Multicompartment macroencapsulation devices

Abstract

To provide multicompartment macroencapsulation devices.SOLUTION: Macroencapsulation devices and their methods of use are disclosed. In one embodiment, a macroencapsulation device may include a first outer membrane, a second outer membrane, and at least one semipermeable membrane disposed therebetween so as to form at least a primary compartment configured to house a first population of cells and a secondary compartment in fluid communication with the primary compartment through the first semipermeable membrane. In some embodiments, the flow of material into and out of the compartments of the macroencapsulation device and / or the application of an appropriate pressure differential between the compartments may be used to control the flow of filtrates, ancillary agents, and other materials between the compartments of the device when positioned in vivo.SELECTED DRAWING: Figure 1B

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62 / 828,915, filed on April 3, 2019. The disclosure of this document is hereby incorporated by reference in its entirety into this specification. The disclosed embodiments relate to multi - chamber macro - encapsulation devices.

Background Art

[0002] To treat metabolic disorders such as diabetes, treatment devices for delivering biological agents can be used. The treatment devices can be implantable to provide biological agents such as insulin over a long period. Some of these devices include macro - encapsulation devices used to contain cells for producing the desired biological agent, a matrix containing cells, or other desired therapeutic agents inside.

Summary of the Invention

Means for Solving the Problems

[0003] In one embodiment, the macro - encapsulation device includes a first outer membrane, a second outer membrane, and a first semi - permeable membrane disposed between the first outer membrane and the second outer membrane. A primary chamber is formed by the first semi - permeable membrane and the first outer membrane, and the primary chamber is configured to contain a first cell population. A secondary chamber is formed by the first semi - permeable membrane and the second outer membrane. The primary chamber and the secondary chamber are in fluid communication through the first semi - permeable membrane.

[0004] In another embodiment, the macro - encapsulation device includes a primary chamber configured to contain a first cell population and a secondary chamber. The primary chamber and the secondary chamber are in fluid communication through a first semi - permeable membrane disposed between the primary chamber and the secondary chamber.

[0005] In yet other embodiments, a method of using a macroencapsulation device includes filling a first cell population into a primary chamber of the macroencapsulation device and applying a pressure difference between the primary chamber and a secondary chamber of the macroencapsulation device to flow filtrate from the primary chamber through a first semipermeable membrane into the secondary chamber.

[0006] In still other embodiments, a method of using a macroencapsulation device includes filling a first cell population into a primary chamber of the macroencapsulation device and flowing an adjuvant from the secondary chamber of the macroencapsulation device through a first semipermeable membrane into the primary chamber.

[0007] Another aspect provided herein is an implantable macroencapsulation device. The device includes a first outer membrane, a second outer membrane, and a first semipermeable membrane attached between the first outer membrane and the second outer membrane. The first semipermeable membrane and the first outer membrane are connected to form a primary chamber configured to provide a primary chamber for containing a cell population. The first semipermeable membrane and the second outer membrane are connected to form a secondary chamber. The cell population includes pancreatic progenitor cells, endocrine cells, or beta cells, or any combination thereof. The device includes a plurality of through-holes through the first outer membrane, the second outer membrane, and the first semipermeable membrane. In some embodiments, the first outer membrane, the second outer membrane, and the first semipermeable membrane are configured to block movement of the cell population out of the device.

[0008] In some embodiments, the device further includes a second semipermeable membrane attached between the first semipermeable membrane and the second outer membrane, forming a tertiary chamber between the primary chamber and the secondary chamber. In some embodiments, the water permeability of the first semipermeable membrane is greater than the water permeability of the first outer membrane, the second outer membrane, or both. In some embodiments, the water permeability of the first semipermeable membrane is at least about 25% greater than the water permeability of the first outer membrane, the second outer membrane, or both. In some embodiments, the water permeability of the first semipermeable membrane is greater than the water permeability of the second semipermeable membrane. In some embodiments, the water permeability of the first semipermeable membrane is less than the water permeability of the second semipermeable membrane. In some embodiments, the porosity of the first semipermeable membrane is greater than the porosity of the first outer membrane, the second outer membrane, or both. In some embodiments, the porosity of the first semipermeable membrane is at least about 25% greater than the porosity of the first outer membrane, the second outer membrane, or both. In some embodiments, the porosity of the first semipermeable membrane is greater than the porosity of the second semipermeable membrane. In some embodiments, the porosity of the first semipermeable membrane is less than the porosity of the second semipermeable membrane. In some embodiments, the flux of the first semipermeable membrane for a given material and driving force (e.g., concentration gradient and / or pressure difference) is greater than the flux of the first outer membrane, the second outer membrane, or both for the same material and driving force. In some embodiments, the flux of the first semipermeable membrane for a given material and driving force (e.g., concentration gradient and / or pressure difference) is at least about 25% greater than the flux of the first outer membrane, the second outer membrane, or both for the same material and driving force. In some embodiments, the flux of the first semipermeable membrane for a given material and driving force (e.g., concentration gradient and / or pressure difference) is greater than the flux of the second semipermeable membrane for the same material and driving force. In some embodiments, the flux of the first semipermeable membrane for a given material and driving force (e.g., concentration gradient and / or pressure difference) is less than the flux of the second semipermeable membrane for the same material and driving force. In some embodiments, the device further includes a primary port in fluid communication with the primary chamber, a secondary port in fluid communication with the secondary chamber, or any combination thereof.In some embodiments, the device further includes a primary port in fluid communication with a primary chamber, a secondary port in fluid communication with a secondary chamber, a tertiary port in fluid communication with a tertiary chamber, or any combination thereof. In some embodiments, at least one of the primary port, the secondary port, or the tertiary port is sealable or resealable.

[0009] Another aspect provided herein is an implantable macroencapsulation device. The device includes a primary chamber configured to house one or more cells and a secondary chamber. The primary chamber and the secondary chamber are separated by a first semipermeable membrane. The secondary chamber and the first semipermeable membrane are configured to i) filter the filtrate from the primary chamber, or ii) provide an adjuvant to one or more cells in the primary chamber, or both i) and ii). The one or more cells are encapsulated within the device in a range of about 10 3 ~ about 10 6 cells per μL of volume within the device.

[0010] In some embodiments, the device further includes a tertiary chamber. The tertiary chamber and the secondary chamber are separated by a second semipermeable membrane. The second semipermeable membrane is configured to i) filter the filtrate from the tertiary chamber, or ii) provide an adjuvant to one or more cells in the tertiary chamber, or both i) and ii). In some embodiments, the device further includes at least one of a primary port in fluid communication with the primary chamber or a secondary port in fluid communication with the secondary chamber. In some embodiments, the device further includes at least one of a primary port in fluid communication with the primary chamber, a secondary port in fluid communication with the secondary chamber, or a tertiary port in fluid communication with the tertiary chamber. In some embodiments, at least one of the primary port, the secondary port, or the tertiary port is sealable or resealable. In some embodiments, the device includes a plurality of through-holes extending through a layered membrane from one side of the device to the opposite side of the device.

[0011] In some embodiments, one or more of the through-holes are surrounded by a bonding portion of the film forming the seal. In some embodiments, the device includes three or more seals. In some embodiments, the device includes two or more self-crossing seals. In some embodiments, the device includes two or more elliptical seals. In some embodiments, the seal is formed by an adhesive, an epoxy, welding, any combination thereof, and / or any other suitable bonding method. In some embodiments, the first semipermeable membrane is configured to block the movement of the one or more cells. In some embodiments, the primary chamber and the secondary chamber are configured to block the movement of the one or more cells. In some embodiments, the primary chamber, the secondary chamber, and the tertiary chamber are configured to block the movement of the one or more cells.

[0012] Another aspect provided herein is a method. The method includes providing a macroencapsulation device including a primary chamber and a secondary chamber configured to contain one or more cells, the primary chamber and the secondary chamber being separated by a first semipermeable membrane, the secondary chamber and the semipermeable membrane being configured to i) filter the filtrate from the primary chamber, or ii) provide an adjuvant to one or more cells in the primary chamber, or both i) and ii); causing pre-angiogenesis in the macroencapsulation device; filling the primary chamber with one or more cells; and applying pressure to the secondary chamber to remove the filtrate from the primary chamber.

[0013] In some embodiments, the filtrate is removed from the primary chamber. In some embodiments, the method further includes administering an adjuvant into the primary chamber, the secondary chamber, or both. In some embodiments, the adjuvant includes a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. In some embodiments, administering the adjuvant is performed after applying a negative pressure to the secondary chamber, although any method that provides a desired pressure difference between the secondary chamber and another chamber of the macroencapsulation device may also be used. In some embodiments, the method further includes expanding the primary chamber, the secondary chamber, or both. In some embodiments, expanding the primary chamber, the secondary chamber, or both is performed before causing angiogenesis in the macroencapsulation device. In some embodiments, the method further includes sealing the primary chamber, the secondary chamber, or both. In some embodiments, the method further includes resealing the primary port, the secondary port, or both. In some embodiments, the housing further includes a tertiary chamber separated from the secondary chamber by a second semipermeable membrane. The method further includes filling the tertiary chamber with one or more cells. In some embodiments, the method further includes administering an adjuvant into the primary chamber, the secondary chamber, the tertiary chamber, or any combination thereof. In some embodiments, the method further includes expanding the primary chamber, the secondary chamber, the tertiary chamber, or any combination thereof. In some embodiments, the method further includes sealing the primary chamber, the secondary chamber, the tertiary chamber, or any combination thereof. In some embodiments, the method further includes resealing the primary port, the secondary port, the tertiary chamber, or any combination thereof.

