Macroencapsulation device and method for forming a macroencapsulation device

Abstract

The present disclosure relates to a macroencapsulation device and related manufacturing method, in which membranes of the device can be attached to corresponding frames in a loose or slack configuration prior to filling with a desired material. In one embodiment, a macroencapsulation device for containing a cell population includes a first membrane and a second membrane disposed on the first membrane. The first and second membranes are joined along the peripheries of the first and second membranes to form an interior volume therebetween, 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, wherein the surface area of ​​the first and / or second membranes is greater than the cross-sectional area of ​​the frame to which the first and second membranes are attached.

Description

Technical Field

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

[0002] The disclosed embodiments relate to a macro - encapsulation device and a method for manufacturing the same.

Background Art

[0003] To treat metabolic disorders such as diabetes, a treatment device for delivering biological products can be used. The treatment device can be implantable to provide biological products such as insulin over a long period. Some of these devices include a macro - encapsulation device that contains cells and is used to generate a desired biological product, a matrix containing cells, or other desired therapeutic agents inside.

Summary of the Invention

Means for Solving the Problems

[0004] In one embodiment, a macro - encapsulation device for containing a cell population includes a first membrane and a second membrane disposed on the first membrane. The first membrane and the second membrane are joined along the periphery of the first and second membranes to form an internal volume therebetween, and the first membrane and / or the second membrane is semi - permeable. 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 to which the first and second membranes are attached.

[0005] In another embodiment, a macroencapsulation device for housing a cell population includes a first membrane and a second membrane disposed on the first membrane. The first and second membranes are joined along their perimeters to form an internal volume therebetween, and the first membrane and / or the second membrane is semipermeable. The device also includes a frame extending along at least a portion of the perimeters of the first and second membranes, and a portion of the first and second membranes connected to the frame is deformed to fit within a region of the frame that is smaller than a region of the portions of the first and second membranes in their undeformed configuration.

[0006] In another embodiment, a method of forming a macroencapsulation device includes deforming a portion of a first membrane and a second membrane disposed on the first membrane in an out-of-plane direction of the first and second membranes, and connecting a frame to the second membrane and / or the first membrane while a portion of the first and second membranes is out-of-plane deformed, the frame restricting a 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 of forming a macroencapsulation device includes deforming an outer perimeter of a first membrane and a second membrane disposed on the first membrane from a first maximum transverse dimension to a second maximum transverse dimension that is smaller than the first maximum transverse dimension, and connecting a frame to the second membrane and / or the first membrane to restrict the maximum transverse dimension of the first and second membranes to the second maximum transverse dimension, the first membrane and / or the second membrane being semipermeable.

[0008] Note that since the present disclosure is not limited in this regard, the foregoing concepts, as well as additional concepts described below, may be arranged in any suitable combination. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying figures.

