6667176 | Funk et al. | Dec 2003 | B1 |
6670169 | Schob et al. | Dec 2003 | B1 |
6670175 | Wang et al. | Dec 2003 | B2 |
6673603 | Baetge et al. | Jan 2004 | B2 |
6673606 | Tennekoon et al. | Jan 2004 | B1 |
6677306 | Veis et al. | Jan 2004 | B1 |
6683192 | Baxter et al. | Jan 2004 | B2 |
6685936 | McIntosh et al. | Feb 2004 | B2 |
6685971 | Xu | Feb 2004 | B2 |
6686198 | Melton et al. | Feb 2004 | B1 |
6696575 | Schmidt et al. | Feb 2004 | B2 |
6699716 | Sullivan et al. | Mar 2004 | B2 |
6703017 | Peck et al. | Mar 2004 | B1 |
6703209 | Baetscher et al. | Mar 2004 | B1 |
6706293 | Quintanilla Almagro et al. | Mar 2004 | B1 |
6709864 | Pittenger et al. | Mar 2004 | B1 |
6712850 | Vyakarnam et al. | Mar 2004 | B2 |
6719969 | Hogaboam et al. | Apr 2004 | B1 |
6719970 | Costantino et al. | Apr 2004 | B1 |
6720340 | Cooke et al. | Apr 2004 | B1 |
6730314 | Jeschke et al. | May 2004 | B2 |
6730315 | Usala et al. | May 2004 | B2 |
6730510 | Roos et al. | May 2004 | B2 |
6733746 | Daley et al. | May 2004 | B2 |
6734000 | Chin et al. | May 2004 | B2 |
6740493 | Long et al. | May 2004 | B1 |
6759039 | Tsang et al. | Jul 2004 | B2 |
6759245 | Toner et al. | Jul 2004 | B1 |
6761883 | Weissman et al. | Jul 2004 | B2 |
6761887 | Kavalkovich et al. | Jul 2004 | B1 |
6767699 | Polo et al. | Jul 2004 | B2 |
6767737 | Wilson et al. | Jul 2004 | B1 |
6767738 | Gage et al. | Jul 2004 | B1 |
6767740 | Sramek et al. | Jul 2004 | B2 |
6770478 | Crowe et al. | Aug 2004 | B2 |
6777227 | Ricci et al. | Aug 2004 | B2 |
6777231 | Katz et al. | Aug 2004 | B1 |
6780612 | Ford et al. | Aug 2004 | B1 |
6787355 | Miller et al. | Sep 2004 | B1 |
6790455 | Chu et al. | Sep 2004 | B2 |
6793939 | Badylak | Sep 2004 | B2 |
6797269 | Mosca et al. | Sep 2004 | B2 |
6797514 | Berenson et al. | Sep 2004 | B2 |
6800480 | Bodnar et al. | Oct 2004 | B1 |
6802971 | Gorsuch et al. | Oct 2004 | B2 |
6805860 | Alt | Oct 2004 | B1 |
6809117 | Enikolopov et al. | Oct 2004 | B2 |
6811773 | Gentz et al. | Nov 2004 | B1 |
6811776 | Kale et al. | Nov 2004 | B2 |
6814961 | Jensen et al. | Nov 2004 | B1 |
6821513 | Fleming | Nov 2004 | B1 |
6821790 | Mahant et al. | Nov 2004 | B2 |
6828145 | Avital et al. | Dec 2004 | B2 |
6833269 | Carpenter | Dec 2004 | B2 |
6835377 | Goldberg et al. | Dec 2004 | B2 |
6835566 | Smith et al. | Dec 2004 | B2 |
6838284 | de Bruijn et al. | Jan 2005 | B2 |
6841150 | Halvorsen et al. | Jan 2005 | B2 |
6841151 | Stringer | Jan 2005 | B2 |
6841294 | Morrissey et al. | Jan 2005 | B1 |
6841355 | Livant | Jan 2005 | B2 |
6841386 | Kraus et al. | Jan 2005 | B2 |
6841542 | Bartelmez et al. | Jan 2005 | B2 |
6844011 | Faustman | Jan 2005 | B1 |
6844187 | Weschler et al. | Jan 2005 | B1 |
6849051 | Sramek et al. | Feb 2005 | B2 |
6849255 | Gazit et al. | Feb 2005 | B2 |
6849454 | Kelly et al. | Feb 2005 | B2 |
6849662 | Enikolopov et al. | Feb 2005 | B2 |
6852308 | Kohn et al. | Feb 2005 | B2 |
6852321 | Colucci et al. | Feb 2005 | B2 |
6852533 | Rafii et al. | Feb 2005 | B1 |
6855242 | Comninellis et al. | Feb 2005 | B1 |
6855542 | DiMilla et al. | Feb 2005 | B2 |
6863900 | Kadiyala et al. | Mar 2005 | B2 |
6866843 | Habener et al. | Mar 2005 | B2 |
6872389 | Faris | Mar 2005 | B1 |
6875430 | McIntosh et al. | Apr 2005 | B2 |
6887600 | Morrissey et al. | May 2005 | B2 |
6887704 | Peled et al. | May 2005 | B2 |
6908763 | Akashi et al. | Jun 2005 | B1 |
6911201 | Merchav et al. | Jun 2005 | B1 |
6914279 | Lu et al. | Jul 2005 | B2 |
6939955 | Rameshwar | Sep 2005 | B2 |
6943008 | Ma | Sep 2005 | B1 |
6965018 | Mikesell et al. | Nov 2005 | B2 |
6969308 | Doi et al. | Nov 2005 | B2 |
6979308 | McDonald et al. | Dec 2005 | B1 |
6979321 | Geis et al. | Dec 2005 | B2 |
6988004 | Kanno et al. | Jan 2006 | B2 |
7008394 | Geise et al. | Mar 2006 | B2 |
7015037 | Furcht et al. | Mar 2006 | B1 |
7029666 | Bruder et al. | Apr 2006 | B2 |
7033339 | Lynn | Apr 2006 | B1 |
7033823 | Chang | Apr 2006 | B2 |
7041493 | Rao | May 2006 | B2 |
7045098 | Stephens | May 2006 | B2 |
7052517 | Murphy et al. | May 2006 | B2 |
7056493 | Kohn et al. | Jun 2006 | B2 |
7112441 | Uemura et al. | Sep 2006 | B2 |
7118672 | Husain et al. | Oct 2006 | B2 |
7122178 | Simmons et al. | Oct 2006 | B1 |
7160719 | Nyberg | Jan 2007 | B2 |
7169295 | Husain et al. | Jan 2007 | B2 |
7172696 | Martinez et al. | Feb 2007 | B1 |
7175763 | Husain et al. | Feb 2007 | B2 |
7192776 | Stephens | Mar 2007 | B2 |
7195711 | Gorsuch et al. | Mar 2007 | B2 |
7250154 | Kohn et al. | Jul 2007 | B2 |
7270996 | Cannon et al. | Sep 2007 | B2 |
7271234 | Kohn et al. | Sep 2007 | B2 |
7294259 | Cote et al. | Nov 2007 | B2 |
7300571 | Cote et al. | Nov 2007 | B2 |
7303676 | Husain et al. | Dec 2007 | B2 |
7303677 | Cote et al. | Dec 2007 | B2 |
7341062 | Chachques et al. | Mar 2008 | B2 |
7358001 | Morrissey et al. | Apr 2008 | B2 |
7361493 | Hammond et al. | Apr 2008 | B1 |
7368169 | Kohn et al. | May 2008 | B2 |
7378271 | Bader | May 2008 | B2 |
7399872 | Webster et al. | Jul 2008 | B2 |
7416884 | Gemmiti et al. | Aug 2008 | B2 |
7425440 | Malinge et al. | Sep 2008 | B2 |
7435586 | Bartlett et al. | Oct 2008 | B2 |
7438902 | Habener et al. | Oct 2008 | B2 |
7439057 | Frangos et al. | Oct 2008 | B2 |
7452529 | Brown, Jr. et al. | Nov 2008 | B2 |
7491388 | Mc Intosh et al. | Feb 2009 | B1 |
7494811 | Wolfinbarger, Jr. et al. | Feb 2009 | B2 |
7514074 | Pittenger et al. | Apr 2009 | B2 |
7514075 | Hedrick et al. | Apr 2009 | B2 |
7524676 | Reiter et al. | Apr 2009 | B2 |
7531351 | Marx et al. | May 2009 | B2 |
7534601 | Wikswo et al. | May 2009 | B2 |
7534609 | Merchav et al. | May 2009 | B2 |
7572374 | Gorsuch et al. | Aug 2009 | B2 |
7579179 | Bryhan et al. | Aug 2009 | B2 |
7585412 | Gorsuch et al. | Sep 2009 | B2 |
7588938 | Ma | Sep 2009 | B2 |
7598075 | Smith et al. | Oct 2009 | B2 |
7608447 | Cohen et al. | Oct 2009 | B2 |
7659118 | Furcht et al. | Feb 2010 | B2 |
7678573 | Merchav et al. | Mar 2010 | B2 |
7682822 | Noll et al. | Mar 2010 | B2 |
7682823 | Runyon | Mar 2010 | B1 |
7718430 | Antwiler | May 2010 | B2 |
7722896 | Kohn et al. | May 2010 | B2 |
D620732 | Andrews | Aug 2010 | S |
7838122 | Kohn et al. | Nov 2010 | B2 |
7838289 | Furcht et al. | Nov 2010 | B2 |
7892829 | Pittenger et al. | Feb 2011 | B2 |
7919307 | Klaus et al. | Apr 2011 | B2 |
7927587 | Blazer et al. | Apr 2011 | B2 |
7989851 | Lu et al. | Aug 2011 | B2 |
8008528 | Kohn et al. | Aug 2011 | B2 |
8034365 | Baluca | Oct 2011 | B2 |
8075881 | Verfaillie et al. | Dec 2011 | B2 |
8147824 | Maziarz et al. | Apr 2012 | B2 |
8147863 | Kohn et al. | Apr 2012 | B2 |
8158120 | Pittenger et al. | Apr 2012 | B2 |
8158121 | Pittenger et al. | Apr 2012 | B2 |
8252280 | Verfaillie et al. | Aug 2012 | B1 |
8252887 | Bolikal et al. | Aug 2012 | B2 |
8288159 | Warren et al. | Oct 2012 | B2 |
8288590 | Kohn et al. | Oct 2012 | B2 |
8298823 | Warren et al. | Oct 2012 | B2 |
8309347 | Antwiler | Nov 2012 | B2 |
8361453 | Uhrich et al. | Jan 2013 | B2 |
8377683 | Lu et al. | Feb 2013 | B2 |
8383397 | Wojciechowski et al. | Feb 2013 | B2 |
8383806 | Rameshwar | Feb 2013 | B2 |
8399245 | Leuthaeuser et al. | Mar 2013 | B2 |
8415449 | Kohn et al. | Apr 2013 | B2 |
8435781 | Kodama | May 2013 | B2 |
8461289 | Kohn et al. | Jun 2013 | B2 |
8476399 | Bolikal et al. | Jul 2013 | B2 |
8486621 | Luo et al. | Jul 2013 | B2 |
8486695 | Danilkovitch et al. | Jul 2013 | B2 |
8492140 | Smith et al. | Jul 2013 | B2 |
8492150 | Parker et al. | Jul 2013 | B2 |
8524496 | Meiron et al. | Sep 2013 | B2 |
8529888 | Meiron et al. | Sep 2013 | B2 |
8540499 | Page et al. | Sep 2013 | B2 |
8551511 | Brandom et al. | Oct 2013 | B2 |
8580249 | Blazar et al. | Nov 2013 | B2 |
8678638 | Wong | Mar 2014 | B2 |
8785181 | Antwiler | Jul 2014 | B2 |
8852570 | Pittenger et al. | Oct 2014 | B2 |
8852571 | Pittenger et al. | Oct 2014 | B2 |
8852572 | Pittenger et al. | Oct 2014 | B2 |
8852573 | Pittenger et al. | Oct 2014 | B2 |
8852574 | Pittenger et al. | Oct 2014 | B2 |
8852575 | Pittenger et al. | Oct 2014 | B2 |
8895291 | DiLorenzo et al. | Nov 2014 | B2 |
9057045 | Gibbons et al. | Jun 2015 | B2 |
9109193 | Galliher et al. | Aug 2015 | B2 |
9175259 | Nankervis | Nov 2015 | B2 |
9220810 | Ma et al. | Dec 2015 | B2 |
9441195 | Wojciechowski et al. | Sep 2016 | B2 |
9534198 | Page et al. | Jan 2017 | B2 |
9732313 | Hirschel et al. | Aug 2017 | B2 |
10093956 | Hirschel et al. | Oct 2018 | B2 |
10494421 | Castillo | Dec 2019 | B2 |
11008547 | Nankervis | May 2021 | B2 |
20010017188 | Cooley et al. | Aug 2001 | A1 |
20010020086 | Hubbell et al. | Sep 2001 | A1 |
20010021516 | Wei et al. | Sep 2001 | A1 |
20010029046 | Beaulieu | Oct 2001 | A1 |
20010033834 | Wilkison et al. | Oct 2001 | A1 |
20010036663 | Kraus et al. | Nov 2001 | A1 |
20010041687 | Mruk | Nov 2001 | A1 |
20010044413 | Pierce et al. | Nov 2001 | A1 |
20010049139 | Lagasse et al. | Dec 2001 | A1 |
20020015724 | Yang et al. | Feb 2002 | A1 |
20020018804 | Austin et al. | Feb 2002 | A1 |
20020028510 | Sanberg et al. | Mar 2002 | A1 |
20020031757 | Ohgushi et al. | Mar 2002 | A1 |
20020037278 | Ueno et al. | Mar 2002 | A1 |
20020045260 | Hung et al. | Apr 2002 | A1 |
20020064869 | Ebner et al. | May 2002 | A1 |
20020076400 | Katz et al. | Jun 2002 | A1 |
20020077687 | Ahn | Jun 2002 | A1 |
20020082698 | Parenteau et al. | Jun 2002 | A1 |
20020116054 | Lundell et al. | Aug 2002 | A1 |
20020128581 | Vishnoi et al. | Sep 2002 | A1 |
20020128582 | Farrell et al. | Sep 2002 | A1 |
20020128583 | Min et al. | Sep 2002 | A1 |
20020128584 | Brown et al. | Sep 2002 | A1 |
20020130100 | Smith | Sep 2002 | A1 |
20020132343 | Lum | Sep 2002 | A1 |
20020139743 | Critz et al. | Oct 2002 | A1 |
20020142457 | Umezawa et al. | Oct 2002 | A1 |
20020146678 | Benvenisty | Oct 2002 | A1 |
20020146817 | Cannon et al. | Oct 2002 | A1 |
20020150989 | Greene et al. | Oct 2002 | A1 |
20020151056 | Sasai et al. | Oct 2002 | A1 |
20020159981 | Peled et al. | Oct 2002 | A1 |
20020160032 | Long et al. | Oct 2002 | A1 |
20020160510 | Hariri | Oct 2002 | A1 |
20020168765 | Prockop et al. | Nov 2002 | A1 |
20020169408 | Beretta et al. | Nov 2002 | A1 |
20020182241 | Borenstein et al. | Dec 2002 | A1 |
20020182664 | Dolecek et al. | Dec 2002 | A1 |
20020188962 | Denhardt et al. | Dec 2002 | A1 |
20020197240 | Chiu | Dec 2002 | A1 |
20030021850 | Xu | Jan 2003 | A1 |
20030022390 | Stephens | Jan 2003 | A1 |
20030027330 | Lanza et al. | Feb 2003 | A1 |
20030027331 | Yan et al. | Feb 2003 | A1 |
20030032143 | Neff et al. | Feb 2003 | A1 |
20030036168 | Ni et al. | Feb 2003 | A1 |
20030040113 | Mizuno et al. | Feb 2003 | A1 |
20030049236 | Kassem et al. | Mar 2003 | A1 |
20030054331 | Fraser et al. | Mar 2003 | A1 |
20030059851 | Smith | Mar 2003 | A1 |
20030059939 | Page et al. | Mar 2003 | A1 |
20030078345 | Morrisey | Apr 2003 | A1 |
20030082795 | Shuler et al. | May 2003 | A1 |
20030086915 | Rader et al. | May 2003 | A1 |
20030089471 | Gehr et al. | May 2003 | A1 |
20030092101 | Ni et al. | May 2003 | A1 |
20030101465 | Lawman et al. | May 2003 | A1 |
20030103957 | McKerracher | Jun 2003 | A1 |
20030104568 | Lee | Jun 2003 | A1 |
20030113813 | Heidaran et al. | Jun 2003 | A1 |
20030113910 | Levanduski | Jun 2003 | A1 |
20030124091 | Tuse et al. | Jul 2003 | A1 |
20030124721 | Cheatham et al. | Jul 2003 | A1 |
