Bioreactor for engineered tissue

A system for generating a tissue construct includes a mixing chamber, a piston chamber, a reaction chamber, and a pump. The mixing chamber is configured to receive a hydrogel solution and a cell suspension solution. The piston chamber includes a first piston and is configured to receive a mixture of the hydrogel solution and the cell suspension solution from the mixing chamber. The first piston is configured to push the mixture through one or more capillaries into the reaction chamber. The reaction is configured to receive the mixture and a cross-linking initiator. The pump is configured to move the mixture through the reaction chamber such that the mixture and the cross-linking initiator combine to form an encapsulated cell material.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage application of International Application Serial No. PCT/US2011/036254, filed on May 12, 2011, the entire disclosure of which is hereby incorporated by reference for all purposes in its entirety as if fully set forth herein.

BACKGROUND

The field of tissue engineering has recently emerged as a strong player in the field of regenerative medicine. Due to their unique properties, hydrogels are ideal candidates for use in tissue engineering applications. Hydrogels are relatively easy to synthesize and they are biocompatible. Hydrogels also allow for the adsorption of biologically active molecules that can influence cellular behavior as well as allow for the mass transport of nutrients and waste. Their similarities with the extra-cellular matrix in structure and sometimes in chemical composition, and their ability to sustain viable and proliferating cells, are desired qualities that hydrogels exhibit for the application of tissue constructs. Their high promise have driven scientists to synthesize structures that are used to mimic tissues that play central roles in our bodies, such as liver tissue, neural tissue, etc.

SUMMARY

An illustrative system for generating a tissue construct includes a mixing chamber, a piston chamber, a reaction chamber, and a pump. The mixing chamber is configured to receive a hydrogel solution and a cell suspension solution. The piston chamber includes a first piston and is configured to receive a mixture of the hydrogel solution and the cell suspension solution from the mixing chamber. The first piston is configured to push the mixture through one or more capillaries into the reaction chamber. The reaction is configured to receive the mixture and a cross-linking initiator. The pump is configured to move the mixture through the reaction chamber such that the mixture and the cross-linking initiator combine to form an encapsulated cell material.

An illustrative process for generating a tissue construct includes mixing a hydrogel solution and a cell suspension solution in a mixing chamber of a tissue generating system. A mixture of the hydrogel solution and the cell suspension solution is drawn from the mixing chamber into a piston chamber. The mixture is pushed through one or more capillaries and into a reaction chamber. The mixture is pumped through the reaction chamber so that the mixture reacts with a cross-linking initiator in the reaction chamber to form an encapsulated cell material.

Another illustrative system for generating a tissue construct includes means for mixing a hydrogel solution and a cell suspension solution in a mixing chamber. The system also includes means for drawing a mixture of the hydrogel solution and the cell suspension solution from the mixing chamber into a piston chamber. The system also includes means for pushing the mixture through one or more capillaries and into a reaction chamber. The system further includes means for pumping the mixture through the reaction chamber so that the mixture reacts with a cross-linking initiator in the reaction chamber to form an encapsulated cell material.

DETAILED DESCRIPTION

FIG. 1is a diagram of a bioreactor100for manufacturing engineered tissue in accordance with an illustrative embodiment. The engineered tissue can be, but is not limited to, bone tissue, cartilage tissue, organ tissue such as liver tissue, pancreatic tissue, or neural tissue, etc. The engineered tissue can be manufactured by bioreactor100in the form of tissue scaffolds as known to those of skill in the art. The tissue scaffolds can be used for, but are not limited to, bone reconstruction, cartilage reconstruction, neural tissue regeneration, etc. Bioreactor100includes, but is not limited to, a mixing chamber105, a piston chamber110, a reaction chamber115with a pump120, and an ejection chamber125. In an illustrative embodiment, one or more or all of the components of bioreactor100can be removable via a threaded connection, friction connection, etc. so that the components can be individually cleaned, sterilized, and/or replaced. One or more or all of the components of bioreactor100may also be disposable. A detailed description of each of these components of bioreactor100is provided with reference toFIGS. 2-5.

FIG. 2is a diagram of mixing chamber105of bioreactor100in accordance with an illustrative embodiment. In one embodiment, mixing chamber105can have a volume of between approximately 100 milliliters (mL) and 1 Liter (L) depending on the size of production. Alternatively, the volume mixing chamber105may be less than 100 ml or greater than 1 L. In an illustrative embodiment, mixing chamber105can be a cylindrical vessel that can be made of a plastic such as but not limited to acrylic (plexi-glass) or a metal such as stainless steel. Both acrylic and stainless steel can be readily sterilized (e.g., plastic can be sterilized in ethylene oxide and stainless steel can be sterilized via heat or ethylene oxide). In some embodiments, the chamber may be designed to be disposable.