[0009] If this specification and the documents incorporated by reference contain disclosures that are inconsistent and / or lack coherence, this specification shall prevail. If two or more documents incorporated by reference contain disclosures that are inconsistent and / or lack coherence with each other, the document with the later effective date shall prevail. The present invention is subject to, for example, the following. (Item 1) A macroencapsulation device for accommodating a cell population, a first membrane, a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along the periphery of the first and second membranes to form an internal volume therebetween, and the first membrane and / or the second membrane is semipermeable, the second membrane, a frame extending along at least a part of the periphery of the first and second membranes, wherein the surface area of the first and / or second membrane is larger than the cross-sectional area of the frame to which the first and second membranes are attached, the frame, and the macroencapsulation device including the same. (Item 2) The macroencapsulation device according to Item 1, wherein the frame extends entirely along the periphery of the first and second membranes. (Item 3) The macroencapsulation device according to any one of Items 1 or 2, wherein the first and second membranes are configured to block the movement of the cell population out of the device. (Item 4) The macroencapsulation device according to Item 3, further including the cell population disposed within the internal volume. (Item 5) The macroencapsulation device according to any one of Items 1 to 4, wherein the internal volume includes a plurality of channels. (Item 6) The macroencapsulation device according to Item 5, further including a plurality of bonding portions of the first and second membranes disposed radially inward from the frame, the bonding portions forming the plurality of channels, and at least a part of the bonding portions being penetrated by through-holes. (Item 7) The macroencapsulation device according to any one of Items 1 to 6, wherein the first membrane and / or the second membrane is sintered. (Item 8) The macroencapsulation device according to any one of Items 1 to 7, wherein the first and / or second membrane includes a hydrophilic coating. (Item 9) A macroencapsulation device for accommodating a cell population, a first membrane, a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along the periphery of the first and second membranes to form an internal volume therebetween, and the first membrane and / or the second membrane is semipermeable, the second membrane, A frame extending along at least a part of the periphery of the first and second membranes, wherein the portions of the first and second membranes connected to the frame are deformed to fit within a region of the frame that is smaller than the regions of the portions of the first and second membranes in the undeformed configuration, the frame; and the macroencapsulation device including the same. (Item 10) The portions of the first and second membranes connected to the frame are a plurality of locations arranged along the periphery of the frame, the macroencapsulation device according to item 9 including the plurality of locations where the first and second membranes are deformed from a first larger region to a second smaller region. (Item 11) The surface area of the first and / or second membrane is larger than the cross-sectional area of the frame to which the first and second membranes are attached. The macroencapsulation device according to any one of items 9 or 10. (Item 12) The frame extends entirely along the periphery of the first and second membranes. The macroencapsulation device according to any one of items 9 to 11. (Item 13) The first and second membranes are configured to block the movement of the cell population out of the device. The macroencapsulation device according to any one of items 9 to 12. (Item 14) Further including the cell population disposed within the internal volume. The macroencapsulation device according to item 13. (Item 15) The internal volume includes a plurality of channels. The macroencapsulation device according to any one of items 9 to 14. (Item 16) A plurality of connecting portions of the first and second membranes disposed radially inward from the frame, further including the connecting portions forming the plurality of channels, at least a part of the connecting portions being penetrated by through holes. The macroencapsulation device according to item 15. (Item 17) The first membrane and / or the second membrane is sintered. The macroencapsulation device according to any one of items 9 to 16. (Item 18) The first and / or second membrane includes a hydrophilic coating. The macroencapsulation device according to any one of items 9 to 17. (Item 19) A method of forming a macroencapsulation device, deforming a first membrane and a part of a second membrane disposed on the first membrane in a direction out of the plane of the first and second membranes; ​ Connecting a frame to the second membrane and / or the first membrane while a part of the first and second membranes is out-of-plane deformed, wherein the frame limits the maximum transverse dimension of the macroencapsulation device and the first membrane and / or the second membrane is semi-permeable, the connecting, and a method comprising the same. (Item 20) The method according to item 19, wherein the surface area of the first and / or second membrane is larger than the cross-sectional area of the frame to which the first and second membranes are attached. (Item 21) The method according to any one of items 19 or 20, wherein the first and second membranes are configured to block the movement of the cell population out of the device. (Item 22) The method according to item 21, further comprising filling the internal volume of the device with the cell population. (Item 23) The method according to any one of items 19 to 22, wherein the first membrane and / or the second membrane is sintered. (Item 24) The method according to any one of items 19 to 23, further comprising coating the first and / or second membrane with a hydrophilic material. (Item 25) The out-of-plane deforming of the part of the first and second membranes includes disposing the surface of the first membrane on the opposite side of the second permeable membrane on a curved support. Any one of items 19 to 24 The method described in any one of the above. (Item 26) The method according to item 25, wherein the curved support includes a spherical dome. (Item 27) The method according to any one of items 25 or 26, further comprising applying a vacuum to one or more non-diffusive portions of the first and second membranes to maintain the first and second membranes adjacent to the curved support. (Item 28) The method according to item 27, wherein the non-diffusive portion is disposed radially outward from the internal volume disposed 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 therebetween 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 joined portions before connecting the frame to the second membrane. (Item 31) A method of forming a macroencapsulation device, comprising: Deforming the outer periphery of the first membrane and the second membrane disposed on the first membrane from a first maximum transverse dimension to a second maximum transverse dimension smaller than the first maximum transverse dimension; 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 is semi-permeable, and the limiting; and the method including the above. (Item 32) The method according to item 31, wherein the surface area of the first and / or second membrane is larger than the cross-sectional area of the frame to which the first and second membranes are attached. (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 device. (Item 34) The method according to any one of items 31 to 33, further including filling the internal volume of the device with the cell population. (Item 35) The method according to any one of items 31 to 34, wherein the first membrane and / or the second membrane is sintered. (Item 36) The method according to any one of items 31 to 35, further including coating the first and / or second membrane with a hydrophilic material. (Item 37) Deforming the outer periphery of the first and second membranes from a first maximum transverse dimension to a second maximum transverse dimension smaller than the first maximum transverse dimension includes disposing the surface of the first membrane on the side opposite the second permeable membrane on a curved support. The method according to any one of items 31 to 36. (Item 38) The method according to item 37, wherein the curved support includes a spherical dome. (Item 39) Maintaining the first and second membranes adjacent to the curved support further includes applying a vacuum to one or more non-diffusive portions of the first and second membranes. The method according to any one of items 37 or 38. (Item 40) The method according to item 39, wherein the non-diffusive portion is disposed radially outward from the internal volume disposed between the first and second membranes. (Item 41) The method according to any one of items 31 to 40, further including joining one or more portions of the first and second membranes to form a plurality of channels therebetween 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 bonding portions before connecting the frame to the second film.

[0010] The attached drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component illustrated in various figures may be represented by the same numerals. For clarity, not all components may be labeled in all of the drawings. In the drawings,

Brief Description of the Drawings

[0011]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 1F

Figure 1G

Figure 1H

Figure 1I

Figure 1J

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 3

Figure 4A

Figure 4B

Figure 4C

Figure 5A

Figure 5B

Figure 5C

Figure 5D

Figure 6A

Figure 6B

Figure 7A

Figure 7B

Figure 8A

Figure 8B

Figure 9

Figure 10A

Figure 10B

DETAILED DESCRIPTION OF THE INVENTION

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

[0013] In view of the above, the inventors recognize the benefits associated with a macroencapsulation device in which the relative sizing and placement of the membrane and the frame of the device can be controlled to vary one or more parameters of the resulting macroencapsulation device. For example, the 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 various dimensions and / or operating parameters. This will be described in detail below. This can include controlling the amount of slack in the membrane held within the frame prior to filling with a desired therapeutic agent such as a cell population.

