Macroencapsulation device and method for forming a macroencapsulation device

Abstract

To provide macroencapsulation devices and methods of forming macroencapsulation devices.SOLUTION: The present disclosure relates to macroencapsulation devices and related methods of manufacture where membranes of a device may be attached to an associated frame in a relaxed, or slack, configuration prior to filling with a desired material. In one embodiment, a macroencapsulation device for housing a population of cells comprises a first membrane, and a second membrane disposed on the first membrane. The first and second membranes are bonded along a perimeter of the first and second membranes to form an internal volume therebetween. The first membrane and / or the second membrane is semipermeable. The device also comprises a frame that extends along at least a portion of the perimeter of the first and second membranes. A surface area of the first and / or second membrane is greater than a transverse cross-sectional area of the frame to which the first and second membranes are attached.SELECTED DRAWING: Figure 4A

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts the benefits under Section 119(e) of U.S. Patent Act, as of U.S. Provisional Application No. 62 / 828,915 (filed on 3 April 2019). The disclosures of that document are incorporated herein by reference in their entirety.

[0002] The disclosed embodiments relate to a macroencapsulation apparatus and a method for manufacturing the same. [Background technology]

[0003] To treat metabolic disorders such as diabetes, therapeutic devices that deliver biological products can be used. These devices may be implantable to deliver biological products, such as insulin, over extended periods. Some of these devices include macroencapsulation devices used to contain cells and generate desired biological products, cell-containing matrices, or other desired therapeutic agents internally. [Overview of the project] [Means for solving the problem]

[0004] In one embodiment, a macroencapsulation device for containing a cell population includes a first membrane and a second membrane positioned on the first membrane. The first and second membranes are joined along their periphery to form an internal volume between them, and the first and / or second membranes are semipermeable. The device also includes a frame extending along at least a portion of the periphery of the first and second membranes, and the surface area of ​​the first and / or second membranes is larger than the cross-sectional area of ​​the frame on which the first and second membranes are mounted.

[0005] In another embodiment, a macroencapsulation device for containing a cell population includes a first membrane and a second membrane positioned on the first membrane. The first and second membranes are joined along the periphery of the first and second membranes to form an internal volume between them, and the first and / or second membranes are semipermeable. The device also includes a frame extending along at least a portion of the periphery of the first and second membranes, and portions of the first and second membranes connected to the frame are deformed to fit into a region of the frame smaller than the region of the undeformed portions of the first and second membranes.

[0006] In another embodiment, a method for forming a macroencapsulation device includes deforming a portion of a first membrane and a portion of a second membrane placed on the first membrane in the out-of-plane direction of the first and second membranes, and connecting a frame to the second membrane and / or the first membrane while the portions of the first and second membranes are being deformed out-of-plane, the frame limiting the maximum transverse dimension of the macroencapsulation device, and the first membrane and / or the second membrane being semipermeable.

[0007] In yet another embodiment, a method for forming a macroencapsulation device includes deforming the outer periphery of a first membrane and a second membrane placed on the first membrane from a first maximum cross-sectional dimension to a second maximum cross-sectional dimension smaller than the first maximum cross-sectional dimension, and connecting a frame to the second membrane and / or the first membrane to limit the maximum cross-sectional dimensions of the first and second membranes to the second maximum cross-sectional dimension, wherein the first membrane and / or the second membrane are semipermeable.

[0008] Since this disclosure is not limited in this respect, it should be noted that the above-mentioned ideas and further ideas described below may be arranged in any preferred combination. Furthermore, other advantages and novel features of this disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered together with the accompanying figures.

[0009] In the event that this Specified and any reference incorporated herein contain conflicting and / or inconsistent disclosures, this Specified shall prevail. If two or more references incorporated herein contain conflicting and / or inconsistent disclosures, the reference with the later effective date shall prevail. The present invention provides, for example, the following: (Item 1) A macroencapsulation device for containing a population of cells, The first membrane and, A second membrane disposed on the first membrane, wherein the first membrane and the second membrane are bonded together along the periphery of the first and second membranes, forming an internal volume between them, and the first membrane and / or the second membrane are semipermeable, A macroencapsulation apparatus comprising: a frame extending along at least a portion of the periphery of the first and second films, wherein the surface area of ​​the first and / or second films is larger than the cross-sectional area of ​​the frame on which the first and second films are mounted. (Item 2) The macroencapsulation apparatus according to item 1, wherein the frame extends throughout along the periphery of the first and second membranes. (Item 3) The macroencapsulation apparatus according to item 1 or 2, wherein the first and second membranes are configured to block the movement of the cell population out of the apparatus. (Item 4) The macroencapsulation apparatus according to item 3, further comprising the cell population arranged within the internal volume. (Item 5) The aforementioned internal volume includes a plurality of channels, as described in any one of items 1 to 4 of the macroencapsulation apparatus. (Item 6) The macroencapsulation apparatus according to item 5, comprising a plurality of bonding portions of the first and second membranes arranged radially inward from the frame, further including the bonding portions that form the plurality of channels, wherein at least a portion of the bonding portions is penetrated by through-holes. (Item 7) The macroencapsulation device according to any one of items 1 to 6, wherein said first membrane and / or said second membrane is sintered. (Item 8) The macroencapsulation device according to any one of items 1 to 7, wherein said first membrane and / or said second membrane comprises a hydrophilic coating. (Item 9) A macroencapsulation device for housing a cell population, comprising: a first membrane; a second membrane disposed on said first membrane, wherein said first membrane and said second membrane are bonded along the peripheries of said first and second membranes to form an internal volume therebetween, and said first membrane and / or said second membrane is semipermeable; a frame extending along at least a portion of said periphery of said first and second membranes, wherein portions of said first and second membranes connected to said frame are deformed to fit within an area of said frame that is smaller than the area of said portions of said first and second membranes in an undeformed configuration; the macroencapsulation device comprising said frame. (Item 10) The macroencapsulation device according to item 9, wherein said portions of said first and second membranes connected to said frame comprise a plurality of locations disposed along the periphery of said frame, at which said first and second membranes are deformed from a first larger area to a second smaller area. (Item 11) The macroencapsulation device according to any one of items 9 or 10, wherein a surface area of said first and / or second membrane is larger than a cross-sectional area of said frame to which said first and second membranes are attached. (Item 12) The macroencapsulation device according to any one of items 9 to 11, wherein said frame extends entirely along said periphery of said first and second membranes. (Item 13) The macroencapsulation device according to any one of items 9 to 12, wherein said first and second membranes are configured to block migration of said cell population out of said device. (Item 14) The macroencapsulation apparatus according to item 13, further comprising the cell population arranged within the internal volume. (Item 15) The aforementioned internal volume includes a plurality of channels, as described in any one of items 9 to 14 of the macroencapsulation apparatus. (Item 16) The macroencapsulation apparatus according to item 15, comprising a plurality of bonding portions of the first and second membranes arranged radially inward from the frame, further including the bonding portions that form the plurality of channels, wherein at least a portion of the bonding portions is penetrated by through-holes. (Item 17) A macroencapsulation apparatus according to any one of items 9 to 16, wherein the first film and / or the second film are sintered. (Item 18) The macroencapsulation apparatus according to any one of items 9 to 17, wherein the first and / or second membrane includes a hydrophilic coating. (Item 19) A method for forming a macroencapsulation device, Deforming a portion of the first film and a portion of the second film placed on the first film in the out-of-plane direction of the first and second films, A method comprising connecting a frame to the second membrane and / or the first membrane while the portions of the first and second membranes are being deformed out of plane, wherein the frame limits the maximum transverse dimension of the macroencapsulation device, and the first membrane and / or the second membrane are semipermeable. (Item 20) The method according to item 19, wherein the surface area of ​​the first and / or second film is larger than the cross-sectional area of ​​the frame on which the first and second films are mounted. (Item 21) The method according to either item 19 or 20, wherein the first and second membranes are configured to block the movement of the cell population out of the apparatus. (Item 22) The method according to item 21, further comprising filling the internal volume of the apparatus with the cell population. (Item 23) The method according to any one of items 19 to 22, wherein the first film and / or the second film are sintered. (Item 24) The method according to any one of items 19 to 23, further comprising coating the first and / or second film with a hydrophilic material. (Item 25) The method according to any one of items 19 to 24, wherein the out-of-plane deformation of the portions of the first and second films is performed by aligning the surface of the first film opposite to the second permeable film on a curved support. (Item 26) The method of item 25, wherein the curved support comprises a spherical dome. (Item 27) The method according to any one of item 25 or 26, further comprising applying a vacuum to one or more non-diffusible portions of the first and second films to maintain the first and second films adjacent to the curved support. (Item 28) The method of item 27, wherein the non-diffusible portion is located radially outward from the internal volume located between the first and second membranes. (Item 29) The method according to any one of items 19 to 28, further comprising joining one or more portions of the first and second membranes to form a plurality of channels between them before connecting the frame to the second membrane. (Item 30) The method according to item 29, further comprising forming one or more through-holes in the one or more joint portions before connecting the frame to the second membrane. (Item 31) A method for forming a macroencapsulation device, The outer periphery of the first film and the second film placed on the first film is deformed from a first maximum cross-sectional dimension to a second maximum cross-sectional dimension that is smaller than the first maximum cross-sectional dimension. The method comprising connecting a frame to the second membrane and / or the first membrane to limit the maximum transverse dimension of the first and second membranes to the second maximum transverse dimension, wherein the first membrane and / or the second membrane are semipermeable. (Item 32) The method according to item 31, wherein the surface area of ​​the first and / or second film is larger than the cross-sectional area of ​​the frame on which the first and second films are mounted. (Item 33) The method according to any one of items 31 to 32, wherein the first and second membranes are configured to block the movement of the cell population out of the apparatus. (Item 34) The method according to any one of items 31 to 33, further comprising filling the internal volume of the apparatus with the cell population. (Item 35) The method according to any one of items 31 to 34, wherein the first film and / or the second film are sintered. (Item 36) The method according to any one of items 31 to 35, further comprising coating the first and / or second film with a hydrophilic material. (Item 37) The method according to any one of items 31 to 36, wherein the outer periphery of the first and second membranes is deformed from a first maximum transverse dimension to a second maximum transverse dimension smaller than the first maximum transverse dimension, the surface of the first membrane opposite to the second permeable membrane is placed on a curved support. (Item 38) The method according to item 37, wherein the curved support comprises a spherical dome. (Item 39) Maintaining the first and second films adjacent to the curved support is further comprising applying a vacuum to one or more non-diffusible portions of the first and second films, according to the method of any one of item 37 or 38. (Item 40) The method according to item 39, wherein the non-diffusible portion is located radially outward from the internal volume positioned between the first and second membranes. (Item 41) The method according to any one of items 31 to 40, further comprising joining one or more portions of the first and second membranes to form a plurality of channels between them before connecting the frame to the second membrane. (Item 42) The method according to item 41, further comprising forming one or more through-holes in the one or more joint portions before connecting the frame to the second membrane.