20030130593 | Gonzalez | Jul 2003 | A1 |
20030133918 | Sherley | Jul 2003 | A1 |
20030138950 | McAllister et al. | Jul 2003 | A1 |
20030143727 | Chang | Jul 2003 | A1 |
20030148152 | Morrisey | Aug 2003 | A1 |
20030149011 | Ackerman et al. | Aug 2003 | A1 |
20030152558 | Luft et al. | Aug 2003 | A1 |
20030157078 | Hall et al. | Aug 2003 | A1 |
20030157709 | DiMilla et al. | Aug 2003 | A1 |
20030161817 | Young et al. | Aug 2003 | A1 |
20030166272 | Abuljadayel | Sep 2003 | A1 |
20030170214 | Bader | Sep 2003 | A1 |
20030180296 | Salcedo et al. | Sep 2003 | A1 |
20030185817 | Thomas et al. | Oct 2003 | A1 |
20030202938 | Rameshwar | Oct 2003 | A1 |
20030203483 | Seshi | Oct 2003 | A1 |
20030204323 | Morrisey | Oct 2003 | A1 |
20030211602 | Atala | Nov 2003 | A1 |
20030211603 | Earp et al. | Nov 2003 | A1 |
20030216718 | Hamblin et al. | Nov 2003 | A1 |
20030219898 | Sugaya et al. | Nov 2003 | A1 |
20030223968 | Yang | Dec 2003 | A1 |
20030224420 | Hellerstein et al. | Dec 2003 | A1 |
20030224510 | Yamaguchi et al. | Dec 2003 | A1 |
20030225010 | Rameshwar | Dec 2003 | A1 |
20030232432 | Bhat | Dec 2003 | A1 |
20030232752 | Freeman et al. | Dec 2003 | A1 |
20030235909 | Hariri et al. | Dec 2003 | A1 |
20040009158 | Sands et al. | Jan 2004 | A1 |
20040009589 | Levenberg et al. | Jan 2004 | A1 |
20040010231 | Leonhardt et al. | Jan 2004 | A1 |
20040014209 | Lassar et al. | Jan 2004 | A1 |
20040018174 | Palasis | Jan 2004 | A1 |
20040018617 | Hwang | Jan 2004 | A1 |
20040023324 | Sakano et al. | Feb 2004 | A1 |
20040023370 | Yu et al. | Feb 2004 | A1 |
20040027914 | Vrane | Feb 2004 | A1 |
20040033214 | Young et al. | Feb 2004 | A1 |
20040033599 | Rosenberg | Feb 2004 | A1 |
20040037811 | Penn et al. | Feb 2004 | A1 |
20040037815 | Clarke et al. | Feb 2004 | A1 |
20040038316 | Kaiser et al. | Feb 2004 | A1 |
20040053869 | Andrews et al. | Mar 2004 | A1 |
20040062753 | Rezania et al. | Apr 2004 | A1 |
20040063205 | Xu | Apr 2004 | A1 |
20040067585 | Wang et al. | Apr 2004 | A1 |
20040071668 | Bays et al. | Apr 2004 | A1 |
20040072259 | Scadden et al. | Apr 2004 | A1 |
20040077079 | Storgaard et al. | Apr 2004 | A1 |
20040079248 | Mayer et al. | Apr 2004 | A1 |
20040087016 | Keating et al. | May 2004 | A1 |
20040091936 | West | May 2004 | A1 |
20040096476 | Uhrich et al. | May 2004 | A1 |
20040097408 | Leder et al. | May 2004 | A1 |
20040101959 | Marko et al. | May 2004 | A1 |
20040107453 | Furcht et al. | Jun 2004 | A1 |
20040110286 | Bhatia | Jun 2004 | A1 |
20040115804 | Fu et al. | Jun 2004 | A1 |
20040115806 | Fu | Jun 2004 | A1 |
20040120932 | Zahner | Jun 2004 | A1 |
20040121461 | Honmou et al. | Jun 2004 | A1 |
20040121464 | Rathjen et al. | Jun 2004 | A1 |
20040126405 | Sahatjian et al. | Jul 2004 | A1 |
20040128077 | Koebler et al. | Jul 2004 | A1 |
20040131601 | Epstein et al. | Jul 2004 | A1 |
20040132184 | Dennis et al. | Jul 2004 | A1 |
20040136967 | Weiss et al. | Jul 2004 | A1 |
20040137612 | Baksh | Jul 2004 | A1 |
20040137613 | Vacanti et al. | Jul 2004 | A1 |
20040143174 | Brubaker | Jul 2004 | A1 |
20040143863 | Li et al. | Jul 2004 | A1 |
20040151700 | Harlan et al. | Aug 2004 | A1 |
20040151701 | Kim et al. | Aug 2004 | A1 |
20040151706 | Shakhov et al. | Aug 2004 | A1 |
20040151729 | Michalopoulos et al. | Aug 2004 | A1 |
20040152190 | Sumita | Aug 2004 | A1 |
20040161419 | Strom et al. | Aug 2004 | A1 |
20040171533 | Zehentner et al. | Sep 2004 | A1 |
20040180347 | Stanton et al. | Sep 2004 | A1 |
20040191902 | Hambor et al. | Sep 2004 | A1 |
20040197310 | Sanberg et al. | Oct 2004 | A1 |
20040197375 | Rezania et al. | Oct 2004 | A1 |
20040208786 | Kevy et al. | Oct 2004 | A1 |
20040214275 | Soejima et al. | Oct 2004 | A1 |
20040219134 | Naughton et al. | Nov 2004 | A1 |
20040219136 | Hariri | Nov 2004 | A1 |
20040219563 | West et al. | Nov 2004 | A1 |
20040224403 | Bhatia | Nov 2004 | A1 |
20040229351 | Rodriguez et al. | Nov 2004 | A1 |
20040234972 | Owens et al. | Nov 2004 | A1 |
20040235158 | Bartlett et al. | Nov 2004 | A1 |
20040235160 | Nishikawa et al. | Nov 2004 | A1 |
20040235166 | Prockop et al. | Nov 2004 | A1 |
20040242469 | Lee et al. | Dec 2004 | A1 |
20040258669 | Dzau et al. | Dec 2004 | A1 |
20040259242 | Malinge et al. | Dec 2004 | A1 |
20040259254 | Honmou et al. | Dec 2004 | A1 |
20040260058 | Scheek et al. | Dec 2004 | A1 |
20040260318 | Hunter et al. | Dec 2004 | A1 |
20040265996 | Schwarz et al. | Dec 2004 | A1 |
20050002914 | Rosen et al. | Jan 2005 | A1 |
20050003460 | Nilsson et al. | Jan 2005 | A1 |
20050003527 | Lang et al. | Jan 2005 | A1 |
20050003534 | Huberman et al. | Jan 2005 | A1 |
20050008624 | Peled et al. | Jan 2005 | A1 |
20050008626 | Fraser et al. | Jan 2005 | A1 |
20050009178 | Yost et al. | Jan 2005 | A1 |
20050009179 | Gemmiti et al. | Jan 2005 | A1 |
20050009181 | Black et al. | Jan 2005 | A1 |
20050013804 | Kato et al. | Jan 2005 | A1 |
20050014252 | Chu et al. | Jan 2005 | A1 |
20050014253 | Ehmann et al. | Jan 2005 | A1 |
20050014254 | Kruse | Jan 2005 | A1 |
20050014255 | Tang et al. | Jan 2005 | A1 |
20050019801 | Rubin et al. | Jan 2005 | A1 |
20050019908 | Hariri | Jan 2005 | A1 |
20050019910 | Takagi et al. | Jan 2005 | A1 |
20050019911 | Gronthos et al. | Jan 2005 | A1 |
20050026836 | Dack et al. | Feb 2005 | A1 |
20050031587 | Tsutsui et al. | Feb 2005 | A1 |
20050031595 | Peled et al. | Feb 2005 | A1 |
20050031598 | Levenberg et al. | Feb 2005 | A1 |
20050032122 | Hwang et al. | Feb 2005 | A1 |
20050032207 | Wobus et al. | Feb 2005 | A1 |
20050032209 | Messina et al. | Feb 2005 | A1 |
20050032218 | Gerlach | Feb 2005 | A1 |
20050036980 | Chaney et al. | Feb 2005 | A1 |
20050037488 | Mitalipova et al. | Feb 2005 | A1 |
20050037490 | Rosenberg et al. | Feb 2005 | A1 |
20050037492 | Xu et al. | Feb 2005 | A1 |
20050037493 | Mandalam et al. | Feb 2005 | A1 |
20050037949 | O'Brien et al. | Feb 2005 | A1 |
20050106119 | Brandom et al. | May 2005 | A1 |
20050106127 | Kraus et al. | May 2005 | A1 |
20050112447 | Fletcher et al. | May 2005 | A1 |
20050112762 | Hart et al. | May 2005 | A1 |
20050118712 | Tsai et al. | Jun 2005 | A1 |
20050130297 | Sarem et al. | Jun 2005 | A1 |
20050136093 | Denk | Jun 2005 | A1 |
20050137517 | Blickhan et al. | Jun 2005 | A1 |
20050142162 | Hunter et al. | Jun 2005 | A1 |
20050149157 | Hunter et al. | Jul 2005 | A1 |
20050152946 | Hunter et al. | Jul 2005 | A1 |
20050158289 | Simmons et al. | Jul 2005 | A1 |
20050172340 | Logvinov et al. | Aug 2005 | A1 |
20050175665 | Hunter et al. | Aug 2005 | A1 |
20050175703 | Hunter et al. | Aug 2005 | A1 |
20050178395 | Hunter et al. | Aug 2005 | A1 |
20050178396 | Hunter et al. | Aug 2005 | A1 |
20050180957 | Scharp et al. | Aug 2005 | A1 |
20050181502 | Furcht et al. | Aug 2005 | A1 |
20050182463 | Hunter et al. | Aug 2005 | A1 |
20050183731 | Hunter et al. | Aug 2005 | A1 |
20050186244 | Hunter et al. | Aug 2005 | A1 |
20050186671 | Cannon et al. | Aug 2005 | A1 |
20050187140 | Hunter et al. | Aug 2005 | A1 |
20050196421 | Hunter et al. | Sep 2005 | A1 |
20050208095 | Hunter et al. | Sep 2005 | A1 |
20050244963 | Teplyashin | Nov 2005 | A1 |
20050249731 | Aslan et al. | Nov 2005 | A1 |
20050255118 | Wehner | Nov 2005 | A1 |
20050261674 | Nobis et al. | Nov 2005 | A1 |
20050277577 | Hunter et al. | Dec 2005 | A1 |
20050281790 | Simmons et al. | Dec 2005 | A1 |
20050282733 | Prins et al. | Dec 2005 | A1 |
20050283844 | Furcht et al. | Dec 2005 | A1 |
20060002900 | Binder et al. | Jan 2006 | A1 |
20060008452 | Simmons et al. | Jan 2006 | A1 |
20060019388 | Hutmacher et al. | Jan 2006 | A1 |
20060019389 | Yayon et al. | Jan 2006 | A1 |
20060054941 | Lu et al. | Mar 2006 | A1 |
20060083720 | Fraser et al. | Apr 2006 | A1 |
20060099198 | Thomson et al. | May 2006 | A1 |
20060166364 | Senesac | Jul 2006 | A1 |
20060172008 | Yayon et al. | Aug 2006 | A1 |
20060193840 | Gronthos et al. | Aug 2006 | A1 |
20060228798 | Verfaillie et al. | Oct 2006 | A1 |
20060233834 | Guehenneux et al. | Oct 2006 | A1 |
20060239909 | Anderson et al. | Oct 2006 | A1 |
20060258586 | Sheppard et al. | Nov 2006 | A1 |
20060258933 | Ellis et al. | Nov 2006 | A1 |
20060259998 | Brumbley et al. | Nov 2006 | A1 |
20060280748 | Buckheit | Dec 2006 | A1 |
20060286077 | Gronthos et al. | Dec 2006 | A1 |
20070005148 | Barofsky et al. | Jan 2007 | A1 |
20070011752 | Paleyanda | Jan 2007 | A1 |
20070042462 | Hildinger | Feb 2007 | A1 |
20070065938 | Gronthos et al. | Mar 2007 | A1 |
20070105222 | Wolfinbarger et al. | May 2007 | A1 |
20070116612 | Williamson | May 2007 | A1 |
20070117180 | Morikawa et al. | May 2007 | A1 |
20070122904 | Nordon | May 2007 | A1 |
20070123996 | Sugaya et al. | May 2007 | A1 |
20070160583 | Lange et al. | Jul 2007 | A1 |
20070166834 | Williamson et al. | Jul 2007 | A1 |
20070178071 | Westenfelder | Aug 2007 | A1 |
20070196421 | Hunter et al. | Aug 2007 | A1 |
20070197957 | Hunter et al. | Aug 2007 | A1 |
20070198063 | Hunter et al. | Aug 2007 | A1 |
20070202485 | Nees et al. | Aug 2007 | A1 |
20070203330 | Kretschmar et al. | Aug 2007 | A1 |
20070208134 | Hunter et al. | Sep 2007 | A1 |
20070231305 | Noll et al. | Oct 2007 | A1 |
20070258943 | Penn et al. | Nov 2007 | A1 |
20070274970 | Gordon et al. | Nov 2007 | A1 |
20070275457 | Granchelli et al. | Nov 2007 | A1 |
20070295651 | Martinez et al. | Dec 2007 | A1 |
20070298015 | Beer et al. | Dec 2007 | A1 |
20070298497 | Antwiler | Dec 2007 | A1 |
20080003663 | Bryhan et al. | Jan 2008 | A1 |
20080009458 | Dornan et al. | Jan 2008 | A1 |
20080032398 | Cannon et al. | Feb 2008 | A1 |
20080050770 | Zhang et al. | Feb 2008 | A1 |
20080063600 | Aguzzi et al. | Mar 2008 | A1 |
20080064649 | Rameshwar | Mar 2008 | A1 |
20080069807 | Jy et al. | Mar 2008 | A1 |
20080095676 | Andretta | Apr 2008 | A1 |
20080095690 | Liu | Apr 2008 | A1 |
20080103412 | Chin | May 2008 | A1 |
20080110827 | Cote et al. | May 2008 | A1 |
20080113426 | Smith et al. | May 2008 | A1 |
20080113440 | Gurney et al. | May 2008 | A1 |
20080153077 | Henry | Jun 2008 | A1 |
20080160597 | van der Heiden et al. | Jul 2008 | A1 |
20080166808 | Nyberg | Jul 2008 | A1 |
20080181879 | Catelas et al. | Jul 2008 | A1 |
20080190857 | Beretta et al. | Aug 2008 | A1 |
20080194017 | Esser et al. | Aug 2008 | A1 |
20080206831 | Coffey et al. | Aug 2008 | A1 |
20080220522 | Antwiler | Sep 2008 | A1 |
20080220523 | Antwiler | Sep 2008 | A1 |
20080220524 | Noll et al. | Sep 2008 | A1 |
20080220526 | Ellison et al. | Sep 2008 | A1 |
20080221443 | Ritchie et al. | Sep 2008 | A1 |
20080227189 | Bader | Sep 2008 | A1 |
20080227190 | Antwiler | Sep 2008 | A1 |
20080248572 | Antwiler | Oct 2008 | A1 |
20080254533 | Antwiler | Oct 2008 | A1 |
20080268165 | Fekety et al. | Oct 2008 | A1 |
20080306095 | Crawford | Dec 2008 | A1 |
20090004738 | Merchav et al. | Jan 2009 | A1 |
20090011399 | Fischer | Jan 2009 | A1 |
20090047289 | Denhardt et al. | Feb 2009 | A1 |
20090074728 | Gronthos et al. | Mar 2009 | A1 |
20090075881 | Catelas et al. | Mar 2009 | A1 |
20090076481 | Stegmann et al. | Mar 2009 | A1 |
20090081770 | Srienc et al. | Mar 2009 | A1 |
20090081797 | Fadeev et al. | Mar 2009 | A1 |
20090092608 | Ni et al. | Apr 2009 | A1 |
20090098103 | Madison et al. | Apr 2009 | A1 |
20090098645 | Fang et al. | Apr 2009 | A1 |
20090100944 | Newby | Apr 2009 | A1 |