[0014] In this specification, the foregoing general concept of controlling the amount of sagging of the membrane during frame attachment can alternatively be referred to as sag attachment or attachment slack. This concept can refer to attaching at least two or more layers of flexible membranes (e.g., a first membrane and a second membrane) under a controlled relaxed tension to form a device that includes an internal chamber of a defined volume and / or height during filling. By adjusting the degree of membrane slack during the sag attachment process, a device with the desired set of geometric properties for accommodating a cell population can be fabricated. For example, in some embodiments, the degree of membrane slack during the sag attachment process can be controlled by combining the degree of deformation introduced into the membrane during manufacturing with the mechanical restraint applied to the membrane (e.g., using a surrounding frame to limit the maximum transverse dimension of the membrane relative to the total surface area of the membrane). This will be further explained below.

[0015] In some embodiments, during the manufacturing process of a macroencapsulation device, at least one (optionally, at least two, or more) flexible membrane of the device can be deformed, at least partially housed within a frame, and then coupled to the frame to form the macroencapsulation device. The frame can hold the membrane in a desired configuration (the membrane having a desired amount of sag extending between opposing portions of the frame). For example, in one embodiment, the outer periphery of a first membrane and a second membrane disposed on the first membrane can be deformed from a first maximum transverse dimension to a second maximum transverse dimension that is smaller than the first maximum transverse dimension before being coupled to the frame. By deforming in this way and subsequently holding the membrane in the deformed configuration, the membrane can be held within the frame with a desired amount of sag and adapted to the excess material contained within the frame. Such deformation and holding can be achieved in many different ways.

[0016] In one embodiment, a frame may be used to limit the maximum transverse dimension of the first and second membranes to a maximum transverse dimension smaller than the maximum transverse dimension of the membranes in the undeformed configuration. Specifically, the frame may be connected to the second membrane and / or the first membrane, while a portion (e.g., the central portion) of the first and second membranes is deformed out of the plane in which the membranes extend in a flat configuration. Then, when the force applying the out-of-plane deformation of the membrane is removed, the frame may limit the maximum transverse dimension of the macroencapsulation device. In this way, the surface area of the first and / or second membranes may become larger than the second maximum transverse dimension due to the frame, and as a result, there is slack in the membrane between the opposing portions of the frame.

[0017] As described above, when a frame is connected to the deformed membranes of the macroencapsulation device during the manufacturing process, the frame may maintain a portion of the membranes in a deformed configuration and impart a desired amount of slack into the membranes. For example, the first and second membranes may be joined along the perimeter of the membranes. This joined portion of the membranes may be deformed to fit within a frame that is joined around the perimeter of the first and / or second membranes and extends along at least a portion thereof, although in some embodiments the frame may also extend along the perimeter of the entire membrane. Specifically, the portions of the first and second membranes connected to the frame may be deformed to fit within a region of the frame that is smaller than the region of the portions of the first and second membranes in the undeformed state. Specifically, a frame having a maximum transverse dimension smaller than the transverse dimension of the membranes in the undeformed state may be connected to the membranes to achieve a desired amount of slack of the membranes within the device. In such embodiments, the portions of the first and second membranes connected to the frame may include locations arranged along the perimeter of the frame where the first and second membranes are deformed to accommodate the reduction in area. For example, in some embodiments, the deformed portions of the membranes may include wrinkles, folds, corrugations, plastically or thermally deformed sections, and / or any other suitable type of deformation that can accommodate the change in area of this portion of the membrane from a first larger region to a second smaller region.

[0018] Depending on the desired configuration, the frame of the macroencapsulation device can be placed at any number of different locations relative to different membranes of the device. For example, in one embodiment, the frame can be connected to an outer surface of one of the outer membranes of the device. In one such embodiment, a first membrane can be placed on a second membrane, and the frame can be placed on and connected to the outer surface of the second membrane on the side opposite the first membrane. In another embodiment, the frame can be connected to both the first and second membranes such that the frame is located between the membranes and is located in or otherwise extends along at least a portion of the vicinity of at least a part of the perimeter of the first and second membranes. Thus, naturally, the present 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 for a given membrane size and corresponding frame size. The amount of sag present within the membrane prior to filling with cells can be related to the difference between the surface area of the first and second membranes during the attachment process relative to the corresponding cross-sectional area of the frame to which the membrane is attached, which can also be referred to as a relative mismatch in the sizing of the membrane and frame areas. The relative difference in these areas, and the resulting sag in the attached membrane, can be controlled by adjusting the size of the frame relative to the size of the membrane. For example, the cross-sectional area of the frame can be smaller than the corresponding surface area of the membrane held within the frame. Thus, the greater the difference between the membrane surface area and the cross-sectional area of the frame to which the membrane is attached, the greater the sag that can be present in the corresponding membrane. Conversely, the smaller the difference between the membrane surface area and the frame cross-sectional area, the smaller the corresponding sag can be.