[0010] The attached drawings are not intended to be drawn to a fixed ratio. In the drawings, identical or nearly identical components illustrated in various figures may be represented by similar numbers. For clarity, not all components may be labeled in all drawings. In the drawings, [Brief explanation of the drawing]

[0011] [Figure 1A] This figure shows the first and second membranes placed within the fastener during the bonding and cutting process according to one embodiment. [Figure 1B] This is a plan view of Figure 1A. [Figure 1C] This figure shows the process of joining parts of the first and second membranes within a fastener according to one embodiment. [Figure 1D] This figure shows the membrane inside the fastener after bonding according to one embodiment. [Figure 1E] Figure 1D is a plan view. [Figure 1F] This figure shows a process for introducing through-holes into a membrane while it is positioned inside a fixing device, according to one embodiment. [Figure 1G] This figure shows the through-holes obtained as a result of formation within the membrane in Figure 1F. [Figure 1H] This figure shows a process in which a portion of the bonding membrane is cut off while it is inside the fixing device, according to one embodiment. [Figure 1I] This figure shows the process of removing the cut portion of the membrane from the fixing device according to one embodiment. [Figure 1J] This is a plan view of the membrane removed from Figure 1I. [Figure 2A] This figure shows a process for positioning a laminate of films on a curved support according to one embodiment. [Figure 2B] This figure shows a laminate of films arranged on a curved support according to one embodiment. [Figure 2C] This figure shows a process of positioning a frame on a laminate of films after it has been positioned on a curved support according to one embodiment. [Figure 2D] This figure shows a frame that, according to one embodiment, is positioned on a laminate of films and then placed on the surface of a second film. [Figure 2E] This figure shows the process of bonding a frame to a second membrane according to one embodiment. [Figure 3] This figure shows a frame positioned between the first and second membranes according to one embodiment. [Figure 4A] This is a side view of a macroencapsulation device before filling, according to one embodiment. [Figure 4B] Figure 4A is a plan view of the macroencapsulation apparatus. [Figure 4C] Figure 4A is a side view of the macroencapsulation apparatus after it has been filled with the desired material. [Figure 5A] This is a schematic diagram of a curved support according to one embodiment. [Figure 5B] Figure 5A is a plan view of the curved support. [Figure 5C] Figure 5A is a cross-sectional view of the central plane of the curved support. [Figure 5D] Figure 5A is a cross-sectional view of the side plane of the curved support. [Figure 6A] This is an image of a laminate of films arranged on a curved support according to one embodiment. [Figure 6B] This is an image of a frame mounted on a laminate of films arranged on a curved support according to one embodiment. [Figure 7A] This is a photograph of the macroencapsulation device before cells are filled into it. [Figure 7B]Figure 7A is a photograph of a part of the macroencapsulation apparatus. [Figure 8A] This is a scanning electron microscope image of a cross-sectional view of a first macroencapsulation device with a first volume of membrane slack filled with beads. [Figure 8B] This is a scanning electron microscope image of a cross-section of a second macroencapsulation device with a second volume of membrane slack filled with beads. [Figure 9] This is a schematic diagram showing the relative change in membrane sag due to changes in frame sizing. [Figure 10A] This is a schematic diagram of a section of a first typical macroencapsulation device with a first amount of membrane slack during loading after filling. [Figure 10B] This is a schematic diagram of a section of a second typical macroencapsulation with a second amount of slack during fitting after filling. [Modes for carrying out the invention]

[0012] Driven by the increasing need to deliver biological products to treat metabolic disorders such as diabetes, different types of implantable therapeutic devices are being designed. However, inventors recognize that typical methods for manufacturing such devices are often cumbersome and difficult to control. For example, precision and control are often insufficient when forming specific structural features associated with the device (e.g., chamber height and volume). In addition, inventors recognize that it is often difficult to controllly fill these devices with the target biological entity (e.g., cell population) to the desired concentration and / or without causing excessive cell death and / or cell aggregation.

[0013] Considering the above, the inventors recognize the benefit associated with macroencapsulation devices, namely that one or more parameters of the resulting macroencapsulation device can be modified by controlling the relative sizing and arrangement of the membrane and the device frame. For example, relative sizing of the membrane and the corresponding frame can provide a simple and easily controllable method for manufacturing macroencapsulation devices with a range of dimensions and / or operating parameters. This will be discussed in detail below. This may include controlling the amount of slack in the membrane held within the frame before filling it with a desired therapeutic agent, such as a population of cells.

[0014] In this specification, the aforementioned schematic concept of controlling the amount of membrane slack during frame mounting may interchangeably be referred to as slack mounting or mounting loosening. This concept may refer to mounting at least two or more layers of flexible membranes (e.g., a first membrane and a second membrane) under controlled loose tension to form a device containing internal chambers of a specified volume and / or height upon filling. By adjusting the degree of membrane loosening during the slack mounting process, a device with a desired set of geometric properties for housing a cell population can be fabricated. For example, in some embodiments, the degree of membrane loosening during the slack mounting process may be controlled by combining the degree of deformation introduced into the membrane during manufacturing with mechanical constraints applied to the membrane (e.g., using a perimeter frame to limit the maximum transverse dimension of the membrane relative to the entire surface area of ​​the membrane). This will be further discussed below.

[0015] In some embodiments, during the manufacturing process of the macroencapsulation apparatus, at least one (and possibly at least two, or more) flexible membranes of the apparatus may be deformed to fit at least partially within a frame and then joined to the frame to form the macroencapsulation apparatus. The frame can hold the membranes in a desired configuration (the membranes having a desired amount of slack extending between opposing portions of the frame). For example, in one embodiment, the outer periphery of a first membrane and a second membrane placed on the first membrane may be deformed from a first maximum cross-sectional dimension to a second maximum cross-sectional dimension smaller than the first maximum cross-sectional dimension before being joined to the frame. By deforming and subsequently holding the membranes in the deformed configuration, the membranes can be held within the frame with a desired amount of slack to accommodate excess material contained within the frame. Such deformation and holding can be achieved in many different ways.

[0016] In one embodiment, a frame can be used to limit the maximum transverse dimensions of the first and second films to a maximum transverse dimension smaller than that of the undeformed film. Specifically, the frame can be connected to the second film and / or the first film, while a portion of the first and second films (e.g., the central portion) is deformed out of plane relative to the plane on which the films extend in a flat configuration. Once the force applying the out-of-plane deformation to the films is removed, the frame can limit the maximum transverse dimensions of the macroencapsulation device. Thus, the frame can make the surface area of ​​the first and / or second films larger than the second maximum transverse dimension, resulting in slack within the films between opposing portions of the frame.

[0017] As mentioned above, when a frame is connected to the deformed membrane of the macroencapsulation apparatus during the manufacturing process, the frame can maintain a portion of the membrane in a deformed configuration, thereby providing a desired amount of slack within the membrane. For example, a first membrane and a second membrane may be joined along the periphery of the membrane. This joined portion of the membrane may be deformed to fit within a frame that is joined around the first and / or second membrane and extends along at least a portion of it, although in some embodiments the frame may also extend along the periphery of the entire membrane. Specifically, portions of the first and second membranes connected to the frame may be deformed to fit within a region of the frame smaller than the region of the undeformed portions of the first and second membranes. Specifically, to achieve a desired amount of membrane slack within the apparatus, a frame with a maximum transverse dimension smaller than the transverse dimension of the undeformed membrane may be connected to the membrane. In such embodiments, portions of the first and second membranes connected to the frame may include a plurality of locations arranged along the periphery of the frame where the first and second membranes are deformed to adapt to the reduction in region. For example, in some embodiments, the deformed portion of the film may include wrinkles, folds, corrugations, plastically or thermally deformed sections, and / or any other suitable type of deformation that can adapt to a regional change in the portion of the film from a first larger region to a second smaller region.