[0014] Another aspect provided herein is a method. The method comprises providing a macroencapsulation device comprising a first outer membrane, a second outer membrane, and a first semipermeable membrane attached between the first outer membrane and the second outer membrane, wherein the first semipermeable membrane and the first outer membrane are connected to form a primary chamber configured to contain a cell population, and the first semipermeable membrane and the second outer membrane are connected to form a secondary chamber; causing pre-angiogenesis in the macroencapsulation device; filling the primary chamber with one or more cells; and applying a pressure difference to the secondary chamber to remove filtrate from the primary chamber.

[0015] In some embodiments, the filtrate is removed from the primary chamber. In some embodiments, the method further includes administering an adjuvant into the primary chamber, or the secondary chamber, or both. In some embodiments, the adjuvant includes a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. In some embodiments, administering the adjuvant is performed after applying a negative pressure or other pressure difference to the secondary chamber. In some embodiments, the method further includes expanding the primary chamber, or the secondary chamber, or both. In some embodiments, expanding the primary chamber, or the secondary chamber, or both is performed before causing angiogenesis in the macroencapsulation device. In some embodiments, the method further includes sealing the primary chamber, or the secondary chamber, or both. In some embodiments, the method further includes resealing the primary port, the secondary port, or both. In some embodiments, the macroencapsulation device further includes a tertiary chamber separated from the secondary chamber by a second semipermeable membrane, and the method further includes filling the tertiary chamber with one or more cells. In some embodiments, the method further includes administering an adjuvant into the primary chamber, the secondary chamber, the tertiary chamber, or any combination thereof. In some embodiments, the filtrate is removed from the primary chamber, the tertiary chamber, or both. In some embodiments, the method further includes expanding the primary chamber, the secondary chamber, the tertiary chamber, or any combination thereof. In some embodiments, the method further includes sealing the primary chamber, the secondary chamber, or the tertiary chamber, or any combination thereof. In some embodiments, the method further includes resealing the primary port, the secondary port, the tertiary chamber, or any combination thereof.

[0016] Since the present disclosure is not limited in this regard, it should be noted that the above-described ideas and the further ideas described below can be arranged in any suitable combination. Furthermore, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.

[0017] If the present specification and the documents incorporated by reference contain disclosures that are inconsistent and / or lack coherence, the present specification shall prevail. If two or more documents incorporated by reference contain disclosures that are inconsistent and / or lack coherence with each other, the document with the later effective date shall prevail. The present invention provides, for example, the following. (Item 1) A macroencapsulation device, a first outer membrane, a second outer membrane, a first semipermeable membrane disposed between the first outer membrane and the second outer membrane, a primary chamber formed by the first semipermeable membrane and the first outer membrane, the primary chamber being configured to accommodate a first cell population, the primary chamber, a secondary chamber formed by the first semipermeable membrane and the second outer membrane, the primary chamber and the secondary chamber being in fluid communication through the first semipermeable membrane, the secondary chamber, comprising the macroencapsulation device. (Item 2) The macroencapsulation device according to item 1, wherein the first semipermeable membrane is configured to block the movement of the first cell population between the primary and secondary chambers and allow the flow of filtrate and / or adjuvant between the primary chamber and the secondary chamber. (Item 3) The macroencapsulation device according to any one of items 1 or 2, further comprising the first cell population disposed in the primary chamber. (Item 4) The macroencapsulation device according to any one of items 1 to 3, wherein the first and second outer membranes are configured to block the movement of the cell population out of the device. (Item 5) The macroencapsulation device according to any one of items 1 to 4, wherein the first and / or second outer membrane is semi-permeable. (Item 6) The macroencapsulation device according to any one of items 1 to 5, further comprising a second semi-permeable membrane disposed between the first semi-permeable membrane and the second outer membrane, and a tertiary chamber disposed between the second semi-permeable membrane and the second outer membrane. (Item 7) The macroencapsulation device according to item 6, wherein the water permeability and / or porosity of the first semi-permeable membrane is different from the water permeability and / or porosity of the second semi-permeable membrane. (Item 8) The macroencapsulation device according to any one of items 6 or 7, wherein the tertiary chamber is configured to accommodate a second cell population. (Item 9) The macroencapsulation device according to item 8, further comprising the first cell population disposed in the primary chamber and the second cell population disposed in the tertiary chamber, wherein the first and second cell populations comprise different types of cells. (Item 10) The macroencapsulation device according to any one of items 1 to 9, wherein the water permeability and / or porosity of the first semi-permeable membrane is different from the water permeability and / or porosity of the first and / or second outer membrane. (Item 11) The macroencapsulation device according to any one of items 1 to 10, further comprising a primary port in fluid communication with the primary chamber and a secondary port in fluid communication with the secondary chamber. (Item 12) The macroencapsulation device according to item 11, wherein the primary port and the secondary port are sealable or resealable. (Item 13) A macroencapsulation device, A primary chamber configured to accommodate a first cell population, A secondary chamber, wherein the primary chamber and the secondary chamber are in fluid communication through a first semipermeable membrane disposed between the primary chamber and the secondary chamber, the macroencapsulation device comprising the secondary chamber. (Item 14) The macroencapsulation device according to item 13, wherein the first semipermeable membrane is configured to block the movement of the first cell population between the primary and secondary chambers and allow the flow of filtrate and / or adjuvant between the primary chamber and the secondary chamber. (Item 15) The macroencapsulation device according to any one of items 13 or 14, further comprising the first cell population disposed in the primary chamber. (Item 16) The macroencapsulation device according to any one of items 13 to 15, further comprising a tertiary chamber, wherein the secondary chamber is disposed between the primary chamber and the tertiary chamber, and the tertiary chamber and the secondary chamber are in fluid communication through a second semipermeable membrane disposed between the secondary chamber and the tertiary chamber. (Item 17) The macroencapsulation device according to item 16, wherein the water permeability and / or porosity of the first semipermeable membrane is different from the water permeability and / or porosity of the second semipermeable membrane. (Item 18) The macroencapsulation device according to any one of items 16 or 17, wherein the tertiary chamber is configured to accommodate a second cell population. (Item 19) The macroencapsulation device according to item 18, further comprising the first cell population disposed in the primary chamber and the second cell population disposed in the tertiary chamber, wherein the first and second cell populations comprise different types of cells. (Item 20) The macroencapsulation device according to any one of items 13 to 19, further comprising a primary port in fluid communication with the primary chamber and a secondary port in fluid communication with the secondary chamber. (Item 21) The macroencapsulation device according to item 20, wherein the primary port and the secondary port are sealable or resealable. (Item 22) A method of using a macroencapsulation device, comprising: filling a first cell population into a primary chamber of the macroencapsulation device; applying a pressure difference between the primary chamber and a secondary chamber of the macroencapsulation device to allow filtrate to flow from the primary chamber to the secondary chamber through a first semipermeable membrane; (Item 23) The method according to item 22, further comprising flowing an adjuvant from the secondary chamber into the primary chamber through the first semipermeable membrane. (Item 24) The method according to item 23, wherein the adjuvant includes a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. (Item 25) The method according to any one of items 22 to 24, further comprising inducing angiogenesis in the macroencapsulation device before filling the first cell population. (Item 26) The method according to item 25, further comprising expanding the primary and / or secondary chambers before angiogenesis. (Item 27) The method according to any one of items 22 to 26, further comprising removing the filtrate from the secondary chamber. (Item 28) The method according to any one of items 22 to 27, further comprising filling a second cell population into a tertiary chamber and applying the pressure difference between the tertiary chamber and the secondary chamber to allow filtrate to flow from the tertiary chamber to the secondary chamber through a second semipermeable membrane. (Item 29) The method according to any one of items 22 to 28, further comprising administering an adjuvant into the secondary chamber and flowing the adjuvant from the secondary chamber into the primary chamber through the first semipermeable membrane. (Item 30) A method using a macroencapsulation device, comprising: filling a first cell population into a primary chamber of the macroencapsulation device; flowing an adjuvant from a secondary chamber of the macroencapsulation device into the primary chamber through a first semipermeable membrane, said method. (Item 31) The method according to Item 30, wherein the adjuvant contains a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. (Item 32) The method according to any one of Items 30 or 31, further comprising causing angiogenesis in the macroencapsulation device before filling the first cell population. (Item 33) The method according to Item 32, further comprising expanding the primary and / or secondary chambers before angiogenesis. (Item 34) The method according to any one of Items 30 to 33, further comprising applying a pressure difference between the primary chamber and the secondary chamber to flow filtrate from the primary chamber to the secondary chamber through the first semipermeable membrane. (Item 35) The method according to any one of Items 30 to 34, further comprising removing the filtrate from the secondary chamber. (Item 36) The method according to any one of Items 30 to 35, further comprising filling a second cell population into a tertiary chamber and flowing the adjuvant from the secondary chamber into the tertiary chamber through a second semipermeable membrane.

[0018] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or almost identical component illustrated in various figures may be represented by the same numerals. For clarity, not all components in all drawings may be labeled. In the drawings.

Brief Description of the Drawings

[0019]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 2A

Figure 2B

Figure 3

Figure 4A

Figure 4B

Figure 5

DETAILED DESCRIPTION OF THE INVENTION

[0020] Some macroencapsulation devices are configured to implant cells into a host without pre-angiogenic support from the surrounding tissue. However, cells implanted through such devices often suffer from hypoxia or nutrient deprivation during the period between implantation and angiogenesis. Since angiogenesis often takes more than a week, such adverse cell states often result in cell necrosis and subsequent outflow of immunogenic cell debris. As a result, a foreign body reaction is induced, ultimately leading to device failure. In contrast, a pre-angiogenized device is implanted into the body in an empty state and integrated with the host before introducing any cell material. Such devices have been shown to enhance cell survival.