[0020] In view of the above, the surface area of one or more membranes mounted within the frame can be greater than the cross-sectional area of the frame on which the one or more membranes are mounted. The surface area of the one or more membranes can include portions of the membranes that are coupled to each other either radially inwardly disposed from the corresponding frame or otherwise disposed within the corresponding frame at the inner portions of the membranes. Further, the surface area of the one or more membranes can be greater than the cross-sectional area of the frame by a ratio 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 suitable ratio. Correspondingly, the surface area of the one or more membranes can be greater than the cross-sectional area of the frame by a ratio of 30% or less, 20% or less, 10% or less, 5% or less and / or any other suitable ratio. The above combinations are also conceivable. For example, the surface area of the one or more membranes is greater than the cross-sectional area by a ratio of 1% to 30% (including both ends). Naturally, both larger and smaller ratios than those described above are also conceivable, and the present disclosure is not limited as described above.

[0021] Similar to the above, one or more portions of the film that are deformed in an out-of-plane direction of the film during the attachment process to the frame can be deformed by any suitable amount after being attached to the frame to impart a desired amount of slack into the film. In some embodiments, this out-of-plane deformation can correspond to an out-of-plane deformation such that the projected two-dimensional area of the film relative to the flat planar configuration of the film will decrease by a ratio of 0.3% or more, 0.5% or more, 1% or more, 2% or more, 3% or more and / or any other suitable ratio. Correspondingly, the deformation can result in the projected two-dimensional area of the film decreasing by a ratio of 7.5% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less and / or any other suitable ratio. Combinations of the above are also contemplated. For example, in the range of 0.3% to 7.5% (including both ends). Further, in some embodiments, this deformation can 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. Of course, the specific deformation range is expected to vary for different frame and film sizes. In any case, both larger and smaller ranges than those described above are contemplated for the ratio of change in area and / or the absolute amount of deformation, and the present disclosure is not limited as described above.

[0022] In some embodiments, deforming the membrane of the device during frame attachment can be assisted by using a support on which the laminated membrane can be disposed during the frame attachment process. The support can extend over an area of at least a portion (and in some cases, the entirety) of the membrane disposed thereon. The specific profile of the support can be adjusted to control the degree of membrane deformation. For example, a laminate of two or more membranes can be disposed on a curved support or other suitably shaped support that can deform the laminate of membranes disposed thereon in a desired manner. The curved support can have any suitable shape. For example, without limitation, a sphere, spherical dome, cylinder, partial cylinder, oval, partial oval, and / or any other suitable shape that can impart a desired deformation to the laminate of membranes disposed thereon or at least partially disposed thereon. In any case, by disposing the first and second membranes of the macroencapsulation device on the support, a portion of the laminate of membranes is deformed out-of-plane of the first and second membranes such that the membrane is deformed from a first maximum transverse dimension associated with an undeformed planar configuration of the membrane to a second smaller maximum transverse dimension associated with a deformed state of the membrane (e.g., a bent or curved configuration of the membrane). And the frame can be attached to the membrane while the membrane is held in the deformed configuration.

[0023] Although the use of a curved support has been described above with respect to deforming a laminate of membranes, the present disclosure is not limited to only using a curved support. For example, in some embodiments, methods for deforming the first and second membranes from a first maximum transverse dimension to a second smaller maximum transverse dimension for attaching a frame thereto can include thermoforming, mechanical deformation, and / or any suitable method that can maintain the desired amount of sagging of at least the desired portion of the membrane between the frames of a flexible configuration while attaching the frame to the membrane in a desired configuration.

[0024] In certain embodiments, it may be desirable to hold a laminate of two or more membranes in a desired position and / or orientation on a support lying horizontally below. This can be done in any suitable manner, but in one embodiment, the support may be configured to apply vacuum suction to one or more portions of the membrane laminate to maintain the membrane adjacent to the support. To avoid consolidation of the diffusive portions of the macroencapsulation device, vacuum can be applied to the non-diffusive portions of one or more membranes. For example, the non-diffusive portions of the first and second membranes can include the bonding regions (e.g., the bonded perimeter and / or the bonded inner portions of the first and second membranes) and / or portions of the membrane disposed outside the active region of the device (e.g., radially outward from a bond extending along the perimeter of the device that forms the internal volume of the device). Thus, vacuum can be applied to a location radially outside the internal volume disposed between the first and second membranes or between other suitable non-diffusive portions of the membranes.

[0025] As described above, the macroencapsulation device can include multiple layers of membranes. At least one outer membrane of these multiple layers of membranes can be semipermeable. However, embodiments are also contemplated in which each membrane is semipermeable or at least one of the membranes in the device is substantially impermeable. Further, the device can include two laminated membranes, three laminated membranes, and / or any other suitable number of membranes, and the present disclosure is not limited as described above. For example, in one embodiment in which two membranes are included, either one of the membranes can be semipermeable and the other impermeable, or both can be semipermeable. Thus, it goes without saying that the present disclosure is not limited to any particular combination of membranes within the laminate structure.

[0026] In some embodiments, the macroencapsulation device can include at least one cell population disposed within the internal volume of the device. For example, the cell population can be disposed within an internal volume formed between two or more opposing outer membranes of the device. The outer edge of the internal volume can be defined by one or more bonds extending around the membrane or other suitable portion of the membrane. In such embodiments, at least the outer membrane of the device can be configured to block 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. Of course, while two outer membranes forming a single internal volume are shown, it is also contemplated to use a plurality of intermediate membranes located between the outer membranes of the device and / or between a plurality of non-connected internal volumes within the device.