20090104163 | Deans et al. | Apr 2009 | A1 |
20090104692 | Bartfeld et al. | Apr 2009 | A1 |
20090104699 | Newby et al. | Apr 2009 | A1 |
20090118161 | Cruz | May 2009 | A1 |
20090181087 | Kraus et al. | Jul 2009 | A1 |
20090183581 | Wilkinson et al. | Jul 2009 | A1 |
20090191627 | Fadeev et al. | Jul 2009 | A1 |
20090191632 | Fadeev et al. | Jul 2009 | A1 |
20090191634 | Martin et al. | Jul 2009 | A1 |
20090203065 | Gehman et al. | Aug 2009 | A1 |
20090203129 | Furcht et al. | Aug 2009 | A1 |
20090203130 | Furcht et al. | Aug 2009 | A1 |
20090214382 | Burgess et al. | Aug 2009 | A1 |
20090214481 | Muhs et al. | Aug 2009 | A1 |
20090214652 | Hunter et al. | Aug 2009 | A1 |
20090215022 | Page et al. | Aug 2009 | A1 |
20090227024 | Baker et al. | Sep 2009 | A1 |
20090227027 | Baker et al. | Sep 2009 | A1 |
20090233334 | Hildinger et al. | Sep 2009 | A1 |
20090233353 | Furcht et al. | Sep 2009 | A1 |
20090233354 | Furcht et al. | Sep 2009 | A1 |
20090258379 | Klein et al. | Oct 2009 | A1 |
20090269841 | Wojciechowski et al. | Oct 2009 | A1 |
20090270725 | Leimbach et al. | Oct 2009 | A1 |
20090280153 | Hunter et al. | Nov 2009 | A1 |
20090280565 | Jolicoeur et al. | Nov 2009 | A1 |
20090291890 | Madison et al. | Nov 2009 | A1 |
20100009409 | Hubbell et al. | Jan 2010 | A1 |
20100021954 | Deshayes et al. | Jan 2010 | A1 |
20100021990 | Edwards et al. | Jan 2010 | A1 |
20100028311 | Motlagh et al. | Feb 2010 | A1 |
20100042260 | Antwiler | Feb 2010 | A1 |
20100075410 | Desai et al. | Mar 2010 | A1 |
20100086481 | Baird et al. | Apr 2010 | A1 |
20100092536 | Hunter et al. | Apr 2010 | A1 |
20100093607 | Dickneite | Apr 2010 | A1 |
20100105138 | Dodd et al. | Apr 2010 | A1 |
20100111910 | Rakoczy | May 2010 | A1 |
20100129376 | Denhardt et al. | May 2010 | A1 |
20100129912 | Su et al. | May 2010 | A1 |
20100136091 | Moghe et al. | Jun 2010 | A1 |
20100144037 | Antwiler | Jun 2010 | A1 |
20100144634 | Zheng et al. | Jun 2010 | A1 |
20100183561 | Sakthivel et al. | Jul 2010 | A1 |
20100183585 | Van Zant et al. | Jul 2010 | A1 |
20100203020 | Ghosh | Aug 2010 | A1 |
20100230203 | Karayianni | Sep 2010 | A1 |
20100248366 | Fadeev et al. | Sep 2010 | A1 |
20100278933 | Sayeski et al. | Nov 2010 | A1 |
20100285453 | Goodrich | Nov 2010 | A1 |
20100285590 | Verfaillie et al. | Nov 2010 | A1 |
20100291180 | Uhrich | Nov 2010 | A1 |
20100291181 | Uhrich et al. | Nov 2010 | A1 |
20100297234 | Sugino et al. | Nov 2010 | A1 |
20100304427 | Faris et al. | Dec 2010 | A1 |
20100304482 | Deshayes et al. | Dec 2010 | A1 |
20100310524 | Bechor et al. | Dec 2010 | A1 |
20100316446 | Runyon | Dec 2010 | A1 |
20110085746 | Wong et al. | Apr 2011 | A1 |
20110111498 | Oh et al. | May 2011 | A1 |
20110129447 | Meretzki et al. | Jun 2011 | A1 |
20110129486 | Meiron | Jun 2011 | A1 |
20110143433 | Oh et al. | Jun 2011 | A1 |
20110159584 | Gibbons et al. | Jun 2011 | A1 |
20110171182 | Abelman | Jul 2011 | A1 |
20110171659 | Furcht et al. | Jul 2011 | A1 |
20110177595 | Furcht et al. | Jul 2011 | A1 |
20110212493 | Hirschel et al. | Sep 2011 | A1 |
20110256108 | Meiron et al. | Oct 2011 | A1 |
20110256160 | Meiron et al. | Oct 2011 | A1 |
20110293583 | Aberman | Dec 2011 | A1 |
20120028352 | Oh et al. | Feb 2012 | A1 |
20120051976 | Lu et al. | Mar 2012 | A1 |
20120058554 | Deshayes et al. | Mar 2012 | A1 |
20120064047 | Verfaillie et al. | Mar 2012 | A1 |
20120064583 | Edwards et al. | Mar 2012 | A1 |
20120086657 | Stanton, IV et al. | Apr 2012 | A1 |
20120118919 | Cianciolo | May 2012 | A1 |
20120122220 | Merchav et al. | May 2012 | A1 |
20120135043 | Maziarz et al. | May 2012 | A1 |
20120145580 | Paruit et al. | Jun 2012 | A1 |
20120156779 | Anneren et al. | Jun 2012 | A1 |
20120178885 | Kohn et al. | Jul 2012 | A1 |
20120189713 | Kohn et al. | Jul 2012 | A1 |
20120208039 | Barbaroux et al. | Aug 2012 | A1 |
20120219531 | Oh et al. | Aug 2012 | A1 |
20120219737 | Sugino et al. | Aug 2012 | A1 |
20120226013 | Kohn et al. | Sep 2012 | A1 |
20120231519 | Bushman et al. | Sep 2012 | A1 |
20120237557 | Lewitus et al. | Sep 2012 | A1 |
20120295352 | Antwiler | Nov 2012 | A1 |
20120308531 | Pinxteren et al. | Dec 2012 | A1 |
20120315696 | Luitjens et al. | Dec 2012 | A1 |
20130004465 | Aberman | Jan 2013 | A1 |
20130039892 | Aberman | Feb 2013 | A1 |
20130058907 | Wojciechowski et al. | Mar 2013 | A1 |
20130059383 | Dijkhuizen Borgart et al. | Mar 2013 | A1 |
20130101561 | Sabaawy | Apr 2013 | A1 |
20130143313 | Niazi | Jun 2013 | A1 |
20130157353 | Dijkhuizen Borgart et al. | Jun 2013 | A1 |
20130259843 | Duda et al. | Oct 2013 | A1 |
20130319575 | Mendyk | Dec 2013 | A1 |
20130323213 | Meiron et al. | Dec 2013 | A1 |
20130337558 | Meiron et al. | Dec 2013 | A1 |
20140004553 | Parker et al. | Jan 2014 | A1 |
20140017209 | Aberman et al. | Jan 2014 | A1 |
20140030805 | Kasuto et al. | Jan 2014 | A1 |
20140051162 | Nankervis | Feb 2014 | A1 |
20140051167 | Nankervis et al. | Feb 2014 | A1 |
20140112893 | Tom et al. | Apr 2014 | A1 |
20140186937 | Smith et al. | Jul 2014 | A1 |
20140193895 | Smith et al. | Jul 2014 | A1 |
20140193911 | Newby et al. | Jul 2014 | A1 |
20140242039 | Meiron et al. | Aug 2014 | A1 |
20140248244 | Danilkovitch et al. | Sep 2014 | A1 |
20140315300 | Oh et al. | Oct 2014 | A1 |
20140342448 | Nagels | Nov 2014 | A1 |
20150004693 | Danilkovitch et al. | Jan 2015 | A1 |
20150104431 | Pittenger et al. | Apr 2015 | A1 |
20150111252 | Hirschel et al. | Apr 2015 | A1 |
20150125138 | Karnieli et al. | May 2015 | A1 |
20150175950 | Hirschel et al. | Jun 2015 | A1 |
20150225685 | Hirschel et al. | Aug 2015 | A1 |
20150247122 | Tom et al. | Sep 2015 | A1 |
20150259749 | Santos et al. | Sep 2015 | A1 |
20160362650 | Wojciechowski et al. | Dec 2016 | A1 |
20160362652 | Page et al. | Dec 2016 | A1 |
20180010082 | Jacques et al. | Jan 2018 | A1 |
20180030398 | Castillo | Feb 2018 | A1 |
20180155668 | Hirschel et al. | Jun 2018 | A1 |
20190194628 | Rao et al. | Jun 2019 | A1 |
Number | Date | Country |
---|---|---|
1016332 | Aug 1977 | CA |
102406926 | Apr 2012 | CN |
3833925 | Sep 1989 | DE |
4007703 | Sep 1991 | DE |
10244859 | Apr 2004 | DE |
10327988 | Jul 2004 | DE |
102012200939 | Jul 2013 | DE |
0220650 | May 1987 | EP |
750938 | Jan 1997 | EP |
906415 | Apr 1999 | EP |
959980 | Dec 1999 | EP |
1007631 | Jun 2000 | EP |
1028737 | Aug 2000 | EP |
1028991 | Aug 2000 | EP |
1066052 | Jan 2001 | EP |
1066060 | Jan 2001 | EP |
1084230 | Mar 2001 | EP |
1147176 | Oct 2001 | EP |
1220611 | Jul 2002 | EP |
1223956 | Jul 2002 | EP |
1325953 | Jul 2003 | EP |
1437404 | Jul 2004 | EP |
1437406 | Jul 2004 | EP |
1447443 | Aug 2004 | EP |
1452594 | Sep 2004 | EP |
1062321 | Dec 2004 | EP |
1484080 | Dec 2004 | EP |
1498478 | Jan 2005 | EP |
1036057 | Oct 2005 | EP |
1605044 | Dec 2005 | EP |
1756262 | Feb 2007 | EP |
1771737 | Apr 2007 | EP |
1882030 | Jan 2008 | EP |
1908490 | Apr 2008 | EP |
1971679 | Sep 2008 | EP |
1991668 | Nov 2008 | EP |
2027247 | Feb 2009 | EP |
2200622 | Jun 2010 | EP |
2208782 | Jul 2010 | EP |
2264145 | Dec 2010 | EP |
2027247 | Jan 2011 | EP |
2303293 | Apr 2011 | EP |
2311938 | Apr 2011 | EP |
2331957 | Jun 2011 | EP |
2334310 | Jun 2011 | EP |
2334783 | Jun 2011 | EP |
2361968 | Aug 2011 | EP |
2366775 | Sep 2011 | EP |
2465922 | Jun 2012 | EP |
2481819 | Aug 2012 | EP |
2548951 | Jan 2013 | EP |
2561066 | Feb 2013 | EP |
2575831 | Apr 2013 | EP |
2591789 | May 2013 | EP |
2624845 | Aug 2013 | EP |
2626417 | Aug 2013 | EP |
2641606 | Sep 2013 | EP |
2689008 | Jan 2014 | EP |
2694639 | Feb 2014 | EP |
2697362 | Feb 2014 | EP |
2739720 | Jun 2014 | EP |
2807246 | Dec 2014 | EP |
1758985 | Jun 2015 | EP |
1414671 | Nov 1975 | GB |
2297980 | Aug 1996 | GB |
2360789 | Oct 2001 | GB |
3285 | May 2007 | HU |
H02245177 | Sep 1990 | JP |
2003052360 | Feb 2003 | JP |
2003510068 | Mar 2003 | JP |
2005278564 | Oct 2005 | JP |
2007000038 | Jan 2007 | JP |
2012-506257 | Mar 2012 | JP |
5548207 | Jul 2014 | JP |
2019-516029 | Jun 2019 | JP |
2019-525765 | Sep 2019 | JP |
101228026 | Jan 2013 | KR |
10-2015-0002762 | Jan 2015 | KR |
101504392 | Mar 2015 | KR |
101548790 | Aug 2015 | KR |
101553040 | Sep 2015 | KR |
10-2017-0076679 | Jul 2017 | KR |
10-2018-0027501 | Mar 2018 | KR |
102027596 | Oct 2019 | KR |
10-2020-0034790 | Mar 2020 | KR |
10-2020-0058433 | May 2020 | KR |
115206 | Apr 2003 | MY |
8602379 | Apr 1986 | WO |
8801643 | Mar 1988 | WO |
WO 8912676 | Dec 1989 | WO |
9002171 | Mar 1990 | WO |
WO-9013306 | Nov 1990 | WO |
WO-9105238 | Apr 1991 | WO |
9107485 | May 1991 | WO |
WO-9106641 | May 1991 | WO |
WO-9109194 | Jun 1991 | WO |
9210564 | Jun 1992 | WO |
WO-9425571 | Nov 1994 | WO |
9504813 | Feb 1995 | WO |
9521911 | Aug 1995 | WO |
WO 9524468 | Sep 1995 | WO |
WO-9629395 | Sep 1996 | WO |
WO-9639035 | Dec 1996 | WO |
WO-9705826 | Feb 1997 | WO |
9716527 | May 1997 | WO |
WO-9729792 | Aug 1997 | WO |
1997-040137 | Oct 1997 | WO |
WO-9739104 | Oct 1997 | WO |
WO-1997-040137 | Oct 1997 | WO |
WO 9822588 | May 1998 | WO |
WO-9831403 | Jul 1998 | WO |
9853046 | Nov 1998 | WO |
WO-9851317 | Nov 1998 | WO |
WO-9851785 | Nov 1998 | WO |
WO-9905180 | Feb 1999 | WO |
WO-9924391 | May 1999 | WO |
WO-9924490 | May 1999 | WO |
WO-9927167 | Jun 1999 | WO |
WO-9949015 | Sep 1999 | WO |
WO-0006704 | Feb 2000 | WO |
WO-0009018 | Feb 2000 | WO |
WO-0016420 | Mar 2000 | WO |
WO-0017326 | Mar 2000 | WO |
WO-0029002 | May 2000 | WO |
WO-0032225 | Jun 2000 | WO |
WO-0044058 | Jul 2000 | WO |
WO 0046354 | Aug 2000 | WO |
WO-0054651 | Sep 2000 | WO |
WO-0056405 | Sep 2000 | WO |
WO-0059933 | Oct 2000 | WO |
WO-0069449 | Nov 2000 | WO |
0075275 | Dec 2000 | WO |
WO-0075196 | Dec 2000 | WO |
WO-0077236 | Dec 2000 | WO |
WO-2001000783 | Jan 2001 | WO |
WO-2001011011 | Feb 2001 | WO |
WO-2001018174 | Mar 2001 | WO |
WO-2001021766 | Mar 2001 | WO |
0123520 | Apr 2001 | WO |
WO-2001025402 | Apr 2001 | WO |
WO-2001029189 | Apr 2001 | WO |
WO-0122810 | Apr 2001 | WO |
WO-2001034167 | May 2001 | WO |
WO-2001049851 | Jul 2001 | WO |
WO-2001054706 | Aug 2001 | WO |
2001-094541 | Dec 2001 | WO |
WO-2001-094541 | Dec 2001 | WO |
0228996 | Apr 2002 | WO |
WO-2002042422 | May 2002 | WO |
WO-2002057430 | Jul 2002 | WO |
WO-2002092794 | Nov 2002 | WO |
WO-2002101385 | Dec 2002 | WO |
WO-2003010303 | Feb 2003 | WO |
WO-2003014313 | Feb 2003 | WO |
WO-2003016916 | Feb 2003 | WO |
WO-2003023018 | Mar 2003 | WO |
WO-2003023019 | Mar 2003 | WO |
WO-2003025167 | Mar 2003 | WO |
WO-2003029402 | Apr 2003 | WO |
WO 03039459 | May 2003 | WO |
WO-2003040336 | May 2003 | WO |
WO-2003042405 | May 2003 | WO |
WO-2003046161 | Jun 2003 | WO |
WO-2003055989 | Jul 2003 | WO |
WO-2003061685 | Jul 2003 | WO |
WO-2003061686 | Aug 2003 | WO |
WO-2003068961 | Sep 2003 | WO |
WO-2003072064 | Sep 2003 | WO |
WO-2003078609 | Sep 2003 | WO |
WO-2003078967 | Oct 2003 | WO |
WO-2003080816 | Oct 2003 | WO |
WO-2003082145 | Oct 2003 | WO |
WO-2003085099 | Oct 2003 | WO |
WO-2003089631 | Oct 2003 | WO |
WO-2003091398 | Nov 2003 | WO |
WO-2003095631 | Nov 2003 | WO |
03105663 | Dec 2003 | WO |
WO-2004001697 | Dec 2003 | WO |
WO-2004012226 | Feb 2004 | WO |
WO-2004016779 | Feb 2004 | WO |
WO-2004018526 | Mar 2004 | WO |
WO-2004018655 | Mar 2004 | WO |
WO-2004026115 | Apr 2004 | WO |
WO-2004029231 | Apr 2004 | WO |
WO-2004042023 | May 2004 | WO |