In some embodiments, mixing chamber105may be connected to a conduit200so that mixing chamber105is able to receive the contents of a reservoir205. Mixing chamber105can be permanently or detachably mounted to conduit200, depending on the embodiment. In one embodiment, mixing chamber105can be connected to conduit200with a screw or other fitting connection. Mixing chamber105is also connected to a conduit210so that mixing chamber105is able to receive the contents of a reservoir215. Mixing chamber105, conduit200, reservoir205, conduit210, and reservoir215may be made from biocompatible material(s) known to those of skill in the art. In one embodiment, the materials used may be a transparent or opaque rigid plastic such as but not limited to acrylic or Teflon. The materials used may also be metallic such as but not limited to stainless steel, or glass. Conduit200includes a valve220that is used to control the flow of the contents of reservoir205into mixing chamber105. Conduit210similarly includes a valve225that is used to control the flow of the contents of reservoir215into mixing chamber105. In an illustrative embodiment, each of valves220and225can have an open position in which the respective reservoir contents are able to flow into mixing chamber105, and a closed position in which content flow is prevented. Valves220and225can be any type of open/close valve(s) known to those of skill in the art. Valves220and225may be manually controlled by an operator of bioreactor100and/or automatically (computer) controlled by a motor or other actuator. In an alternative embodiment, valves220and/or225may not be included.

In an illustrative embodiment, the contents of reservoir205may include a hydrogel solution with uncrosslinked hydrogel materials, and the contents of reservoir215may include a cell suspension. Examples of uncrosslinked hydrogel materials may include but are not limited to alginate, polyacrylamide, gels made with hyaluronic acid, polyethylene, etc. In an alternative embodiment, reservoir205may include the cell suspension and reservoir215may include the hydrogel solution. The cell suspension may include, but is not limited to, neural cells, liver cells, stem cells, cartilage cells, or other types of cells, depending on the type of tissue to be manufactured. The hydrogel solution that is used can be based on the type of cells in the cell suspension. For example, osteoblast cells may be suspended in a PEG-PLA hydrogel or a Peptide amphiphile-Ti composite hydrogel, fibroblast cells may be suspended in a PEG hydrogel, heptocyte cells may be suspended in a HA hydrogel, an alginate hydrogel, or a carboxymethylcellulose hydrogel, etc. Additional examples of cells and corresponding hydrogels can be found in an article titled “Hydrogels in Regenerative Medicine” by Slaughter et al. (from Adv. Mater. 2009, 21, 3307-3329), the entire disclosure of which is hereby incorporated by reference.

Mixing chamber105also includes a venting valve235. Venting valve235can be any type of air valve known to those of skill in the art. In an alternative embodiment, venting valve235may be a semi-permeable membrane that allows air to be released from mixing chamber105. In an illustrative embodiment, venting valve235does not allow air to flow in to mixing chamber105. Venting valve235is used to release air from mixing chamber105that is displaced when the hydrogel solution and/or cell suspension are added to mixing chamber105. In an illustrative embodiment, venting valve235can have an open position in which the displaced air from mixing chamber105is released, and a closed position in which air from mixing chamber105is unable to escape. In such an embodiment, venting valve235can be controlled manually by an operator of bioreactor100and/or automatically by a computer controlled motor or other actuator. In an illustrative embodiment, venting valve235is placed into the open position as the hydrogel solution and cell suspension are being transferred to mixing chamber105, and placed into the closed position once the transfer is complete. In an alternative embodiment, venting valve235may only have an open position such that displaced air from mixing chamber105is always able to be released.