[0027] In addition to retaining a cell population within the device, in some embodiments, the membrane of the device can be configured to protect one or more cell populations disposed within the device from an immune attack while allowing the movement of desired biological products (e.g., insulin) produced by the cells as well as waste and nutrients used and produced by the cells. In some embodiments, the membrane is configured to protect the cells from an immune attack in the absence of immunosuppressive therapy.

[0028] The membrane of the macroencapsulation device can be formed from any suitable biocompatible material. The biocompatible material can be substantially inert with respect to the cells and surrounding tissue contained within the macroencapsulation device. Biocompatible materials include synthetic or naturally occurring polymers. In some embodiments, the polymer can also be a linear polymer, a crosslinked polymer, a network polymer, an addition polymer, a condensation polymer, an elastomer, a fibrous polymer, a thermoplastic polymer, a non-degradable polymer, combinations of the foregoing, and / or any other suitable type of polymer, and the present disclosure is not limited as described above. Suitable types of polymers include the following. Polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), polystyrene (PS), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyurethane (PU), polyamide (nylon), polyethylene terephthalate (PET), polyethersulfone (PES), polyetherimide (PEI), polyvinylidene difluoride (PVDF), polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), poly-L-lactide (PLLA), any combination of these, and / or any other suitable polymeric material. Synthetic methods that can be used to form one or more porous membranes from the foregoing polymeric materials can include, but are not limited to, the following. Swelling, solution casting, immersion precipitation and phase separation, electrospinning, methods for obtaining an isoreticular network, methods for obtaining a columnar network, or any other suitable method for forming a porous polymeric membrane.

[0029] The porosity and flux characteristics of a membrane can be altered using sintering of the membrane. For example, through sintering, the porosity of the membrane can be increased while maintaining its pore structure. Also, through sintering, the mechanical stability and diffusional flux of the membrane can be improved. Thus, the porosity and / or mechanical properties of a membrane can be altered using sintering, and the membrane can be used to adjust the porosity and flux characteristics of a macroencapsulation device. Thus, in some embodiments, any desired combination of sintered and / or unsintered membranes can be used. For example, two outer membranes of a device can be joined to each other. An unsintered and a sintered membrane can be joined to each other, two sintered membranes can be joined to each other, or two unsintered membranes can be joined to each other. Further, any number of intermediate membranes positioned between these outer membranes can be used. These intermediate membranes can be sintered or unsintered.

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

[0031] To obtain the desired selectivity, the porous membranes used with the macroencapsulation devices disclosed herein have an open porous structure and an average pore size of about 1 nm or greater, 5 nm or greater, 10 nm or greater, 15 nm or greater, 20 nm or greater, 30 nm or greater, 40 nm or greater, 50 nm or greater, 60 nm or greater, 70 nm or greater, 80 nm or greater, 90 nm or greater, 100 nm or greater, 200 nm or greater, 300 nm or greater, and / or can be of any other suitable size range. Correspondingly, the average pore size of the various membranes described herein can 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 can be of any other suitable size range. The aforementioned combinations are also contemplated. For example, the average pore size can be 1 nm to 20 nm (including both ends), 1 nm to 2500 nm (including both ends), and / or any other suitable combination. Of course, while specific average pore sizes have been described above, any suitable average pore size can be used for the various membranes described herein, and it should be noted that, for example, both average pore sizes larger and smaller than those described above can be included.

[0032] To obtain sufficient strength and / or rigidity for the macroencapsulation device, the various membranes and frames can be formed from sufficiently rigid materials. The desired rigidity can be obtained through an appropriate combination of the Young's modulus, thickness, and overall configuration of the material that can be balanced with the desired permeability of the device. Suitable Young's moduli for the various membranes and frames described herein are at least 10 5 Pa, 10 6 Pa, 10 7 Pa, 10 8 Pa, 10 9 Pa, 10 10It can be Pa and / or any other suitable elastic modulus that is both greater than and less than these ranges. Of course, the ranges between the aforementioned Young's moduli are also considered to be included. For example, about 10 6 Pa to 10 10 Pa (including both ends) is the Young's modulus.

[0033] In some embodiments, it may be desirable for one or more of the membranes contained within the 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, biological compounds, therapeutic agents, cell nutrients, cell waste, and / or other materials through the membrane of the device. Further, with a hydrophilic outer membrane, the occurrence of fibrosis can also be reduced when the device is located in vivo. Accordingly, the membrane of the macroencapsulation device can be formed from a hydrophilic material and / or treated with a hydrophilic coating. Suitable hydrophilic materials can include, but are not limited to, the following. Suitable hydrophilic polymers, polyethylene glycol, polyvinyl alcohol, polydopamine, any combination thereof, and / or any other suitable hydrophilic material that can form a coating on or form the membrane.