WO-2004042033 | May 2004 | WO |
WO-2004042040 | May 2004 | WO |
WO-2004044127 | May 2004 | WO |
WO-2004044158 | May 2004 | WO |
WO-2004046304 | Jun 2004 | WO |
WO-2004050826 | Jun 2004 | WO |
WO-2004053096 | Jun 2004 | WO |
WO-2004055155 | Jul 2004 | WO |
WO-2004056186 | Jul 2004 | WO |
WO-2004065616 | Aug 2004 | WO |
WO-2004069172 | Aug 2004 | WO |
WO-2004070013 | Aug 2004 | WO |
WO-2004072264 | Aug 2004 | WO |
WO-2004073633 | Sep 2004 | WO |
WO-2004074464 | Sep 2004 | WO |
WO-2004076642 | Sep 2004 | WO |
WO-2004076653 | Sep 2004 | WO |
2004090112 | Oct 2004 | WO |
WO-2004087870 | Oct 2004 | WO |
WO-2004094588 | Nov 2004 | WO |
WO-2004096975 | Nov 2004 | WO |
WO-2004104166 | Dec 2004 | WO |
WO-2004106499 | Dec 2004 | WO |
WO-2004113513 | Dec 2004 | WO |
WO-2005001033 | Jan 2005 | WO |
WO-2005001081 | Jan 2005 | WO |
WO-2005003320 | Jan 2005 | WO |
WO-2005007799 | Jan 2005 | WO |
WO-2005010172 | Feb 2005 | WO |
WO-2005011524 | Feb 2005 | WO |
WO-2005012480 | Feb 2005 | WO |
WO-2005012510 | Feb 2005 | WO |
WO-2005012512 | Feb 2005 | WO |
WO-05014775 | Feb 2005 | WO |
WO-2005028433 | Mar 2005 | WO |
WO-05044972 | May 2005 | WO |
WO-2005056747 | Jun 2005 | WO |
WO-05051316 | Jun 2005 | WO |
WO-2005063303 | Jul 2005 | WO |
WO-2005075636 | Aug 2005 | WO |
2005087915 | Sep 2005 | WO |
WO 2005104755 | Nov 2005 | WO |
WO-2005107760 | Nov 2005 | WO |
WO-2006009291 | Jan 2006 | WO |
WO-2006032075 | Mar 2006 | WO |
WO-2006032092 | Mar 2006 | WO |
WO 2006037022 | Apr 2006 | WO |
WO-2006108229 | Oct 2006 | WO |
WO-2006113881 | Oct 2006 | WO |
WO-2006121445 | Nov 2006 | WO |
WO-06124021 | Nov 2006 | WO |
WO-06129312 | Dec 2006 | WO |
WO 2007038572 | Apr 2007 | WO |
WO 2007059473 | May 2007 | WO |
WO-2007115367 | Oct 2007 | WO |
WO-2007115368 | Oct 2007 | WO |
WO 2007117765 | Oct 2007 | WO |
2007136821 | Nov 2007 | WO |
2007139742 | Dec 2007 | WO |
2007139746 | Dec 2007 | WO |
2007139747 | Dec 2007 | WO |
2007139748 | Dec 2007 | WO |
WO-2008006168 | Jan 2008 | WO |
WO-2008011664 | Jan 2008 | WO |
WO-2008017128 | Feb 2008 | WO |
WO-2008028241 | Mar 2008 | WO |
WO-08040812 | Apr 2008 | WO |
WO 2008073635 | Jun 2008 | WO |
2008109674 | Sep 2008 | WO |
WO-2008116261 | Oct 2008 | WO |
WO-2008149129 | Dec 2008 | WO |
2009034186 | Mar 2009 | WO |
WO-2009026635 | Mar 2009 | WO |
WO-09058146 | May 2009 | WO |
WO-09080054 | Jul 2009 | WO |
WO-09081408 | Jul 2009 | WO |
WO-2009140452 | Nov 2009 | WO |
WO-09132457 | Nov 2009 | WO |
WO-2009144720 | Dec 2009 | WO |
WO-10005527 | Jan 2010 | WO |
WO-2010019886 | Feb 2010 | WO |
WO-10014253 | Feb 2010 | WO |
WO-10019997 | Feb 2010 | WO |
WO-2010026573 | Mar 2010 | WO |
WO-2010026574 | Mar 2010 | WO |
WO-2010026575 | Mar 2010 | WO |
WO 2010036760 | Apr 2010 | WO |
WO-2010036760 | Apr 2010 | WO |
WO-2010059487 | May 2010 | WO |
WO-10061377 | Jun 2010 | WO |
WO-10068710 | Jun 2010 | WO |
WO-10071826 | Jun 2010 | WO |
WO-10083385 | Jul 2010 | WO |
WO-10111255 | Sep 2010 | WO |
WO-10119036 | Oct 2010 | WO |
WO-10123594 | Oct 2010 | WO |
WO-2011025445 | Mar 2011 | WO |
WO 2011098592 | Aug 2011 | WO |
WO 2011130617 | Oct 2011 | WO |
WO-2011132087 | Oct 2011 | WO |
WO-2011147967 | Dec 2011 | WO |
WO-2012072924 | Jun 2012 | WO |
WO-2012127320 | Sep 2012 | WO |
WO-2012138968 | Oct 2012 | WO |
WO-2012140519 | Oct 2012 | WO |
2012171026 | Dec 2012 | WO |
2012171030 | Dec 2012 | WO |
WO-2012171026 | Dec 2012 | WO |
WO-2012171030 | Dec 2012 | WO |
WO 2013085682 | Jun 2013 | WO |
WO-2013110651 | Aug 2013 | WO |
WO-2014037862 | Mar 2014 | WO |
WO-2014037863 | Mar 2014 | WO |
WO-2014068508 | May 2014 | WO |
WO-2014128306 | Aug 2014 | WO |
WO-2014128634 | Aug 2014 | WO |
WO-2014131846 | Sep 2014 | WO |
WO-2014141111 | Sep 2014 | WO |
WO-2015004609 | Jan 2015 | WO |
WO 2015059714 | Apr 2015 | WO |
2015073913 | May 2015 | WO |
WO 2015069943 | May 2015 | WO |
WO 2015118148 | Aug 2015 | WO |
WO 2015118149 | Aug 2015 | WO |
WO-2015131143 | Sep 2015 | WO |
WO 2016130940 | Aug 2016 | WO |
WO 2017072201 | May 2017 | WO |
WO 2017158611 | Sep 2017 | WO |
WO 2017207822 | Dec 2017 | WO |
WO 2018183426 | Oct 2018 | WO |
WO 2019155032 | Aug 2019 | WO |
WO 2019238919 | Dec 2019 | WO |
WO 2020020569 | Jan 2020 | WO |
WO 2020079274 | Apr 2020 | WO |
Entry |
---|
Communication pursuant to Article 94(3) EPC, European Patent Application No. 15718657.8, dated Jul. 21, 2017. |
Communication pursuant to Article 94(3) EPC, European Patent Application No. 15718657.8, dated Mar. 22, 2018. |
First Office Action, Chinese Patent Application No. 201580020869.5, dated Apr. 27, 2018 (English language translation included). |
International Search Report and Written Opinion, PCT/US2015/022541, dated Jul. 17, 2015. |
Rejection of the Application, Japanese Patent Application No. 2016-558755, dated Feb. 5, 2019 (English language translation included). |
Rejection of the Application, Japanese Patent Application No. 2016-558755, dated Jan. 28, 2020 (English language translation included). |
Second Office Action, Chinese Patent Application No. 201580020869.5, dated May 21, 2019 (English language translation included). |
Third Office Action, Chinese Patent Application No. 201580020869.5, dated Nov. 6, 2019 (English language translation included). |
Chang et al., “Membrane Bioreactors: Present and Prospects”, Advances in Biochemical Engineering, 1991, pp. 27-64, vol. 44. |
Chang, Ho Nam, “Membrane Bioreactors: Engineering Aspects”, Biotech. Adv., 1987, pp. 129-145, vol. 5. |
Edgington, Stephen M., “New Horizons for Stem-Cell Bioreactors”, Biotechnology, Oct. 1992, pp. 1099-1106, vol. 10. |
Gastens et al., “Good Manufacturing Practice-Compliant Expansion of Marrow-Derived Stem and Progenitor Cells for Cell Therapy”, Cell Transplantation, 2007, pp. 685-696, vol. 16. |
Gramer et al., “Screening Tool for Hollow-Fiber Bioreactor Process Development”, Biotechnol. Prog., 1998, pp. 203-209, vol. 14. |
Hirschel et al., “An Automated Hollow Fiber System for the Large Scale Manufacture of Mammalian Cell Secreted Product”, Large Scale Cell Culture Technology, ed. Bjorn K. Lydersen, 1987, pp. 113-144, Hanser Publishers. |
Infanger et al., “Simulated weightlessness changes the cytoskeleton and extracellular matrix proteins in papillary thyroid carcinoma cells”, Cell and Tissue Research, 2006, 324(2): 267-277. |
Jones et al., “Genetic stability of bone marrow-derived human mesenchymal stromal cells in the Quantum System”, Cytotherapy, 2013; 15: 1323-1339. |
Liu et al., “Ex vivo Expansion of Hematopoietic Stem Cells Derived from Umbilical Cord Blood in Rotating Wall Vessel”, Journal of Biotechnology, 2006, 124:592-601. |
Nankervis et al., “Shear Stress Conditions in the Quantum Cell Expansion System”, Poster Session—TERMIS AM Annual Conference 2013, Nov. 12, 2013. |
Nguyen et al., “QUANTUM® Cell Expansion System: Automated Expansion of Human Mesenchymal Stem Cells from Precultured Cells Using the Quantum Cell Expansion System”, Terumo BCT, Inc., 2012. |
Nielsen, Lars Keld, “Bioreactors for Hematopoietic Cell Culture”, Annu. Rev. Biomed. Eng., 1999, vol. 1, pp. 129-152. |
Office Action, Chinese Patent Application No. 201580020869.5, dated Apr. 27, 2018. (English language translation included). |
Office Action, Chinese Patent Application No. 201580020869.5, dated May 21, 2019. (English language translation included). |
Official Communication, European Patent Application No. 15718657.8, dated Jul. 21, 2017. |
Official Communication, European Patent Application No. 15718657.8, dated Mar. 22, 2018. |
Pörtner et al., “An Overview on Bioreactor Design, Prototyping and Process Control for Reproducible Three-Dimensional Tissue Culture”, Drug Testing in Vitro: Breakthroughs and Trends in Cell Culture Technology, ed. Uwe Marx and Volker Sandig, 2007, Wiley-VCH, pp. 53-78. |
The Extended European Search Report, European Patent Application No. 19202519.5, dated Nov. 15, 2019. |
Zhao et al., “Perfusion Bioreactor System for Human Mesenchymal Stem Cell Tissue Engineering: Dynamic Cell Seeding and Construct Development”, Biotechnology and Bioengineering, Aug. 20, 2005, vol. 91, No. 4, pp. 482-493. |
“The Effect of Rocking Rate and Angle on T Cell Cultures Grown in XuriTM Cell Expansion Systems,” GE Healthcare UK Limited, Cell therapy bioreactor systems, Application note 29-1166-55 AA, Aug. 2014, www.gelifesciences.com/xuri. |
Abumiya et al., “Shear Stress Induces Expression of Vascular Endothelial Growth Factor Receptor Flk-1/KDR Through the CT-Rich Sp1 Binding Site,” Ateriosclerosis, Thrombosis, and Vascular Biology, vol. 22, Jun. 2002, pp. 907-913. |
Akiyama et al., “Ultrathin Poly(N-isopropylacrylamide) Grafted Layer on Polystyrene Surfaces for Cell Adhesion/Detachment Control,” Langmuir, vol. 20, No. 13, May 26, 2004, pp. 5506-5511. |
Akram et al., “Mesenchymal Stem Cells Promote Alveolar Epithelial Cell Wound Repair in vitro through Distinct Migratory and Paracrine Mechanisms,” Respiratory Research, vol. 14, No. 9, 2013, pp. 1-16. |
Alenazi et al., “Modified Polyether-sulfone Membrane: a Mini Review,” Designed Monomers And Polymers, vol. 20, No. 1, 2017, pp. 532-546. |
Anamelechi et al., “Streptavidin Binding and Endothelial Cell Adhesion to Biotinylated Fibronectin,” Langmuir, vol. 23, No. 25, Dec. 4, 2007, pp. 12583-12588. |
Azar et al., “Heart Rates of Male and Female Sprague-Dawley and Spontaneously Hypertensive Rats Housed Singly or in Groups,” Journal of the American Association for Laboratory Animal Science, vol. 50, No. 2, Mar. 2011, pp. 175-184. |
Baecher-Allan et al., “CD4+CD25high Regulatory Cells in Human Peripheral Blood,” The Journal of Immunology, vol. 167, 2001, pp. 1245-1253. |
Bai et al., “Expansion of Primitive Human Hematopoietic Stem Cells by Culture in a Zwitterionic Hydrogel,” Nature Medicine, vol. 25, Oct. 2019, pp. 1566-1575. |
Barker et al., “CD34+ Cell Content of 126 341 Cord Blood Units in the US Inventory: Implications for Transplantation and Banking,” Blood Advances, vol. 3, No. 8, Apr. 23, 2019, pp. 1267-1271. |
Boitano et al., “Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells,” Science, vol. 329, No. 5997, published Sep. 10, 2010. corrected May 6, 2011, pp. 1345-1348. |
Brunstein et al., “Infusion of ex vivo Expanded T Regulatory Cells in Adults Transplanted with Umbilical Cord Blood: Safety Profile and Detection Kinetics,” Blood, vol. 117, No. 3, Jan. 20, 2011, pp. 1061-1070. |
Bryce et al., “In vitro Micronucleus Assay Scored by Flow Cytometry Provides a Comprehensive Evaluation of Cytogenetic Damage and Cytotoxicity,” Mutation Research, vol. 630, Mar. 19, 2007, pp. 78-91. |
Bryce et al., “Interlaboratory Evaluation of a Flow Cytometric, High Content in vitro Micronucleus Assay,” Mutation Research, vol. 650, Jan. 7, 2008, pp. 181-195. |
Camacho Villa et al., “CD133+CD34+ and CD133+CD38+ Blood Progenitor Cells as Predictors of Platelet Engraftment in Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation,” Transfusion and Apheresis Science, vol. 46, 2012, pp. 239-244. |
Cano et al., “Immobilization of endo-1,4-β-xylanase on Polysulfone Acrylate Membranes: Synthesis and Characterization,” Journal of Membrane Science, vol. 280, Feb. 28, 2006, pp. 383-388. |
Carvell et al., “Monitoring Live Biomass in Disposable Bioreactors,” BioProcess International, vol. 14, No. 3, Mar. 2016, pp. 40-48. |