[0021] While advantageous, the inventors understand that filling a macroencapsulation device surrounded by and integrated with host tissue with cells has proven difficult thus far. First, introducing cells into a pre-angiogenized macroencapsulation device typically involves using ultrafiltration and pressure and / or very high concentrations of cells within the device to provide the desired amount of cells within the device. While it may be possible to introduce an effective cell density within the device by ultrafiltration and pressure, the forces exerted through the membrane during ultrafiltration can lead to dissociation of the device from the newly formed microvasculature and / or exacerbation of the foreign body reaction due to tissue trauma. Additionally, filling the macroencapsulation device with a high concentration of cells can result in shear forces on the surface of the cells during filling. As a result, cell aggregation may occur, which can form blockages within the device, damaging the cells and / or preventing the device from being filled to the desired effective cell density.

[0022] In view of the above, the inventors appreciate the benefits associated with a macroencapsulation device that includes a plurality of internal chambers having at least partially the same extent and that are in fluid communication with each other through one or more semipermeable inner membranes disposed between these chambers. Such a configuration can allow at least one of the chambers to be configured to receive one or more desired cell populations, while at least one of the other chambers (e.g., a secondary chamber) can be in fluid communication with one or more of the chambers containing cells. As a result, the filtrate from one or more of the chambers containing cells can flow through the semipermeable membrane into one or more other chambers (e.g., a secondary chamber). Optionally, this filtrate can be removed from this secondary chamber. Also, a desired adjuvant can be introduced into the device using this secondary chamber. The adjuvant can then flow through the semipermeable membrane disposed between the chambers into one or more of the chambers containing cells. Such a device can substantially prevent and / or at least reduce trauma to the integrated tissue around the device and the cells contained within the device during the filling process.

[0023] In one embodiment, a macroencapsulation device can be formed by a first outer membrane and a second outer membrane. The first and second outer membranes can be joined to each other in any suitable manner to form an internal volume between the first and second outer membranes. For example, portions of the first and second outer membranes that extend at least partially along the perimeter of the membrane can be joined to each other directly or indirectly. For example, the membrane can be folded back and joined along its free edge so that a single membrane functions as both the first and second outer membranes. Alternatively, two separate outer membranes can be joined at portions that extend along their entire perimeter, but any suitable method of forming an internal volume using a membrane material can be used. In either case, the macroencapsulation device can also include at least a first semipermeable membrane disposed between the first and second outer membranes. The first semipermeable membrane divides the internal volume into a primary chamber and a secondary chamber that are in fluid communication with each other through the first semipermeable membrane. The first chamber can be configured to accommodate a first cell population that can be filled in the primary chamber. Thus, the macroencapsulation device can be configured such that filtrate from the primary chamber can flow into the secondary chamber and / or an adjuvant can be introduced into the secondary chamber and then flow into the primary chamber where the cells are placed as described in detail below.

[0024] In some embodiments, the macroencapsulation device can also include at least a second semipermeable membrane disposed between the first semipermeable membrane and the second outer membrane. A secondary chamber can be formed between the first and second semipermeable membranes, and a tertiary chamber can be formed between the second semipermeable membrane and the second outer membrane. Thus, the tertiary chamber can be in fluid communication with the secondary chamber through the second semipermeable membrane. Further, in some embodiments, the secondary chamber can be disposed between the primary and tertiary chambers. In some embodiments, the tertiary chamber can also be configured to accommodate a second cell population. Thus, it is the same as described above that filtrate can also flow from the tertiary chamber into the secondary chamber and / or an adjuvant can flow from the secondary chamber into the tertiary chamber. Depending on the particular embodiment, the second cell population can be the same as and / or different from the cell population held in the primary chamber of the macroencapsulation device.

[0025] It should be understood that the filtrate and / or adjuvant flowing through various compartments of the macroencapsulation device can be urged to flow through the compartments in some suitable manner. For example, in some embodiments, a pressure difference can be applied between adjacent compartments to induce the filtrate and / or adjuvant to flow from one compartment to another. For example, the pressure in a particular compartment can be increased by the flow of material into the compartment and / or the pressure in an adjacent compartment can be decreased using the vacuum applied to that compartment. In either case, the hydrostatic pressure, pressure difference, flow rate, shear stress, and / or other suitable operating parameters applied to the cells can be controlled to avoid cell aggregation and / or death. For example, in some embodiments, the pressure difference between two adjacent compartments can be maintained below a threshold pressure to help maintain cell viability. Further, in some embodiments where an adjuvant is applied, the adjuvant can be introduced into a secondary compartment, although there may be little or no pressure difference between the secondary compartment and the adjacent compartment containing the cell population. In such embodiments, when the concentration of the adjuvant in the secondary compartment is greater than the concentration of the adjuvant in the adjacent compartment containing the cell population, the adjuvant can flow into these other compartments by diffusion of the adjuvant due to concentration gradient-induced diffusion.

[0026] Suitable types of filtrate that can be used when filling the compartments of the macroencapsulation device with a cell population can include, but are not limited to: cell culture medium, alginate, extracellular matrix protein, platelet-rich plasma, thrombin, poly(vinyl alcohol), poly(ethylene glycol), propylene glycol, cryopreservation solutions, and pectin. It should of course be understood that any suitable type of filtrate that is biologically compatible with the host and cell population can be used, since the present disclosure is not limited to any particular type of filtrate.

[0027] In embodiments where an adjuvant is provided to the secondary chamber of the macroencapsulation device, the adjuvant can correspond to any suitable agent, as the present disclosure is not limited to any particular agent. For example, in some embodiments, it may be desirable to provide an agent that promotes oxygen addition to cells, a secondary therapeutic agent for the host, and / or any other suitable agent to provide a desired function for the macroencapsulation device. Thus, the present disclosure is not so limited, and the adjuvant may include therapeutic agents such as drugs, oxygen producers, anticoagulants, nutrients, anti-inflammatory agents, steroids, growth factors, prodrugs, immunomodulatory molecules, differentiation factors, any combination thereof, and / or any other suitable agent.

[0028] As described above, in some cases, it may be useful to induce pre-angiogenesis in the macroencapsulation device prior to introducing the cell population. Again, this can improve the flow of nutrients to the cells placed inside the device, increase the flow of waste products and / or therapeutic agents from the device to the host, and / or reduce the occurrence of fibrosis in response to implantation of the device. Thus, in some embodiments, the macroencapsulation device can be implanted to induce pre-angiogenesis during a first period. In such embodiments, at least one of the first and second membranes is configured to allow angiogenesis of the cells within the device. In some embodiments, at least one of the first and second membranes is configured to enable, support, or allow angiogenesis of the cells inside and around the device, in the absence of an immunosuppressive therapeutic agent or with fewer immunosuppressive therapeutic agents compared to an equivalent device that does not support such angiogenesis. In some cases, this may include using a plurality of through-holes extending from a first surface of the macroencapsulation device through an intervening membrane to a second opposing surface of the macroencapsulation device. In such embodiments, vascular structures can grow through and within these through-holes.

[0029] During this pre-angiogenesis period, it may be useful to expand the device to help maintain the membrane of the macroencapsulation device and the corresponding compartments in an appropriate configuration for subsequently filling the device with a cell population. Thus, in some embodiments, fluid may be introduced into one or more compartments of the macroencapsulation device either before, during, and / or after implantation to expand one or more compartments. This may include expanding the primary, secondary, and / or tertiary compartments of the macroencapsulation device. Suitable types of fluid that may be used to expand the various compartments of the macroencapsulation device may include, but are not limited to, the following: oxygen, saline, cell culture medium, alginate, chitosan, glucose, perfluorocarbon, combinations thereof, and / or any other suitable fluid that can expand the device. In some cases, the outer membrane of the macroencapsulation device may be configured to hold the expansion fluid inside the device during implantation to prevent collapse of the membrane structure during the pre-angiogenesis period. And the macroencapsulation device may be left implanted for an appropriate period of time to allow the macroencapsulation device to integrate with the surrounding tissue and for the vasculature to establish a desired flow of nutrients to the macroencapsulation device. And one or more desired cell populations may be filled into one or more compartments of the macroencapsulation device as further described below.

[0030] In some embodiments of the various macroencapsulation devices disclosed herein, at least one of the first outer membrane and the second outer membrane is semipermeable. For example, either one of the outer membranes can be semipermeable and the other substantially impermeable, or both can be semipermeable. In some embodiments, the semipermeability of the first membrane, the second membrane, or both, is configured to protect the cells from immune attack and / or block the movement of cell populations out of the device, while allowing the movement of desired biological agents produced by the cells and the waste products and nutrients used and produced by the cells. In some embodiments, the semipermeability of the first membrane, the second membrane, or both, is configured to protect the cells from immune attack in the absence of immunosuppressive therapy. Thus, the first outer membrane, the second outer membrane, or both can be configured to be substantially impermeable to one or more cell populations within the device, the filtrate contained within the device, adjuvants, or any combination thereof.

[0031] In addition to the relative durability of the outer membrane, one or more semipermeable membranes placed within the internal volume of the macroencapsulation device can also be appropriately configured to control the flow of one or more materials between the various compartments of the macroencapsulation device. For example, in the various embodiments described herein, the first semipermeable membrane, the second semipermeable membrane, and / or any suitable number of semipermeable membranes disposed within the internal volume of the device can be substantially permeable to the filtrate flowing from one compartment to another, the adjuvants to be provided to the interior of the device, or both. Further, the internal semipermeable membranes can also be substantially impermeable to one or more cell populations disposed within the macroencapsulation device. Thus, the internal semipermeable membranes can be configured to prevent the flow of cells between adjacent compartments while allowing the flow of filtrate and / or adjuvants between them.

