Multi-compartment large capsule device

Abstract

A macrocapsule device and methods of using the same are disclosed. In one embodiment, the macrocapsule device may include a first outer membrane, a second outer membrane, and at least one semipermeable membrane disposed therebetween to form at least a primary compartment configured to house a first cell population and a secondary compartment in fluid communication with the primary compartment through the first semipermeable membrane. In some embodiments, when positioned in vivo, the flow of materials into and out of the compartments of the macrocapsule device and / or the application of an appropriate pressure differential between the compartments can be used to control the flow of filtrate, adjuvants, and other materials between the compartments of the device.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 828,915, filed on April 3, 2019, under 35 U.S.C. 119(e), the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The disclosed embodiments relate to a multi-compartment macrocapsule device. Background Art

[0004] Therapeutic devices that deliver biological products can be used to treat metabolic disorders, such as diabetes. Therapeutic devices can be implanted to provide biological products, such as insulin, over an extended period of time. Some of these devices include large capsule devices for containing cells for producing the desired biological product, a matrix containing the cells, or other desired therapeutic agents therein. Summary of the invention

[0005] In one embodiment, a macrocapsule device comprises: 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 compartment is formed by the first semi-permeable membrane and the first outer membrane, and the primary compartment is configured to accommodate a first cell population. A secondary compartment is formed by the first semi-permeable membrane and the second outer membrane. The primary compartment and the secondary compartment are in fluid communication through the first semi-permeable membrane.

[0006] In another embodiment, a macrocapsule device comprises: a primary compartment configured to contain a first cell population; and a secondary compartment, wherein the primary compartment and the secondary compartment are in fluid communication through a first semi-permeable membrane disposed between the primary compartment and the secondary compartment.

[0007] In yet another embodiment, a method of using a macrocapsule device comprises: loading a first cell population into a primary compartment of a macrocapsule device; and applying a pressure differential between the primary compartment and a secondary compartment of the macrocapsule device to cause filtrate to flow from the primary compartment to the secondary compartment through a first semipermeable membrane.

[0008] In yet another embodiment, a method of using a macrocapsule device comprises: loading a first cell population into a primary compartment of a macrocapsule device; and flowing an auxiliary agent from a secondary compartment of the macrocapsule device into the primary compartment across a first semipermeable membrane.

[0009] Another aspect provided herein is an implantable macrocapsule device, the device comprising: a first outer membrane; a second outer membrane; and a first semipermeable membrane, the first semipermeable membrane being 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 compartment, the primary compartment being configured to provide a primary compartment for accommodating a cell population; wherein the first semipermeable membrane and the second outer membrane are connected to form a secondary compartment; wherein the cell population comprises pancreatic progenitor cells, endocrine cells or beta cells or any combination thereof; and wherein the device comprises a plurality of through holes passing 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 the cell population from leaving the device.

[0010] In some embodiments, the device further comprises: a second semipermeable membrane, the second semipermeable membrane being attached between the first semipermeable membrane and the second outer membrane to form a tertiary compartment between the primary compartment and the secondary compartment. In some embodiments, the hydraulic permeability of the first semipermeable membrane is greater than the hydraulic permeability of the first outer membrane, the hydraulic permeability of the second outer membrane, or both. In some embodiments, the hydraulic permeability of the first semipermeable membrane is at least about 25% greater than the hydraulic permeability of the first outer membrane, the hydraulic permeability of the second outer membrane, or both. In some embodiments, the hydraulic permeability of the first semipermeable membrane is greater than the hydraulic permeability of the second semipermeable membrane. In some embodiments, the hydraulic permeability of the first semipermeable membrane is less than the hydraulic 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 porosity of 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 porosity of the second outer membrane, or both. In some embodiments, the porosity of the first semi-permeable film is greater than the porosity of the second semi-permeable film. In some embodiments, the porosity of the first semi-permeable film is less than the porosity of the second semi-permeable film. In some embodiments, for a given material and bias (e.g., concentration gradient and / or pressure difference), the flux of the first semi-permeable film is greater than the flux of the first outer film, the flux of the second outer film, or both for the same material and bias. In some embodiments, for a given material and bias (e.g., concentration gradient and / or pressure difference), the flux of the first semi-permeable film is greater than the flux of the first outer film, the flux of the second outer film, or both for the same material and bias. In some embodiments, for a given material and bias (e.g., concentration gradient and / or pressure difference), the flux of the first semi-permeable film is greater than the flux of the first outer film, the flux of the second outer film, or both for the same material and bias. In some embodiments, for a given material and bias (e.g., concentration gradient and / or pressure difference), the flux of the first semi-permeable film is greater than the flux of the second semi-permeable film for the same material and bias. In some embodiments, for a given material and bias (e.g., a concentration gradient and / or a pressure differential), the flux of the first semi-permeable membrane is less than the flux of the second semi-permeable membrane for the same material and bias. In some embodiments, the device further comprises: a primary port, the primary port being in fluid communication with the primary compartment; a secondary port, the secondary port being in fluid communication with the secondary compartment; or any combination thereof. In some embodiments, the device further comprises: a primary port, the primary port being in fluid communication with the primary compartment; a secondary port, the secondary port being in fluid communication with the secondary compartment; a tertiary port, the tertiary port being in fluid communication with the tertiary compartment; 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.

[0011] Another aspect provided herein is an implantable macrocapsule device comprising: a primary compartment configured to contain one or more cells; and a secondary compartment, wherein the primary compartment and the secondary compartment are separated by a first semi-permeable membrane, wherein the secondary compartment and the first semi-permeable membrane are configured to: i) filter filtrate from the primary compartment, or ii) provide an adjuvant to the one or more cells in the primary compartment, or both i) and ii); and wherein the one or more cells are present at a volume of about 10 μL per μL. 3 to about 10 6 A range of cells are encapsulated within the device.

[0012] In some embodiments, the device further comprises: a tertiary compartment, wherein the tertiary compartment and the secondary compartment are separated by a second semi-permeable membrane, wherein the second semi-permeable membrane is constructed to: i) filter the filtrate from the tertiary compartment, or ii) provide an auxiliary agent to one or more cells in the tertiary compartment, or both i) and ii). In some embodiments, the device further comprises at least one of the following: a primary port, the primary port is in fluid communication with the primary compartment; or a secondary port, the secondary port is in fluid communication with the secondary compartment. In some embodiments, the device further comprises at least one of the following: a primary port, the primary port is in fluid communication with the primary compartment; a secondary port, the secondary port is in fluid communication with the secondary compartment; or a tertiary port, the tertiary port is in fluid communication with the tertiary compartment. In some embodiments, at least one of the primary port, the secondary port or the tertiary port is sealable or resealable. In some embodiments, wherein the device comprises a plurality of through holes, the plurality of through holes extending from one side of the device through the layered membrane to the opposite side of the device.

[0013] In some embodiments, one or more of the through holes are surrounded by the bonding portion of the film to form a seal. In some embodiments, the device includes three or more seals. In some embodiments, the device includes two or more self-intersecting seals. In some embodiments, the device includes two or more elliptical seals. In some embodiments, the seal is formed by adhesive, epoxy resin, welding, any combination thereof and / or any other suitable bonding method. In some embodiments, the first semi-permeable membrane is constructed to block the one or more cells from passing through. In some embodiments, the primary compartment and the secondary compartment are constructed to block the one or more cells from passing through. In some embodiments, the primary compartment, the secondary compartment and the tertiary compartment are constructed to block the one or more cells from passing through.

[0014] Another aspect provided herein is a method comprising: providing a macrocapsule device comprising a primary compartment configured to accommodate one or more cells and a secondary compartment, wherein the primary compartment and the secondary compartment are separated by a first semi-permeable membrane, wherein the secondary compartment and the semi-permeable membrane are configured to: i) filter a filtrate from the primary compartment, or ii) provide an adjuvant to one or more cells in the primary compartment, or both i) and ii); prevascularizing the macrocapsule device; loading one or more cells into the primary compartment; and applying pressure to the secondary compartment to remove the filtrate from the primary compartment.