Carvell et al., “On-line Measurements and Control of Viable Cell Density in Cell Culture Manufacturing Processes Using Radio Frequency Impedance,” Cytotechnology, 2006, vol. 50, pp. 35-48. |
Cuchiara et al., “Covalent immobilization of SCF and SDF1α for in vitro Culture of Hematopoietic Progenitor Cells,” Acta Biomaterials, vol. 9, No. 12, Dec. 2013, pp. 9258-9269. |
Da Silva et al., “Smart Thermoresponsive Coatings and Surfaces for Tissue Engineering: Switching Cell-Material Boundaries,” Trends in Biotechnology, vol. 15, No. 12, 2007, pp. 577-583. |
Garlie et al., “T Cells Coactivated with Immobilized Anti-CD3 and Anti-CD28 as Potential Immunotherapy for Cancer,” Journal of immunotherapy, vol. 22, No. 4, 1999, pp. 336-345. |
Gloeckner et al., “New Miniaturized Hollow-Fiber Bioreactor for in Vivo Like Cell Culture, Cell Expansion, and Production of Cell-Derived Products,” Biotechnology Progress, vol. 17, Aug. 21, 2001, pp. 828-831. |
Hao et al., “A Functional Comparison of CD34+ CD38-Cells in Cord Blood and Bone Marrow,” Blood, vol. 86, No. 10, Nov. 15, 1995, pp. 3745-3753. |
Harimoto et al., “Novel Approach for Achieving Double-Layered Cell Sheets Co-Culture: Overlaying Endothelial Cell Sheets onto Monolayer Hepatocytes Utilizing Temperature-Responsive Culture Dishes,” Journal of Biomedical Material Research, vol. 62, 2002, pp. 464-470. |
Högstedt et al., “Frequency and Size Distribution of Micronuclei in Lymphocytes Stimulated with Phytohemagglutinin and Pokeweed Mitogen in Workers Exposed to Piperazine,” Hereditas, vol. 109, 1998, pp. 139-142. |
Horwitz et al., “Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo with Nicotinamide,” Journal of Clinical Oncology, vol. 37, No. 5, Dec. 4, 2018, pp. 367-376. |
Itkin et al., “SDF-1 Keeps HSC Quiescent at Home,” Blood, vol. 117, No. 2, Jan. 13, 2011, pp. 373-374. |
Jang et al., “Syndecan-4 Proteoliposomes Enhance Fibroblast Growth Factor-2 (FGF-2)-Induced Proliferation, Migration, and Neovascularization of Ischemic Muscle,” PNAS, vol. 109, No. 5, Jan. 31, 2012, pp. 1679-1684. |
Johansson et al., “Pancreatic Islet Survival and Engraftment Is Promoted by Culture on Functionalized Spider Silk Matrices,” PLoS ONE, Jun. 19, 2015, pp. 1-21. |
Klein et al., “Affinity Membranes Prepared from Hydrophilic Coatings on Microporous Polysulfone Hollow Fibers,” Journal of Membrane Science, vol. 90, 1994, pp. 69-80. |
Koestenbauer et al., “Protocols for Hematopoietic Stem Cell Expansion from Umbilical Cord Blood,” Cell Transplantation, vol. 18, May 6, 2009, pp. 1059-1068. |
Koller et al., “Clinical-scale Human Umbilical Cord Blood Cell Expansion in a Novel Automated Perfusion Culture System,” Bone Marrow Transplantation, vol. 21, 1998, pp. 653-663. |
Lang et al., “Generation of Hematopoietic Humanized Mice in the Newborn BALB/C-Rag2null II2rγnull Mouse Model: A Multivariable Optimization Approach,” Clinical Immunology, vol. 140, Apr. 14, 2011, pp. 102-116. |
Lataillade et al., “Chemokine SDF-1 Enhances Circulating CD341 Cell Proliferation in Synergy with Cytokines: Possible Role in Progenitor Survival,” Blood, vol. 95, No. 3, Feb. 1, 2000, pp. 756-768. |
Lee et al., “Long-Term Outcomes Following CD19 CAR T Cell Therapy for B-ALL Are Superior in Patients Receiving a Fludarabine/Cyclophosphamide Preparative Regimen and Post-CAR Hematopoietic Stem Cell Transplantation,” Blood, vol. 128, No. 22, Dec. 2, 2016, Ab. 218. |
Li et al., “Heparin-induced Conformation Changes of Fibronectin within the Extracellular Matrix Promote hMSC Osteogenic Differentiation,” Biomaterials Science, vol. 3, 2015, pp. 73-84. |
Malin et al., “Noninvasive Prediction of Glucose by Near-Infrared Diffuse Reflectance Spectroscopy,” Clinical Chemistry, vol. 45, No. 9, 1999, pp. 1651-1658. |
Marek-Trzonkowska et al., “Administration of CD4+ CD25high CD127-Regulatory T Cells Preserves β-Cell Function in Type 1 Diabetes in Children,” Diabetes Care, vol. 35, No. 9, Sep. 2012, pp. 1817-1820. |
Murugappan et al., “Human Hematopoietic Progenitor Cells Grow Faster under Rotational Laminar Flows,” Biotechnology Progress—Cell Culture & Tissue Engineering, Online, Apr. 22, 2010. |
Nelson et al., “Emergent Patterns of Growth Controlled by Multicellular Form and Mechanics,” PNAS, vol. 102, No. 33, Aug. 16, 2005, pp. 11594-11599. |
Nicolette et al., “In Vitro Micronucleus Screening of Pharmaceutical Candidates by Flow Cytometry in Chinese Hamster V79 Cells,” Environmental and Molecular Mutagenesis, vol. 52, Oct. 20, 2010, pp. 355-362. |
Nugent et al., “Adventitial Endothelial Implants Reduce Matrix Metalloproteinase-2 Expression and Increase Luminal Diameter in Porcine Arteriovenous Grafts,” Journal of Vascular Surgery, vol. 46, No. 3, Sep. 2007, pp. 548-556.e2. |
Okano et al., “Mechanism of Cell Detachment from Temperature-Modulated, Hydrophilic-Hydrophobic Polymer Surfaces,” Biomaterials, vol. 16, No. 4, 1995, pp. 297-303. |
Putnam et al., “Expansion of Human Regulatory T-Cells from Patients with Type 1 Diabetes,” Diabetes, vol. 58, Mar. 2009, pp. 652-662. |
Rahmahwati et al., “The Synthesis of Polyethersuifone (PES) Derivatives for the Immobilization of Lipase Enzyme,” Key Engineering Materials, vol. 811, Jul. 8, 2019, pp. 14-21. |
Rodrigues et al., “Stem Cell Cultivation in Bioreactors,” Biotechnology Advances, vol. 29, Jun. 25, 2011, pp. 815-829. |
Ronco et al., “Blood and Dialysate Flow Distributions in Hollow-Fiber Hemodialyzers Analyzed by Computerized Helical Scanning Technique,” Journal of the American Society of Nephrology, vol. 13, 2002, pp. S53-S61. |
Ryu et al., “Near-infrared Light Responsive Synthetic c-di-GMP Module for Optogenetic Applications,” ACS Synthetic Biology, vol. 3, Jan. 28, 2014, pp. 802-810. |
Shimizu et al., “Fabrication of Pulsatile Cardiac Tissue Grafts Using a Novel 3-Dimensional Cell Sheet Manipulation Technique and Temperature-Responsive Cell Culture Surfaces,” Circulation Research, vol. 90, Feb. 22, 2002, e40-e48, pp. 1-9. |
Smith et al., “Expansion of Neutrophil Precursors and Progenitors in Suspension Cultures of CD34+ Cells Enriched from Human Bone Marrow,” Experimental Hematology, vol. 21, 1993, pp. 870-877. |
Streltsova et al., “Recurrent Stimulation of Natural Killer Cell Clones with K562 Expressing Membrane-Bound Interleukin-21 Affects Their Phenotype, Interferon-γ Production, and Lifespan,” International Journal of Molecular Sciences, vol. 20, No. 443, 2019, pp. 1-18. |
Takezawa et al., “Cell Culture on a Thermo-responsive Polymer Surface,” Nature, Bio/Technology, vol. 8, Sep. 1990, pp. 854-856. |
Tiziani et al., “Metabolomic Profiling of Drug Response in Acute Myeloid Leukemia Cell lines,” PLoS ONE, vol. 4, Issue 1, Jan. 22, 2009, e4251. |
Ueda et al., “Interaction of Natural Killer Cells with Neutrophils Exerts a Significant Antitumor Immunity in Hematopoietic Stem Cell Transplantation Recipients,” Cancer Medicine, vol. 5, No. 1, 2016 pp. 49-60. |
Urbich et al., “Fluid Shear Stress-induced Transcriptional Activation of the Vascular Endothelial Growth Factor Receptor-2 Gene Requires Sp1-Dependent DNA Binding,” FEBS Letters, 535, 2003, pp. 87-93. |
Von Laer, “Loss of CD38 Antigen on CD34 CD38 Cells during Short-term Culture,” Leukemia, Correspondence, 1999 pp. 947-948. |
Wagner et al., “Phase I/II Trial of StemRegenin-1 Expanded Umbilical Cord Blood Hematopoietic Stem Cells Supports Testing as a Stand-alone Graft,” Cell Stem Cell, Jan. 7, 2016, vol. 18, pp. 144-155. |
Weaver et al., “An Analysis of Engraftment Kinetics as a Function of the CD34 Content of the Peripheral Blood Progenitor Cell Collections in 692 Patients after the Administration of Myeloblative Chemotherapy,” Blood, vol. 86, No. 10, Nov. 15, 1995, pp. 3691-3969. |
Yang et al., “Suspension Culture of Mammalian Cells Using Thermosensitive Microcarrier that Allows Cell Detachment without Proteolytic Enzyme Treatment,” Cell Transplantation, vol. 19, Aug. 18, 2010, pp. 1123-1132. |
Yi et al., “A Readily Modified Polyethersuifone with Amino-Substituted Groups: Its Amphiphilic Copolymer Synthesis and Membrane Application,” Polymer, vol. 53, Dec. 2, 2011, pp. 350-358. |
Zheng et al., “Differential Effects of Cyclic and Static Stretch on Coronary Microvascular Endothelial Cell Receptors and Vasculogenic/Angiogenic Responses,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 295, Aug. 2008, H794-H800. |
Afzali B, Edozie FC, Fazekasova H, Scotta C, Mitchell PJ, Canavan JB, Kordasti SY, Chana PS, Ellis R, Lord GM, John S, Hilton R, Lechler RI, Lombardi G. Comparison of regulatory T cells in hemodialysis patients and healthy controls: implications for cell therapy in transplantation. Clin J Am Soc Nephrol. 2013;8(8):1396-405. |
Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Fibroblasts and Their Transformations: The Connective-Tissue Cell Family. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26889. |
Almeida L, Lochner M, Berod L, Sparwasser T. Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 2016;28(5):514-524. |
Amy Putnam, Todd M. Brusko, Michael R. Lee, Weihong Liu, Gregory L. Szot, Taumoha Ghosh, Mark A. Atkinson, and Jeffrey A. Bluestone. Expansion of human regulatory T-Cells from patients with Type 1 Diabetes. Diabetes, 58: 652-662, 2009. |
Anurathapan et al., “Engineered T cells for cancer treatment,” Cytotherapy, vol. 16, pp. 713-733, 2014. |
Aronowski J, Samways E, Strong R, Rhoades HM, Grotta JC. An alternative method for the quantitation of neuronal damage after experimental middle cerebral artery occlusion in rats: Analysis of behavioral deficit. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1996;16:705-713. |
Arrigoni, Chiara, et al. “Rotating versus perfusion bioreactor for the culture of engineered vascular constructs based on hyaluronic acid.” Biotechnology and bioengineering 100.5 (2008): 988-997. |
Bai/Delaney (Nohla Therapeutics) showed that expanding Cord Blood-derived CD34+CD38− CD45RA− HSPCs in a biodegradable zwitterionic hydrogel with a rNotch ligand cocktail for 24 days mitigated HSPC differentiation and promoted self-renewal of lymphoid and myeloid cell phenotypes in an NSG mouse model (Nature Medicine, 2019). |
Ballas CB, Zielske SP, Gerson SL (2002) Adult bone marrow stem cells for cell and gene therapies: implications for greater use. J Cell Biochem Suppl 38: 20-28. |
Ballke C, Gran E, Baekkevold ES, Jahnsen FL. Characterization of Regulatory T-Cell Markers in CD4+ T Cells of the Upper Airway Mucosa. PLoS One. 2016;11(2):e0148826. |
Baraniak PR, McDevitt TC (2010) Stem cell paracrine actions and tissue regeneration. Regen Med 5(1): 121-143. |
Barckhausen C, Rice B, Baila S, et al. (2016) GMP-Compliant Expansion of Clinical-Grade Human Mesenchymal Stromal/Stem Cells Using a Closed Hollow Fiber Bioreactor. Methods Mol Biol 1416: 389-412. |
Bazarian JJ, Cernak I, Noble-Haeusslein L, Potolicchio S, Temkin N. Long-term neurologic outcomes after traumatic brain injury. The Journal of head trauma rehabilitation. 2009;24:439- 451. |
Bending D, Pesenacker AM, Ursu S, Wu Q, Lom H, Thirugnanabalan B, Wedderburn LR. Hypomethylation at the regulatory T cell-specific demethylated region in CD25hi T cells is decoupled from FOXP3 expression at the inflamed site in childhood arthritis. J Immunol. 2014;193(6):2699-708. |