[0032] In view of the above, the water permeability, pore size, and / or porosity of the internal semipermeable membrane (e.g., the first and / or second semipermeable membrane) may be different from those of the first and / or second outer membranes of the macroencapsulation device. For example, the water permeability of the first and / or second semipermeable membrane may be greater than that of one or both of the first and second outer membranes. This may correspond to an increase in the porosity, pore size of the internal semipermeable membrane relative to the outer membrane, or other suitable differences in material parameters. Similarly, depending on the particular embodiment, the first outer membrane and the second outer membrane may have the same or different water permeability, pore size, and / or porosity from each other. For example, if different materials are contained in separate compartments formed by the first and second outer membranes (e.g., different cell populations are contained), the water permeability exhibited by the first outer membrane may be smaller or larger than that of the second outer membrane so as to obtain a desired combination of membrane properties adapted separately to each cell population. Similarly, in situations where multiple internal semipermeable membranes (e.g., the first and second semipermeable membranes disposed between two outer membranes) are used, the water permeability, pore size, and / or porosity exhibited by the internal semipermeable membranes may be the same and / or different. For example, the water permeability of the first semipermeable membrane may be greater or smaller than that of the second semipermeable membrane.

[0033] In view of the above, in some embodiments, the water permeability exhibited by the internal semipermeable membrane (e.g., the first and / or second semipermeable membrane) disposed between two outer membranes may be at least about 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% greater than the water permeability of either or both of the outer membranes. Ranges spanning between any of the aforementioned percentages are also contemplated. For example, the water permeability of the internal semipermeable membrane may be about 25% to 100% greater than the water permeability of either or both of the outer membranes. In some embodiments, this difference in water permeability may be with respect to the outer membrane in which the internal semipermeable membrane is disposed to form the corresponding compartment. Of course, the present disclosure is not so limited, and greater and smaller water permeabilities than those described above are also contemplated.

[0034] The relative water permeability of the various membranes described above can be measured by any suitable method. For example, the relative water permeability of different membrane materials can be measured using constant head or constant pressure measurements with a suitable fluid (e.g., water) for a given sample configuration, as is known in the art. Of course, since the present disclosure is not limited to a particular method of measuring these relative parameters, the relative water permeability of the membranes can be determined using any suitable flow testing method, calculation, or modeling method.

[0035] As described above, in some embodiments, the porosity and / or pore size of one or more of the internal semipermeable membranes of the macroencapsulation device may be greater than the porosity and / or pore size of one or both of the first and second outer membranes in order to provide a desired difference in the relative water permeability of the various membranes of the macroencapsulation device. Again, in some embodiments, this difference may be with respect to adjacent outer membranes. In either case, the porosity and / or pore size of the internal semipermeable membrane may be at least about 25%, 30%, 35%, 40%, 45%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% greater than the porosity and / or pore size of one or both of the outer membranes. Ranges spanning between any of the aforementioned percentages are also contemplated. For example, the porosity and / or pore size of the internal semipermeable membrane may be about 25% to 100% greater than the pore size and / or porosity of one or both of the outer membranes. In addition to the foregoing, in some embodiments, the porosity and / or pore size of the first semipermeable membrane may differ from the porosity and / or pore size of the second semipermeable membrane disposed between the outer membranes.

[0036] Taking into account the differences in the above material parameters, the flux of a given material across the internal semipermeable membrane under a given pressure difference and / or concentration gradient may be greater than the flux of the same material across either or both of the outer membranes under the same pressure difference and / or concentration gradient. Similarly, depending on the desired application, the hydraulic properties exhibited by the first and second outer membranes may be the same or different. Thus, the flux of material across the first and second outer membranes of the macroencapsulation device under a particular pressure difference and / or concentration gradient may be substantially the same as or different from each other. For example, the flux across the first outer membrane may be smaller or larger than the flux across the second outer membrane under the same biasing. Similarly, the flux of material across the first semipermeable membrane disposed between the outer membranes of the device may be different from (i.e., smaller or larger than) the flux of material across the second semipermeable membrane. The difference in the flux of material across different membranes may be greater than about a 5% difference in relative flux. Suitable materials that may be subject to this difference in flux may include, but are not limited to, the following: insulin, small molecule therapeutics, growth factors, antibodies, antibody fragments, immunomodulatory factors, complement complexes, cell fragments, enzymes, alginate, saline, and cell culture media. Again, the present disclosure is not limited as to how the relative flux is measured, and the relative flux of a given material across various membranes may be measured using any suitable flow testing method, calculation, or modeling method, including the following: for example, constant head or pressure difference measurements, concentration gradient measurements across the membrane, and / or any other suitable method.

[0037] Note that the various relationships of permeability, pore size, porosity, relative flux, and other material parameters described herein may apply to any of the described embodiments of the macroencapsulation device. However, note that the present disclosure is not limited to only such a specific range of material properties and relative performance parameters. For example, the range of permeability, pore size, porosity, relative flux, and other material parameters exhibited by both the internal semipermeable membrane and the outer membranes is not so limited by the present disclosure and may be greater or smaller than the specific ranges and relationships described herein.

[0038] The various membranes of the macroencapsulation device (including the outer membrane and / or the internal semipermeable membrane) can be formed from any suitable biocompatible material. The biocompatible material can be substantially inert with respect to the cells, filtrate, adjuvants, or any combination thereof contained within the macroencapsulation device. The biocompatible material can include synthetic polymers or naturally occurring polymers. In some embodiments, without being so limited in this disclosure, the polymer can also be a linear polymer, a crosslinked polymer, a network polymer, an addition polymer, a condensation polymer, an elastomer, a fibrous polymer, a thermoplastic polymer, a non-degradable polymer, combinations thereof, and / or any other suitable type of polymer. Suitable types of polymers can include the following. Polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), polystyrene (PS), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyurethane (PU), polyamide (nylon), polyethylene terephthalate (PET), polyethersulfone (PES), polyetherimide (PEI), polyvinylidene difluoride (PVDF), polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), poly-L-lactide (PLLA), any combination thereof, and / or any other suitable polymeric material. Synthetic methods used to form one or more of the porous membranes from the aforementioned polymeric materials can include, but are not limited to, the following. Swelling, solution casting method, immersion precipitation and phase separation, electrospinning, methods for obtaining an isotropic network, methods for obtaining a columnar network, or any other suitable method for forming a porous polymer membrane. In some embodiments, sintering of the porous polymer membrane can be used to change the porosity of the membrane. This can then be used to adjust the porosity and flux characteristics of the macroencapsulation device. Thus, in some embodiments, any desired combination of external and / or internal semipermeable membranes can be sintered or non-sintered using any suitable sintering method according to the specific membrane material.

[0039] The polymeric material is as described above, although embodiments are contemplated in which the membrane is at least partially formed from a non-polymeric material. The present disclosure is not limited to any particular material from which the membrane is formed, and suitable membrane materials can include, for example, ceramic materials, polymer-ceramic composite materials, and / or any other suitable material that can function as a membrane within an embedded macroencapsulation device.

[0040] The inner and outer membranes of the macroencapsulation device described herein can be formed from a porous membrane material configured to allow the following to be transported through the membrane of the material. For example, a biological agent having a molecular weight of less than about 3000 kDa, less than 2000 kDa, less than 1000 kDa, less than 500 kDa, less than 400 kDa, less than 300 kDa, less than 200 kDa, less than 100 kDa, less than 50 kDa, less than 40 kDa, less than 30 kDa, less than 20 kDa, less than 10 kDa, less than 6 kDa, less than 5 kDa, less than 4 kDa, less than 3 kDa, less than 2 kDa, less than 1 kDa, and / or any other suitable range of molecular weights depending on the desired application. For example, one or more membranes of the macroencapsulation device can be configured to allow insulin having a molecular weight of about 5.8 kDa to flow through the membrane.

[0041] To provide the desired selectivity, the porous membrane used with the macroencapsulation device disclosed herein has an open porous structure and an average pore size of about 1 nm or more, 5 nm or more, 10 nm or more, 15 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, 50 nm or more, 60 nm or more, 70 nm or more, 80 nm or more, 90 nm or more, 100 nm or more, 200 nm or more, 300 nm or more, and / or any other suitable size range. Correspondingly, the average pore size of the various membranes described herein is such that the average pore size is 2500 nm or less, 2000 nm or less, 1700 nm or less, 1500 nm or less, 1400 nm or less, 1300 nm or less, 1200 nm or less, 1100 nm or less, 1000 nm or less, 900 nm or less, 800 nm or less, 700 nm or less, 600 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, 200 nm or less, 100 nm or less, 90 nm or less, 80 nm or less, 70 nm or less, 60 nm or less, 50 nm or less, 40 nm or less, 30 nm or less, 20 nm or less, and / or any other suitable size range. The foregoing combinations are contemplated, for example, an average pore size of 1 nm to 20 nm (including both ends), 1 nm to 2500 nm (including both ends), and / or any other suitable combination. Of course, while a particular average pore size has been described above, any suitable average pore size may be used for the various membranes described herein, and it should be noted that this includes both average pore sizes larger and smaller than those described above.