[0015] In some embodiments, the filtrate is removed from the primary compartment. In some embodiments, the method further comprises: applying an adjuvant to the primary compartment, the secondary compartment, or both. In some embodiments, the adjuvant comprises a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. In some embodiments, applying the adjuvant is performed after applying a negative pressure to the secondary compartment, but any method for providing a desired pressure difference to the secondary compartment relative to another compartment of the large capsule device may also be used. In some embodiments, the method further comprises: inflating the primary compartment, the secondary compartment, or both. In some embodiments, inflating the primary compartment, the secondary compartment, or both before prevascularizing the large capsule device. In some embodiments, the method further comprises: sealing the primary compartment, the secondary compartment, or both. In some embodiments, the method further comprises: resealing the primary port, the secondary port, or both. In some embodiments, the housing further comprises: a tertiary compartment, the tertiary compartment being separated from the secondary compartment by a second semi-permeable membrane, and wherein the method further comprises: loading one or more cells into the tertiary compartment. In some embodiments, the method further comprises: applying an adjuvant to the primary compartment, the secondary compartment, or the tertiary compartment, or any combination thereof. In some embodiments, the method further comprises: inflating the primary compartment, the secondary compartment, or the tertiary compartment, or any combination thereof. In some embodiments, the method further comprises: sealing the primary compartment, the secondary compartment, or the tertiary compartment, or any combination thereof. In some embodiments, the method further comprises: resealing the primary port, the secondary port, the tertiary port, or any combination thereof.

[0016] Another aspect provided herein is a method comprising: providing a large capsule device comprising: a first outer membrane; a second outer membrane; and a first semi-permeable membrane, wherein the first semi-permeable membrane is attached between the first outer membrane and the second outer membrane; wherein the first semi-permeable membrane and the first outer membrane are connected to form a primary compartment configured to accommodate a cell population; and wherein the first semi-permeable membrane and the second outer membrane are connected to form a secondary compartment; pre-vascularizing the large capsule device; loading one or more cells into the primary compartment; and applying a pressure differential to the secondary compartment to remove filtrate from the primary compartment.

[0017] In some embodiments, the filtrate is removed from the primary compartment. In some embodiments, the method further comprises: applying an adjuvant to the primary compartment, or the secondary compartment, or both. In some embodiments, the adjuvant comprises a drug, an oxygen-producing substance, an anticoagulant, a nutrient, or any combination thereof. In some embodiments, applying the adjuvant is performed after applying a negative pressure or other pressure difference to the secondary compartment. In some embodiments, the method further comprises: inflating the primary compartment, or the secondary compartment, or both. In some embodiments, inflating the primary compartment, or the secondary compartment, or both before prevascularizing the large capsule device. In some embodiments, the method further comprises: sealing the primary compartment, or the secondary compartment, or both. In some embodiments, the method further comprises: resealing the primary port, the secondary port, or both. In some embodiments, the large capsule device further comprises: a tertiary compartment, the tertiary compartment is separated from the secondary compartment by a second semi-permeable membrane, and wherein the method further comprises: loading one or more cells into the tertiary compartment. In some embodiments, the method further comprises: applying an adjuvant to the primary compartment, the secondary compartment, or the tertiary compartment, or any combination thereof. In some embodiments, the filtrate is removed from the primary compartment, the tertiary compartment, or both. In some embodiments, the method further comprises: inflating the primary compartment, the secondary compartment, the tertiary compartment, or any combination thereof. In some embodiments, the method further comprises: sealing the primary compartment, the secondary compartment, or the tertiary compartment, or any combination thereof. In some embodiments, the method further comprises: resealing the primary port, the secondary port, the tertiary port, or any combination thereof.

[0018] It should be understood that the aforementioned concepts and the additional concepts discussed below can be arranged in any suitable combination, as the present disclosure is not limited in this regard. In addition, 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.

[0019] In the event that this specification and the documents incorporated by reference include conflicting and / or inconsistent disclosures, this specification shall prevail. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosures relative to each other, the document with the later effective date shall prevail. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component shown in various figures may be represented by the same number. For clarity, not every component is labeled in every drawing. In the drawings:

[0021] Figure 1A shows a top view of a macrocapsule device according to some embodiments;

[0022] Figure 1B Show Figure 1A A perspective cutaway view of a macrocapsule device;

[0023] Figure 1C Show Figure 1A A perspective cutaway view of a port of a macrocapsule device;

[0024] Figure 1D Show Figure 1A A perspective cross-sectional view of a membrane layer of a large capsule device;

[0025] Figure 2A shows a cross-sectional schematic diagram of a macrocapsule device including three internal compartments according to some embodiments;

[0026] Figure 2B Show Figure 2A An exploded cross-sectional schematic diagram of a macrocapsule device;

[0027] Figure 3 shows an exploded cross-sectional schematic diagram of a macrocapsule device including three internal compartments according to some embodiments;

[0028] Figure 4A shows a cross-sectional schematic diagram of a macrocapsule device including two internal compartments according to some embodiments;

[0029] Figure 4B Show Figure 3 An exploded cross-sectional schematic diagram of a macrocapsule device;

[0030] FIG. 5A to FIG. 5C A cross-sectional diagram showing the use of a macrocapsule device comprising three compartments for vascularization, cell filling, filtration, and application of adjuvants, according to some embodiments. DETAILED DESCRIPTION

[0031] Some large capsule devices are constructed to implant cells into a host without prevascularization support from surrounding tissues. However, cells implanted by such devices often suffer from hypoxia or malnutrition during the time period between implantation and vascularization. Since vascularization typically spans a week or longer, such harmful cell conditions often cause cell necrosis and subsequent outflow of immunogenic cell debris, which triggers a foreign body response that ultimately causes device failure. In contrast, prevascularized devices are implanted into the body when empty to integrate with the host before any cellular material is introduced. Such devices have been shown to achieve greater cell survival rates.

[0032] Although advantageous, the inventors have recognized that loading cells into a macrocapsule device surrounded by and integrated with host tissue has heretofore proven difficult. First, the introduction of cells into a prevascularized macrocapsule device typically uses ultrafiltration and pressurization and / or very high concentrations of cells within the device to provide a desired amount of cells within the device. Although ultrafiltration and pressurization can introduce an effective cell density into the device, the forces applied by the membrane during ultrafiltration can cause the device to separate from the newly formed microvasculature and / or exacerbate foreign body reactions due to tissue trauma. In addition, loading a large concentration of cells into a macrocapsule device can apply shear forces to the cell surface during loading. This can cause cell aggregation, which can form blockages within the interior of the device, which can damage the cells and / or inhibit the device from being loaded to the desired effective cell density.

[0033] In view of the above, the inventors have recognized the benefits associated with a large capsule device, which includes a plurality of at least partially coextensive internal compartments, which are fluidically connected to each other through one or more semi-permeable internal membranes disposed between these compartments. This configuration allows at least one of the compartments to be configured to receive one or more desired cell populations, while at least one of the other compartments (e.g., a secondary compartment) can be fluidically connected to one or more compartments containing cells. This allows filtrate from one or more compartments containing cells to flow through a semi-permeable membrane into one or more other compartments (e.g., a secondary compartment). In some instances, this filtrate can be removed from this secondary compartment. This secondary compartment can also be used to introduce a desired adjuvant into the device, which can then flow through a semi-permeable membrane between the compartments into one or more compartments containing cells. This device can substantially prevent and / or at least reduce damage to the integrated tissue surrounding the device and the cells contained therein during the filling process.

[0034] In one embodiment, the macrocapsule device can be formed by the first adventitia and the second adventitia. The first adventitia and the second adventitia can be combined with each other in any appropriate manner to form an internal volume between the first adventitia and the second adventitia. For example, a part of the first adventitia and the second adventitia extending at least partially around the periphery of the film can be directly or indirectly combined with each other. For example, the film can be folded and combined along its free edge so that a single film is used as the first adventitia and the second adventitia. Alternatively, two separate adventitia can be combined at the part extending along its entire periphery, but any appropriate method utilizing a membrane material to form an internal volume can be used. In either case, the macrocapsule device may also include at least a first semi-permeable membrane arranged between the first adventitia and the second adventitia, and the at least first semi-permeable membrane divides the internal volume into a primary compartment and a secondary compartment that are fluidly connected to each other through the first semi-permeable membrane. The first compartment can be constructed to accommodate the first cell mass that can be loaded into the primary compartment. Thus, the macrocapsule device can be configured such that filtrate from the primary compartment can flow into the secondary compartment and / or adjuvants can be introduced into the secondary compartment which can then flow into the primary compartment where the cells are located, as described in detail below.