Berendse M, Grounds MD, Lloyd CM (2003) Myoblast structure affects subsequent skeletal myotube morphology and sarcomere assembly. Exp Cell Res 291(2): 435-450. |
Bernard, A., Payton, Mar. 1995. “Fermentation and Growth of Escherichia coli for Optimal Protein Production”, John Wiley & Sons. Current Protocols in Protein Science (1995) 5.3.1-5.3.18. |
Berney SM, Schaan T, Wolf RE, van der Heyde H, Atkinson TP. CD2 (OKT11) augments CD3-mediated intracellular signaling events in human T lymphocytes. J Investig Med. 2000;48(2):102-9. |
Bioheart Clinical Trial Clinica 1302 Apr. 18, 2008. |
Biomolecular and Cellular Interactions with the Hollow Fiber Membrane Currently Used in the Quantum® Cell Expansion System. 12th NJ Symposium on Biomaterials Science, Oct. 6- 7, 2014, New Brunswick, NJ. |
Blache C, Chauvin JM, Marie-Cardine A, Contentin N, Pommier P, Dedreux I, Francois S, Jacquot S, Bastit D, Boyer O. Reduced frequency of regulatory T cells in peripheral blood stem cell compared to bone marrow transplantations. Biol Blood Marrow Transplant. 2010;16(3):430-4. |
Bluestone et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Science Translational Medicine 7(315):1-34, 2015. |
Bluestone JA, Tang Q. Treg cells-the next frontier of cell therapy. Science. 2018;362(6411):154-155. |
Bluestone, Jeffrey A., et al. “Type 1 diabetes immunotherapy using polyclonal regulatory T cells.” Science translational medicine 7.315 (2015): 315ra189-315ra189. |
Blum S, Moore AN, Adams F, Dash PK. A mitogen-activated protein kinase cascade in the ca1/ca2 subfield of the dorsal hippocampus is essential for long-term spatial memory. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999;19:3535-3544. |
Bojun Li et al. Heparin-induced conformation changes of fibronectin within the extracellular matrix promote hMSC osteogenic differentiation. Biomaterials Science 3: 73-84, 2015. |
Boquest AC, Shahdadfar A, Brinchmann JE, Collas P. Isolation of Stromal Stem Cells from Human Adipose Tissue. Methods Mol Biol. 2006;325:35-46. doi: 10.1385/1-59745-005-7:35. PMID: 16761717. |
Borden, M. and Longo, M., “Dissolution Behavior of Lipid Monolayer-Coated, Air-Filled Microbubbles: Effect of Lipid Hydrophobic Chain Length,” Langmuir, vol. 18, pp. 9225-9233, 2002. |
Bourke, Sharon L., and Joachim Kohn. “Polymers derived from the amino acid L-tyrosine: polycarbonates, polyarylates and copolymers with poly (ethylene glycol).” Advanced drug delivery reviews 55.4 (2003): 447-466. |
Brand, K. and Hermfisse, U., “Aerobic Glycolysis by Proliferating Cells: a Protective Strategy against Reactive Oxygen Species,” The FASEB Journal, vol. 11, pp. 388-395, Apr. 1997. |
Brentjens et al., “CD19-Targeted T Cells Rapidly Induce Molecular Remission in Adults with Chemotherapy-Refractory Acute Lympohblastic Leukemia,” Science Translational Medicine, vol. 5, Issue 177, pp. 1-9, Mar. 20, 2013. |
Brentjens et al., “Safety and Persistance of Adoptively Transferred Autologous CD19-Target T Cells in Patients with Relapsed or Chemotherapy Refractory B-Cell Leukemias,” Blood, vol. 118, No. 18, pp. 4817-4828, Nov. 3, 2011. |
Carswell, K. and Papoutsakis, E. “Culture of Human T Cells in Stirred Bioreactors for Cellular Immunotherapy Applications: Shear, Proliferation, and the IL-2 Receptor,” Biotechnology and Bioengineering, vol. 68, No. 3, pp. 329-338, May 5, 2000. |
Chapman NM, Chi H. mTOR signaling, Tregs and immune modulation. Immunotherapy. 2014;6(12):1295-311. |
Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, Jack RS, Wunderlich FT, Bruning JC, Muller W, Rudensky AY. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011;34(4):566-78. |
Chen, C. and Broden, M., “The Role of Poly(theylene glycol) Brush Architecture in Complement Activation on Targeted Microbubble Surfaces,” Biomaterials, vol. 32, No. 27, pp. 6579-6587, Jun. 17, 2011. |
Choi W, Kwon SJ, Jin HJ, et al. (2017) Optimization of culture conditions for rapid clinical-scale expansion of human umbilical cord blood-derived mesenchymal stem cells. Clin Transl Med 6(1): 38. |
Chullikana A, Majumdar AS, Gottipamula S, et al. (2015) Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy 17(3): 250-261. |
Claudio G. Brunstein, Jeffrey S. Miller, Qing Cao, Daivd H. McKenna, Keli L. Hippen, Julie Curtsinger, Todd Defor, Bruce L. Levine, Carl H. June, Pablo Rubinstein, Philip B. McGlave, Bruce R. Blazar, and John E. Wagner. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood, 117(3): 1061-1070, 2010. |
Coeshott C, Vang B, Jones M, Nankervis B. Large-scale expansion and characterization of CD3(+) T-cells in the Quantum((R)) Cell Expansion System. J Transl Med. 2019;17(1):258. |
Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F. Regulatory T cells and intestinal homeostasis. Immunol Rev. 2005;204:184-94. |
Coquillard C. mTOR Signaling in Regulatory T cell Differentiation and Expansion. SOJ Immunology. 2015;3(1):1-10. |
Creed JA, DiLeonardi AM, Fox DP, Tessler AR, Raghupathi R. Concussive brain trauma in the mouse results in acute cognitive deficits and sustained impairment of axonal function. Journal of neurotrauma. 2011;28:547-563. |
Dash PK, Hochner B, Kandel ER. Injection of the camp-responsive element into the nucleus of aplysia sensory neurons blocks long-term facilitation. Nature. 1990;345:718-721. |
Dash PK, Johnson D, Clark J, Orsi SA, Zhang M, Zhao J, Grill RJ, Moore AN, Pati S. Involvement of the glycogen synthase kinase-3 signaling pathway in tbi pathology and neurocognitive outcome. PloS one. 2011;6:e24648. |
Dash PK, Mach SA, Blum S, Moore AN. Intrahippocampal wortmannin infusion enhances long-term spatial and contextual memories. Learn Mem. 2002;9:167-177. |
Dash PK, Orsi SA, Zhang M, Grill RJ, Pati S, Zhao J, Moore AN. Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PloS one. 2010;5:e11383. |
Dash PK, Zhao J, Orsi SA, Zhang M, Moore AN. Sulforaphane improves cognitive function administered following traumatic brain injury. Neuroscience letters. 2009;460:103-107. |
Davila et al., “Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B cell Acute Lymphoblastic Leukemia,” Science Translational Medicine, vol. 6, No. 224, pp. 1-10, Feb. 19, 2014. |
Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and ve-cadherin in the control of vascular permeability. Journal of cell science. 2008;121:2115-2122. |
Dejana E, Spagnuolo R, Bazzoni G. Interendothelial junctions and their role in the control of angiogenesis, vascular permeability and leukocyte transmigration. Thrombosis and haemostasis. 2001;86:308-315. |
Dejana E, Tournier-Lasserve E, Weinstein BM. The control of vascular integrity by endothelial cell junctions: Molecular basis and pathological implications. Developmental cell. 2009;16:209- 221. |
Del Pino A, Ligero G, Lopez MB, et al. (2015) Morphology, cell viability, karyotype, expression of surface markers and plasticity of three primary cell line cultures before and after the cryostorage in LN2 and GN2. Cryobiology 70(1): 1-8. |
Delaney, Colleen, et al. “Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution.” Nature medicine 16.2 (2010): 232-236. |
Ding, Zhongli, Guohua Chen, and Allan S. Hoffman. “Synthesis and purification of thermally Sensitive oligomer? enzyme conjugates of poly (N-isopropylacrylamide)? trypsin.” Bioconjugate chemistry 7.1 (1996): 121-125. |
Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL. A controlled cortical impact model of traumatic brain injury in the rat. Journal of neuroscience methods. 1991;39:253-262. |
Dominici M, Le Blanc K, Mueller I, et al. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4): 315-317. |
Durrani S, Konoplyannikov M, Ashraf M, Haider KH (2010) Skeletal myoblasts for cardiac repair. Regen Med 5(6): 919-932. |
Esensten JH, Muller YD, Bluestone JA, Tang Q. Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier. J Allergy Clin Immunol. 2018;142(6):1710-1718. |
Fakin R, Hamacher J, Gugger M, Gazdhar A, Moser H, Schmid RA. Prolonged amelioration of acute lung allograft rejection by sequential overexpression of human interleukin-10 and hepatocyte growth factor in rats. Exp Lung Res. 2011;37(9):555-62. |
Fedorov et al., “PD-1- and CTLA-4-Based Inhibitory Chimeric Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses,” Science Translational Medicine, vol. 5, No. 215, pp. 1-12, Dec. 11, 2013. |
Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Next-generation regulatory T cell therapy. Nat Rev Drug Discov. 2019;18(10):749-769. |
Fischbach, Michael A., Jeffrey A. Bluestone, and Wendell A. Lim. “Cell-based therapeutics: the next pillar of medicine.” Science translational medicine 5.179 (2013): 179ps7-179ps7. |
Fisk, Nicholas M., et al. “Can routine commercial cord blood banking be scientifically and ethically justified ?. ” PLoS medicine 2.2 (2005): e44. |
Forbes Jun. 23, 2014 article “Will this man cure cancer?”. |
Fowler DH. Rapamycin-resistant effector T-cell therapy. Immunol Rev. 2014;257(1):210-25. |
Fraser H, Safinia N, Grageda N, Thirkell S, Lowe K, Fry LJ, Scotta C, Hope A, Fisher C, Hilton R, Game D, Harden P, Bushell A, Wood K, Lechler RI, Lombardi G. A Rapamycin-Based GMP-Compatible Process for the Isolation and Expansion of Regulatory T Cells for Clinical Trials. Mol Ther Methods Clin Dev. 2018;8:198-209. |
Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16(6):769-77. |
Fuchs A, Gliwinski M, Grageda N, Spiering R, Abbas AK, Appel S, Bacchetta R, Battaglia M, Berglund D, Blazar B, Bluestone JA, Bornhauser M, Ten Brinke A, Brusko TM, Cools N, Cuturi MC, Geissler E, Giannoukakis N, Golab K, Hafler DA, van Ham SM, Hester J et al. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization. Front Immunol. 2017;8:1844. |
G0211: Study for Gamma Irradiation of Bioreactor Membranes, undated, author unknown, 3 pages. |
Galgani M, De Rosa V, La Cava A, Matarese G. Role of Metabolism in the Immunobiology of Regulatory T Cells. J Immunol. 2016;197(7):2567-75. |
Gedaly R, De Stefano F, Turcios L, Hill M, Hidalgo G, Mitov MI, Alstott MC, Butterfield DA, Mitchell HC, Hart J, Al-Attar A, Jennings CD, Marti F. mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation. Transplantation. 2019;103(4):705- 715. |
Gimble, Jeffrey M., Adam J. Katz, and Bruce A. Bunnell. “Adipose-derived stem cells for regenerative medicine.” Circulation research 100.9 (2007): 1249-1260. |
Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001;15(7):807-26. |
Godin, Michel, et al. “Measuring the mass, density, and size of particles and cells using a suspended microchannel resonator.” Applied physics letters 91.12 (2007): 123121. |
Goh, Celeste, Sowmya Narayanan, and Young S. Hahn. “Myeloid-derived suppressor cells: the dark knight or the joker in viral infections ?. ” Immunological reviews 255.1 (2013): 210-221. |
Golab K, Leveson-Gower D, Wang XJ, Grzanka J, Marek-Trzonkowska N, Krzystyniak A, Millis JM, Trzonkowski P, Witkowski P. Challenges in cryopreservation of regulatory T cells (Tregs) for clinical therapeutic applications. Int Immunopharmacol. 2013;16(3):371-5. |
Goldring CE, Duffy PA, Benvenisty N, Andrews PW, Ben-David U, Eakins R, French N, Hanley NA, Kelly L, Kitteringham NR, Kurth J, Ladenheim D, Laverty H, McBlane J, Narayanan G, Patel S, Reinhardt J, Rossi A, Sharpe M, Park BK. Assessing the safety of stem cell therapeutics. Cell stem cell. 2011;8:618-628. |