[0042] To provide sufficient strength and / or rigidity to the macroencapsulation device, the various membranes can be formed from sufficiently rigid materials. The desired rigidity can be provided through an appropriate combination of the Young's modulus, thickness, and overall configuration of the material that can be balanced with the desired permeability of the device. Suitable Young's moduli for the various membranes described herein are at least 10 5 Pa, 10 6 Pa, 10 7 Pa, 10 8 Pa, 10 9 Pa, 10 10It can be Pa, and / or any other suitable elastic modulus that is both greater than and less than these ranges. Of course, it is considered that the ranges between the above-mentioned Young's moduli are included. For example, about 10 6 Pa to 10 10 Pa (including both ends) is the Young's modulus.

[0043] In some embodiments, it may be desirable for one or more of the membranes included within the macroencapsulation device to be hydrophilic in order to facilitate filling the device with cells and / or to facilitate the flow of one or more filtrates, biological compounds, therapeutic agents, or other materials into, out of, and / or between different compartments of the device. Additionally, a hydrophilic outer membrane may reduce the occurrence of fibrosis when the device is located within a living body. Thus, the inner and outer membranes of the macroencapsulation device can be formed from hydrophilic materials and / or treated with a hydrophilic coating. Suitable materials for forming the hydrophilic coating can include, but are not limited to, the following. Suitable hydrophilic polymers, polyethylene glycol, polyvinyl alcohol, polydopamine, any combination thereof, and / or any other suitable hydrophilic material capable of forming a coating on the membrane.

[0044] The present disclosure is not so limited, and the membranes described in various embodiments of the macroencapsulation device described herein may be bonded to each other using any suitable bonding method. For example, adjacent membranes can be bonded to each other using the following. Adhesives, epoxies, welding or other fusion-based techniques (such as ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using frames or fixtures, and / or any other suitable bonding method. In one particular embodiment, the bonding of adjacent membranes can be performed using a heated tool used to press or abut two or more membranes against each other for a set fusion time with a predetermined pressure and / or force. It should be noted that in view of the above, the present disclosure is not limited to using any particular method for bonding the membranes to each other.

[0045] The macroencapsulation device described in this specification may have any suitable combination of internal volume, outer dimensions, and / or other suitable physical parameters. For example, the internal volume enclosed by the outer membrane of the macroencapsulation device may be from 40 μL to 250 μL (including both ends). Also, the width or maximum cross-sectional dimension of the macroencapsulation device may be about 20 mm to 80 mm. Further, in order to perform desired oxygen diffusion into the macroencapsulation device to support the cells contained therein, the maximum oxygen diffusion distance from the outside of the device containing the cell population to the inside of the device may be less than 50 μm, less than 100 μm, less than 150 μm, less than 200 μm, less than 250 μm, less than 300 μm, less than 350 μm, less than 400 μm, less than 450 μm, or less than 500 μm. Correspondingly, the maximum thickness of the entire device and / or the dimension perpendicular to the maximum cross-sectional dimension of the chamber within the device may be less than 50 μm, less than 100 μm, less than 150 μm, less than 200 μm, less than 250 μm, less than 300 μm, less than 350 μm, less than 400 μm, less than 450 μm, or less than 500 μm. Further, in some embodiments, the surface area-to-volume ratio of the device is about 20 cm -1 or more, 40 cm -1 or more, 60 cm -1 or more, 80 cm -1 or more, 100 cm -1 or more, 120 cm -1 or more, or 150 cm -1 or more. Ranges spanning between any of the aforementioned values for the various dimensions and parameters are also contemplated. Further, while specific ranges of parameters for the entire macroencapsulation device have been shown above, the present disclosure is not limited to any particular size or configuration, and larger and smaller operating parameters and dimensions than those described above are contemplated.

[0046] As described in detail below, in some embodiments, the formation of the chambers within the macroencapsulation device can be performed such that the internal volume of these chambers is subdivided into a plurality of interconnected channels. The channels can be shaped like lumens in some embodiments, although any suitable shape or configuration of the channels can also be used. The maximum cross-sectional dimension (e.g., inner diameter) inside the channels can be 40 μm or more, 50 μm or more, 100 μm or more, 200 μm or more, 300 μm or more, 400 μm or more, and / or any other suitable dimension. Correspondingly, the maximum cross-sectional dimension inside the channels can be 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, and / or any other suitable dimension. The aforementioned combinations are contemplated, for example, the maximum cross-sectional dimension inside the plurality of channels is 40 μm to 800 μm (including both ends). Further, the density of the interconnected channels forming the various chambers of the device is such that the density per unit area within the cross-section of the device is about 10 channels / cm 2 or more, 15 channels / cm 2 or more, 20 channels / cm 2 or more, 25 channels / cm 2 or more, 30 channels / cm 2 or more, 35 channels / cm 2 or more, 40 channels / cm 2 or more, 45 channels / cm 2 or more, 50 channels / cm 2 or more, 60 channels / cm 2 or more, 70 channels / cm 2 or more, 80 channels / cm 2 or more, 90 channels / cm 2 or more, 100 channels / cm 2 or more, 110 channels / cm 2 or more, 120 channels / cm 2 or more, 130 channels / cm 2 or more, 140 channels / cm 2 or more, 150 channels / cm 2 or more, 175 channels / cm2 or more, or 200 channels / cm 2The above is the case. Ranges spanning between any of the aforementioned channel densities are also conceivable. For example, the channel density is about 10 channels / cm 2 ~200 channels / cm 2 (including both ends). However, both greater and smaller densities than the aforementioned ranges are also conceivable.

[0047] Specific dimensions and relationships related to the macroencapsulation device and the materials from which the macroencapsulation device is formed have been described above. Naturally, however, the present disclosure is not limited in this way, and dimensions and relationships greater and smaller than those described above are conceivable. Thus, depending on the desired application, any suitable size, configuration, and / or relative performance parameters may be used for the device.

[0048] In some embodiments, the cell population contained within the chamber of the macroencapsulation device can be a population of insulin-secreting cells. In some embodiments, the cell population includes at least one cell obtained from stem cell-derived cells. In some embodiments, the at least one cell is a genetically modified cell. Optionally, the at least one cell is genetically modified to suppress the immune response in the subject at the time of device implantation compared to an equivalent cell that has not been genetically modified. In some embodiments, the cell population is a stem cell-derived cell capable of glucose-stimulated insulin secretion (GSIS). For example, suitable cell populations can include pancreatic progenitor cells, endocrine cells, beta cells, a matrix comprising one or more of the foregoing, or any combination thereof. Further, the matrix can include isolated islet cells, isolated cells from the pancreas, isolated cells from a tissue, stem cells, stem cell-derived cells, induced pluripotent cells, differentiated cells, transformed cells, or an expression system (capable of synthesizing one or more biological agents). Optionally, in some embodiments, the matrix can include a second type of cell that supports a first type of cell that synthesizes one or more biological agents. In some embodiments, the cells can be encapsulated prior to being placed within the matrix. In such embodiments, the cells can be encapsulated within microcapsules or conformally coated. However, naked (i.e., uncoated) cells can also be used.

[0049] Depending on a particular embodiment, a therapeutically effective density of cells can be loaded into one or more compartments of a macroencapsulation device. A suitable cell density disposed within the compartment can be about 1000 cells / μL or more, 10,000 cells / μL or more, 50,000 cells / μL or more, 100,000 cells / μL or more, 500,000 or more, and / or any other suitable cell density. Also, a suitable cell density disposed within the compartment can be about 1,000,000 cells / μL or less, 500,000 cells / μL or less, 100,000 cells / μL or less, 50,000 cells / μL or less, 10,000 cells / μL or less, and / or any other suitable cell density. The foregoing combinations are contemplated and cell densities from about 1000 cells / μL to 1,000,000 cells / μL are included. Of course, depending on the desired application and the cell type being used, both cell densities greater than and less than those described above can also be used.

[0050] The macroencapsulation devices described herein can be implanted at various sites within the body of a subject. In one example, the device can be implanted into the subject by preperitoneal or retromuscular implantation. In another example, the device can be placed by omental implantation. In another example, the device can be placed by subcutaneous implantation. In another example, the device can be placed by suprahepatic implantation. In some cases, the macroencapsulation devices described herein can be fixed at the implantation site within the body using any suitable fixation method (e.g., application of a tissue adhesive, etc.). Suitable tissue adhesives can include, but are not limited to, the following. Fibrin, cyanoacrylate, polyethylene glycol, albumin-based adhesives, polymer-based adhesives, and / or any other suitable adhesive. The present disclosure is not so limited and in another example, fixation of the device may be performed using platelet-rich plasma and / or any other suitable fixation method.

[0051] With reference to the figures, specific non-limiting embodiments will be described in more detail. Of course, the present disclosure is not limited only to the specific embodiments described herein, and the various systems, components, features, and methods described for these embodiments can be used separately and / or in any desired combination.

[0052] FIGS. 1A-1D illustrate one embodiment of an implantable macroencapsulation device 100 configured to encapsulate a cell population. Again, the cell population can include at least one of pancreatic progenitor cells, endocrine cells, beta cells, and / or any other suitable cell population, as described herein. In the illustrated embodiment, the macroencapsulation device has a generally flat planar configuration that extends in a direction parallel to the cross-section in which the device is oriented. Although the macroencapsulation device shown in the figures has a generally round planar shape, the present disclosure is not so limited, and other shapes including squares, rectangles, hexagons, triangles, and / or any other suitable shape including non-planar configurations are also contemplated.