[0034] The membranes described in the various embodiments of the macroencapsulation device described herein may be joined to each other using any suitable joining method, and the present disclosure is not limited as described above. For example, adjacent membranes can be joined to each other using the following. Adhesives, epoxies, welding or other fusion-based techniques (such as ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using frames or fixtures, and / or any other suitable joining method. In one particular embodiment, the joining of adjacent membranes can be performed using a heated tool that is used to press or abut two or more membranes against each other for a set fusion time by a predetermined pressure and / or force. It should be noted that in view of the above, the present disclosure is not limited to using any particular method for joining the membranes to each other.

[0035] In some embodiments, after the membranes are joined together, and optionally after a frame is attached to the membranes, one or more heat treatments may be applied to the laminate of joined membranes. For example, the membranes may be joined with a bond extending along the perimeter of the membranes, and / or one or more bonds may be formed inside the interior region of the membranes (e.g., inside the joined perimeter) before heat treating the membranes. Thereafter, the bond of the membranes in the bond region may be strengthened by the bond heat treatment. The specific heat treatment temperature and duration for improving the bond between the membranes 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 membrane.

[0036] In certain embodiments, it may be desirable or possible to limit the maximum thickness of the macroencapsulation device in a direction perpendicular to the plane in which the maximum transverse dimension of the device lies. Thus, one or more interior portions of the first and second membranes disposed within the frame may be joined to each other to limit the extent to which the membranes can move relative to each other. These joined portions of the membranes may be uniformly dispersed among the interior portions of the membranes disposed within the frame. These joined portions may have any suitable shape, e.g., dots, lines, curves, or any other suitable shape. The joined interior portions may have any suitable size for the desired application, but in one embodiment using joined dots, the diameter of the joined dots may be about 0.5 mm or greater, 0.75 mm or greater, 1 mm or greater, 1.25 mm or greater, 1.5 mm or greater, and / or any other suitable diameter. Correspondingly, the diameter of the dots may be about 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 foregoing ranges are also contemplated. For example, a diameter of 0.5 mm to 3 mm (including both ends). Although specific shapes and size ranges have been set forth above, it will of course be appreciated that other shapes and sizes smaller and larger than those described above are also contemplated and the present disclosure is not limited as such.

[0037] In some embodiments, it may be desirable to improve angiogenesis of the macroencapsulation device. Thus, in one embodiment, one or more through-holes can be formed within one or more coupling portions disposed within an inner portion of a membrane disposed radially inward from the frame of the device. These through-holes can enable 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 within the coupling portions of the membrane can be performed using laser ablation, mechanical puncturing, cutting, or any other suitable method that forms through-holes within one or more coupling portions of the membrane.

[0038] In some embodiments, the aforementioned coupling portions and corresponding through-holes within the inner region of the device can be formed prior to attaching the frame onto the device while the membrane is disposed in a flat planar configuration. This can simplify the manufacturing process when handling a flexible membrane that is attached to the frame with a desired amount of slack that can complicate forming other features after attachment to the frame.

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

[0040] The macroencapsulation device described herein may have any suitable combination of internal volume, outer dimensions, and / or other suitable physical parameters. For example, the internal volume encapsulated by the outer membrane of the macroencapsulation device can be from 40 μL to 250 μL (including both ends). Also, the width or maximum cross-sectional dimension of the macroencapsulation device can be about 20 mm to 80 mm. Further, to perform desired oxygen diffusion inside the macroencapsulation device to support the cells contained therein, the maximum oxygen diffusion distance from the outside of the device to the internal part of the device containing the cell population can 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 the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the internal volume disposed within the device can 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. Further, in some embodiments, the surface area-to-volume ratio of the device is about 20 cm -1 or more, 40 cm -1 or more, 60 cm -1 or more, 80 cm -1 or more, 100 cm -1 or more, 120 cm -1 or more, or 150 cm -1 or more. Ranges extending between any of the foregoing values for the various dimensions and parameters, as well as both larger and smaller ranges than those described above, are also contemplated.

[0041] Specific dimensions, parameters, and relationships related to the macroencapsulation device, as well as the materials from which the macroencapsulation device is formed, have been described above. However, of course, larger and smaller dimensions, parameters, and relationships than those described above are also contemplated, and the present disclosure is not limited as described above. Thus, depending on the desired application, any suitable combination of size, configuration, material properties, and / or relative performance parameters can be used for the device.

[0042] In some embodiments, the cell population contained within the internal volume of the macroencapsulation device can be an insulin-secreting cell population. In some embodiments, the cell population includes at least one cell obtained from stem cell-derived cells. In some embodiments, the at least one cell is a genetically modified cell. Optionally, the at least one cell is genetically modified to suppress the immune response in the subject at the time of device implantation compared to an equivalent cell that has not been genetically modified. In some embodiments, the cell population is stem cell-derived cells capable of glucose-stimulated insulin secretion (GSIS). For example, suitable cell populations can include pancreatic progenitor cells, endocrine cells, beta cells, a matrix comprising one or more of the foregoing, or any combination thereof. Further, the matrix can include isolated islet cells, isolated cells from the pancreas, isolated cells from tissue, stem cells, stem cell-derived cells, induced pluripotent cells, differentiated cells, transformed cells, or an expression system (capable of synthesizing one or more biological products). Optionally, in some embodiments, the matrix can include a second type of cell that supports a first type of cell that synthesizes one or more biological products. In some embodiments, the cells can be encapsulated prior to being placed within the matrix. In such embodiments, the cells can be encapsulated within microcapsules or conformally coated. However, naked (i.e., uncoated) cells can also be used.