In an illustrative embodiment, valves220and225are used to place desired amounts of hydrogel solution and cell suspension into mixing chamber105from the respective reservoirs. In an illustrative embodiment, approximately 1-10 mL of cell suspension are added to mixing chamber105for approximately every 100 mL of hydrogel solution added to mixing chamber105. In alternative embodiments, different amounts of cell suspension and/or hydrogel solution may be used as known in the art for a particular purpose and/or cell type. In one embodiment, the hydrogel solution and cell suspension are simultaneously added to mixing chamber105. In the case of non-viscous pre-polymeric solutions, sedimentation of the cells in the cell suspension may occur, preventing the cells from flowing into mixing chamber105. In such an embodiment, reservoir215may not be used and the cell suspension may be directly added to mixing chamber105through an aperture in mixing chamber105. In the case of viscous pre-polymeric solutions, cell sedimentation should not occur and reservoir215can be used. In alternative embodiments, the cell suspension may be added before or after the hydrogel solution. The entire contents of reservoirs205and215can be added to mixing chamber105. In an alternative embodiment, only a portion of the contents of reservoir205and/or reservoir215are added to mixing chamber105. A ratio of hydrogel solution to cell suspension can be controlled by computer software which can determine how long valves220and225should remain open. In one embodiment, the quantity from each of reservoirs205and215can be determined by a user and can depend on the type of hydrogel used. For example, a small volume of a highly concentrated cell suspension can be added to the pre-polymeric materials, and the water in the cell suspension can complement the water used in the hydrogel solution. In an illustrative embodiment, reservoir210, reservoir215, and mixing chamber105can all be mounted to bioreactor100with a connection such as but not limited to a screw, with a threaded connection, with a fitted connection, etc. As such, these components can be removed for cleaning, sterilizing, disposal, and/or replacement.

Mixing chamber105may include an impeller230for mixing the hydrogel solution and the cell suspension within mixing chamber105. Impeller230can refer to one or more blades, one or more magnetic stirrers, or any other object(s) that can be used for mixing. Impeller230can be made from a biocompatible material known to those of skill in the art. Impeller230can be manually activated by an operator of bioreactor100and/or automatically activated by a motor or other actuator. Impeller230can be activated before, during, or after the hydrogel solution and cell suspension are added into the mixing chamber. In an alternative embodiment, the mixing can be performed by shaking, rocking, inverting, or otherwise moving mixing chamber105. In another alternative embodiment, the mixing can be performed by applying external force waves such as ultrasound waves, microwaves, etc. to mixing chamber105. The amount of time that the mixing occurs may depend on the size of mixing chamber105, the hydrogel, the temperature, and optionally other factors as known in the art. For smaller mixing chambers that are approximately less than a liter, mixing for one to several minutes may be sufficient. For larger mixing chambers in the range of 1 or more liters, a longer mixing time may be used such as 5 minutes, 10 minutes, 15 minutes, 30 minutes, 60 minutes, etc.

FIG. 3Ais a diagram illustrating a piston300of piston chamber110in a compressed position in accordance with an illustrative embodiment.FIG. 3Bis a diagram illustrating piston300of piston chamber110in an uncompressed position in accordance with an illustrative embodiment. Piston chamber110includes piston300and a conduit305that includes a valve310. Valve310can be any type of valve known to those of skill in the art. Valve310has an open position in which the contents of mixing chamber105are able to flow into piston chamber110, and a closed position that blocks the flow of the contents of mixing chamber105into piston chamber110. In an illustrative embodiment, piston chamber110can be made of materials such as but not limited to acrylic or stainless steel. In alternative embodiments, other materials may be used. In another illustrative embodiment, piston chamber110can have a size and shape similar to that of mixing chamber105.

After the hydrogel solution and cell suspension are mixed in mixing chamber105, valve310is opened with piston300in the compressed position (as illustrated inFIG. 3A). Venting valve235illustrated with reference toFIG. 2may also be in the open position. In an illustrative embodiment, bioreactor100may be used in a laminar hood prevent bacteria or other contaminants from entering bioreactor through venting valve235. In an alternative embodiment, venting valve235may include a semi-permeable membrane to let air in and to block out contaminants. In an illustrative embodiment, piston300is sized to form an airtight seal with the interior wall of piston chamber110. As such, moving piston300from the compressed position to the uncompressed position creates a suction that draws the mixture from mixing chamber105into piston chamber110. Piston300can be moved manually by an operator of bioreactor100and/or automatically by a motor or other actuator. In one embodiment, the speed at which the piston moves can depend on the cells utilized to help prevent cell damage. Alternatively, a single piston speed may be used regardless of the cells used. Valve310is closed once piston300is moved to the uncompressed position as illustrated inFIG. 3B. In an alternative embodiment, piston300may initially be in the uncompressed position and the hydrogel/cell mixture may be allowed to flow into piston chamber110by gravity.