[0053] The macroencapsulation device 100 includes a first outer membrane 102, which is disposed on a second outer membrane 104. At least a portion of the first and second outer membranes can be joined to each other to form an internal volume disposed therebetween. For example, as illustrated in the figures, the first and second outer membranes can be joined to each other at least at a portion 106 or other suitable portion that extends along the perimeter of the membrane to form a desired internal volume. In some embodiments, the device may also include a frame 108 attached to one or more portions of the device. In the illustrated embodiment, the frame is attached to and extends along the outer perimeter of the macroencapsulation device. However, a situation where the frame extends only along a part of the perimeter of the device is also contemplated. The present disclosure is not so limited, and the frame may be attached to the outer membrane using any suitable method including, but not limited to, adhesives, epoxies, mechanical fasteners, thermal bonding, and / or any other suitable bonding method.

[0054] As described above, the macroencapsulation device described in this specification may include two or more internal compartments having at least partially the same extent as each other in a plane parallel to the plane in which the macroencapsulation device can extend substantially. Further, in some embodiments, two or more compartments may have the same extent as each other along substantially their entire transverse region parallel to this plane. The embodiment shown in FIGS. 1A-1D is a three-compartment device including a primary compartment 120, a secondary compartment 122, and a tertiary compartment 124. For clarity, a single group of compartments is illustrated. However, of course, the present disclosure is not limited to devices using a single group of compartments extending across the entire surface area of the device, and macroencapsulation devices including multiple groups of related compartments arranged in different parts of the macroencapsulation device are also contemplated. The specific arrangement of the membranes and these compartments will be further described below.

[0055] As illustrated in the figure, the macroencapsulation device 100 may include a first outer membrane 102, a second outer membrane 104, a first semipermeable membrane 116, and a second semipermeable membrane 118. The device may also include a primary compartment 120, a secondary compartment 122, and a tertiary compartment 124. In the illustrated embodiment, the first semipermeable membrane is disposed relative to the first outer membrane, the second semipermeable membrane is disposed on the side opposite the first outer membrane relative to the first semipermeable membrane, and the second outer membrane is disposed on the side opposite the first outer membrane and the first semipermeable membrane relative to the second semipermeable membrane. The various membranes may be bonded to each other and / or connected in other ways using any of the bonding methods shown so far. Thus, the first semipermeable membrane may be attached between the first outer membrane and the second semipermeable membrane, and the second semipermeable membrane may be attached between the first semipermeable membrane and the second outer membrane. Further, the membranes may be appropriately shaped and disposed such that the first semipermeable membrane and the first outer membrane form a primary compartment between the opposing surfaces of the first semipermeable membrane and the first outer membrane. Correspondingly, the second semipermeable membrane and the second outer membrane may cooperate to form a secondary compartment between the opposing surfaces of the second semipermeable membrane and the second outer member. Also, the first semipermeable membrane and the second semipermeable membrane may form a tertiary compartment between the opposing surfaces of the first and second semipermeable membranes.

[0056] The figures illustrate a single continuous membrane for various membranes, but in some embodiments, one or more of the first outer membrane 102, the second outer membrane 104, the first semipermeable membrane 116, and the second semipermeable membrane 118 can be formed from a plurality of connected membranes used to form the entire membrane.

[0057] In view of the above configuration, the primary chamber 120 and the secondary chamber 122 can be separated by the first semipermeable membrane 116. Similarly, the tertiary chamber 124 and the secondary chamber 122 can be separated by the second semipermeable membrane 118. Thus, in an embodiment using three chambers, the secondary chamber is disposed between the primary chamber and the tertiary chamber. Further, the primary, secondary, and / or tertiary chambers can have the same extent as each other over at least a part (substantially all in some embodiments) of their cross-sectional areas with respect to a cross-section parallel to the plane in which the entire macroencapsulation device extends. The first and second semipermeable membranes placed inside the device are configured to be permeable to at least some materials (e.g., filtrate and / or adjuvants), so that the primary chamber can be in fluid communication with the secondary chamber through the first semipermeable membrane, and the secondary chamber and the tertiary chamber can be in fluid communication through the second semipermeable membrane.

[0058] As described above, in some embodiments, the macroencapsulation device 100 may include a plurality of through-holes 114 distributed across the planar surface of the device. The through-holes may extend from a first outer surface of the macroencapsulation device to an opposing outer surface of the macroencapsulation device and, in the illustrated embodiment, may correspond to through-holes that extend from the outer surface of the first outer membrane 102 to the opposing outer surface of the second outer membrane 104. The through-holes may be surrounded by corresponding bonding portions 110. The bonding portions may include the bonding portions of the first and second outer membranes, as well as any intermediate inner membranes (e.g., the first and second semi-permeable membranes 116 and 118) located between the outer membranes. The bonding portion surrounding each through-hole may form a seal between the interior of the device and the through-hole. By using these through-holes, more cells per unit area may be possible compared to a device with a flat configuration. This is because the amount of nutrients provided to the cells throughout the matrix can increase to support the viability and activity of the cells. Specifically, when implanted in vivo, the through-holes may allow vascular structures to grow around and through the device. In contrast, in the case of a typical device without through-holes, the vascular structures are limited to forming on the top and bottom surfaces of the device. The maximum cross-sectional dimension (e.g., diameter) of the through-hole may be measured at its narrowest point within a cross-section parallel to the cross-section in which the maximum cross-sectional dimension of the entire device extends. The size, number, and / or density of the through-holes may be appropriately selected to provide the desired performance of the device when located in vivo.

[0059] In some embodiments, at least one of the primary chamber 120, the secondary chamber 122, and the tertiary chamber 124 may include a continuous chamber. Alternatively, at least one of the primary chamber 120, the secondary chamber 122, and the tertiary chamber 124 may include a plurality of continuous interconnected chambers having any suitable shape. For example, the internal chambers shown in the figures correspond to a plurality of interconnected channels 112 corresponding to the internal volume of the chambers disposed between adjacent bonding portions 110 of the membrane corresponding to the locations of the plurality of through holes 114 located on the surface of the device. However, of course, the present disclosure is not limited in this way, and any suitable arrangement and / or shape of interconnected volumes and / or a single continuous volume may be used for each of the internal chambers.

[0060] In the foregoing embodiments, the primary chamber 120, the tertiary chamber 124, or both may be configured to provide a volume for accommodating one or more cell populations that may be the same as or different from each other. Correspondingly, the secondary chamber 122 may be configured to remove filtrate from the primary chamber, the secondary chamber, or both. The secondary chamber may also be configured to provide adjuvants to the primary chamber, the tertiary chamber, or both. Thus, in the illustrated embodiment, the first outer membrane 102, the second outer membrane 104, the first semipermeable membrane 116, and the second semipermeable membrane 118 may each be configured to block the movement of cell populations. Also, the first semipermeable membrane may be configured to allow filtrate to pass from the primary chamber to the secondary chamber. Similarly, the second semipermeable membrane may be configured to allow filtrate to pass from the tertiary chamber to the secondary chamber. Also, the first and / or second semipermeable membranes may be configured to allow adjuvants to pass from the tertiary chamber to the primary and tertiary chambers, respectively.

[0061] Also, as shown in FIGS. 1A-1B, the macroencapsulation device 100 can include at least one port that provides fluid communication between the exterior of the device and one or more chambers contained within the device. For example, a primary port 126 can be in fluid communication with a primary chamber 120, a secondary port 128 can be in fluid communication with a secondary chamber 122, and a tertiary port 130 can be in fluid communication with a tertiary chamber 124. In some embodiments, at least one (and in some cases, each) of the primary, secondary, and tertiary ports can be sealable or resealable to provide selective fluid communication between the corresponding internal chamber and the exterior of the macroencapsulation device. The primary port, secondary port, tertiary port, or any combination thereof can be configured to enable percutaneous access. In any case, as further described below, the various ports can provide access to the corresponding internal chambers of the device, introduce a cell population into the corresponding chamber, remove filtrate from the corresponding chamber, and / or introduce an adjuvant through one or more of the ports into the corresponding chamber.

[0062] The figures illustrate embodiments that use ports, but the present disclosure is not limited to macroencapsulation devices that include ports. For example, embodiments of macroencapsulation devices that can be completely sealed without using a primary, secondary, or tertiary port are also contemplated.

[0063] Figures 2A-2B show a simplified schematic view and an exploded schematic view of a macroencapsulation device 100 including first and second outer membranes 102 and 104 and first and second semipermeable membranes disposed therebetween. As described above, the membranes and the internal semipermeable membranes can be appropriately arranged and coupled to each other to form the aforementioned primary chamber 120, secondary chamber 122, and tertiary chamber 124 inside the device. Further, in the schematic view, a flat laminated arrangement consisting of each of these separate membranes within the coupling region is clearly illustrated. In an alternative embodiment, as shown in FIG. 3, the first and second semipermeable membranes disposed inside the device can be formed as a single internal membrane. In the illustrated embodiment, the semipermeable membrane is formed as an elongated lumen disposed between opposing first and second outer membranes. Thus, when the membranes are coupled to each other, the upper portion of the internal membrane adjacent to the first outer membrane can function as the first semipermeable membrane 116, and the lower portion of the internal membrane adjacent to the second outer membrane can function as the second semipermeable membrane member 118. Further, although separate first and second outer membranes are illustrated in the figure, of course, embodiments in which a single membrane is folded back to function as the first and second outer membranes are also conceivable.

[0064] The foregoing embodiments include three chambers, but in some embodiments, the macroencapsulation device 100 may not include the second semipermeable membrane 118. In such embodiments, the device may include only a primary chamber and a corresponding secondary chamber. For example, in FIGS. 4A and 4B, the macroencapsulation device 100 can be configured to encapsulate a cell population as described above. The device can include a first outer membrane 102, a second outer membrane 104, and a first semipermeable membrane 116 disposed between the first and second outer membranes. Thus, a primary chamber can be formed between the first semipermeable membrane and the first outer membrane, and a secondary chamber can be formed between the first semipermeable membrane and the second outer membrane. Similar to the three-chamber embodiments described above, the macroencapsulation device can include one or more ports (e.g., primary and secondary ports) in fluid communication with each of the primary and secondary chambers to provide fluid communication between the exterior of the device and the interior chambers. Again, in some embodiments, these ports can be sealable or resealable.