[0035] In some embodiments, the macrocapsule device may also include at least a second semipermeable membrane disposed between the first semipermeable membrane and the second outer membrane. The secondary compartment may be formed between the first semipermeable membrane and the second semipermeable membrane, and the tertiary compartment may be formed between the second semipermeable membrane and the second outer membrane. Therefore, the tertiary compartment may be in fluid communication with the secondary compartment through the second semipermeable membrane. In addition, in some embodiments, the secondary compartment may be disposed between the primary compartment and the tertiary compartment. In some embodiments, the tertiary compartment may also be configured to accommodate the second cell mass. Therefore, similar to what has been described above, the filtrate may also flow into the secondary compartment from the tertiary compartment and / or the adjuvant may flow into the tertiary compartment from the secondary compartment. According to a specific embodiment, the second cell mass may be identical and / or different from the cell mass maintained in the primary compartment of the macrocapsule device.

[0036] It should be understood that the filtrate and / or adjuvant flowing between each compartment of the large capsule device can be biased so as to flow between compartments in any appropriate manner. For example, in some embodiments, a pressure difference can be applied between adjacent compartments to induce filtrate and / or adjuvant to flow from one compartment to another compartment. For example, the pressure in a compartment can increase due to the flow of material into the compartment, and / or the pressure in the adjacent compartment can be reduced using the vacuum applied to this compartment. In either case, static pressure, pressure difference, flow rate, shear stress applied to cells and / or other appropriate operating parameters can be controlled to avoid cell aggregation and / or death. For example, in some embodiments, the pressure difference between two adjacent compartments can be kept below a threshold pressure to help maintain cell viability. In addition, in some embodiments in which an adjuvant is applied, an adjuvant can be introduced into a secondary compartment, however, there may be little to no pressure difference between the secondary compartment and the adjacent compartment comprising a cell mass. In such an embodiment, the adjuvant may flow into these other compartments due to diffusion of the adjuvant caused by diffusion induced by a concentration gradient of the adjuvant, wherein the concentration of the adjuvant in the secondary compartment is greater than the concentration of the adjuvant in the adjacent compartment comprising the cell population.

[0037] The filtrate of the appropriate type that can be used in the compartment of the large capsule device that loads the cell mass may include, but is not limited to, cell culture medium, alginate, extracellular matrix proteins, platelet-rich plasma, thrombin, poly(vinyl alcohol), poly(ethylene glycol), propylene glycol, cryopreservation solution, and pectin. Of course, it should be understood that any appropriate type of filtrate that is biocompatible with the host and cell colony may be used, as the present disclosure is not limited to any particular type of filtrate.

[0038] In embodiments where an adjuvant has been provided to the secondary compartment of the macrocapsule device, the adjuvant may 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 cellular oxygenation, a secondary therapeutic agent for the host, and / or any other suitable agent that provides a desired function for the macrocapsule device. Thus, the adjuvant may include a therapeutic agent such as a drug, an oxygen-producing substance, an anticoagulant, a nutrient, an anti-inflammatory drug, a steroid, a growth factor, a prodrug, an immunomodulatory molecule, a differentiation factor, any combination thereof, and / or any other suitable agent, as the present disclosure is not limited in this manner.

[0039] As described above, in some cases, it may be advantageous to prevascularize the macrocapsule device before introducing the cell population. Likewise, this can improve the flow of nutrients to cells disposed within the interior of the device, increase the outflow of waste and / or therapeutic agents from the device to the host, and / or can also reduce the occurrence of fibrotic reactions to device implantation. Therefore, in some embodiments, the macrocapsule device can be implanted and prevascularized within a first time period. In such embodiments, at least one of the first membrane and the second membrane is constructed to enable vascularization of cells within the device. In some embodiments, at least one of the first membrane and the second membrane is constructed to achieve, support or allow vascularization of cells within and around the device in the absence of immunosuppressive therapy, or in the case of reduced immunosuppressive therapy compared to comparable devices that do not support such vascularization. In some cases, this may include the use of a plurality of through holes extending from a first surface of the macrocapsule device through an intermediate membrane to a second opposing surface of the macrocapsule device. In such embodiments, the vascular system may grow into and through these through holes.

[0040] During this prevascularization period, the device is inflated to help maintain the membrane and associated compartment of the large capsule device in an appropriate configuration, which may be advantageous for subsequently loading a cell mass into the device. Therefore, in some embodiments, fluid may be introduced into one or more compartments of the large capsule device before, during, and / or after the implantation device to inflate one or more compartments. This may include inflating the primary compartment, secondary compartment, and / or tertiary compartment of the large capsule device. The appropriate type of fluid that can be used to inflate each compartment of the large capsule device may include, but is not limited to, oxygen, saline, cell culture medium, alginate, chitosan, dextrose, perfluorocarbon, its combination, and / or any other appropriate fluid that can inflate the device. In some cases, the outer membrane of the large capsule device may be constructed to keep the inflation fluid in the interior of the device during implantation to prevent the membrane structure from collapsing during the prevascularization period. Then the large capsule device may be implanted for an appropriate period of time to allow the large capsule device to be integrated with the surrounding tissue, and allow the vascular system to establish the desired nutrient flow leading to the large capsule device. One or more compartments of the macrocapsule device can then be loaded with one or more desired cell populations, as further described below.

[0041] In some embodiments of various large capsule devices disclosed herein, at least one of the first adventitia and the second adventitia is semi-permeable. For example, any one of the adventitia may be semi-permeable, and the other may be substantially impermeable, or both may be semi-permeable. In some embodiments, the semi-permeability of the first film, the second film, or both is constructed to protect cells from immune attack and / or block cell mass from leaving the device, while allowing the desired biological product produced by the cell and the waste and nutrients used and produced by the cell to pass through. In some embodiments, the semi-permeability of the first film, the second film, or both is constructed to protect cells from immune attack in the absence of immunosuppressive therapy. Therefore, the first adventitia, the second adventitia, or both may be configured to be substantially impermeable to one or more cell masses in the device, the filtrate contained in the device, an adjuvant, or any combination thereof.

[0042] In addition to the relative persistence of the outer membrane, one or more semipermeable membranes in the internal volume of the large capsule device can also be appropriately constructed to control the flow of one or more materials between the various compartments of the large capsule device. For example, in various embodiments described herein, the first semipermeable membrane, the second semipermeable membrane and / or any appropriate number of semipermeable membranes arranged in the internal volume of the device can be substantially permeable to the filtrate flowing from one compartment to another compartment, the auxiliary agent to be provided in the device interior, or both. In addition, the inner semipermeable membrane can also be substantially impermeable to one or more cell groups arranged in the large capsule device. Therefore, the inner semipermeable membrane can be constructed to stop cells from flowing between adjacent compartments, while allowing filtrate and / or auxiliary agent to flow therebetween.

[0043] In view of the above, the hydraulic permeability, pore size and / or porosity of the inner semipermeable membrane (such as the first semipermeable membrane and / or the second semipermeable membrane) may be different from the hydraulic permeability, pore size and / or porosity of the first outer membrane and / or the second outer membrane of the large capsule device. For example, the hydraulic permeability of the first semipermeable membrane and / or the second semipermeable membrane may be greater than the hydraulic permeability of one or both of the first outer membrane and the second outer membrane. This may correspond to other appropriate differences in the increased porosity, pore size or material parameters of the inner semipermeable membrane relative to the outer membrane. Similarly, according to a specific embodiment, the first outer membrane and the second outer membrane may have hydraulic permeabilities, pore sizes and / or porosities that are equal or different from each other. For example, if different materials are contained in separate compartments formed by the first outer membrane and the second outer membrane, such as accommodating different cell populations, the hydraulic permeability exhibited by the first outer membrane may be less than or greater than the hydraulic permeability of the second outer membrane, to provide a desired combination of membrane properties individually customized for each cell population. Similarly, where multiple inner semipermeable membranes are used, such as a first semipermeable membrane and a second semipermeable membrane disposed between two outer membranes, the inner semipermeable membranes may exhibit the same and / or different hydraulic permeabilities, pore sizes, and / or porosities. For example, the hydraulic permeability of the first semipermeable membrane may be greater than or less than the hydraulic permeability of the second semipermeable membrane.