[0018] Depending on the desired configuration, the frame of the macroencapsulation device may be positioned at any number of different locations relative to the different membranes of the device. For example, in one embodiment, the frame may be connected to one of the outer surfaces of the outer membranes of the device. In one such embodiment, the first membrane may be positioned on the second membrane, and the frame may be positioned on the outer surface of the second membrane opposite to the first membrane and connected to it. In another embodiment, the frame may be connected to both the first and second membranes, so that the frame is positioned between the membranes and in the vicinity of at least a portion of the periphery of the first and second membranes, or otherwise extending along at least a portion of them. Naturally, this disclosure is not limited to any specific positioning of the frame relative to the individual membranes of the device.

[0019] In some embodiments, the volume and height associated with one or more portions of the internal volume of the macroencapsulation device can be controlled by adjusting the degree of membrane slack (i.e., sag) of the first and second membranes relative to a given membrane size and corresponding frame size. The amount of sag present in the membrane before cell filling may relate to the difference between the surface areas of the first and second membranes during the loading process and the corresponding cross-sectional areas of the frame on which the membranes are loaded, which can also be described as a relative mismatch in the sizing of the membrane and frame areas. The relative differences in these areas, and the resulting sag in the loaded membrane, can be controlled by adjusting the frame size relative to the membrane size. For example, the cross-sectional area of ​​the frame may be smaller than the corresponding surface area of ​​the membrane held within the frame. Therefore, the greater the difference between the membrane surface area and the frame cross-sectional area on which the membranes are loaded, the greater the corresponding sag in the membrane. Conversely, the smaller the difference between the membrane surface area and the frame cross-sectional area, the smaller the corresponding sag.

[0020] Considering the above, the surface area of ​​one or more films mounted within a frame may be larger than the cross-sectional area of ​​the frame on which the one or more films are mounted. The surface area of ​​one or more films may include portions of films that are radially inward from the corresponding frame or otherwise bonded to each other in the internal portions of the films that are located within the corresponding frame. Furthermore, the surface area of ​​one or more films may be larger than the cross-sectional area of ​​the frame by a percentage of 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 10% or more, 20% or more, and / or any other appropriate percentage. Correspondingly, the surface area of ​​one or more films may be larger than the cross-sectional area of ​​the frame by a percentage of 30% or less, 20% or less, 10% or less, 5% or less, and / or any other appropriate percentage. The aforementioned combinations are also possible. For example, the surface area of ​​one or more films may be 1% to 30% (including both ends) larger than the cross-sectional area. Naturally, both larger and smaller percentages than those described above are possible, and this disclosure is not limited as stated above.

[0021] As previously stated, one or more portions of the film that are deformed out of plane during the mounting process to the frame may, once mounted to the frame, be deformed by any appropriate amount to give the film a desired amount of slack. In some embodiments, this out-of-plane deformation may correspond to a deformation in which the projected two-dimensional area of ​​the film relative to the flat planar configuration of the film is reduced by a percentage of 0.3% or more, 0.5% or more, 1% or more, 2% or more, 3% or more, and / or any other appropriate percentage. Correspondingly, the deformation may result in a reduction of the projected two-dimensional area of ​​the film by a percentage of 7.5% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, and / or any other appropriate percentage. The aforementioned combinations are also possible, for example, in the range of 0.3% to 7.5% (including both ends). Furthermore, in some embodiments, this deformation may correspond to an out-of-plane deformation of about 1 mm to 10 mm (including both ends) in the out-of-plane direction of the film in a flat planar configuration. Naturally, the specific deformation range is expected to vary for various frame and film sizes. In any case, both larger and smaller ranges than those described above are possible for the rate of change and / or absolute amount of deformation, and this disclosure is not limited as stated above.

[0022] In one embodiment, deformation of the film of the apparatus during frame mounting can be assisted by using a support on which the laminated film can be placed during the frame mounting process. The support may extend over at least a portion (and possibly all) of the area of ​​the film placed on it. The degree of film deformation can be controlled by adjusting the specific profile of the support. For example, a laminate of two or more films may be placed on a curved support or other appropriately shaped support capable of deforming the laminated film placed on it in a desired manner. The curved support may also have any suitable shape, for example, a sphere, a spherical dome, a cylinder, a partial cylinder, an oval, a partial oval, and / or any other suitable shape capable of giving a desired deformation to the laminated film placed on it or at least partially placed on it. In either case, by placing the first and second membranes of the macroencapsulation device on a support, a portion of the membrane laminate can be deformed out of plane to the first and second membranes so that the membrane is deformed from a first maximum transverse dimension, which is larger than that of an undeformed planar configuration membrane, to a second maximum transverse dimension, which is smaller than that of a deformed membrane (e.g., a bent or curved configuration membrane). A frame can then be attached to the membrane while it is held in the deformed configuration.

[0023] While the use of a curved support has been described above for deforming a laminate of film, the disclosure is not limited to the use of a curved support. For example, in some embodiments, methods for deforming first and second film from a first maximum transverse dimension to a second smaller maximum transverse dimension in order to mount a frame thereon may include deforming the film using thermoforming, mechanical deformation, and / or some suitable method that allows the frame to be mounted on the film in a desired configuration while at least a desired portion of the film is allowed to stretch between the flexible frame with a desired amount of slack.

[0024] In some embodiments, it may be desirable to hold a laminate of two or more films in a desired position and / or orientation on a support lying beneath it. This can be done in some suitable way, but in one embodiment, the support may be configured to maintain the films adjacent to the support by applying vacuum suction to one or more portions of the laminate of films. To avoid compaction of the diffusive portion of the macroencapsulation device, vacuum may be applied to one or more non-diffusive portions of the films. For example, non-diffusive portions of the first and second films may include portions of the films located outside the bonded region (e.g., the bonded periphery and / or bonded interior portion of the first and second films) and / or outside the active region of the device (e.g., radially outward from the bond extending along the periphery of the device that forms the internal volume of the device). Thus, vacuum may be applied to locations radially outward from the internal volume located between the first and second films or between other suitable non-diffusive portions of the films.

[0025] As previously mentioned, the macroencapsulation device may include a multilayer membrane. At least one of these multilayer membranes may be semipermeable. However, embodiments may also be conceivable in which each membrane is semipermeable or at least one of the membranes in the device is substantially impermeable. Furthermore, the device may also include two-layer membranes, three-layer membranes, and / or any other suitable number of membranes, and the disclosure is not limited as stated above. For example, in one embodiment including two membranes, one membrane may be semipermeable and the other impermeable, or both may be semipermeable. Naturally, the disclosure is not limited to any particular combination of membranes in a multilayer structure.

[0026] In some embodiments, a macroencapsulation device may contain at least one population of cells located within the internal volume of the device. For example, the cell population may be located within an internal volume formed between two or more opposing outer membranes of the device. The outer edge of the internal volume may be defined by one or more bindings extending around the membrane or other suitable portion of the membrane. In such embodiments, at least the outer membrane of the device may be configured to prevent the movement of one or more cell populations out of the device. Thus, one or more cell populations can be retained within the internal volume of the device. While it is obvious that we have shown the use of two outer membranes forming a single internal volume, it is also conceivable to use multiple intermembranes located between the outer membranes of the device and / or between multiple disconnected internal volumes within the device.

[0027] In addition to holding cell populations inside the device, in some embodiments, the device's membrane may be configured to protect one or more cell populations located inside the device from immune attack, while allowing the movement of desired biological products produced by the cells (e.g., insulin) as well as waste and nutrients used and generated by the cells. In some embodiments, the membrane is configured to protect cells from immune attack in the absence of immunosuppressive therapy.

[0028] The membrane of the macroencapsulation device may be formed from any suitable biocompatible material. The biocompatible material may be substantially inert to the cells and surrounding tissues contained within the macroencapsulation device. Biocompatible materials include synthetic polymers or naturally occurring polymers. In some embodiments, the polymer may also be linear polymers, crosslinked polymers, network polymers, addition polymers, condensation polymers, elastomers, fibrous polymers, thermoplastic polymers, non-degradable polymers, combinations of the foregoing, and / or any other suitable type of polymer, and the disclosure is not limited as stated above. Suitable types of polymers 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 difluoride (PVDF), polycaprolactone (PCL), poly(glycolic acid lactate) (PLGA), poly-L-lactide (PLLA), any combination thereof, and / or any other suitable polymer material. Synthesis methods used to form one or more porous membranes from the aforementioned polymer materials may include (but are not limited to): expansion, solution casting, immersion deposition and phase separation, electrospinning, methods for obtaining an isocellular network, methods for obtaining a columnar network, or any other suitable method for forming a porous polymer membrane.