FIG. 4is a partial view of bioreactor100illustrating the interaction between piston chamber110and reaction chamber115in accordance with an illustrative embodiment. Reaction chamber115includes capillaries400through which the mixture from piston chamber110passes as it enters reaction chamber115. Passing the mixture through capillaries400subjects the hydrogels to shear forces that help shape the hydrogels into worm-like structures for eventual encapsulation of the cells. The worm-like structures are formed due to the cylindrical shape of capillaries400. Cell encapsulation is described in more detail below with reference to reaction chamber115. Capillaries400are mounted to an endplate405of reaction chamber. In an illustrative embodiment, endplate405includes holes or openings to which capillaries400are mounted. In an illustrative embodiment, capillaries400can have a diameter of between approximately 0.5 millimeters (mm) and 5 mm depending on the desired dimensions of the worm-like structures. In alternative embodiments, the diameter of capillaries may be less than 0.5 mm or larger than 5 mm. In one embodiment, capillaries can have a diameter of approximately 2 mm or less to allow for sufficient mass transport of nutrients.

A valve410is used to control access between piston chamber110and reaction chamber115. In some embodiments, valve410may be implemented as a movable door that has an open position in which the mixture can flow from piston chamber110to reaction chamber115and a closed position in which reaction chamber115is separated from piston chamber110to prevent back flow. In one embodiment, valve410can be implemented through the use of a material that allows material to flow into reaction chamber115but that prevents back flow into piston chamber110. For example, valve410may be configured as a membrane that separates the piston chamber110from the reaction chamber115, wherein the membrane only allows unidirectional flow from the piston chamber110to the reaction chamber115, so that a new mixture can be introduced into the piston chamber110after the mixture is pushed into the reaction chamber115. Valve410may be formed from any biocompatible material such as but not limited to plastic, glass, stainless steel, etc.

In an illustrative embodiment, piston300is in the uncompressed position and valve310is in the closed position prior to transferring the mixture of hydrogel solution and cell suspension from piston chamber110to reaction chamber115. The mixture can be moved into reaction chamber115by opening valve410and moving piston300into the compressed position as illustrated inFIG. 4. In one embodiment, valve410is configured to automatically open as piston300begins moving into the compressed position. In an alternative embodiment, valve410may be manually controlled and/or computer controlled. As piston300is moved from the uncompressed position to the compressed position, the mixture is forced through capillaries400and into reaction chamber115. In one embodiment, partial compression of piston300(e.g., an embodiment in which piston300is not fully compressed) may be sufficient to force the mixture through capillaries400. Valve410is closed to separate piston chamber110from reaction chamber115when piston300reaches the compressed position and the mixture is transferred.

In an illustrative embodiment, reaction chamber115includes a cross-linking initiator solution that is based at least in part on the type of hydrogel used in the hydrogel solution. In an illustrative embodiment, reaction chamber115has sufficient volume to hold both the cross-linking initiator solution and the mixture of hydrogel solution and cell suspension. The composition of the cross-linking initiator solution may depend on the chemistry of the hydrogel used. For example, in the case of alginate hydrogels or hydrogels that are cross-linked in the presence of ions, a solution with the appropriate ion can be used as known to those of skill in the art. As an example, if the hydrogel used is an alginate suspension, the cross-linking initiator solution can include Ca2+such that cross-linking occurs between the hydrogel and the cells. In one embodiment in which alginate is used as the hydrogel, a solution with calcium chloride (CaCl) can be used to crosslink the hydrogel by exposing the pre-polymeric materials to the CaCl solution. In an illustrative embodiment, the Ca2+containing solution can be made at different concentrations to adjust the time that it takes for crosslinking to occur (e.g., a higher concentration can decrease the time that it takes for crosslinking to occur) and/or the desired final properties of the hydrogel. In one embodiment, the initial concentration of Ca2+ used can be approximately 50 milli-Moles (mM), however other concentrations such as 10 mM, 25 mM, 60 mM, 80 mM, etc. can be used depending on the embodiment. In the case of hydrogels that involve a chemical initiation, a solution with the chemical initiator at the appropriate concentration can be used as known to those of skill in the art.

Referring again toFIG. 1, reaction chamber115includes pump120that is connected to an inlet conduit130of reaction chamber115and to an outlet conduit135of reaction chamber115. Pump120circulates the cross-linking initiator solution in reaction chamber115and creates a fluid current (or flow) through reaction chamber115. The fluid flow rate (or current) can depend at least in part on the size of capillaries400. If each capillary has a diameter of 0.5 mm, the flow rate in each capillary can be approximately 1-2 milliliters/minute (mL/min). This flow rate can be increased by using capillaries with larger diameters, or decreased by using capillaries with smaller diameters. The fluid flow rate can also depend at least in part on the flow rate of pump120. Pump120can be any type of fluid pump known to those of skill in the art. In an illustrative embodiment, due to their mass, the cells and hydrogels are not circulated through outlet conduit135, pump120, and inlet conduit130. In another alternative embodiment, reaction chamber115may include one or more additional pumps and corresponding conduits to help circulate the cross-linking initiator and create the fluid flow.