[0044] In view of the foregoing, in some embodiments, the hydraulic permeability exhibited by the inner semipermeable membrane (such as the first semipermeable membrane and / or the second semipermeable membrane disposed between the 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 hydraulic permeability of one or two outer membranes. The range extending between any of the aforementioned percentages is encompassed. For example, the hydraulic permeability of the inner semipermeable membrane may be between about 25% and 100% greater than the hydraulic permeability of one or two outer membranes. In some embodiments, this difference in hydraulic permeability may be related to the outer membrane against which the inner semipermeable membrane is disposed to form the corresponding compartment. Of course, hydraulic permeabilities greater than and less than those described above are also contemplated, because the present disclosure is not limited in this manner.

[0045] The above relative hydraulic permeabilities of various membranes can be measured in any suitable manner. For example, for a given sample geometry as known in the art, the relative hydraulic permeabilities of different membrane materials can be measured using constant head or constant pressure, using measurements of an appropriate fluid (such as water). Of course, any suitable flow test method, calculation or modeling method can be used to determine the relative hydraulic permeability of a membrane, as the present disclosure is not limited to a particular method in which these relative parameters are measured.

[0046] Similar to the above, in order to provide the desired difference of the relative permeability of the various membranes of the large capsule device, in some embodiments, the porosity and / or pore size of one or more of the inner semi-permeable membranes of the large capsule device may be greater than the porosity and / or pore size of one or both of the first and second outer membranes. Similarly, in some embodiments, this difference may be related to adjacent outer membranes. In either case, the porosity and / or pore size of the inner semi-permeable 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. The range extending between any of the aforementioned percentages is included. For example, the porosity and / or pore size of the inner semi-permeable membrane may be between about 25% and 100% of the pore size and / or porosity of one or two outer membranes. In addition to the foregoing, in some embodiments, the porosity and / or pore size of the first semipermeable membrane can be different than the porosity and / or pore size of the second semipermeable membrane disposed between the outer membranes.

[0047] In view of the above-mentioned difference of material parameters, the flux of predetermined material across inner semi-permeable membrane under predetermined pressure difference and / or concentration gradient can be greater than the flux of same material across one or two adventitia under same pressure difference and / or concentration gradient.Similarly, depending on the desired application, the first adventitia and the second adventitia can show the same or different hydraulic properties.Therefore, the flux of material across the first adventitia and the second adventitia of large capsule device under specific pressure difference and / or concentration gradient can be substantially the same or different from each other.For example, under the same bias, the flux across the first adventitia can be less than or greater than the flux across the second adventitia.Similarly, the flux of material across the first semi-permeable membrane between the adventitia of device can be different from (that is, less than or greater than) the flux of material across the second semi-permeable membrane.The difference of material across the flux of different membranes is comparable to the difference of relative flux of about 5%.The suitable material that can experience this flux difference can include but is not limited to insulin, small molecule therapeutic agent, growth factor, antibody, antibody fragment, immunomodulatory factor, complement complex, cell fragment, enzyme, alginate, saline and cell culture medium. Likewise, the relative fluxes of a predetermined material across various membranes may be measured using any appropriate flux testing method, calculation, or modeling approach, including, for example, constant head or differential pressure measurements, concentration gradient measurements across a membrane, and / or any other appropriate method, as the present disclosure is not limited to how the relative fluxes are measured.

[0048] It should be understood that the various relationships of permeability, pore size, porosity, relative flux and other material parameters described herein may be applicable to any of the described embodiments of the macrocapsule device. However, it should also be understood that the present disclosure is not limited to these specific ranges of material properties and relative performance parameters. For example, both the inner semipermeable membrane and the outer membrane may exhibit ranges of permeability, pore size, porosity, relative flux and other material parameters that are greater than or less than the specific ranges and relationships described herein, as the present disclosure is not limited in this manner.

[0049] The various membranes of the macrocapsule device, including the outer membrane and / or the inner semipermeable membrane, can be formed by any suitable biocompatible material. The biocompatible material can be substantially inert to the cells, filtrate, adjuvant or any combination thereof contained in the macrocapsule device. The biocompatible material can include synthetic polymers or naturally occurring polymers. In some embodiments, the polymer can also be a linear polymer, a cross-linked polymer, a network polymer, an addition polymer, a condensation polymer, an elastomer, a fiber polymer, a thermoplastic polymer, a non-degradable polymer, a combination of the foregoing and / or any other suitable type of polymer, because the present disclosure is not limited in this manner. Suitable types of polymers may include 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 fluoride (PVDF), polycaprolactone (PCL), poly (lactic acid-co-glycolic acid) (PLGA), poly-L-lactide (PLLA), any combination of the foregoing, and / or any other suitable polymer material. Synthetic methods for forming one or more porous membranes from the above-mentioned polymer materials may include, but are not limited to, expansion, solvent casting, impregnation precipitation and phase separation, electrospinning, methods for producing iso-reticular networks, methods for producing trabecular networks, or any other suitable methods for forming porous polymer membranes. In some embodiments, sintering of porous polymer membranes can be used to change the porosity of the membrane, which in turn can be used to tune the porosity and flux properties of large capsule devices. Thus, in some embodiments, any desired combination of outer semipermeable membrane and / or inner semipermeable membrane may or may not be sintered using any suitable sintering method, depending on the particular membrane materials.

[0050] Although polymeric materials are mentioned above, embodiments are contemplated in which the membrane is at least partially made of non-polymeric materials. For example, suitable membrane materials may include ceramic materials, polymer ceramic composites, and / or any other suitable material capable of being used as a membrane in an implanted macrocapsule device, as the present disclosure is not limited to any particular material forming the membrane.

[0051] The inner membrane and outer membrane of a macrocapsule device as described herein can be made of a porous membrane material that is configured to allow materials (such as biological products) to be transported through the membrane, and the molecular weight of the material is less than about 3000kDa, 2000kDa, 1000kDa, 500kDa, 400kDa, 300kDa, 200kDa, 100kDa, 50kDa, 40kDa, 30kDa, 20kDa, 10kDa, 6kDa, 5kDa, 4kDa, 3kDa, 2kDa, 1kDa and / or any other suitable range of molecular weight, depending on the desired application. For example, one or more membranes of a macrocapsule device can be configured to allow insulin having a molecular weight of about 5.8kDa to flow through the membrane.

[0052] To provide the desired selectivity, the porous membrane used with the macrocapsule devices disclosed herein may have an open porous structure with an average pore size greater than or equal to about 1 nm, 5 nm, 10 nm, 15 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 200 nm, 300 nm and / or any other suitable size range. Correspondingly, the average pore size of various films described herein can have an average pore size less than or equal to 2500nm, 2000nm, 1700nm, 1500nm, 1400nm, 1300nm, 1200nm, 1100nm, 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, 200nm, 100nm, 90nm, 80nm, 70nm, 60nm, 50nm, 40nm, 30nm, 20nm and / or any other suitable size range. Conceive of the aforementioned combination, including, for example, between or equal to 1nm and 20nm, 1nm and 2500nm and / or any other suitable combination of average pore size. Of course, although the above describes a specific average pore size, it should be understood that any suitable average pore size can be used for various films described herein, including an average pore size greater than and less than those described above.

[0053] In order to provide sufficient strength and / or rigidity for the large capsule device, the various membranes can be made of sufficiently hard materials. The desired hardness can be provided by an appropriate combination of material Young's modulus, thickness, and overall construction, which can be balanced with the desired permeability of the device. Suitable Young's modulus for the various membranes described herein can be at least 10 5 Pa, 10 6 Pa, 10 7 Pa, 10 8 Pa, 10 9 Pa, 10 10Pa and / or any other suitable modulus greater than and less than these ranges. Of course, ranges between the foregoing Young's moduli are contemplated, including, for example, between or equal to about 10 6 Pa and 10 10 Young's modulus between Pa.

[0054] In some embodiments, it may be desirable that one or more membranes included in the macrocapsule device be hydrophilic to facilitate loading of cells into the macrocapsule device and / or facilitate inflow of one or more filtrates, biocomplexes, therapeutic agents or other materials into, outflow of different compartments of the device and / or flow between the different compartments. In addition, when the device is positioned in vivo, the hydrophilic outer membrane can also reduce the occurrence of fibrosis. Therefore, the inner membrane and outer membrane of the macrocapsule device can be made of hydrophilic materials and / or treated with a hydrophilic coating. Suitable materials for forming a hydrophilic coating may include, but are not limited to, 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 film.