[0029] The porosity and flux properties of a film can be altered by sintering. For example, sintering can increase the porosity of a film while maintaining its pore structure. Sintering can also improve the mechanical stability and diffusion flux of a film. Therefore, the porosity and / or mechanical properties of a film can be altered by sintering, and the porosity and flux properties of the macroencapsulation device can be adjusted using that film. Accordingly, in some embodiments, any desired combination of sintered and / or unsintered films can be used. For example, two outer films of the device can be bonded together. This could be by bonding a sintered and an unsintered film together, two sintered films together, or two unsintered films together. Furthermore, any number of intermediate films can be used between these outer films. These intermediate films can be sintered or unsintered.

[0030] The membranes of the macroencapsulation devices described herein may be formed from porous membrane materials configured to allow the transport of the following through the membrane: for example, biological products with molecular weights of less than approximately 3000 kDa, less than 2000 kDa, less than 1000 kDa, less than 500 kDa, less than 400 kDa, less than 300 kDa, less than 200 kDa, less than 100 kDa, less than 50 kDa, less than 40 kDa, less than 30 kDa, less than 20 kDa, less than 10 kDa, less than 6 kDa, less than 5 kDa, less than 4 kDa, less than 3 kDa, less than 2 kDa, less than 1 kDa, and / or any other suitable range of molecular weights depending on the desired application. For example, one or more membranes of the macroencapsulation device may be configured to allow insulin with a molecular weight of approximately 5.8 kDa to flow through the membrane.

[0031] To obtain the desired selectivity, the porous membrane used with the macroencapsulation apparatus disclosed herein is an open porous structure and may have an average pore diameter of approximately 1 nm or more, 5 nm or more, 10 nm or more, 15 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, 50 nm or more, 60 nm or more, 70 nm or more, 80 nm or more, 90 nm or more, 100 nm or more, 200 nm or more, 300 nm or more, and / or any other suitable size range. Correspondingly, the average pore diameters of the various films described herein may be 2500 nm or less, 2000 nm or less, 1700 nm or less, 1500 nm or less, 1400 nm or less, 1300 nm or less, 1200 nm or less, 1100 nm or less, 1000 nm or less, 900 nm or less, 800 nm or less, 700 nm or less, 600 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, 200 nm or less, 100 nm or less, 90 nm or less, 80 nm or less, 70 nm or less, 60 nm or less, 50 nm or less, 40 nm or less, 30 nm or less, 20 nm or less, and / or any other suitable size range. The aforementioned combinations are also possible. For example, the average pore diameters may be 1 nm to 20 nm (including both ends), 1 nm to 2500 nm (including both ends), and / or any other suitable combination. Naturally, specific average pore sizes have been mentioned above, but it should be noted that any appropriate average pore size may be used for the various membranes described herein, and this may include, for example, both larger and smaller average pore sizes than those mentioned above.

[0032] To obtain sufficient strength and / or rigidity for the macroencapsulation device, various membranes and frames can be formed from sufficiently rigid materials. The desired rigidity can be achieved through a suitable combination of Young's modulus, thickness, and overall configuration of the material that balances with the desired permeability of the device. A suitable Young's modulus for the various membranes and frames described herein is 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 of elasticity that is both greater than and less than these ranges. Naturally, the range between the aforementioned Young's moduli is also considered to be included. For example, about 10 6 Pa~10 10 This is the Young interest rate at Pa (including both ends).

[0033] In some embodiments, it may be desirable for one or more of the membranes contained within a macroencapsulation device to be hydrophilic in order to facilitate the filling of cells into the macroencapsulation device and / or to facilitate the flow of one or more fluids, biocompounds, therapeutic agents, cellular nutrients, cellular waste, and / or other materials through the membrane of the device. Furthermore, a hydrophilic outer membrane may also reduce the occurrence of fibrosis when the device is located in vivo. Therefore, the membrane of a macroencapsulation device may be formed from a hydrophilic material and / or treated with a hydrophilic coating. Suitable hydrophilic materials 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 that can form a coating on or on a membrane.

[0034] The membranes described in the various embodiments of the macroencapsulation apparatus described herein may be joined to one another using any suitable bonding method, and this disclosure is not limited as stated above. For example, adjacent membranes may be joined to one another using: adhesives, epoxy, welding or other fusion-based techniques (e.g., ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using a frame or fixture, and / or any other suitable bonding method. In one particular embodiment, the joining of adjacent membranes may be performed using a heated tool used to press or abut two or more membranes against each other for a set fusion time by a predetermined pressure and / or force. Considering the above, it should be noted that this disclosure is not limited to using any particular method for joining membranes to one another.

[0035] In some embodiments, one or more heat treatments may be applied to the laminate of bonded films after the films have been bonded together, and possibly after a frame has been attached to the films. For example, the films may be bonded together with bonds extending along the periphery of the films, and / or one or more bonds may be formed inside the internal regions of the films (e.g., inside the bonded periphery) before the films are heat-treated. This post-bonding heat treatment can strengthen the bond between the films in the bonded regions. The specific heat treatment temperature and duration for improving the bond between the films may vary depending on the specific materials used. However, in some embodiments, the heat treatment temperature may be between the glass transition temperature and the melting temperature of the polymer film.

[0036] In some embodiments, it may be desirable to limit the maximum thickness of the macroencapsulation device in a direction perpendicular to a plane whose maximum transverse dimension is desired. Therefore, one or more internal portions of the first and second membranes, arranged within the frame, can be coupled to each other to limit the extent to which the membranes can move relative to one another. These coupling portions of the membranes can be uniformly distributed within the internal portions of the membranes arranged within the frame. These coupling portions can have any suitable shape, e.g., dots, lines, curves, or any other suitable shape. The coupled internal portions can have any suitable size for the desired application, but in one embodiment using coupled dots, the diameter of the coupled dots may be approximately 0.5 mm or more, 0.75 mm or more, 1 mm or more, 1.25 mm or more, 1.5 mm or more, and / or any other suitable diameter. Correspondingly, the diameter of the dots may be approximately 3 mm or less, 2.75 mm or less, 2.5 mm or less, 2.25 mm or less, 2.0 mm or less, and / or any other suitable diameter. Combinations of the aforementioned ranges are also possible, for example, diameters from 0.5 mm to 3 mm (including both ends). While specific shapes and size ranges have been described above, naturally, other shapes and sizes smaller and larger than those described above are also conceivable, and this disclosure is not limited to those described above.

[0037] In some embodiments, it may be desirable to improve angiogenesis of a macroencapsulation device. Accordingly, in one embodiment, one or more through-holes may be formed in one or more bonding portions disposed within an inner portion of a membrane disposed radially inward from a frame of the device. These through-holes may allow vasculature to grow through the through-holes, in addition to growing around the upper and lower surfaces of the device. Forming one or more through-holes in the bonding portion of the membrane may be performed by laser ablation, mechanical puncture, cutting, or any other suitable method that forms through-holes in one or more bonding portions of the membrane.

[0038] In some embodiments, the aforementioned bonding portions and corresponding through-holes in the inner region of the device may be formed while the membrane is disposed in a flat planar configuration, prior to mounting the frame onto the device. This may simplify the manufacturing process when handling flexible membranes that are mounted to a frame with a desired amount of slack that may complicate formation of other features after mounting to the frame.

[0039] As described in detail below, in some embodiments, one or more portions of adjacent membranes may be bonded to each other such that the internal volume within the device is subdivided into a plurality of interconnected channels. The channels may be shaped like lumens in some embodiments, but any suitable shape or configuration of the channels may also be used. The maximum internal cross-sectional dimension of the channels (e.g., inner diameter) may be 40 µm or more, 50 µm or more, 100 µm or more, 200 µm or more, 300 µm or more, 400 µm or more, and / or any other suitable dimension. Correspondingly, the maximum internal cross-sectional dimension of the channels may be 800 µm or less, 700 µm or less, 600 µm or less, 500 µm or less, 400 µm or less, and / or any other suitable dimension. Combinations of the foregoing are also contemplated. For example, the maximum internal cross-sectional dimension within the plurality of channels is 40 µm to 800 µm, inclusive. Further, the density of interconnected channels forming the various compartments of the device, expressed as density per unit area within a cross-section of the device, is about 10 channels / cm 2The above is 15 Channels / cm 2 The above is 20 Channels / cm 2 The above is 25 Channels / cm 2 Above 30 channels / cm 2 Above: 35 channels / cm 2 Above 40 channels / cm 2 The above is 45 channels / cm 2 Above 50 Channels / cm 2 Above 60 channels / cm 2 Above 70 Channels / cm 2 Above 80 channels / cm 2 Above 90 channels / cm 2 Above 100 Channels / cm 2 Above 110 Channels / cm 2 Above 120 Channels / cm 2 The above is 130 channels / cm 2 The above is 140 channels / cm 2 Above 150 Channels / cm 2 Above 175 channels / cm² or 200 channels / cm² 2 The above is possible. A range extending between any of the aforementioned channel densities is also conceivable. For example, a channel density of approximately 10 channels / cm³ 2 ~200 channels / cm 2 (Including both ends). However, both densities larger and smaller than the aforementioned range are possible.