[0065] The first chamber 120 and the second chamber 122 can be separated from each other by the first semipermeable membrane 116 and be in fluid communication with each other through the first semipermeable membrane. In this embodiment, the first chamber, the second chamber, or both can be configured to provide a volume for accommodating one or more cell populations. Further, the second chamber can be configured to remove filtrate from the first chamber, provide adjuvants to the first chamber, or both, as described above.

[0066] In view of the above, the first outer membrane 102, the second outer membrane 104, and the first semipermeable membrane 116 can each be configured to block the movement of cell populations contained within the device. Also, the first semipermeable membrane can be configured such that filtrate can pass through the first semipermeable membrane from the first chamber 120 to the second chamber 122. Further, the first semipermeable membrane can be configured such that adjuvants can pass through the first semipermeable membrane from the second chamber to the first chamber, as described above.

[0067] For clarity, a method for using a macroencapsulation device including three internal chambers (i.e., a first chamber, a second chamber, and a third chamber) will be described in connection with FIGS. 5A - 5C. However, the present disclosure is not limited to using devices that include only two or three related chambers, and the relative flow of the methods and materials described below can be applied to devices including two, three, four, or any number of chambers.

[0068] Figures 5A - 5C show cross - sectional views of the macro - encapsulation device 100 taken through a portion of the device that includes a plurality of through - holes 114 similar to those described above in connection with Figures 1A - 1D. Thus, the macro - encapsulation device may include first and second outer membranes 102 and 104 together with first and second semi - permeable membranes 116 and 118. These cooperate to form a primary chamber 120, a secondary chamber 122, and a tertiary chamber 124. As will be described in more detail below, using the macro - encapsulation device may include any suitable combination of one or more of the following: implanting the device, pre - angiogenic activation of the device to form a microvascular system 132 that extends around and / or through the through - holes of the device, filling one or more cell populations into the primary and / or tertiary chambers, applying a pressure difference between the secondary chamber and the first and / or tertiary chambers to remove filtrate 136 from the primary and / or tertiary chambers, filling the secondary chamber with an adjuvant 138 (the adjuvant 138 can then flow into the first and / or tertiary chambers).

[0069] As described above, in some cases, after pre - angiogenic activation of the macro - encapsulation device 100, one or more cell populations 134 can be filled into the primary and / or tertiary chambers 120 and 124, although situations where the macro - encapsulation device is used without pre - angiogenesis are also contemplated. As shown in Figure 5A, pre - angiogenic activation of the device can be done by implanting the device for a predetermined angiogenesis period. During this period, the microvascular system can grow around and / or through the through - holes 114 of the device. The angiogenesis period can be 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 7 days or more, 8 days or more, 9 days or more, 10 days or more, or any other suitable period. Also, the angiogenesis period can be 10 weeks or less, 9 weeks or less, 8 weeks or less, 7 weeks or less, 6 weeks or less, 5 weeks or less, 4 weeks or less, 3 weeks or less, 2 weeks or less, 1 week or less, and / or any other suitable period. Combinations as described above are contemplated, for example, an angiogenesis period of 1 day to 10 weeks (including both ends). Of course, the present disclosure is not so limited, and both larger and smaller angiogenesis periods than those described above are also contemplated.

[0070] In some cases, it may be useful to expand the chambers of the device during the angiogenesis period to maintain the chambers in a desired expanded configuration. Thus, during pre-angiogenesis of the macroencapsulation device, the primary chamber 120, the secondary chamber 122, the tertiary chamber 124, or any combination thereof may be expanded. For example, fluid can be flowed into the primary, secondary, and / or tertiary chambers through one or more corresponding ports (not shown). Suitable fluids that can be used to expand the chambers can include any suitable biocompatible fluid. In some embodiments, it may be possible to retain fluid inside the device based on the corresponding properties of an outer membrane and / or an internal semipermeable membrane configured to retain fluid inside the device. Some examples of suitable fluids for expanding the chambers can include, but are not limited to, the following: oxygen, saline, cell culture medium, alginate, chitosan, glucose, perfluorocarbon, and combinations thereof. Once expanded to the desired pressure, volume, and / or other suitable parameters, the ports associated with the primary, secondary, and tertiary chambers can be sealed to maintain the corresponding chambers in the desired expanded configuration during angiogenesis of the device. After angiogenesis, the ports can be opened again and the fluid used to expand the chambers can be removed in some suitable manner.

[0071] As described above, in some embodiments, at least one of the primary chamber 120 and the tertiary chamber 124 may be configured to contain and hold one or more cell populations 134 therein. Also in this case, the primary chamber and the secondary chamber 122 may be separated by the first semipermeable membrane 116. Similarly, the secondary chamber and the tertiary chamber may be separated by the second semipermeable membrane 118. The first and second semipermeable membranes may be configured to filter the filtrate 136 from the primary chamber and / or the tertiary chamber. Thus, when the cell population is filled in the primary and / or tertiary chamber, the filtrate 136 is mixed with the cell population during filling and can flow from the primary and / or tertiary chamber, through the corresponding first and / or second semipermeable membrane, into the secondary chamber. The flow of materials into the secondary chamber can be facilitated by a pressure difference applied between the secondary chamber and at least one or both of the primary and tertiary chambers. This pressure difference can be provided by applying suction to the secondary chamber, an increase in pressure due to the flow of materials into the primary and / or tertiary chambers, the aforementioned combination, and / or any other suitable method of applying a bias to flow the filtrate into the secondary chamber. Further, in some embodiments, the filtrate can be removed through a corresponding port (not shown) during and / or after the filling process. Such filling of cells and removal of the filtrate can be performed percutaneously, but the present disclosure is not limited to only removing the filtrate through a percutaneously accessible port. Also in this case, although the figure shows a three-chamber device, the present disclosure is not limited in this way, and the aforementioned method may be applied to devices including two chambers and / or any other suitable number of chambers.

[0072] After filling the desired cell population 134 and / or removing the filtrate 136 within the macroencapsulation device 100, the adjuvant 138 can be provided to one or more cell populations that can be disposed within the primary chamber 120 and / or the tertiary chamber 124. For example, the adjuvant can be introduced into the secondary chamber 122 through a corresponding port (not shown). And the adjuvant can flow from the secondary chamber into the primary chamber and / or the tertiary chamber through the corresponding first and second semipermeable membranes 116 and 118. The flow of the adjuvant from the secondary chamber into the primary and tertiary chambers can be due to diffusion resulting from the concentration gradient between adjacent chambers and / or the pressure difference between adjacent chambers caused by the flow of the adjuvant into the secondary chamber. Similar to the case of removing the filtrate, in some embodiments, the adjuvant 138 can be filled transcutaneously into the secondary chamber, but other methods of introducing the adjuvant are also conceivable. In one particular embodiment, the administration of the adjuvant can be performed by connecting an indwelling tube to a subcutaneously placed port of the secondary chamber and flowing the adjuvant through the port into the secondary chamber and then into the primary and secondary chambers. The subcutaneously placed port can include a vascular access port. Of course, embodiments of directly filling the adjuvant into the primary and / or tertiary chambers through one or more corresponding ports are also conceivable. The present disclosure is not limited in this way, and as described above, the adjuvant may include anti-inflammatory drugs, oxygen-producing substances, differentiation factors, anticoagulation factors, nutrients, any combination thereof, and / or any other suitable drugs.

[0073] In the foregoing embodiments, the administration of the adjuvant can be performed one or more times at regular intervals. The regular intervals at which the adjuvant can be provided to the cells via the secondary chamber can be 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 1 hour or more, 2 hours or more, 5 hours or more, 10 hours or more, 1 day or more, 2 days or more, 5 days or more, and / or any other suitable time interval. Correspondingly, the time intervals between administering the adjuvant can be 60 weeks or less, 50 weeks or less, 20 weeks or less, 10 weeks or less, 5 weeks or less, 1 week or less, 5 days or less, 2 days or less, 1 day or less, and / or any other suitable time interval. Combinations within the above-described ranges are conceivable, for example, time intervals of 1 minute to 60 weeks (including both ends). Naturally, the present disclosure is not limited in this way, and both larger and smaller time intervals than those described above are also conceivable.

[0074] As described above, in some embodiments, a pressure difference can be applied between two or more of the chambers of the macroencapsulation device 100 to facilitate one or more of flowing cells into the chambers, flowing filtrate and / or adjuvant between the chambers, flowing filtrate out of the ports of the chambers, and / or flowing adjuvant through the ports into the corresponding chambers. For example, a pressure difference can be applied between the secondary chamber 122 and one or both of the primary chamber 120 and the tertiary chamber 124 to remove the filtrate 138 from the primary and tertiary chambers after pre-angiogenesis in the device. Applying a pressure difference between the secondary chamber and the primary and / or tertiary chambers can be performed simultaneously with or after filling of the cell population 134. Further, a negative pressure and / or a positive pressure can be applied to the corresponding chamber to generate a desired pressure difference. The present disclosure is not limited in this way, and for example, suction or vacuum can be applied to the chamber, a material can flow into another chamber to increase the pressure in that chamber, the above combinations, and / or any other suitable method can be used to generate a desired pressure difference. Further, in some cases, a concentration gradient can be used to induce the flow of material between the chambers. For example, a high concentration of adjuvant can be placed in the secondary chamber and can diffuse into other adjacent chambers that can have a much lower concentration of adjuvant.