Griesche, Nadine, et al. “A simple modification of the separation method reduces heterogeneity of adipose-derived stem cells.” cells tissues organs 192.2 (2010): 106-115. |
Gutcher I, Donkor MK, Ma Q, Rudensky AY, Flavell RA, Li MO. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity. 2011;34(3):396-408. |
Haack-Sorensen M, Follin B, Juhl M, et al. (2016) Culture expansion of adipose derived stromal cells. A closed automated Quantum Cell Expansion System compared with manual flask-based culture. J Transl Med 14(1): 319. |
Hall ED, Sullivan PG, Gibson TR, Pavel KM, Thompson BM, Scheff SW. Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: More than a focal brain injury. Journal of neurotrauma. 2005;22:252-265. |
Hami et al., “GMP Production and Testing of Xcellerated T Cells for the Treatment of Patients with CLL,” Cytotherapy, pp. 554-562, 2004. |
Hamm RJ, Dixon CE, Gbadebo DM, Singha AK, Jenkins LW, Lyeth BG, Hayes RL. Cognitive deficits following traumatic brain injury produced by controlled cortical impact. Journal of neurotrauma. 1992;9:11-20. |
Hanley PJ, Mei Z, Durett AG, et al. (2014) Efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the Quantum Cell Expansion System. Cytotherapy 16(8): 1048- 1058. |
He N, Fan W, Henriquez B, Yu RT, Atkins AR, Liddle C, Zheng Y, Downes M, Evans RM. Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci USA. 2017;114(47):12542-12547. |
He X, Landman S, Bauland SC, van den Dolder J, Koenen HJ, Joosten I. A TNFR2-Agonist Facilitates High Purity Expansion of Human Low Purity Treg Cells. PLoS One. 2016;11(5):e0156311. |
Heskins, Michael, and James E. Guillet. “Solution properties of poly (N-isopropylacrylamide).” Journal of Macromolecular Science-Chemistry 2.8 (1968): 1441-1455. |
Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity. 2007;27(5):786-800. |
Hollyman et al., “Manufacturing Validation of Biologicall Functional T Cells Targeted to CD19 Antigen for Autologous Adoptive Cell Therapy,” J Immunother, vol. 32, No. 2, pp. 169-180, Feb.-Mar. 2009. |
Horwitz, Mitchell E., et al. “Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide.” Journal of Clinical Oncology 37.5 (2019): 367-373. |
http://www.ucdenver.edu/academics/colleges/medicalschool/centers/cancercenter/Research/sharedresources/AnimalImaging/smallanimalimaging/Pages/MRI.aspx. |
ISCT Webinar “vol. Reduction technology for Large Scale Harvest or Post-thaw Manipulation of Cellular Therapeutics”. |
Iwashima, Shigejiro, et al. “Novel culture system of mesenchymal stromal cells from human subcutaneous adipose tissue.” Stem cells and development 18.4 (2009): 533-544. |
Jarocha D, Stangel-Wojcikiewicz K, Basta A, Majka M (2014) Efficient myoblast expansion for regenerative medicine use. Int J Mol Med 34(1): 83-91. |
Jin, H., and J. Bae. “Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow.” 22nd Annual ISCT Meeting (2016): S29. |
Jo CH, Lee YG, Shin WH, et al. (2014) Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 32(5): 1254-1266. |
John Nicolette, et al.(Abbott Laboratories). In Vitro Micronucleus Screening of Pharmaceutical Candidates by Flow Cyto9metry in Chinese Hamster V79 Cells, Environmental and Molecular Mutagenesis 00:000-000, 2010. |
Johnson, Patrick A., et al. “Interplay of anionic charge, poly (ethylene glycol), and iodinated tyrosine incorporation within tyrosine ?derived polycarbonates: Effects on vascular smooth muscle cell adhesion, proliferation, and motility.” Journal of Biomedical Materials Research Part A: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials 93.2 (2010): 505-514. |
Johnston LC, Su X, Maguire-Zeiss K, Horovitz K, Ankoudinova I, Guschin D, Hadaczek P, Federoff HJ, Bankiewicz K, Forsayeth J. Human interleukin-10 gene transfer is protective in a rat model of Parkinson's disease. Mol Ther. 2008;16(8):1392-9. |
Jones2016ISCT 2016 Poster 69. |
Joy, Abraham, et al. “Control of surface chemistry, substrate stiffness, and cell function in a novel terpolymer methacrylate library.” Langmuir 27.5 (2011): 1891-1899. |
Kalamasz et al., “Optimization of Human T-Cell Expansion Ex Vivo Using Magnetic Beads Conjugated with Anti-CD3 and Anti-CD28 Antibodies,” J Immunother, vol. 27, No. 5, pp. 405-418, Sep.-Oct. 2004. |
Kim, Do-Hyung, et al. “mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery.” Cell 110.2 (2002): 163-175. |
Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM. Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. Immunity. 2017;47(5):875-889 e10. |
Klapper et al., “Single-Pass, Closed-System Rapid Expansion of Lymphocyte Cultures for Adoptive Cell Therapy,” Journal of Immunological Methods, 345, pp. 90-99, Apr. 21, 2009. |
Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G, Oburoglu L, Mongellaz C, Floess S, Fritz V, Matias MI, Yong C, Surh N, Marie JC, Huehn J, Zimmermann V, Kinet S, Dardalhon V, Taylor N. Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal. 2015;8(396):ra97. |
Korpanty et al., “Tageting Vascular Enothelium with Avidin Microbubbles,” Ultrasound in Medicine and Biology, vol. 31, No. 9, pp. 1279-1283, May 24, 2005. |
Krauss et al., “Signaling Takes a Breath—New Quantitative Perspectives on Bioenergetics and Signal Transduction,” Immunity, vol. 15, pp. 497-502, Oct. 2001. |
Kulikov, A. V., et al. “Application of multipotent mesenchymal stromal cells from human adipose tissue for compensation of neurological deficiency induced by 3-nitropropionic acid in rats.” Bulletin of experimental biology and medicine 145.4 (2008): 514-519. |
Kumar P, Marinelarena A, Raghunathan D, Ragothaman VK, Saini S, Bhattacharya P, Fan J, Epstein AL, Maker AV, Prabhakar BS. Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation. Cell Mol Immunol. 2019;16(2):138-153. |
Kwan, J. and Borden, M., “Lipid Monolayer Collapse and Microbubble Stability,” Advances in Colloid and Interface Science, vols. 183-184, pp. 82-99, Aug. 21, 2012. |
Lampugnani MG, Caveda L, Breviario F, Del Maschio A, Dejana E. Endothelial cell-to-cell junctions. Structural characteristics and functional role in the regulation of vascular permeability and leukocyte extravasation. Bailliere's clinical haematology. 1993;6:539-558. |
Lee et al., “Continued Antigen Stimulation Is Not Required During CD4+ T Cell Clonal Expansion,” The Journal of Immunology, 168, pp. 1682-1689, 2002. |
Lee, Jae W., et al. “Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung.” Proceedings of the national academy of Sciences 106.38 (2009): 16357-16362. |
Levine, B., “T Lymphocyte Engineering ex vivo for Cancer and Infectious Disease,” Expert Opinion on Biological Therapy, vol. 4, No. 4, pp. 475-489, 2008. |
Lindstein, Tullia, et al. “Regulation of lymphokine messenger RNA stability by a surface- mediated T cell activation pathway.” Science 244.4902 (1989): 339-343. |
Liotta, Francesco, et al. “Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma.” BJU international 107.9 (2011): 1500-1506. |
Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701-1711. |
Lum et al., “Ultrasound Radiation Force Enables Targeted Deposition of Model Drug Carriers Loaded on Microbubbles,” Journal of Controlled Release, 111, pp. 128-134, 2006. |
Malone et al., “Characterization of Human Tumor-Infiltrating Lymphocytes Expanded in Hollow-Fiber Bioreactors for Immunotherapy of Cancer,” Cancer Biotherapy & Radiopharmaceuticals, vol. 16, No. 5, pp. 381-390, 2001. |
Mao AS, Mooney DJ (2015) Regenerative medicine: current therapies and future directions. Proc Natl Acad Sci USA 112(47): 14452-14459. |
Markgraf CG, Clifton GL, Aguirre M, Chaney SF, Knox-Du Bois C, Kennon K, Verma N. Injury severity and sensitivity to treatment after controlled cortical impact in rats. Journal of neurotrauma. 2001;18:175-186. |
Mathew et al. A Phase | Clinical Trials I with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants. Nature, Scientific Reports 8:7428 (1-12), 2018. |
Matthay, Michael A., et al. “Therapeutic potential of mesenchymal stem cells for severe acute lung injury.” Chest 138.4 (2010): 965-972. |
Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY, Weaver CT. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3-precursor cells in the absence of interleukin 10. Nat Immunol. 2007;8(9):931-41. |
McKenna DH, Jr., Sumstad D, Kadidlo DM, et al. Optimization of cGMP purification and expansion of umbilical cord blood-derived T-regulatory cells in support of first-in-human clinical trials. Cytotherapy 2017;19:250-62. |
McLimans W, Kinetics of Gas Diffusion in Mammalian Cell Culture Systems. Biotechnology and Bioengineering 1968; 10:725-740. |
McMurtrey, Richard J. “Analytic models of oxygen and nutrient diffusion, metabolism dynamics, and architecture optimization in three-dimensional tissue constructs with applications and insights in cerebral organoids.” Tissue Engineering Part C: Methods 22.3 (2016): 221-249. |
Menge, Tyler, et al. “Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury.” Science translational medicine 4.161 (2012): 161ra150-161ra150. |
Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, Zhang P, Panek Wk, Cordero A, Han Y, Ahmed AU, Chandel NS, Lesniak MS. HIF-1alpha Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma. Cell Rep. 2019;27(1):226-237 e4. |
Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899-911. |
Nankervis B, Jones M, Vang B et al. (2018) Optimizing T Cell Expansion in a Hollow-Fiber Bioreactor. Curr Stem Cell Rep. Advanced online publication. https://doi.org/10.1007/s40778-018-0116-x. |
Nankervis, Brian, et al. “Optimizing T cell expansion in a hollow-fiber bioreactor.” Current Stem Cell Reports 4.1 (2018): 46-51. |
Nedoszytko B, Lange M, Sokolowska-Wojdylo M, Renke J, Trzonkowski P, Sobjanek M, Szczerkowska-Dobosz A, Niedoszytko M, Gorska A, Romantowski J, Czarny J, Skokowski J, Kalinowski L, Nowicki R. The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part II: The Treg role in skin diseases pathogenesis. Postepy Dermatol Alergol. 2017;34(5):405-417. |
Nehlin JO, Just M, Rustan AC (2011) Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism. Biogerontology 12: 349-365. |
New victories for adult Stem Cell Research New York Feb. 6, 2007. |
Newton R, Priyadharshini B, Turka LA. Immunometabolism of regulatory T cells. Nat Immunol. 2016;17(6):618-25. |
Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC. Regulation of adaptive immunity; the role of interleukin-10. Front Immunol. 2013;4:129. |
Nikolaychik, V. V., M. M. Samet, and P. I. Lelkes. “A New, Cryoprecipitate Based Coating For Improved Endothelial Cell Attachment And Growth On Medical Grade Artificial Surfaces.” ASAIO Journal (American Society for Artificial Internal Organs: 1992) 40.3 (1994): M846-52. |
Nish SA, Schenten D, Wunderlich FT, Pope SD, Gao Y, Hoshi N, Yu S, Yan X, Lee HK, Pasman L, Brodsky I, Yordy B, Zhao H, Bruning J, Medzhitov R. T cell-intrinsic role of IL-6 signaling in primary and memory responses. Elife. 2014;3:e01949. |
Niwayama, Jun, et al. “Analysis of hemodynamics during blood purification therapy using a newly developed noninvasive continuous monitoring method.” Therapeutic Apheresis and Dialysis 10.4 (2006): 380-386. |
Okano et al.(Tokyo Women's Medical College, Japan) demonstrated the recovery of endothelial cells and hepatocytes from plasma-treated polystyrene dishes grafted with PNIAAm (Journal of Biomedical Materials Research, 1993). |
Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci U S A. 2008;105(29):10113-8. |
Onyszchuk G, LeVine SM, Brooks WM, Berman NE. Post-acute pathological changes in the thalamus and internal capsule in aged mice following controlled cortical impact injury: A magnetic resonance imaging, iron histochemical, and glial immunohistochemical study. Neuroscience letters. 2009;452:204-208. |
Pacella I, Procaccini C, Focaccetti C, Miacci S, Timperi E, Faicchia D, Severa M, Rizzo F, Coccia EM, Bonacina F, Mitro N, Norata GD, Rossetti G, Ranzani V, Pagani M, Giorda E, Wei Y, Matarese G, Barnaba V, Piconese S. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci U S A. 2018;115(28):E6546-E6555. |
Parhi, Purnendu, Avantika Golas, and Erwin A. Vogler. “Role Of Proteins And Water In The Initial Attachment Of Mammalian Cells To Biomedical Surfaces: A Review.” Journal of Adhesion Science and Technology 24.5 (2010): 853-888. |
Pati S, Gerber MH, Menge TD, Wataha KA, Zhao Y, Baumgartner JA, Zhao J, Letourneau PA, Huby MP, Baer LA, Salsbury JR, Kozar RA, Wade CE, Walker PA, Dash PK, Cox CS, Jr., Doursout MF, Holcomb JB. Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock. PloS one. 2011;6:e25171. |
Pati S, Khakoo AY, Zhao J, Jimenez F, Gerber MH, Harting M, Redell JB, Grill R, Matsuo Y, Guha S, Cox CS, Reitz MS, Holcomb JB, Dash PK. Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/beta-catenin signaling. Stem cells and development. 2011;20:89-101. |
Pati, Shibani, and Todd E. Rasmussen. “Cellular therapies in trauma and critical care medicine: Looking towards the future.” PLoS Medicine 14.7 (2017): e1002343. |
Pati, Shibani, et al. “Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock.” PloS one 13.2 (2018): e0192363. |
Peters JH, Preijers FW, Woestenenk R, Hilbrands LB, Koenen HJ, Joosten I. Clinical grade Treg: GMP isolation, improvement of purity by CD127 Depletion, Treg expansion, and Treg cryopreservation. PLoS One. 2008;3(9):e3161. |
Peters, R.; Jones, M.; Brecheisen, M.; Startz, T.; Vang, B.; Nankervis, B.; Frank, N.; Nguyen, K. (2012) TerumoBCT. https://www.terumobct.com/location/north-america/products-and-services/Pages/Quantum-Materials.aspx. |
Porter CM, Horvath-Arcidiacono JA, Singh AK, Horvath KA, Bloom ET, Mohiuddin MM. Characterization and expansion of baboon CD4+CD25+ Treg cells for potential use in a non-human primate xenotransplantation model. Xenotransplantation. 2007;14(4):298-308. |
Povsic TJ, O'Connor CM, Henry T, et al. (2011) A double-blind, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction. Am Heart J 162(4): 654-662. |
Prockop, Darwin J., Carl A. Gregory, and Jeffery L. Spees. “One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues.” Proceedings of the National Academy of Sciences 100.suppl_1 (2003): 11917-11923. |
Q. L. Hao, et al. A functional comparison of CD34+ CD38= cells in cord blood and bone marrow. Blood 86:3745-3753, 1995. |
Rey-Jurado, Emma, et al. “Assessing the importance of domestic vaccine manufacturing centers: an overview of immunization programs, vaccine manufacture, and distribution.” Frontiers in immunology 9 (2018): 26. |
Roballo KC, Dhungana S, Z. J, Oakey J, Bushman J. Localized delivery of immunosuppressive regulatory T cells to peripheral nerve allografts promotes regeneration of branched segmental defects. Biomaterials. 2019;209:1-9. |
Ronco C1, Levin N, Brendolan A, Nalesso F, Cruz D, Ocampo C, Kuang D, Bonello M, De Cal M, Corradi V, Ricci Z. Flow distribution analysis by helical scanning in polysulfone hemodialyzers: effects of fiber structure and design on flow patterns and solute clearances. Hemodial Int. Oct. 2006; 10(4):380-8. |
Rosenblum MD, Way SS, Abbas AK. Regulatory T cell memory. Nat Rev Immunol. 2016;16(2):90-101. |
Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR, Jr., Muller W, Rudensky AY. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008;28(4):546-58. |
Rudensky, Alexander Y. “Regulatory T cells and Foxp3.” Immunological reviews 241.1 (2011): 260-268. |
Safinia N, Grageda N, Scotta C, Thirkell S, Fry LJ, Vaikunthanathan T, Lechler RI, Lombardi G. Cell Therapy in Organ Transplantation: Our Experience on the Clinical Translation of Regulatory T Cells. Front Immunol. 2018;9:354. |
Sahay A, Scobie KN, Hill AS, O'Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466-470. |
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151-64. |
Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001;182:18-32. |
Schild, Howard G. “Poly (N-isopropylacrylamide): experiment, theory and application.” Progress in polymer science 17.2 (1992): 163-249. |
Schmitz R, Alessio A, Kina P. The Physics of PET/CT scanners. Imaging Research Laboratory, Department of Radiology, University of Washington http://depts.washington.edu/imreslab/education/Physics%20of%20PET.pdf. |
Schwartz Rh. T cell anergy. Annu Rev Immunol. 2003;21:305-34. |
Shevkoplyas et al., “The Force Acting on a Superparamagnetic Bead due to an Applied Magnetic Field,” Lab on a Chip , 7, pp. 1294-1302, 2007. |
Shimazu Y, Shimazu Y, Hishizawa M, Hamaguchi M, Nagai Y, Sugino N, Fujii S, Kawahara M, Kadowaki N, Nishikawa H, Sakaguchi S, Takaori-Kondo A. Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia. Cancer Immunol Res. 2016;4(2):136-45. |
Sigma-Aldrich Cheimcals Mitomycin C (M4287) MSDS, v4.4, Jul. 7, 2011. |
Sirsi, S. and Borden, M., “Microbubble Composition, Properties, and Biomedical Applications,” Bubble Science, Engineering & Technolology, vol. 1, No. 1-2, pp. 3-17, 2009. |
Smith C, Okern G, Rehan S, et al. Ex vivo expansion of human T cells for adoptive immunotherapy using the novel Xeno-free CTS Immune Cell Serum Replacement. Clinical & Translational Immunology 2015;4:e31. |
Somerville et al., “Clinical Scale Rapid Expansion of Lymphocytes for Adoptive Cell Transfer Therapy in the WAVE® Bioreactor,” Journal of Translational Medicine, vol. 10, No. 69, pp. 1-11, 2012. |
Somerville, R. and Dudley, M., “Bioreactors Get Personal,” Oncolmmunology, vol. 1, No. 8, pp. 1435-1437, Nov. 2012. |
Spectrum Labs KrosFlo Research IIi TFF System, undated, Spectrum Laboratories, Inc., 4 pages. |
Stafano Tiziani, et al. Metabolomic Profiling of Drug Response in Acute Myeloid Leukaemia Cell lines. PLOSone 4(1): e4251 (Jan. 22, 2009). |
StAR_Abstract, undated, author unknown, 1 page. |
Startz et al May 2016 TBCT T-cell White Paper. |
Startz, T., et al. “Maturation of dendritic cells from CD14+ monocytes in an automated functionally closed hollow fiber bioreactor system.” Cytotherapy 16.4 (2014): S29. |
Stuart, Martien A. Cohen, et al. “Emerging applications of stimuli-responsive polymer materials.” Nature materials 9.2 (2010): 101-113. |
Su LF, Del Alcazar D, Stelekati E, Wherry EJ, Davis MM. Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood. Proc Natl Acad Sci U S A. 2016;113(41):E6192-E6198. |
Trzonkowski et al., “Ex Vivo Expansion of CD4+ CD25+ T Regulatory Cells for Immunosuppressive Therapy,” Cytometry Part A, 75A, pp. 175-188, 2009. |
Trzonkowski, Piotr, et al. “First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+ CD25+ CD127? T regulatory cells.” Clinical immunology 133.1 (2009): 22-26. |
Tsvetkov, Ts, et al. “Isolation and cryopreservation of human peripheral blood monocytes.” Cryobiology 23.6 (1986): 531-536. |
Underwood, P. Anne, et al. “Effects of base material, plasma proteins and FGF2 on endothelial cell adhesion and growth.” Journal of Biomaterials Science, Polymer Edition 13.8 (2002): 845-862. |
van der Net JB, Bushell A, Wood KJ, Harden PN. Regulatory T cells: first steps of clinical application in solid organ transplantation. Transpl Int. 2016;29(1):3-11. |
van der Windt GJ, Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev. 2012;249(1):27-42. |
Vera et al., “Accelerated Production of Antigen-Specific T-Cells for Pre-Clinical and Clinical Applications Using Gas-Permeable Rapid Expansion Cultureware (G-Rex),” J Immunother, vol. 33, No. 3, pp. 305-315, Apr. 2010. |
Villa, Alma Y. Camacho, et al. “CD133+ CD34+ and CD133+ CD38+ blood progenitor cells as predictors of platelet engraftment in patients undergoing autologous peripheral blood stem cell transplantation.” Transfusion and Apheresis Science 46.3 (2012): 239-244. |
Visser EP1, Disselhorst JA, Brom M, Laverman P, Gotthardt M, Oyen WJ, Boerman OC. Spatial resolution and sensitivity of the Inveon small-animal PET scanner. J Nucl Med. Jan. 2009;50(1):139-47. |
Walker, Peter A., et al. “Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NF?B-mediated increase in interleukin-6 production.” Stem cells and development 19.6 (2010): 867-876. |
Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871-82. |
Wang, Jiamian, John A. Jansen, and Fang Yang. “Electrospraying: possibilities and challenges of engineering carriers for biomedical applications-a mini review.” Frontiers in Chemistry 7 (2019): 258. |
Ward H, Vigues S, Poole S, Bristow AF. The rat interleukin 10 receptor: cloning and sequencing of cDNA coding for the alpha-chain protein sequence, and demonstration by western blotting of expression in the rat brain. Cytokine. 2001;15(5):237-40. |
Wawman, Rebecca Ellen, Helen Bartlett, and Ye Htun Oo. “Regulatory T cell metabolism in the hepatic microenvironment.” Frontiers in immunology 8 (2018): 1889. |
Weber et al., “White Paper on Adoptive Cell Therapy for Cancer with Tumor-Infiltrating Lymphocytes: A Report of the CTEP Subcommittee on Adoptive Cell Therapy,” Clinical Cancer Research, vol. 17, No. 7, pp. 1664-1673, Apr. 1, 2011. |
Weiss RA, Weiss MA, Beasley KL, Munavalli G (2007) Autologous cultured fibroblast injection for facial contour deformities: a prospective, placebo-controlled, Phase III clinical trial. Dermatol Surg 33(3): 263-268. |
Widdel, F. 2010. “Theory and measurement of bacterial growth” http://www.mpi- bremen.de/Binaries/Binary13037/Wachstumsversuch.pdf. |
Yamada, Noriko, et al. “Thermo?responsive polymeric surfaces; control of attachment and detachment of cultured cells.” Die Makromolekulare Chemie, Rapid Communications 11.11 (1990): 571-576. |
Yoshinari, Masao, et al. “Effect of cold plasma-surface modification on surface wettability and initial cell attachment.” International Journal of Biomedical and Biological Engineering 3.10 (2009): 507-511. |
Zappasodi et al., “The Effect Of Artificial Antigen-Presenting Cells with Preclustered Anit-CD28/-CD3/LFA-1 Monoclonal Antibodies on the Induction of ex vivo Expansion of Functional Human Antitumor T Cells,” Haematologica, vol. 93, No. 10, pp. 1523-1534, 2008. |
Zemmour D, Zilionis R, Kiner E, Klein AM, Mathis D, Benoist C. Publisher Correction: Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat Immunol. 2018;19(6):645. |
Zeng B, Kwak-Kim J, Liu Y, Liao AH. Treg cells are negatively correlated with increased memory B cells in pre-eclampsia while maintaining suppressive function on autologous B-cell proliferation. Am J Reprod Immunol. 2013;70(6):454-63. |
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20180119094 A1 | May 2018 | US |
Number | Date | Country | |
---|---|---|---|
61970274 | Mar 2014 | US |
Number | Date | Country | |
---|---|---|---|
Parent | 14668659 | Mar 2015 | US |
Child | 15849309 | US |