[0040] The macroencapsulation devices described herein may have any suitable combination of internal volume, external dimensions, and / or other suitable physical parameters. For example, the internal volume enclosed by the outer membrane of the macroencapsulation device may be 40 μL to 250 μL (including both ends). The width or maximum transverse dimension of the macroencapsulation device may be approximately 20 mm to 80 mm. Furthermore, in order to allow the desired oxygen diffusion into the interior of the macroencapsulation 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 containing the cell population may be less than 50 μm, less than 100 μm, less than 150 μm, less than 200 μm, less than 250 μm, less than 300 μm, less than 350 μm, less than 400 μm, less than 450 μm, or less than 500 μm. Correspondingly, the maximum thickness (or dimension perpendicular to the maximum transverse dimension) of the entire device and / or the internal volume located within the device may be 50 μm, less than 100 μm, less than 150 μm, less than 200 μm, less than 250 μm, less than 300 μm, less than 350 μm, less than 400 μm, less than 450 μm, or less than 500 μm. Furthermore, in some embodiments, the external surface area to volume ratio of the device is approximately 20 cm². -1 Over 40cm -1 Over 60cm -1 More than 80cm -1 More than 100cm -1 Over 120cm -1 Above, or 150cm -1 The above is possible. A range extending between any of the aforementioned values ​​for various dimensions and parameters is also conceivable, as are both a range greater than and a range smaller than those mentioned above.

[0041] While specific dimensions, parameters, and relationships related to macroencapsulation devices, as well as the materials on which they are formed, have been described above, larger and smaller dimensions, parameters, and relationships than those described above are naturally possible, and this disclosure is not limited as stated above. Therefore, any suitable combination of size, configuration, material properties, and / or relative performance parameters can be used for the device depending on the desired application.

[0042] In some embodiments, the cell population contained within the internal volume of the macroencapsulation device may be an insulin-secreting cell population. In some embodiments, the cell population 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, at least one cell is genetically modified to suppress the immune response in the subject at implantation of the device compared to a non-genetically modified equivalent cell. In some embodiments, the cell population is a stem cell-derived cell capable of glucose-promoting insulin secretion (GSIS). For example, a suitable cell population may include pancreatic progenitor cells, endocrine cells, beta cells, a matrix containing one or more of the aforementioned, or any combination thereof. Furthermore, the matrix may include isolated islet cells, isolated cells from the pancreas, isolated cells from tissue, stem cells, stem cell-derived cells, induced pluripotent cells, differentiated cells, transformed cells, or expression systems (capable of synthesizing one or more biological products). Optionally, in some embodiments, the matrix may include a second type of cell supporting a first type of cell that synthesizes one or more biological products. In some embodiments, the cells may be encapsulated before being placed in the matrix. In such embodiments, cells may be encapsulated in microcapsules or conformally coated. However, exposed (i.e., uncoated) cells may also be used.

[0043] Depending on the specific embodiment, cells of a therapeutically effective density may be filled into the internal volume of the macroencapsulation device. Appropriate cell densities to be placed in the internal volume may be approximately 1,000 cells / μL or more, 10,000 cells / μL or more, 50,000 cells / μL or more, 100,000 cells / μL or more, 500,000 or more, and / or any other appropriate cell density. Appropriate cell densities to be placed in the cubicles may be approximately 1,000,000 cells / μL or less, 500,000 cells / μL or less, 100,000 cells / μL or less, 50,000 cells / μL or less, 10,000 cells / μL or less, and / or any other appropriate cell density. Combinations of the above are also possible. For example, cell densities of approximately 1,000 cells / μL to 1,000,000 cells / μL. Naturally, depending on the desired application and the cell type being used, both higher and lower cell densities than those mentioned above can be used.

[0044] The macroencapsulation devices described herein can be implanted in the living body of a subject at various sites. In one example, the device can be implanted in the subject by preperitoneal or post-rectus myofascial implantation. In another example, the device can be placed by intraretinal implantation. In yet another example, the device can be placed by subcutaneous implantation. In yet another example, the device can be placed by suprahepatic implantation. In some cases, the macroencapsulation devices described herein can be fixed in the living body at the implantation site using any suitable fixation method (e.g., application of tissue adhesive). Suitable tissue adhesives may include, but are not limited to, fibrin, cyanoacrylate, polyethylene glycol, albumin-based adhesives, polymer-based adhesives, and / or any other suitable adhesive. In another example, the device may be fixed using platelet-rich plasma and / or any other suitable fixation method, and this disclosure is not limited as described above.

[0045] Certain non-limiting embodiments will be described in more detail with reference to the figures. Naturally, the various systems, components, features, and methods described for these embodiments can be used individually and / or in any desired combination, for this disclosure is not limited to the specific embodiments described herein. For clarity, the figures are described in relation to methods and apparatus that include only the first and second outer films coupled together. Naturally, however, the methods and apparatus described in relation to the figures may include any number of interlayer films placed between these outer films, and this disclosure is not limited as stated above.

[0046] Figures 1A to 1H show one embodiment of a process for bonding two or more films together and forming various other features on the films before attaching a frame to them.

[0047] As shown in Figures 1A-1B, the first membrane 102 is positioned on the lower part of the fixture 106 so that the first membrane 102 is positioned directly or indirectly on the lower surface of the fixture. The second membrane 104 is positioned on the surface of the first membrane 102 opposite to the lower part of the fixture. In some embodiments, the lower part of the fixture may include one or more sensors 110 distributed across the lower surface of the fixture where the membranes are positioned. These sensors may be configured to detect force, pressure, and / or temperature applied to corresponding portions of the first and second membranes.

[0048] Once the first membrane 102 and the second membrane 104 are properly positioned on the lower part 106 of the fixture, the upper part 108 of the fixture may be brought into contact with one or more portions of the second membrane so that both the first membrane 102 and the second membrane 104 are clamped, or otherwise held in place, between the upper and lower parts of the fixture. In the illustrated embodiment, the first and second membranes are held in a substantially planar configuration on the planar surface of the lower fixture. However, embodiments in which the membranes are held in a different configuration during the initial forming step are also conceivable. Also as illustrated in the figure, the upper part 108 of the fixture includes an opening (or other arrangement) in which the central portions of the laminated first and second membranes are left uncovered or otherwise exposed for further processing. Thus, the lower and upper parts of the fixture may be configured to clamp one or more peripheral portions of the first and second membranes that are radially outward from the central uncovered portion of the membranes intended to form part of the macroencapsulation device. This arrangement of the exposed central portion of the membranes is best illustrated in Figure 1B. While the figure illustrates a circular opening at the top of the fastener, this disclosure is naturally not limited to any particular shape of the exposed portion of the film, and / or how the film is held in place during bonding and the initial forming process.

[0049] After positioning the first membrane 102 and the second membrane 104 within the fixture, the membranes can undergo many different processes (e.g., bonding at one or more locations). Figures 1C-1E illustrate one embodiment of the process of bonding the first and second membranes to each other. Referring to Figure 1C, the first and second membranes are bonded to each other at desired locations using a bonding tool 120. In one particular embodiment, the bonding tool includes a heated tip located at a desired location on the upper surface of the second membrane, which is pressed downward with a predetermined temperature and force for a predetermined duration to form a bond between the two membranes. One or more of the aforementioned sensors 110 distributed across the lower surface of the fixture 106 may transmit signals to a corresponding processor (not shown) to perform feedback control of the bonding process. Once a bond is formed at the desired location, the bonding tool may be moved to adjacent portions of the membranes that at least partially overlap with a portion of the already formed bond, and this may be done until a desired shape and size of a particular bond is formed, although different bonding methods may also be used as described above. The tool can then be advanced to form any number of other bonds between the two membranes at any number of desired locations using any number of desired patterns, depending on the specific application. For example, as shown in Figures 1D and 1E, the first and second membranes can be bonded along the periphery 122 of the active portion of the membranes, intended to form an internal volume between them.

[0050] As best illustrated in the plan view of Figure 1E, in some embodiments, a bonding tool may also be used to bond one or more portions 124 of the membrane located radially inward from the resulting bonded perimeter 122. In this particular embodiment, these bonded portions located within the bonded perimeter 122 may take the form of bonded dots distributed across the surface area of ​​the membrane. However, any suitable shape and / or configuration of these bonded regions may also be used. The presence of these bonded regions located radially inward from the bonded perimeter of the membrane means that the internal volume formed between the membranes, once a filling configuration is achieved, may take the form of multiple interconnected channels 126 corresponding to the unbonded areas of the membrane extending between these bonded portions.

[0051] In some cases, the bonding portions of membranes 102 and 104 may have substantially low membrane permeability due to the bonding process and can be considered non-diffusive portions of the membrane. This may include both the bonded periphery 122 of the membrane and the internal bonding portion 124 located radially inward from the bonded periphery. In contrast, the unbonded portions of the membrane (e.g., the channel 126 in the illustrated embodiment) can be considered diffusive portions of the membrane. The diffusive portions may have significantly higher membrane permeability than the non-diffusive portions and, in some embodiments, may be substantially indistinguishable from the parent material. In addition to the fact that the bonding portions of the membrane can be considered non-diffusive portions of the membrane, portions of the membrane located radially outward from the bonded periphery 122, which do not have direct fluid contact with the resulting internal volume formed between them, can also be considered non-diffusive portions of the membrane for the purposes of this explanation.