[0075] Any suitable pressure difference can be applied to generate a desired flow of material within various portions of the macroencapsulation device. In some embodiments, however, the pressure difference applied between two adjacent chambers can be about 1 atmosphere or greater, 1.25 atmospheres or greater, 1.3 atmospheres or greater, 1.35 atmospheres or greater, 1.4 atmospheres or greater, 1.45 atmospheres or greater, 1.5 atmospheres or greater, and / or any other suitable pressure difference. Correspondingly, the pressure difference can be 3 atmospheres or less, 2.75 atmospheres or less, 2.5 atmospheres or less, 2.25 atmospheres or less, 2 atmospheres or less, 1.9 atmospheres or less, 1.8 atmospheres or less, 1.6 atmospheres or less, and / or another suitable pressure difference. Combinations of the ranges described above are contemplated, for example, including a pressure difference of about 1 atmosphere to 3 atmospheres (including both ends). Of course, it should be understood that any suitable pressure difference (including pressure differences greater than and less than those described above) can be used depending on the particular application.

[0076] Although the present teachings have been described in connection with various embodiments and examples, the present teachings are not intended to be limited to such embodiments or examples. On the contrary, the present teachings include various alternatives, modifications, and equivalents, as will be apparent to those skilled in the art. Accordingly, the foregoing description and drawings are merely illustrative.

Claims

1. A macroencapsulation device, wherein the macroencapsulation device comprises: a first outer membrane; a second outer membrane; a first semipermeable membrane disposed between the first outer membrane and the second outer membrane; a second semipermeable membrane disposed between the first semipermeable membrane and the second outer membrane; a primary chamber formed by the first semipermeable membrane and the first outer membrane, the primary chamber being configured to accommodate a first cell population; a secondary chamber formed by the first semipermeable membrane and the second semipermeable membrane, the primary chamber and the secondary chamber being in fluid communication through the first semipermeable membrane; a tertiary chamber disposed between the second semipermeable membrane and the second outer membrane, at least one of the internal volumes of the primary chamber, the secondary chamber, and the tertiary chamber being subdivided into a plurality of interconnected channels; A macroencapsulation device comprising the above.

2. The macroencapsulation device according to claim 1, wherein the first semipermeable membrane is configured to block the movement of the first cell population between the primary chamber and the secondary chamber and to allow the flow of filtrate and / or adjuvant between the primary chamber and the secondary chamber.

3. The macroencapsulation device according to claim 1 or claim 2, further comprising the first cell population disposed in the primary chamber.

4. The macroencapsulation device according to any one of claims 1 to 3, wherein the first outer membrane and the second outer membrane are configured to block the movement of the first cell population out of the macroencapsulation device.

5. The macroencapsulation device according to any one of claims 1 to 4, wherein the first outer membrane and / or the second outer membrane is semipermeable.

6. The macroencapsulation device according to any one of claims 1 to 5, wherein each of the primary chamber, the secondary chamber, and the tertiary chamber is formed as a plurality of interconnected channels.

7. The macroencapsulation device according to any one of claims 1 to 6, wherein the water permeability and / or porosity of the first semipermeable membrane is different from the water permeability and / or porosity of the second semipermeable membrane.

8. The macroencapsulation device according to any one of claims 1 to 7, wherein the tertiary chamber is configured to accommodate a second cell population.

9. The macroencapsulation device further includes the first cell population disposed in the primary chamber and the second cell population disposed in the tertiary chamber, the first cell population includes cells of a first type, the second cell population includes cells of a second type, and the second type is different from the first type. The macroencapsulation device according to claim 8.

10. The macroencapsulation device according to any one of claims 1 to 9, wherein the water permeability and / or porosity of the first semipermeable membrane is different from the water permeability and / or porosity of the first outer membrane and / or the second outer membrane.

11. The macroencapsulation device according to any one of claims 1 to 10, further including a primary port in fluid communication with the primary chamber and a secondary port in fluid communication with the secondary chamber.

12. The macroencapsulation device according to claim 11, wherein the primary port and the secondary port are sealable or resealable.

13. Each channel of the plurality of interconnected channels is formed as an elongated lumen. The macroencapsulation device according to any one of claims 1 to 12.

14. Each channel of the plurality of interconnected channels has a maximum inner diameter of 40 μm or more and 800 μm or less. The macroencapsulation device according to claim 13.

15. A macroencapsulation device, wherein the macroencapsulation device a primary chamber configured to accommodate a first cell population; a secondary chamber, wherein the primary chamber and the secondary chamber are in fluid communication through a first semipermeable membrane disposed between the primary chamber and the secondary chamber; a tertiary chamber, wherein the secondary chamber is disposed between the primary chamber and the tertiary chamber, the tertiary chamber and the secondary chamber are in fluid communication through a second semipermeable membrane disposed between the secondary chamber and the tertiary chamber, and at least one of the internal volumes of the primary chamber, the secondary chamber, and the tertiary chamber is subdivided into a plurality of interconnected channels. A macroencapsulation device including

16. The macroencapsulation device according to claim 15, wherein the first semipermeable membrane is configured to block the movement of the first cell population between the primary chamber and the secondary chamber and to allow the flow of filtrate and / or adjuvant between the primary chamber and the secondary chamber.

17. The macroencapsulation device according to any one of claims 15 or 16, further comprising the first cell population disposed in the primary chamber.

18. The macroencapsulation device according to any one of claims 15 or 16, wherein each of the primary chamber, the secondary chamber, and the tertiary chamber is formed as a plurality of interconnected channels.

19. The macroencapsulation device according to any one of claims 15 or 16 or 18, wherein the water permeability and / or porosity of the first semipermeable membrane is different from the water permeability and / or porosity of the second semipermeable membrane.

20. The macroencapsulation device according to any one of claims 15 or 16 or 18 or 19, wherein the tertiary chamber is configured to accommodate a second cell population.

21. The macroencapsulation device according to claim 20, further comprising the first cell population disposed in the primary chamber and the second cell population disposed in the tertiary chamber, wherein the first cell population includes cells of a first type, the second cell population includes cells of a second type, and the second type is different from the first type.

22. The macroencapsulation device according to any one of claims 15 to 21, further comprising a primary port in fluid communication with the primary chamber and a secondary port in fluid communication with the secondary chamber.

23. The macroencapsulation device according to claim 22, wherein the primary port and the secondary port are sealable or resealable.

24. The macroencapsulation device according to any one of claims 15 to 23, wherein each of the plurality of interconnected channels is formed as an elongated lumen.

25. The macroencapsulation device according to claim 24, wherein each of the plurality of interconnected channels has a maximum inner diameter of 40 μm or more and 800 μm or less.

26. A method of forming a macroencapsulation device without implantation or pre-angiogenesis, the method comprising: filling a first cell population into a primary chamber of the macroencapsulation device; applying a pressure difference between the primary chamber of the macroencapsulation device and a secondary chamber of the macroencapsulation device to cause filtrate to flow from the primary chamber through a first semipermeable membrane into the secondary chamber; filling a second cell population into a tertiary chamber and flowing an auxiliary agent from the secondary chamber through a second semipermeable membrane into the tertiary chamber, wherein at least one of the primary chamber, the secondary chamber, and the tertiary chamber is subdivided into a plurality of interconnected channels; A method comprising the above.

27. The method according to claim 26, further comprising flowing an auxiliary agent from the secondary chamber through the first semipermeable membrane into the primary chamber.

28. The method according to claim 27, wherein the auxiliary agent comprises a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof.

29. The method according to any one of claims 26 to 28, further comprising removing the filtrate from the secondary chamber.

30. The method according to any one of claims 26 to 29, further comprising filling a second cell population into a tertiary chamber and applying the pressure difference between the tertiary chamber and the secondary chamber to cause filtrate to flow from the tertiary chamber through a second semipermeable membrane into the secondary chamber.

31. The method according to any one of claims 26 to 30, further comprising administering an auxiliary agent into the secondary chamber and flowing the auxiliary agent from the secondary chamber through the first semipermeable membrane into the primary chamber.

32. The method according to any one of claims 26 to 31, wherein each of the plurality of interconnected channels is formed as an elongated lumen.

33. The macroencapsulation device according to claim 32, wherein each of the plurality of interconnected channels has a maximum inner diameter of 40 μm or more and 800 μm or less.

34. A method of forming a macroencapsulation device without implantation or pre-angiogenesis, the method comprising: Filling a first cell population into a primary chamber of a macroencapsulation device; Flowing an auxiliary agent from a secondary chamber of the macroencapsulation device into the primary chamber through a first semipermeable membrane; Filling a second cell population into a tertiary chamber and flowing the auxiliary agent from the secondary chamber into the tertiary chamber through a second semipermeable membrane, wherein at least one of the primary chamber, the secondary chamber, and the tertiary chamber is subdivided into a plurality of interconnected channels; A method comprising the above steps. **Claim 35** The method according to claim 34, wherein the auxiliary agent comprises a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. **Claim 36** The method according to any one of claims 34 to 35, further comprising flowing filtrate from the primary chamber to the secondary chamber through the first semipermeable membrane by applying a pressure difference between the primary chamber and the secondary chamber. **Claim 37** The method according to claim 36, further comprising removing the filtrate from the secondary chamber. **Claim 38** The method according to any one of claims 34 to 37, wherein each of the plurality of interconnected channels is formed as an elongated lumen. **Claim 39** The macroencapsulation device according to claim 38, wherein each of the plurality of interconnected channels has a maximum inner diameter of 40 μm or more and 800 μm or less.

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