[0055] The films described in the various embodiments of the large capsule device described herein can be combined with each other using any appropriate bonding method, because the present disclosure is not limited in this way. For example, adhesives, epoxy resins, welding or other technologies based on fusion (e.g., ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using a frame or a fixture and / or any other appropriate bonding method can be used to combine adjacent films with each other. In a specific embodiment, a heated tool can be used to combine adjacent films, and the heated tool is used to press or impact two or more films against each other with a predetermined pressure and / or force to set the fusion time. In view of the foregoing, it should be understood that the present disclosure is not limited to using any specific method to combine films together.

[0056] As described herein, the macrocapsule device may have any suitable combination of internal volume, external dimensions, and / or other suitable physical parameters. For example, the internal volume surrounded by the outer membrane of the macrocapsule device may be between or equal to 40 μL and 250 μL. The width or maximum lateral dimension of the macrocapsule device may also be between about 20 mm and 80 mm. In addition, in order to provide the desired oxygen diffusion to the interior of the macrocapsule device to support the cells contained therein, the maximum oxygen diffusion distance from the outside of the device to the internal portion of the device including the cell group may be less than 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm. Correspondingly, the maximum thickness or dimension perpendicular to the maximum lateral dimension of the overall device and / or compartments within the device may be less than 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm. In addition, in some embodiments, the ratio of the external surface area to the volume of the device may be greater than or equal to about 20 cm -1 、40cm -1 、60cm -1 、80cm -1 、100cm -1 、120cm -1 or 150cm -1 Ranges extending between any of the foregoing values ​​of the various dimensions and parameters are also contemplated. Additionally, while specific parameter ranges for the overall macrocapsule device are given above, operating parameters and dimensions greater and less than those described above are contemplated, as the invention is not limited to any particular size or configuration.

[0057] As described in detail below, in some embodiments, the compartments within the macrocapsule device may be formed so that the internal volume of these compartments is subdivided into multiple interconnected channels, which may be shaped similar to a lumen in some embodiments, although any suitable shape or configuration of the channel may also be used. The channel may have an inner maximum transverse dimension greater than or equal to 40 μm, 50 μm, 100 μm, 200 μm, 300 μm, 400 μm and / or any other suitable size, such as an inner diameter. Correspondingly, the channel may have an inner maximum transverse dimension less than or equal to 800 μm, 700 μm, 600 μm, 500 μm, 400 μm and / or any other suitable size. It is contemplated that the aforementioned combination includes, for example, the inner maximum transverse dimension of multiple channels between or equal to 40 μm and 800 μm. In addition, the density of the interconnected channels forming the various compartments of the device may have greater than or equal to about 10 channels / cm in the transverse plane of the device. 2 , 15 channels / cm 2 , 20 channels / cm 2 , 25 channels / cm2 , 30 channels / cm 2 , 35 channels / cm 2 , 40 channels / cm 2 , 45 channels / cm 2 , 50 channels / cm 2 , 60 channels / cm 2 , 70 channels / cm 2 , 80 channels / cm 2 , 90 channels / cm 2 , 100 channels / cm 2 , 110 channels / cm 2 , 120 channels / cm 2 , 130 channels / cm 2 , 140 channels / cm 2 , 150 channels / cm 2 , 175 channels / cm2 or 200 channels / cm 2 Also contemplated are ranges extending between any of the above channel densities, including, for example, between or equal to about 10 channels / cm 2 and 200 channels / cm 2 Although densities greater and less than the above ranges are also contemplated.

[0058] Although specific dimensions and relationships related to large capsule devices and their manufacturing materials are described above, it should be understood that dimensions and relationships greater than and less than those described above are contemplated, as the present disclosure is not limited in this manner. Thus, any appropriate size, configuration, and / or relative performance parameters may be used for the device, depending on the desired application.

[0059] In some embodiments, the cell group contained in the compartment of the large capsule device may be an insulin secreting cell group. In some embodiments, the cell group includes at least one cell derived from stem cell derived cells. In some embodiments, at least one cell is a genetically modified cell. In some cases, compared with genetically engineered comparable cells, at least one cell is genetically engineered to reduce the immune response of the subject after the device is implanted. In some embodiments, the cell group is a stem cell derived cell that can perform glucose stimulated insulin secretion (GSIS). For example, a suitable cell group may include pancreatic progenitor cells, endocrine cells, beta cells, a matrix comprising one or more of the aforementioned cells, or any combination thereof. In addition, the matrix may include isolated islet cells, isolated cells from the pancreas, isolated cells from tissues, stem cells, stem cell derived cells, induced pluripotent cells, differentiated cells, transformed cells or expression systems, which can synthesize one or more biological products. Optionally, in some embodiments, the matrix may include a second type of cell that supports the synthesis of one or more biological products. In some embodiments, the cell may be encapsulated and then placed in the matrix. In this embodiment, the cell may be encapsulated in a microcapsule or the cell may be conformably coated. However, naked (ie, unencapsulated) cells may also be used.

[0060] According to a specific embodiment, the cells of the effective density of treatment can be loaded into one or more compartments of the macrocapsule device. The suitable cell density arranged in the compartment can be greater than or equal to about 1000 cells / μL, 10,000 cells / μL, 50,000 cells / μL, 100,000 cells / μL, 500,000 and / or any other suitable cell density. The suitable cell density arranged in the compartment can also be less than or equal to about 1,000,000 cells / μL, 500,000 cells / μL, 100,000 cells / μL, 50,000 cells / μL, 10,000 cells / μL and / or any other suitable cell density. It is contemplated that the aforementioned combination includes the cell density between about 1000 cells / μL and 1,000,000 cells / μL. Of course, it is also possible to use a cell density greater than and less than those mentioned above, depending on the desired application and the cell type used.

[0061] The large capsule device described herein can be implanted in different parts of the subject's body. In one example, the device can be implanted in the subject's body by extraperitoneal or retrorectus implantation. In other examples, the device can be placed by intraomental implantation. In another example, the device can be placed by subcutaneous implantation. In another example, the device can be placed by supra-liver implantation. In some cases, any appropriate fixation method (including, for example, applying a tissue adhesive) can be used to fix the large capsule device described herein at the implantation site in the body. Suitable tissue adhesives may include, but are not limited to, fibrin, cyanoacrylate, polyethylene glycol, albumin-based adhesives, polymer-based adhesives, and / or any other appropriate adhesives. In another example, platelet-rich plasma and / or any other appropriate fixation method can be used to fix the device, because the present disclosure is not limited in this way.

[0062] Turning to the drawings, specific non-limiting embodiments are described in further detail. It should be understood that the various systems, components, features, and methods described with respect to these embodiments may be used alone and / or in any desired combination, as the present disclosure is not limited to only the specific embodiments described herein.

[0063] Figures 1A to 1D One embodiment of an implantable macrocapsule device 100 configured to encapsulate a cell population is shown. Likewise, the cell population may include at least one of pancreatic progenitor cells, endocrine cells, beta cells, and / or any other suitable cell population described herein. In the depicted embodiment, the macrocapsule device has a generally flat planar configuration extending in a direction parallel to the transverse plane of the device orientation. The macrocapsule device depicted in the figure has a generally circular planar shape, however other shapes are also contemplated, including squares, rectangles, hexagons, triangles, and / or any other suitable shapes, including non-planar configurations, as the present disclosure is not limited in this manner.

[0064] The large capsule device 100 includes a first outer membrane 102 disposed on a second outer membrane 104. At least a portion of the first outer membrane and the second outer membrane can be combined with each other to form an internal volume disposed between the outer membranes. For example, as shown in the figure, the first outer membrane and the second outer membrane can be combined with each other at least at a portion 106 extending around the periphery or other appropriate portion 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 parts of the overall device. In the depicted embodiment, the frame is attached to the outer periphery of the large capsule device and extends around the outer periphery. However, it is also conceivable that the frame extends only around a portion of the periphery of the device. The frame can be attached to the outer membrane using any appropriate method, and any appropriate method includes but is not limited to adhesives, epoxy resins, mechanical fasteners, thermal bonding and / or any other appropriate bonding methods, because the present invention is not limited in this way.

[0065] As previously described, the macrocapsule devices described herein may include two or more internal compartments that are at least partially coextensive with each other in a plane parallel to the plane in which the macrocapsule device may generally extend. In addition, in some embodiments, the two or more compartments may be substantially coextensive with each other along their entire lateral area parallel to this plane. Figures 1A to 1D The embodiment shown is a three-compartment device including a primary compartment 120, a secondary compartment 122, and a tertiary compartment 124. For clarity, a single set of compartments has been shown. However, it should be understood that a large capsule device including multiple sets of associated compartments disposed in different portions of the large capsule device is also contemplated, as the present disclosure is not limited to devices in which a single set of compartments extending over the entire surface area of ​​the device is used. The specific arrangement of the membrane and these compartments is further described below.