[0052] In some embodiments, after joining portions of the first and second films 102 and 104 together, one or more through-holes 132 may be formed in one or more of the joining portions 122 and 124. For example, referring to Figures 1F-1G, through-holes 132 may be formed in one or more of the joining portions of the first film 102 and the second film 104 using an apparatus such as a laser, punch, cutter, or other suitable apparatus. In one particular embodiment, the through-holes may be formed by laser ablation, where the joining portion of the first and second films is removed by the laser, while the surrounding joining portion is left to function as a seal between the internal volume formed by the films and the outside of the apparatus.

[0053] If the shape and size of the bonded film are already in the final desired configuration, the bonded film can simply proceed to the next step in the manufacturing process. Alternatively, in some embodiments, one or more peripheral portions of the film may be cut from the film to give the bonded film a desired size and / or shape. One embodiment of such processing is illustrated in Figure 1H, where a blade 140 (or other cutting tool) may be used to form a cut extending along the bonded periphery 122 of the film. In the illustrated embodiment, after the blade has been extended through the first and second films, it is moved relative to the film along an arbitrary desired cutting profile around the bonded periphery of the film to cut off one or more peripheral portions of the film that are held in a fixture and positioned radially outward from the bonded periphery. Of course, although the figure shows the blade being moved relative to a film held in a fixture, any suitable method may be used to cut off the peripheral region of the bonded film to give the bonded film a desired size and shape, and the disclosure is not limited as stated above.

[0054] Regardless of whether the cutting process has been performed, after various desired portions of membranes 102 and 104 have been joined together, the bonded membrane can be removed from the fixture corresponding to the upper and lower fixture portions 106 and 108, as shown in Figure 1I. This can be done in any number of ways, for example, by simply opening the fixture and manually removing the bonded membrane. Alternatively, the system can automatically lift the membrane and remove it from the fixture. For example, the system can apply a vacuum to one or more non-diffusible portions of the bonded membrane to lift it from the surface of the fixture. However, any suitable method for removing the bonded membrane from the fixture or other device may be used, and the disclosure is not limited to the foregoing.

[0055] Figure 1J illustrates a plan view of the resulting bonded film stack. In the figure, the upper surface of the second film 104 is shown along with the bonded perimeter 122 of the film (for example, where the first and second films are bonded) that extends along the perimeter of the bonded film. Although the bonded perimeter is shown to extend to the outer edge of the film, embodiments in which the bond extending along the perimeter of the film is inserted from the outer edge of the film are also conceivable. The bonded film also includes one or more bond portions 124 located radially inward from the bonded perimeter. Furthermore, through-holes 132 may be formed within one or more bond portions. The through-holes extend from the outer surface of the first film to the opposing outer surface of the second film. The presence of the bond portions of the film located radially inward from the perimeter bond allows the internal volume formed between the first and second films to be formed into a plurality of interconnected channels 126 corresponding to the unbonded portions of the films.

[0056] In some embodiments, after the films have been bonded together (for example, the periphery and / or interior portions of the first and second films have been bonded together), the first and second films may be coated with a hydrophilic material and / or subjected to other treatments that may not be compatible with the bonding process. This may include various high-temperature treatments that can be applied to the films, which in some embodiments may enhance the bonding of the films.

[0057] In some embodiments, a pre-bonded film laminate (e.g., the bonding of the first and second films described above) can be mounted to the frame. Alternatively, in some embodiments, the film laminates can be bonded together around their perimeters and mounted to the frame simultaneously. In either case, a method can be used to mount the film to the frame such that, once mounted, it provides a desired amount of slack within the film. One such embodiment will be described in more detail later with reference to Figures 2A-2E.

[0058] Figures 2A-2B illustrate the concept of deforming the first and second membranes 102 and 104 from a first maximum transverse dimension before mounting (for example, in Figure 2A, the membranes are in a relatively flat planar configuration) to a second maximum transverse dimension afterwards (for example, in Figure 2B, the membranes are deformed to conform to the shape of the support 200 lying beneath them). Specifically, the surface of the first membrane opposite the second membrane is positioned on the curved surface 206 of the support 200 and conforms to its shape, so that parts of the first and second membranes can be deformed out of plane. For example, because the central portion of the membrane is deformed out of plane by the curved surface beneath the support, the outer periphery of the first and second membranes is deformed from the first transverse dimension in the planar configuration of Figure 2A to a smaller transverse dimension in Figure 2B. In some embodiments, the curved surface of the support is a spherical dome, as illustrated in Figures 2A-2E. However, embodiments using supports with different shapes are also conceivable.

[0059] In some embodiments, the support 200 may include one or more raised portions 202 positioned near the edges of the curved surface 206 of the support 200, on which the film laminates 102 and 104 are supported. These raised portions are positioned at multiple locations around the periphery of the support so that the first and second films 102 and 104, positioned on the curved support 200, may flare out near their periphery and / or otherwise deform as described above to accommodate the presence of excess film material at these locations. Specific examples of the interaction between these raised portions and the films positioned thereon will be described in more detail later with reference to Figures 5A-6B. That being said, in the illustrated embodiments, the bonded film laminate (including the first and second films 102 and 104) is positioned on the support 200. The periphery of the first and second films contact the raised portions 202, causing deformation of the portions of the films adjacent to the curved surface of the support. In the illustrated embodiment, the raised portion may help deform a portion of the membrane by forming wrinkles, folds, waves, folds, or otherwise deforming the membrane in order to accommodate excess material that is forced into a smaller area when the membrane is deformed from a larger first transverse dimension (e.g., a planar configuration) to a smaller second transverse dimension (e.g., a deformed configuration placed on a support).

[0060] Although the above embodiment illustrates the use of raised portions, it is naturally possible to use any method to deform one or more locations around the periphery of the bonding film from a first larger region to a second smaller region.

[0061] In some cases, it may be desirable to maintain the orientation and / or position of the laminate of films on the support while a frame is mounted thereon. Therefore, in some embodiments, as illustrated, a vacuum may be applied to one or more non-diffusive portions of the first and second films to maintain the first and second films adjacent to the curved support. For example, referring to Figure 2B, the curved support 200 may include a vacuum chamber 210 connected to a vacuum source (not shown) to provide negative pressure. The vacuum chamber may be fluidly connected to one or more suction holes 212 located on the surface of the curved support 200. The suction holes may be located on any desired portion of the support surface, but in some embodiments, the suction holes may be located on the surface portion of the support where the corresponding non-diffusive portions of the bonded films can be located, e.g., the bonded perimeter 122 of the films, portions of the films located radially outward from the bonded perimeter, bonded portions 124 of the films located within the bonded perimeter, and / or any other suitable portion of the films. For example, multiple suction holes may be positioned adjacent to or on the raised portion 202 around the curved surface 206 of the support. Naturally, other methods may be used to maintain the position and / or orientation of the membrane relative to the support lying below. These include, but are not limited to, mechanical fixation, clamping, temporary adhesive, and / or any other suitable temporary fixation method.

[0062] After the first and second films 102 and 104 have been deformed from a first maximum cross-sectional dimension to a second maximum cross-sectional dimension smaller than that of the first, a frame 220 may be attached to the film, as shown in Figures 2C and 2D. Specifically, the frame 220 (e.g., a periphery frame) may be positioned on the laminated film while the central portion of the film is out-of-plane deformed by a curved support 200 lying underneath. The frame may extend around at least a portion of the periphery of the bonded film (in some embodiments, around the entire periphery). The size and shape of the frame may be selected to maintain the maximum cross-sectional film at a smaller second maximum cross-sectional dimension after attachment. The maximum cross-sectional dimension may be measured within the plane on which the planar frame extends. For example, the maximum cross-sectional dimension in the illustrated embodiment may correspond to the diameter of a circular frame positioned on the bonded film. However, embodiments using frames and films with different shapes and sizes are also conceivable.

[0063] As mentioned above, in some embodiments, the frame 220 may extend along at least a portion of the periphery of the bonded membranes 102 and 104. To avoid reducing the active diffusible region of the bonded membrane, at least a portion of the frame, and possibly the entire frame, may be aligned with the bonded periphery 122 of the membrane and / or positioned radially outward from the bonded periphery. This can prevent the frame from being positioned above the diffusible portion of the bonded membrane and obstructing diffusion through the portion of the membrane lying below. Thus, the frame may form the internal volume of the membrane with a transverse dimension equal to or slightly larger than the bond extending along the periphery of the membrane. For example, referring to Figure 2D, the frame 220 overlaps only a portion of the bonded periphery 122 of the membrane. Naturally, in the illustrated embodiment, the membrane does not extend beyond the frame, but embodiments are conceivable in which the frame extends beyond this bond into a region positioned radially inward from the bonded periphery.