As described above, the hydrogel solution and cell suspension mixture is passed through capillaries400so that the hydrogels are formed into worm-like cylindrical structures. The current within reaction chamber115helps draw the mixture into reaction chamber115. The current also helps maintain the hydrogels as worm-like structures as the hydrogels are released from capillaries400. The cross-linking initiator solution in reaction chamber115causes the worm-like hydrogels to encapsulate the cells and form encapsulated cells (or tissue scaffolds) as known to those of skill in the art. The encapsulation is possible due at least in part to the pores inside the hydrogels which partially or fully encapsulate the cells as a result of contact with the cross-linking initiator. The chemical or physical crosslinking in the hydrogel has a pore size distribution. As the crosslinks are initiated, the cells are encaged within these pores inside the polymer. As long as the hydrogel maintains its structure, the cells can be encapsulated within the pores of the gel. In one embodiment, the hydrogel can also be used for chemical signaling. For example, if biologically active chemicals, peptides, or proteins are used to decorate the hydrogel structure, these chemicals can be used to stimulate the cells in many different ways as known to those of skill in the art. In the simplest form, the hydrogel should serve as the platform in which the cells are encaged, supporting them in a three-dimensional structure. In an illustrative embodiment, the hydrogel dimensions also allow for the mass transfer of nutrients to the cells and increases the viability of the cells in the artificial constructs as known to those of skill in the art.

Reaction chamber115includes a valve137that is used to separate reaction chamber115from ejection chamber125. Valve137can be made from any biocompatible material known to those of skill in the art. Depending on the embodiment, valve137can be manually controlled and/or automatically controlled by a motor or other actuator. When valve137is in an open position (as illustrated inFIG. 1), the fluid flow (or current) within reaction chamber115causes the encapsulated cells to accumulate within ejection chamber125. In some embodiments, outlet conduit135may be re-positioned on a side, etc. of reaction chamber115to help accumulate the encapsulated cells in ejection chamber125.FIG. 1illustrates an accumulation of encapsulated cells140within ejection chamber125. Once the encapsulated cells are accumulated within ejection chamber125, valve137is closed such that ejection chamber125is separated from reaction chamber115.

FIG. 5Ais a partial view of bioreactor100illustrating reaction chamber115and ejection chamber125in accordance with an illustrative embodiment.FIG. 5Bis a partial view of bioreactor100illustrating ejection of encapsulated cells140in accordance with an illustrative embodiment. InFIGS. 5A and 5B, valve137is in the closed position such that ejection chamber125is separated from reaction chamber115. Ejection chamber125includes a piston500that is configured to eject encapsulated cells140from bioreactor100. Ejection chamber125also includes a valve505through which encapsulated cells140are ejected. Valve505is in the closed position inFIG. 5A, and in the open position inFIG. 5B. In one embodiment, ejection chamber125can be detachable from reaction chamber115through, in non-limiting examples, a threaded connection, friction fit, etc. so that ejection chamber125and encapsulated cells140can be removed and transported to another location as appropriate. In another embodiment, ejection chamber125and/or piston500may not be included. In such an embodiment, encapsulated cells140can be removed directly from reaction chamber115by scooping, etc.

In an illustrative embodiment, encapsulated cells140are accumulated in ejection chamber125as described above with reference toFIG. 4. Once encapsulated cells140are within ejection chamber125, valve137is placed in the closed position. In one embodiment, a microscopy tool may be used to determine when to close valve137and/or when to eject encapsulated cells140. Any microscopy tool known to those of skill in the art may be used. The microscopy tool can be any type of optical tool that can be used to determine that encapsulated cells140have been formed and/or are ready for removal. In one embodiment, the microscopy tool can form part of bioreactor100. Alternatively, the microscopy tool may be a handheld or other tool that can be used independent of bioreactor100. In another alternative embodiment, the microscopy tool may not be used. The encapsulated cells140are removed from bioreactor100by opening valve505and activating piston500as illustrated inFIG. 5B. The encapsulated cells140(or tissue scaffolds) can be used to form tissue as known to those of skill in the art.