[0066] As shown, the large capsule device 100 may include the first adventitia 102, the second adventitia 104, the first semi-permeable film 116 and the second semi-permeable film 118. The device may also include a primary compartment 120, a secondary compartment 122 and a tertiary compartment 124. In the depicted embodiment, the first semi-permeable film is arranged against the first adventitia, the second semi-permeable film is arranged against the first semi-permeable film and the first adventitia, and the second adventitia is arranged against the second semi-permeable film and the first adventitia and the first semi-permeable film. Various films can be combined with each other and / or otherwise connected using any previously described bonding method. Therefore, the first semi-permeable film can be attached between the first adventitia and the second semi-permeable film, and the second semi-permeable film can be attached between the first semi-permeable film and the second adventitia. In addition, the film can be appropriately shaped and arranged so that the first semi-permeable film and the first adventitia form a primary compartment between the opposing surfaces of the first semi-permeable film and the first adventitia. Correspondingly, the second semipermeable membrane and the second outer membrane can cooperate to form a secondary compartment between the opposing surfaces of the second semipermeable membrane and the second outer membrane.The first semipermeable membrane and the second semipermeable membrane can also form a tertiary compartment between the opposing surfaces of the first semipermeable membrane and the second semipermeable membrane.

[0067] Although a single continuous film is shown for the various films in the figures, in some embodiments, one or more of the first outer film 102, the second outer film 104, the first semi-permeable membrane 116, and the second semi-permeable membrane 118 may be made of multiple connected films to form an integral film.

[0068] In view of the above structure, the primary compartment 120 and the secondary compartment 122 can be separated by the first semi-permeable membrane 116. Similarly, the tertiary compartment 124 and the secondary compartment 122 can be separated by the second semi-permeable membrane 118. Therefore, in the embodiment using three compartments, the secondary compartment is arranged between the primary compartment and the tertiary compartment. In addition, the primary compartment, the secondary compartment and / or the tertiary compartment can be coextensive with each other at least a portion of its cross-sectional area, and in some embodiments substantially all relative to the transverse plane parallel to the plane in which the overall large capsule device extends. Due to the first semi-permeable membrane and the second semi-permeable membrane located in the device interior, it is configured to penetrate at least some materials (such as filtrate and / or adjuvant), so the primary compartment can be communicated with the secondary compartment fluid through the first semi-permeable membrane, and the secondary compartment and the tertiary compartment can be communicated through the second semi-permeable membrane fluid.

[0069] As previously described, in some embodiments, the large capsule device 100 may include a plurality of through holes 114 distributed across the flat surface of the device. The through holes may extend from the first external surface of the large capsule device to the opposite external surface of the large capsule device, and the through holes may correspond to the through holes extending from the external surface of the first outer membrane 102 to the opposite external surface of the second outer membrane 104 in the depicted embodiment. The through holes may be surrounded by corresponding binding portions 110. The binding portion may include a binding portion of the first outer membrane and the second outer membrane, and any intermediate internal membrane positioned between the outer membranes (such as the first semi-permeable membrane 116 and the second semi-permeable membrane 118). The binding portion around each through hole may form a seal between the interior of the device and the through hole. Compared with a device with a flat configuration, the use of these through holes may allow more cells per unit area to exist, because an increased amount of nutrients may be provided to the cells throughout the matrix to support their viability and activity. Specifically, when implanted in vivo, the through holes may allow the vascular system to grow around the device and pass through the through holes. In contrast, a typical device without through-holes is limited by the vasculature formed on the top and bottom surfaces of the device. The maximum transverse dimension (such as diameter) of the through-hole can be measured at its narrowest point in a transverse plane parallel to the transverse plane in which the maximum transverse dimension of the overall device extends. The size, number and / or density of the through-holes can be appropriately selected to provide the desired performance of the device when positioned in the body.

[0070] In some embodiments, at least one of the primary compartment 120, the secondary compartment 122, and the tertiary compartment 124 may include a continuous compartment. Alternatively, at least one of the primary compartment 120, the secondary compartment 122, and the tertiary compartment 124 may include a plurality of continuous interconnected compartments that may have any suitable shape. For example, the internal compartment shown in the figure corresponds to a plurality of interconnected channels 112, which correspond to the internal volume of the compartment disposed between adjacent binding portions 110 of the membrane, and the adjacent binding portions 110 correspond to the positions of a plurality of through holes 114 located on the face of the device. However, it should be understood that any suitable arrangement and / or shape of interconnected volumes and / or a single continuous volume may be used for each of the internal compartments, because the present disclosure is not limited in this manner.

[0071] In the above-mentioned embodiment, one-level compartment 120, three-level compartment 124 or both can be configured to provide for accommodating the volume of one or more cell masses that can be identical or different from each other. Correspondingly, two-level compartment 122 can be configured to remove filtrate from one-level compartment, two-level compartment or both. Two-level compartment can also be configured to provide adjuvant to one-level compartment, three-level compartment or both. Therefore, in the embodiment described, each in the first adventitia 102, the second adventitia 104, the first semi-permeable membrane 116 and the second semi-permeable membrane 118 can be configured to block cell mass from passing through. The first semi-permeable membrane can also be configured to allow filtrate to be transferred to the two-level compartment from the one-level compartment. Similarly, the second semi-permeable membrane can be configured to allow filtrate to be transferred to the two-level compartment from the three-level compartment. The first semi-permeable membrane and / or the second semi-permeable membrane can also be configured to allow adjuvant to be transferred to the one-level compartment and the three-level compartment respectively from the three-level compartment.

[0072] Also like Figure 1A to Figure 1B As shown, the large capsule device 100 may also include at least one port, which provides fluid communication between the outside of the device and one or more compartments contained therein. For example, the primary port 126 may be in fluid communication with the primary compartment 120, the secondary port 128 may be in fluid communication with the secondary compartment 122, and the tertiary port 130 may be in fluid communication with the tertiary compartment 124. In some embodiments, at least one of the primary port, the secondary port, and the tertiary port, and each may be sealable or resealable in some cases, to provide selective fluid communication between the associated internal compartment and the outside of the large capsule device. The primary port, the secondary port, the tertiary port, or any combination thereof may be configured to be able to enter via the skin. In any case, various ports may provide access to the associated internal compartment of the device, so that a cell mass may be introduced into the associated compartment, a filtrate may be removed from the associated compartment, and / or an adjuvant may be introduced into the associated compartment by one or more of the ports, as further described below.

[0073] Although embodiments have been shown in the figures using ports, the present disclosure is not limited to large capsule devices including ports. For example, embodiments of large capsule devices that can be completely sealed without using primary, secondary or tertiary ports are also envisioned.

[0074] FIG. 2A to FIG. 2B A simplified schematic and exploded schematic diagram of a macrocapsule device 100 is shown, which includes a first outer membrane 102 and a second outer membrane 104, and a first semipermeable membrane and a second semipermeable membrane disposed therebetween. As previously described, the membranes and the inner semipermeable membrane can be appropriately arranged and bonded to each other to form the previously described primary compartment 120, secondary compartment 122, and tertiary compartment 124 within the interior of the device. In addition, the planar stacking arrangement of each of these separate membranes within the bonding area is clearly shown in the schematic diagram. In alternative embodiments, as Figure 3 As shown, the first semipermeable membrane and the second semipermeable membrane disposed within the interior of the device can be formed as a single integrated membrane. In the depicted embodiment, the semipermeable membrane is formed as an elongated lumen disposed between the first and second outer membranes relative to each other. Therefore, when the membranes are combined together, the upper portion of the integrated membrane adjacent to the first outer membrane can be used as the first semipermeable membrane 116, and the lower portion of the integrated membrane adjacent to the second outer membrane can be used as the second semipermeable membrane 118. In addition, although the separated first and second outer membranes have been shown in the figures, it should be understood that embodiments in which a single membrane that has been folded to serve as the first and second outer membranes are also contemplated.