[0043] Depending on a particular embodiment, a therapeutically effective density of cells can be filled within the internal volume of the macroencapsulation device. A suitable cell density disposed within the internal volume can be about 1000 cells / μL or more, 10,000 cells / μL or more, 50,000 cells / μL or more, 100,000 cells / μL or more, 500,000 or more, and / or any other suitable cell density. Also, a suitable cell density disposed within the chamber can be about 1,000,000 cells / μL or less, 500,000 cells / μL or less, 100,000 cells / μL or less, 50,000 cells / μL or less, 10,000 cells / μL or less, and / or any other suitable cell density. The aforementioned combinations are also contemplated. For example, a cell density of about 1000 cells / μL to 1,000,000 cells / μL. Of course, depending on the desired application and the cell type being used, both cell densities greater than and less than those described above can also be used.

[0044] The macroencapsulation device described herein can be implanted at various sites within the body of a subject. In one example, the device can be implanted within the subject by preperitoneal or retrorectus implantation. In another example, the device can be placed by omental implantation. In another example, the device can be placed by subcutaneous implantation. In another example, the device can be placed by suprahepatic implantation. In some cases, the macroencapsulation device described herein can be fixed at the implantation site within the body using any suitable fixation method (e.g., application of a tissue adhesive, etc.). Suitable tissue adhesives can include, but are not limited to, the following. Fibrin, cyanoacrylate, polyethylene glycol, albumin-based adhesives, polymer-based adhesives, and / or any other suitable adhesive. In another example, fixation of the device can be performed using platelet-rich plasma and / or any other suitable fixation method, and the present disclosure is not limited as described above.

[0045] With reference to the figures, specific non-limiting embodiments will be described in more detail. Of course, the various systems, components, features, and methods described with respect to these embodiments can be used separately and / or in any desired combination, because the present disclosure is not limited to only the specific embodiments described herein. For clarity, the figures are described in relation to a method and apparatus that includes only a first and a second outer membrane joined to each other. However, of course, the method and apparatus described in relation to the figures may include any number of intermediate membranes disposed between these outer membranes, and the present disclosure is not limited as described above.

[0046] Figures 1A - 1H show one embodiment of a process for joining two or more membranes to each other and forming various other features on the membranes before attaching a frame to the membranes.

[0047] As shown in FIGS. 1A - 1B, a first membrane 102 is placed on the lower portion of a fixture 106 such that the first membrane 102 is disposed directly or indirectly on the surface of the lower portion of the fixture. A second membrane 104 is placed on the surface of the first membrane 102 opposite the lower portion of the fixture. In some embodiments, the lower portion of the fixture may include one or more sensors 110 distributed across the surface of the lower portion of the fixture on which the membranes are disposed. These sensors may be configured to detect forces, pressures, and / or temperatures 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 can 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 a predetermined position 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 are also contemplated where the membranes are held in a different configuration during the initial forming step. Also, as illustrated in the figure, the upper part 108 of the fixture includes an opening (or other arrangement) where the central portion of the laminated first and second membranes is either uncovered or otherwise left exposed for further processing. Thus, the lower and upper parts of the fixture can be configured to clamp one or more peripheral portions of the first and second membranes disposed 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 membrane is best illustrated in FIG. 1B. Although the figure illustrates a circular opening at the very top of the fixture, it will of course be understood that the present disclosure is not limited to any particular shape of the exposed portion of the membrane and / or how the membranes are held in a predetermined position during the bonding and initial forming processes.

[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). FIGS. 1C - 1E illustrate one embodiment of the process of bonding the first and second membranes to each other. Referring to FIG. 1C, a bonding tool 120 is used to bond the first and second membranes to each other at a desired location. In one particular embodiment, the bonding tool includes a heated tip that is positioned at a desired location on the upper surface of the second membrane and is pressed downwardly at 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 can transmit signals to a corresponding processor (not shown) to implement feedback control of the bonding process. Once a bond is formed at the desired location, the bonding tool can be moved to an adjacent portion of the membrane that at least partially overlaps with a portion of the already formed bond and this can be done until the desired shape and size of the particular bond is formed, although different bonding methods can also be used as described above. Then the tool can 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 particular application. For example, as shown in FIGS. 1D and 1E, the first and second membranes can be bonded along the periphery 122 around the active portion of the membranes intended to form an internal volume therebetween.

[0050] As best shown in the plan view of FIG. 1E, in some embodiments, a bonding tool can be used to also bond one or more portions 124 of the membrane that are disposed radially inward from the resulting bonded periphery 122. In this particular embodiment, these bonded portions disposed within the bonded periphery 122 can 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 can also be used. Due to the presence of these bonded regions disposed radially inward from the bonded periphery of the membrane, the internal volume formed between the membranes, when in a filled configuration, can take the form of a plurality of interconnected channels 126 that correspond to unbonded regions of the membrane that extend between these bonded portions.