In an illustrative embodiment, bioreactor100is able to mass produce encapsulated cells in a continuous and efficient manner. For example, as soon as a first mixture is transferred from mixing chamber105to piston chamber110, valve310is closed so that mixing chamber105can receive additional hydrogel solution and cell suspension to form a second mixture. As soon as the first mixture is pushed into reaction chamber115by piston300, valve410is closed, valve310is opened, and piston300is moved from the compressed position into the uncompressed position to draw the second mixture into piston chamber110. The first mixture goes through reaction chamber115and the encapsulated cells140are gathered in ejection chamber125. Once valve137is closed to separate reaction chamber115and ejection chamber125, encapsulated cells140formed from the first mixture are ejected and the second mixture is introduced into reaction chamber115. The process continues with a third mixture, fourth mixture, etc. such that bioreactor100is able to generate encapsulated cells in a continuous manner. In some embodiments, one or more portions (or the entire device) are replaced and/or cleaned and sterilized in between batches.

FIG. 6is a flow diagram illustrating operations performed by a bioreactor in accordance with an illustrative embodiment. In alternative embodiments, fewer, additional, and/or different operations may be performed. In addition, the use of a flow diagram is not meant to be limiting with respect to the order of operations performed. A hydrogel solution and cell suspension are mixed in a mixing chamber in an operation600. The mixing chamber can be mixing chamber105described with reference toFIGS. 1-5. In an illustrative embodiment, the hydrogel solution and the cell suspension are provided to the mixing chamber through respective reservoirs that are in fluid communication with the mixing chamber.

The mixture is transferred from the mixing chamber to a piston chamber in an operation605. In one embodiment, piston chamber is piston chamber110described with reference toFIGS. 1-5. The piston chamber can include a piston that is used to draw the mixture from the mixing chamber into the piston chamber through a valve that separates the two chambers. Once the mixture is drawn into the piston chamber, the valve can be placed into the closed position to separate the mixing chamber from the piston chamber. The mixture is forced through capillaries and into a reaction chamber in an operation610. In an illustrative embodiment, reaction chamber can be reaction chamber115described with reference toFIGS. 1-5. In one embodiment, a valve separates the piston chamber from the reaction chamber. With the valve placed in an open position, the piston within piston chamber can be used to force the mixture through the capillaries and into the reaction chamber. The valve can be placed in a closed position once the mixture is within the reaction chamber. As such, additional mixture can be drawn into the piston chamber.

The mixture is reacted with a crosslinking initiator to form encapsulated cells in an operation615. In an illustrative embodiment, the reaction occurs within the reaction chamber. The crosslinking initiator can be circulated throughout the reaction chamber using one or more pumps such that a current is formed in the reaction chamber. The encapsulated cells are gathered in an ejection chamber in an operation620. In an illustrative embodiment, the encapsulated cells are pushed into the ejection chamber at least in part by the current generated in the reaction chamber as a result of the crosslinking initiator flow. The encapsulated cells are ejected from the ejection chamber in an operation625.

FIG. 7is a block diagram illustrating a computer system700for controlling a bioreactor in accordance with an illustrative embodiment. Computer system700can be in wired or wireless communication with the bioreactor, depending on the embodiment. Computer system700includes a memory705, a processor710, a transceiver715, and a user interface720. Memory705can be any type of computer memory known to those of skill in the art. In an illustrative embodiment, memory705can store computer-readable instructions that, when executed, cause a bioreactor to perform any of the operations described herein. Examples of computer controlled operations can include, but are not limited to, controlling the valves to place desired amounts of the hydrogel solution and/or the cell suspension from their respective reservoirs into the mixing chamber, controlling the venting valve of the mixing chamber, controlling the impeller or other method for mixing the hydrogel solution and the cell suspension in the mixing chamber, control the amount of time that mixing occurs in the mixing chamber, controlling the valve between the mixing chamber and the piston chamber, controlling movement of the piston, controlling operation of the pump and/or flow rate of the pump, controlling movement of the valve that is used to separate the reaction chamber from the ejection chamber, controlling the valve through which encapsulated cells140are ejected from the ejection chamber, etc. Processor710, which can be any type of processor known to those of skill in the art, can be configured to execute the computer-readable instructions stored in memory705. Transceiver715can be used to transmit and receive data from remote sources. In one embodiment, transceiver715is configured to receive instructions for controlling the bioreactor from a remote location. User interface720allows an operator to interact with and control computer system700and/or the bioreactor. User interface720can include a keyboard, a display, a mouse, a touch screen, etc.