[0075] Although the above embodiment includes three compartments, in some embodiments, the large capsule device 100 may not include the second semi-permeable membrane 118. In such an embodiment, the device may include only a primary compartment and a corresponding secondary compartment. Figure 4A and Figure 4B In the embodiment of the present invention, the macrocapsule device 100 can be configured to encapsulate a cell population, as previously described. The device may include a first outer membrane 102, a second outer membrane 104, and a first semi-permeable membrane 116 disposed between the first outer membrane and the second outer membrane. Therefore, the first semi-permeable membrane and the first outer membrane may form a primary compartment therebetween, and the first semi-permeable membrane and the second outer membrane may form a secondary compartment therebetween. Similar to the above-mentioned three-compartment embodiment, the macrocapsule device may include one or more ports, such as a primary port and a secondary port that are respectively in fluid communication with the primary compartment and the secondary compartment to provide fluid communication between the outside and the internal compartment of the device. Similarly, in some embodiments, these ports may be sealable or resealable.

[0076] The primary compartment 120 and the secondary compartment 122 can be separated from each other by the first semi-permeable membrane 116, and can be in fluid communication with each other by the first semi-permeable membrane. In this embodiment, the primary compartment, the secondary compartment, or both can be configured to provide a volume for accommodating one or more cell populations. In addition, the secondary compartment can be configured to remove filtrate from the primary compartment, provide an adjuvant to the primary compartment, or both, as previously described.

[0077] In view of the above, each of the first outer membrane 102, the second outer membrane 104, and the first semi-permeable membrane 116 can be configured to block the passage of the cell population contained in the device. The first semi-permeable membrane can also be configured to allow the filtrate to pass through the first semi-permeable membrane from the primary compartment 120 to the secondary compartment 122. In addition, the first semi-permeable membrane can be configured to allow the auxiliary agent to pass through the first semi-permeable membrane from the secondary compartment to the primary compartment, as previously described.

[0078] For the sake of clarity, FIG. 5A to FIG. 5C Methods for using a macrocapsule device comprising three internal compartments (i.e., a primary compartment, a secondary compartment, and a tertiary compartment) are described. However, the relative flow of the methods and materials described below is applicable to devices comprising two, three, four, or any number of compartments, as the present disclosure is not limited to use with devices comprising only two or three associated compartments.

[0079] FIG. 5A to FIG. 5C A cross-section of a macrocapsule device 100 is depicted taken through a portion of the device including a plurality of through-holes 114 similar to those described above with respect to Figures 1A to 1D Thus, the macrocapsule device may include a first outer membrane 102 and a second outer membrane 104 and a first semipermeable membrane 116 and a second semipermeable membrane 118, wherein the first semipermeable membrane 116 and the second semipermeable membrane 118 cooperate to form a primary compartment 120, a secondary compartment 122, and a tertiary compartment 124. As further described below, use of the macrocapsule device may include any suitable combination of one or more of the following: implanting the device; prevascularizing the device to form a microvasculature 132 extending around the device and / or through the through-holes of the device; loading one or more cell populations into the primary compartment and / or the secondary compartment; applying a pressure differential between the secondary compartment and the primary compartment and / or the tertiary compartment to remove a filtrate 136 from the primary compartment and / or the tertiary compartment; and loading an auxiliary agent 138 into the secondary compartment, which auxiliary agent 138 may then flow into the primary compartment and / or the tertiary compartment.

[0080] As described above, in some cases, after prevascularization of the macrocapsule device 100, one or more cell populations 134 may be loaded into the primary compartment 120 and / or the tertiary compartment 124, although situations are also contemplated in which a macrocapsule device is used without prevascularization. Figure 5A As shown, the prevascularization device can be performed by implanting the device for a predetermined vascularization period, during which the microvasculature can grow around the device and / or through the through-holes 114. The vascularization period can be greater than or equal to 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or any other suitable time period. The vascularization period can also be less than or equal to 10 weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2 weeks, 1 week, and / or any other suitable time period. Combinations of the foregoing are contemplated, including, for example, vascularization periods between or equal to 1 day and 10 weeks. Of course, vascularization periods greater than and less than those described above are contemplated, as the present disclosure is not limited in this manner.

[0081] In some cases, it may be advantageous to maintain the compartment in the desired expansion configuration during the vascularization period. Therefore, during the pre-vascularization period of the large capsule device, the first-level compartment 120, the second-level compartment 122, the third-level compartment 124 or any combination thereof can be inflated. For example, fluid can flow into the first-level compartment, the second-level compartment and / or the third-level compartment through one or more associated ports (not shown). Suitable fluids that can be used for compartment inflation may include any suitable biocompatible fluid. In some embodiments, based on the corresponding properties of external membrane and / or inner semi-permeable membrane, fluid may be able to be retained in the inside of the device, and the external membrane and / or inner semi-permeable membrane may be constructed to retain fluid in the inside of the device. Several examples for suitable fluids for compartment inflation may include but are not limited to oxygen, saline, cell culture medium, alginate, chitosan, dextrose, perfluorocarbon and combinations thereof. During vascularization of the device, once inflated to a desired pressure, volume, and / or other appropriate parameters, the ports associated with the primary, secondary, and tertiary compartments may be sealed to maintain the associated compartments in the desired inflated configuration. After vascularization, the ports may be reopened and the fluid used to inflate the compartments may be removed in any appropriate manner.

[0082] As previously described, in some embodiments, at least one of the primary compartment 120 and the tertiary compartment 124 can be configured to accommodate one or more cell groups 134 and retain them therein. Likewise, the primary compartment and the secondary compartment 122 can be separated by the first semi-permeable membrane 116. Similarly, the secondary compartment and the tertiary compartment can be separated by the second semi-permeable membrane 118. The first semi-permeable membrane and the second semi-permeable membrane can be configured to filter the filtrate 136 from the primary compartment and / or the tertiary compartment. Therefore, when the cell group is loaded into the primary compartment and / or the tertiary compartment, the filtrate 136 combined with the cell group during loading can flow from the primary compartment and / or the tertiary compartment into the secondary compartment through the associated first semi-permeable membrane and / or the second semi-permeable membrane. The flow of material into the secondary compartment can be assisted by the pressure difference applied between the secondary compartment and at least one or both of the primary compartment and the tertiary compartment. This pressure differential can be provided using suction applied to the secondary compartment, an increase in pressure due to the flow of material into the primary compartment and / or the tertiary compartment, a combination of the foregoing, and / or any other suitable method of applying a bias to cause the filtrate to flow into the secondary compartment. In addition, in some embodiments, the filtrate can be removed through an associated port (not depicted) during and / or after the loading process. This loading of cells and removal of the filtrate can be accomplished percutaneously, but the present disclosure is not limited to removing the filtrate only through ports accessible percutaneously. Similarly, although a three-compartment device has been depicted in the figures, the above method can also be applied to devices comprising two compartments and / or any other suitable number of compartments, as the present disclosure is not limited in this manner.

[0083] After the desired cell population 134 is loaded into the macrocapsule device 100 and / or the filtrate 136 is removed, an adjuvant 138 may be provided to one or more cell populations that may be disposed in the primary compartment 120 and / or the tertiary compartment 124. For example, the adjuvant may be introduced into the secondary compartment 122 through an associated port (not depicted). The adjuvant may then flow from the secondary compartment into the primary compartment and / or the tertiary compartment through the associated first semi-permeable membrane 116 and the second semi-permeable membrane 118. The flow of the adjuvant from the secondary compartment into the primary compartment and the tertiary compartment may be due to diffusion caused by a concentration gradient between adjacent compartments and / or by a pressure difference between adjacent compartments due to the flow of the adjuvant into the secondary compartment. Similar to removing the filtrate, in some embodiments, the adjuvant 138 may be loaded into the secondary compartment via the skin, but other methods of introducing the adjuvant may also be envisioned. In a specific embodiment, providing an adjuvant can be performed by connecting the built-in tubing to the subcutaneous port of the secondary compartment and allowing the adjuvant to flow through the port into the secondary compartment and then into the primary compartment and the secondary compartment. The subcutaneously placed port may include a vascular access port. Of course, it is also envisioned that the adjuvant is directly loaded into the primary compartment and / or the tertiary compartment through one or more associated ports. As previously described, the adjuvant may include an anti-inflammatory drug, an oxygen-producing substance, a differentiation factor, an anticoagulant factor, a nutrient, any combination thereof, and / or any other suitable agent, because the present disclosure is not limited in this manner.