[0064] As shown in Figure 2E, the frame 220 can be bonded to the film after it has been positioned on the bonded film layers 102 and 104. In some embodiments, the frame and film can be bonded at multiple locations around the frame using adhesive, heat scribing, welding (heat, ultrasonic, etc.), mechanical fastening, or another suitable method. For example, the frame and film can be bonded to each other at each location where they contact the raised portion 202 positioned along the periphery of the curved surface 206 of the support 200. In the illustrated embodiment, a fixing device 230 can be used to form bonding points between the frame and portions of the first and second films at one or more desired locations. The fixing device 230 may correspond to a combination of a port used to dispense a curing adhesive and a light source that can be used to cure the adhesive once it has been placed on the frame and film. The duration of bonding and the viscosity of the adhesive can be selected to avoid excessive absorption of the adhesive into the diffusive portions of the film. Furthermore, although specific bonding methods have been described, other suitable types of bonding can also be used as previously stated. After the frame is bonded to the membrane, the resulting macroencapsulation device, including the frame and the mounted membrane, can be removed from the curved support. After the membrane is initially fixed to the frame in this manner, further processing of the mounted frame and membrane may then be performed. For example, additional planar adhesive may be added between the mounted frame and the membrane to improve the bond between them.

[0065] In the embodiments described above, the frame is connected to the outer surface of the second membrane 104 opposite to the first membrane 102, which rests on the support 220. However, an embodiment is also conceivable in which the frame 220 is positioned between the first membrane 102 and the second membrane 104, as shown in Figure 3. In such an embodiment, portions of the first and second membranes extending radially outward from the bonding 122 that extends along the periphery of the membranes may be left open, and the frame can be positioned between the membranes at a location radially outward from the periphery bonding of the membranes. Then, as described above, the first and second membranes can be bonded to the frame using any suitable bonding method. The figures show specific angular orientations of the frame, membranes, and the underlying support, but of course, any suitable orientation of these components may be used, and this disclosure is not limited as described above. In any case, the frame may still function to maintain the desired transverse dimensions of the membranes once removed from the underlying support.

[0066] Figures 4A-4B show one embodiment of a macroencapsulation device after the membrane has been mounted on the corresponding frame and before it is filled with the desired material, such as a cell population. Specifically, as illustrated in the figures, the macroencapsulation device may include a first membrane 102, a second membrane 104, and a frame 220 extending along at least a portion of the periphery of the first and second membranes. The device is illustrated in an unfilled, loose state. In this state, the surface areas of the first and second membranes are excessive relative to the cross-sectional area of ​​the frame on which the membrane is mounted, resulting in slack within the membrane and causing the encapsulated membrane to hang down below the frame. Since the binding portions 122, through-holes 132, and other suitable features are already formed on the membrane and located within the internal region of the device, the macroencapsulation device can be easily filled with the desired material (e.g., a cell population) with minimal further processing and handling. The internal volume can be filled using ports, openings in the periphery binding, and / or any other suitable method. In either case, after the macroencapsulation device is filled with the desired material, the internal volume contained between the first and second membranes 102 and 104 can expand, eliminating slack within the membranes. This is because the expansion of the internal volume between the membranes places the membranes under tension in the filled configuration. As a result, the first and second membranes deform, and the membranes can generally stretch in a direction substantially parallel to the plane of the frame 220 (see Figure 4C). Correspondingly, due to this increase in the internal volume of the filled device, the first and second membranes can extend approximately equal distances outward from the opposing surfaces of the frame. In situations where portions 132 of the membranes are connected to each other at locations radially inward from the frame, the expanded structure again forms multiple interconnected channels 126.

[0067] The macroencapsulation device can be filled using any suitable filling method. For example, a cell population (or other desired material) can be flowed into the internal volume of the macroencapsulation device formed between the outer membranes of the device. This can be achieved by using sealable or removable ports extending into the internal volume and / or by the presence of subsequently sealable openings within the periphery and / or frame of the macroencapsulation device. Material can be flowed into the internal volume of the device using any suitable inlet to the internal volume, but the desired filling of the internal volume can be achieved by controlling this flow of material in many different ways. For example, in one embodiment, applying pressure to the internal volume of the macroencapsulation device may correspond to the presence of a desired amount of tension within the membrane of the device in a filling configuration. Thus, filling the device may continue until a predetermined pressure and / or membrane tension threshold is reached. However, any suitable method for controlling the amount of material flowing into the internal volume may be used, and the disclosure is not limited as described above. This may include, for example, control based on the absolute volume of material flowing into the internal volume, the duration for a given flow rate, and / or any other suitable control method.

[0068] Figures 5A–5D show specific embodiments of a support 200 that can be used during the mounting of a frame to a film held on a support. The support may include a curved support surface 206 used to support the active diffusive portion of the film laminate during the frame mounting process. In the illustrated embodiments, the support surface is a spherical dome, but other suitable shapes may be used for the support surface as described above. The support surface can be used to support and deform the film placed thereon, as described above in relation to Figures 2A–2E. The support may also include a corrugated surface extending along the periphery of the primary curved support surface. For example, the corrugated surface may include a plurality of alternating ridges 202 and valleys 204 extending radially outward from adjacent portions of the curved support surface. In some cases, the ridges may extend vertically upward above adjacent portions of the curved support surface, and the valleys may extend vertically downward below adjacent portions of the curved support surface. However, different vertical arrangements of the ridges and valleys relative to adjacent curved support surfaces are also possible. In either case, the corrugated surface, whose height varies along its length, may extend at least partially (and entirely in the illustrated embodiment) along the perimeter of an adjacent curved support surface. As further detailed in the following examples, this corrugated surface may guide a portion of the film laminate into a desired folded, pleated, corrugated, or otherwise deformed configuration, helping to handle excess film material at that location during the framing process.

[0069] In the embodiments described above, the vertical direction of the support may be defined as upward perpendicular to the base of the support lying beneath the curved surface of the support.

[0070] In some embodiments, as described above, the support 200 may be configured to apply a vacuum to the film laminate placed thereon. For example, as shown in the figure, the vacuum connection 208 may be fluidly connected to a central vacuum chamber 210 formed within the support. This central vacuum chamber may also be fluidly connected to suction holes 212 extending upward to the curved support surface 206 of the support on which the film laminate may be placed. These suction holes may be distributed along the periphery of the support surface, but suction holes may also be located in other suitable locations. For example, as illustrated in the figure, the distribution of suction holes may be such that at least one suction hole is located on each of the ridges 202 and valleys 204 of the corrugated surface extending around the curved support surface 206. However, of course, any suitable arrangement of suction holes may be used, and this disclosure is not limited to using suction holes only in these locations. Again, in some embodiments, the arrangement of suction holes may be such that they can be applied to non-diffusible portions of the film that are placed on the suction holes during the frame mounting process. In short, the suction holes can apply vacuum suction from the vacuum connection to one or more portions of the laminate of films placed on the support surface, thereby helping to maintain the orientation and / or position of the laminate of films on the support.

[0071] Example: Manufacturing of a macroencapsulation device

[0072] Figures 6A-6B illustrate the use of a support 200 similar to that described above in relation to Figures 5A-5D. In this case as well, the support may include a curved support surface 206 and a corrugated surface including a plurality of alternating ridges 202 and valleys 204 that extend at least partially along the periphery of the curved support surface. A laminate of bonding films 214 is placed on the support surface, with the outer portion of the film extending over the ridges and valleys of the corrugated surface. Because the size of the undeformed planar configuration of the film does not match the diameter of the curved support surface adjacent to the corrugated surface, the size of the film at this location is larger than the diameter of the curved support. The resulting excess material of the film extends outward onto the corrugated surface, but can be deformed to conform to the shape of the ridges and valleys of the corrugated surface and adapt to the presence of this excess material. Deformation of the laminate of films can be performed using a vacuum applied to one or more portions of the film by a vacuum connection portion 208 of the support, but other fixing methods, such as mechanical clamping, temporary adhesive, and other suitable methods, may also be used. In any case, the laminate of membranes can be deformed to a folded, pleated, wrinkled, corrugated, or otherwise deformed shape, thereby deforming the membranes from a first larger region to a second smaller region within the cross-section of the system, taking into account the aforementioned size mismatch. Due to the periodic nature of the corrugated surface, such deformations that reduce the laminate of membranes to smaller regions can be arranged along the periphery of the laminate of membranes. Once the deformed configuration is appropriately positioned and held on the support, the frame 220 can be placed on the surface in the illustrated embodiment. The frame contacts portions of the membranes located on a plurality of ridges extending around the curved support. The frame can then be bonded to the laminate of membranes by performing the subsequent bonding processes described above.

[0073] Figures 7A-7B are photographs of a macroencapsulation device manufactured using the same process as described above. The device is in a relaxed state before cells are packed in, and visible deformed areas (i.e., wrinkles) within the attached membrane are distributed along the perimeter of the device, which is due to the presence of slack within the membrane. The device contains an array of channels arranged between junctions (indicated by indented dots) formed on the first and second membranes. In Figure 7B, channel 126 and junction 124 are clearly shown.

[0074] Example: Equipment filling

[0075] Figures 8A and 8B are scanning electron micrographs of macroencapsulation devices in two cross-sectional sections with different amounts of membrane looseness (i.e., frame undersize of 5% and 10% relative to the corresponding membrane size). The devices were filled with 150 μm beads. The bead size represents the average diameter of human pancreatic islets and measures the chamber height of the filled device. As shown, the first device shown in Figure 8A corresponds to a 5% frame undersize and contained fewer beads than the second device shown in Figure 8B, which corresponds to a 10% frame undersize. The first device also corresponds to a smaller chamber height than the second device. Therefore, both the chamber height and the filled volume are larger in devices with a greater degree of frame undersize relative to the corresponding mounted membrane. Furthermore, we attempted to fill a device with 0% membrane looseness. The device could not be filled, confirming that it may be easier to fill the device with cells or other materials if the membrane is mounted in a loose configuration with some slack.