[0084] In the above-mentioned embodiment, adjuvant can be provided once or repeatedly at periodic intervals. The periodic intervals at which adjuvant can be provided to cells via the secondary compartment can be greater than or equal to 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 1 day, 2 days, 5 days and / or any other appropriate time interval. Correspondingly, the time interval between the application of adjuvant can be less than or equal to 60 weeks, 50 weeks, 20 weeks, 10 weeks, 5 weeks, 1 week, 5 days, 2 days, 1 day and / or any other appropriate time interval. It is contemplated that the combination of the aforementioned range includes, for example, the time interval between or equal to 1 minute and 60 weeks. Of course, it is also contemplated that the time interval is greater than and less than those mentioned above, because the present disclosure is not limited in this way.

[0085] As described above, in some embodiments, a pressure differential may be applied between two or more compartments of the macrocapsule device 100 to facilitate one or more of the following: flow of cells into the compartments; flow of filtrate and / or adjuvants between the compartments; flow of filtrate from the ports of the compartments; and / or flow of adjuvants through the ports and into the associated compartments. For example, after prevascularization of the device, a pressure differential may be applied between the secondary compartment 122 and one or both of the primary compartment 120 and the tertiary compartment 124 to remove the filtrate 138 from the primary compartment and the tertiary compartment. Applying a pressure differential between the secondary compartment and the primary compartment and / or the tertiary compartment may be performed simultaneously with or after loading the cell population 134. In addition, negative and / or positive pressure may be applied to the associated compartments to generate a desired pressure differential. For example, suction or vacuum may be applied to the compartments, and the material may flow into another compartment to increase the pressure in the compartment, and the desired pressure differential may be generated using the above combination and / or any other appropriate method, as the present invention is not limited thereto. Furthermore, in some cases, concentration gradients may be used to induce the flow of materials between compartments. For example, a large concentration of an adjuvant may be placed in a secondary compartment, which may then diffuse into other adjacent compartments that may have a lower concentration of the adjuvant.

[0086] Although any suitable pressure difference can be applied to generate the desired material flow in each part of the large capsule device, in some embodiments, the pressure difference applied between two adjacent compartments can be greater than or equal to about 1atm, 1.25atm, 1.3atm, 1.35atm, 1.4atm, 1.45atm, 1.5atm and / or any other suitable pressure difference. Correspondingly, the pressure difference can be less than or equal to 3atm, 2.75atm, 2.5atm, 2.25atm, 2atm, 1.9atm, 1.8atm, 1.6atm and / or another suitable pressure difference. It is contemplated that the combination of the above range includes, for example, a pressure difference between or equal to about 1atm and 3atm. Of course, it should be understood that, depending on the specific application, any suitable pressure difference can be used, including a pressure difference greater than and less than those mentioned above.

[0087] Although the present teachings have been described in conjunction with various embodiments and examples, the present teachings are not intended to be limited to such embodiments and examples. On the contrary, the present teachings encompass various substitutions, modifications and equivalents as will be appreciated by those skilled in the art. Therefore, the foregoing description and accompanying drawings are intended only as examples.

Claims

1. A large capsule device, comprising: first outer membrane; Second outer membrane; as well as a first semi-permeable membrane, the first semi-permeable membrane being disposed between the first outer membrane and the second outer membrane; a primary compartment formed by the first semipermeable membrane and the first outer membrane, wherein the primary compartment is configured to house a first population of cells; as well as a secondary compartment formed by the first semi-permeable membrane and a second semi-permeable membrane, wherein the primary compartment and the secondary compartment are in fluid communication across the first semi-permeable membrane; The second semi-permeable membrane is disposed between the first semi-permeable membrane and the second outer membrane; as well as A tertiary compartment is disposed between the second semi-permeable membrane and the second outer membrane, and wherein an interior volume of at least one of the primary compartment, the secondary compartment, and the tertiary compartment is formed as a plurality of interconnected channels.

2. The macrocapsule device of claim 1 , wherein the first semipermeable membrane is configured to block the first cell population from passing between the primary compartment and the secondary compartment, and to allow filtrate and / or auxiliary agents to flow between the primary compartment and the secondary compartment, wherein the auxiliary agents include drugs, nutrients, or any combination thereof.

3. The large capsule device of claim 1, wherein the first semi-permeable membrane is constructed to block the first cell population from passing between the primary compartment and the secondary compartment, and to allow filtrate and / or auxiliary agents to flow between the primary compartment and the secondary compartment, wherein the auxiliary agents include oxygen-generating substances, anticoagulants, or any combination thereof.

4. The large capsule device according to claim 1, further comprising: The first cell population is disposed in the primary compartment.

5. The macrocapsule device of claim 1, wherein the first outer membrane and the second outer membrane are configured to block the cell population from leaving the device.

6. The large capsule device of claim 1, wherein the first outer membrane and / or the second outer membrane is semi-permeable.

7. The large capsule device of any one of claims 1 to 6, wherein each of the primary compartment, the secondary compartment, and the tertiary compartment is formed as a plurality of interconnected channels.

8. The macrocapsule device of any one of claims 1-6, wherein the hydraulic permeability and / or porosity of the first semi-permeable membrane is different from the hydraulic permeability and / or porosity of the second semi-permeable membrane.

9. The macrocapsule device of any one of claims 1-6, wherein the tertiary compartment is configured to accommodate a second cell population.

10. The large capsule device of claim 9, further comprising: The first cell population is disposed in the primary compartment, and the second cell population is disposed in the tertiary compartment, and wherein the first cell population and the second cell population include different types of cells.

11. The macrocapsule device of any one of claims 1-6 and 10, wherein the hydraulic permeability and / or porosity of the first semipermeable membrane is different from the hydraulic permeability and / or porosity of the first outer membrane and / or the second outer membrane.

12. The macrocapsule device according to any one of claims 1 to 6 and 10, further comprising: a primary port in fluid communication with the primary compartment; and a secondary port in fluid communication with the secondary compartment.

13. The large capsule device of claim 12, wherein the primary port and the secondary port are sealable.

14. The large capsule device of claim 12, wherein the primary port and the secondary port are resealable.

15. A large capsule device comprising: a primary compartment configured to house a first population of cells; a secondary compartment, wherein the primary compartment and the secondary compartment are in fluid communication through a first semi-permeable membrane disposed between the primary compartment and the secondary compartment; as well as A tertiary compartment, wherein the secondary compartment is disposed between the primary compartment and the tertiary compartment, wherein the tertiary compartment and the secondary compartment are fluidly connected through a second semi-permeable membrane disposed between the secondary compartment and the tertiary compartment, and wherein the internal volume of at least one of the primary compartment, the secondary compartment and the tertiary compartment is formed as a plurality of interconnected channels.

16. The macrocapsule device of claim 15, wherein the first semipermeable membrane is configured to block the first cell population from passing between the primary compartment and the secondary compartment, and to allow filtrate and / or auxiliary agents to flow between the primary compartment and the secondary compartment, wherein the auxiliary agents include drugs, nutrients, or any combination thereof.

17. The large capsule device of claim 15, wherein the first semi-permeable membrane is constructed to block the first cell population from passing between the primary compartment and the secondary compartment, and to allow filtrate and / or auxiliary agents to flow between the primary compartment and the secondary compartment, wherein the auxiliary agents include oxygen-generating substances, anticoagulants, or any combination thereof.

18. The macrocapsule device according to any one of claims 15 to 17, further comprising: The first cell population is disposed in the primary compartment.

19. The large capsule device of any one of claims 15-17, wherein each of the primary compartment, the secondary compartment, and the tertiary compartment is formed as a plurality of interconnected channels.

20. The large capsule device of claim 19, wherein the hydraulic permeability and / or porosity of the first semi-permeable membrane is different from the hydraulic permeability and / or porosity of the second semi-permeable membrane.

21. The macrocapsule device of claim 19, wherein the tertiary compartment is configured to house a second cell population.

22. The large capsule device of claim 21, further comprising: The first cell population is disposed in the primary compartment, and the second cell population is disposed in the tertiary compartment, and wherein the first cell population and the second cell population include different types of cells.

23. The macrocapsule device of any one of claims 15-17, 20 and 22, further comprising: a primary port in fluid communication with the primary compartment; and a secondary port in fluid communication with the secondary compartment.

24. The large capsule device of claim 23, wherein the primary port and the secondary port are sealable.

25. The large capsule device of claim 23, wherein the primary port and the secondary port are resealable.

Images