[0076] Examples: Various frame dimensions

[0077] Figure 9 illustrates the concept of membrane slack, where membranes of a predetermined size are mounted on frames of different diameters. As shown, the diameter of a pair of bonded membranes (for example, the first and second membranes bonded around their perimeter) is 42.3 mm, and they are mounted on frames of various sizes (e.g., 42.3 mm, 40.2 mm, and 38.3 mm in diameter). The degree of frame undersizing was calculated as the ratio of the difference in diameter between the membrane and the surrounding frame to the diameter of the membrane laminate. Undersizing of the frame by 0%, 5%, and 10% corresponded to surrounding frames of 42.3 mm, 40.3 mm, and 38.3 mm, respectively. To accommodate the excess surface area of ​​the membrane module when mounting the membrane on an undersized frame, an increase in the degree of membrane slack (i.e., membrane sagging) was observed with increasing the degree of frame undersizing relative to the membrane size.

[0078] Example: Internal volume dimensions vs. sag

[0079] Figures 10A and 10B illustrate diagrams of filled macroencapsulation devices. The two devices differ in the amount of undersizing of the frame relative to the undeformed dimensions of the corresponding membranes. Specifically, macroencapsulation device 300A in Figure 10A was modeled using a smaller amount of undersizing compared to macroencapsulation device 300B in Figure 10B. Similar to the embodiments described above, the device may include a first membrane 104 and a second membrane 104, which are joined along their periphery to form an internal volume 250 between the membranes. The illustrated device also includes a joining portion 124, and a through-hole 132 is located within the central portion of the membrane, which is positioned within a frame (not shown). Mathematical modeling was used to determine the membrane structure when filled to a membrane with a predetermined tension under equilibrium conditions. The determined chamber height H, corresponding to the channel forming the internal volume 250, can be measured in a direction perpendicular to the plane in which the membrane and the corresponding frame are roughly located, as shown. Apparatus 300A in Figure 10A, which has a smaller degree of frame undersizing, was observed to have a smaller chamber height after filling compared to Apparatus 300B in Figure 10B, which has a larger degree of undersizing and correspondingly a greater amount of membrane loosening or sagging.

[0080] Example: Control of device structure

[0081] While not bound by theory, the chamber height and total internal volume of the channels formed within the apparatus can be controlled by controlling the degree of under-sizing of the frame relative to the size of the corresponding membrane. As previously described, a 42.3 mm diameter membrane can be mounted on frames of various diameters, and channels with fixed channel spacing and diameter can be formed within the membrane. Using mathematical modeling, the chamber height and volume were estimated by fixing the geometric properties of the channels (e.g., channel spacing, channel diameter). The internal volume and chamber height were then predicted at packing equilibrium. The prediction was made by comparing the surface area of ​​a bonded membrane mounted under tension with a loosely mounted state obtained by reducing the surface area corresponding to the frame dimensions. As shown in the table below, both the chamber height and total internal volume increased with decreasing frame diameter. This corresponds to an increase in the mismatch between the membrane and frame regions and an increase in the amount of membrane sag before packing. [Table 1]

[0082] Although this instruction has been described in relation to various embodiments and examples, it is not intended to be limited to such embodiments or examples. Rather, as those skilled in the art will see, this instruction encompasses a variety of substitutes, modifications, and equivalents. Therefore, the foregoing description and drawings are merely examples.

Claims

1. A macroencapsulation device for containing a population of cells, wherein the macroencapsulation device comprises: The first membrane and, A second membrane disposed on the first membrane, wherein the first membrane and the second membrane are bonded together along the periphery where they are joined, thereby forming an internal volume between them, and the first membrane and / or the second membrane are semipermeable to the second membrane. A frame extending around at least a portion of the outer edges of the first and second membranes, wherein the frame is positioned radially outward from the joined periphery, and A macroencapsulation device equipped with the following features.

2. The macroencapsulation apparatus according to claim 1, wherein the surface area of ​​the first film and / or the second film is larger than the cross-sectional area of ​​the frame on which the first film and the second film are mounted.

3. The macroencapsulation apparatus according to claim 1 or claim 2, wherein the frame extends overall around the periphery of the first membrane and the second membrane.

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

5. The macroencapsulation apparatus according to any one of claims 1 to 4, further comprising the cell population arranged within the internal volume.

6. The macroencapsulation apparatus according to claim 5, wherein the cell population is an insulin-secreting cell population.

7. The macroencapsulation apparatus according to any one of claims 1 to 6, wherein the first membrane and / or the second membrane are configured to enable the transport of insulin.

8. The macroencapsulation apparatus according to any one of claims 1 to 7, wherein the internal volume includes a plurality of channels.

9. The macroencapsulation apparatus according to claim 8, further comprising a plurality of bonding portions of the first membrane and the second membrane, which are arranged radially inward from the frame, wherein the plurality of bonding portions form the plurality of channels.

10. The macroencapsulation apparatus according to claim 9, wherein at least some of the plurality of coupling portions include through holes passing through them.

11. The macroencapsulation apparatus according to any one of claims 1 to 10, wherein the first film and / or the second film are sintered.

12. The macroencapsulation apparatus according to any one of claims 1 to 11, wherein the first film and / or the second film comprises a hydrophilic coating.

13. The macroencapsulation apparatus according to any one of claims 1 to 12, further comprising a filling port formed in the frame, wherein the filling port is configured to allow the cell population to flow into the apparatus.

14. The macroencapsulation apparatus according to any one of claims 1 to 13, wherein the periphery of the bond includes an opening, the opening being configured to allow the cell population to flow into the internal volume.

15. The macroencapsulation apparatus according to any one of claims 1 to 14, wherein a portion of the first membrane and the second membrane connected to the frame is deformed to fit within a region of the frame that is smaller than the region of the portion of the first membrane and the second membrane in an undeformed configuration.

16. The macroencapsulation apparatus according to any one of claims 1 to 15, wherein the surface area of ​​the first film and / or the second film is 1% to 30% (including both ends) larger than the cross-sectional area of ​​the frame.

17. The macroencapsulation apparatus according to claim 16, wherein the ratio is 5% to 10% (including both ends).

18. A method for forming a macroencapsulation device for containing a population of cells, wherein the method is: The method involves forming an internal volume between a first membrane and a second membrane by bonding the first membrane to the second membrane along the periphery of the first membrane and / or the second membrane, wherein the first membrane and / or the second membrane are semipermeable. Connecting a frame to the first and second membranes along at least a portion of the outer edges of the first and second membranes, wherein the frame is positioned radially outward from the joined periphery. Methods that include...

19. The method according to claim 18, wherein the surface area of ​​the first film and / or the second film is larger than the cross-sectional area of ​​the frame on which the first film and the second film are mounted.

20. The method according to either claim 18 or claim 19, wherein the first membrane and the second membrane are configured to block the movement of the cell population out of the apparatus.

21. The method according to claim 20, further comprising filling the internal volume with the cell population.

22. The method according to any one of claims 18 to 21, wherein the first film and / or the second film are sintered.

23. The method according to any one of claims 18 to 22, further comprising coating the first film and / or the second film with a hydrophilic material.

24. The method according to any one of claims 18 to 23, further comprising deforming the first and second membranes in the out-of-plane direction of the first and second membranes, wherein the step of connecting the frame is performed while the portions of the first and second membranes are being deformed out-of-plane, and the frame limits the maximum transverse dimension of the macroencapsulation device.

25. The method according to claim 24, wherein the out-of-plane deformation of the first film and the second film includes aligning the surface of the first film opposite to the second film on a curved support.

26. The method according to claim 25, wherein the curved support comprises a spherical dome.

27. ​​The method according to any one of claim 25 or 26, further comprising maintaining the first and second films adjacent to the curved support by applying a vacuum to one or more non-diffusible portions of the first and second films.

28. The method according to claim 27, wherein the non-diffusive portion is arranged radially outward from the internal volume.

29. The method according to any one of claims 18 to 28, further comprising forming a plurality of channels between them by joining one or more portions of the first membrane and the second membrane before connecting the frame to the first membrane and the second membrane.

30. The method according to claim 29, further comprising forming one or more through-holes in one or more joint portions before connecting the frame to the second membrane.

31. The method according to any one of claims 18 to 30, further comprising deforming the outer periphery of the first membrane and the second membrane from a first maximum transverse dimension to a second maximum transverse dimension smaller than the first maximum transverse dimension, and connecting the frame restricts the maximum transverse dimensions of the first membrane and the second membrane to the second maximum transverse dimension.

32. The method according to claim 31, wherein the deformation of the outer periphery of the first and second films from the first maximum transverse dimension to the second maximum transverse dimension includes arranging the surface of the first film opposite to the second film on a curved support.

33. The method according to claim 32, wherein the curved support comprises a spherical dome.

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