[0051] In some cases, the bonded portions of membranes 102 and 104 can have substantially reduced membrane permeability due to the bonding process and can be considered non-diffusive portions of the membrane. This can include both the bonded perimeter 122 of the membrane and the internal bonding portion 124 disposed radially inward from the bonded perimeter. In contrast, the unbonded portions of the membrane (e.g., channel 126 in the illustrated embodiment) can be considered diffusive portions of the membrane. The diffusive portions can have significantly higher permeability than the non-diffusive portions of the membrane and, in some embodiments, can be substantially the same as the parent membrane material. In addition to the bonded portions of the membrane being considered non-diffusive portions of the membrane, portions of the membrane disposed radially outward from the bonded perimeter 122 that do not have direct fluid communication with the resulting internal volume formed therebetween can also be considered non-diffusive portions of the membrane for the purposes of this description.

[0052] In some embodiments, after bonding a portion of the first and second membranes 102 and 104 to each other, one or more through-holes 132 can be formed in one or more of the bonded portions 122 and 124. For example, referring to FIGS. 1F - 1G, one or more through-holes 132 can be formed in one or more of the bonded portions of the first membrane 102 and the second membrane 104 using an apparatus such as a laser, punch, cutter, or other suitable apparatus. In one particular embodiment, the through-holes can be formed via laser ablation. Here, while the laser removes the bonded portions of the first and second membranes, the bonded portions surrounding the membranes are left to function as a seal between the internal volume formed by the membranes and the exterior of the apparatus.

[0053] In a situation where the outer shape and size of the conjunctiva are already in the final desired configuration, the conjunctiva can simply proceed to the next step of the manufacturing process. Alternatively, in some embodiments, one or more peripheral portions of the membrane can be cut away from the membrane to give the desired size and / or shape to the conjunctiva. One embodiment of such a process is illustrated in FIG. 1H. Here, a slit can be formed along the joined periphery 122 of the membrane using a blade 140 (or other cutting tool). In the illustrated embodiment, after extending the blade through the first and second membranes, the blade is moved relative to the membrane along any desired cutting profile around the joined periphery of the membrane to cut away one or more peripheral portions of the membrane that are held within the fixture and disposed radially outward from the joined periphery. Of course, while the figure shows the blade being moved relative to the membrane held within the fixture, any suitable method for cutting away the peripheral region of the conjunctiva to give the desired size and shape of the conjunctiva may be used, and the present disclosure is not limited as described above.

[0054] Regardless of whether the cutting process has been performed, after various desired portions of membranes 102 and 104 are joined to each other, as shown in FIG. 1I, the conjunctiva can be removed from the fixture corresponding to the upper and lower fixture portions 106 and 108. This can be done in any number of ways, for example, simply opening the fixture and manually removing the conjunctiva. 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-diffusive portions of the conjunctiva to lift it from the surface of the fixture. However, any suitable method for removing the conjunctiva from the fixture or other device may be used, and the present disclosure is not limited as described above.

[0055] A plan view of the resulting combined film laminate is illustrated in FIG. 1J. In the figure, the upper surface of the second film 104 is shown together with a combined perimeter 122 of the films (e.g., where the first and second films are joined) that extends along the perimeter of the bonding film. Although it is shown that the combined perimeter extends to the outer edge of the film, embodiments are also contemplated where the bonding that extends along the perimeter of the film is inserted from the outer edge of the film. The bonding film also includes one or more bonding portions 124 disposed radially inward from the combined perimeter. Further, through-holes 132 may be formed within one or more of the bonding 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 bonding portions of the film disposed radially inward from the perimeter bonding 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 film.

[0056] In some embodiments, after the films are joined together (e.g., joining the perimeters and / or internal portions of the first and second films), the first and second films may be coated with a hydrophilic material and / or other treatments that may not be compatible with the joining process may be performed. This may include various heat treatments that may strengthen the bonding of the films in some embodiments and various high-temperature treatments that may be performed on the films.

[0057] In some embodiments, a pre-joined film laminate (e.g., the joining of the first and second films described above) may be attached to a frame. Alternatively, in some embodiments, the perimeters of the film laminate may be joined together and attached to the frame simultaneously. In either case, a method for attaching the film to the frame may be used such that, once attached, a desired amount of slack is provided within the film. One such embodiment will be described in more detail later in connection with FIGS. 2A-2E.

[0058] Figures 2A - 2B illustrate the concept of deforming the first and second membranes 102 and 104 from a first maximum cross - sectional dimension before attachment (e.g., in Figure 2A the membrane is in a relatively flat planar configuration) to a later second maximum cross - sectional dimension (e.g., in Figure 2B the membrane is deformed to conform to the shape of the underlying support 200). Specifically, the surface of the first membrane on the side opposite the second membrane is disposed on the curved surface 206 of the support 200 and conforms to its shape, such that a portion of the first and second membranes can be deformed in an out - of - plane direction of the first and second membranes. For example, because the central portion of the membrane is deformed in an out - of - plane direction of the membrane by the underlying curved surface of the support, the outer peripheral portions of the first and second membranes are deformed from the first cross - sectional dimension in the planar configuration of Figure 2A to the much smaller cross - sectional dimension of Figure 2B. In some embodiments, as illustrated in Figures 2A - 2E, the curved surface of the support is a spherical dome. However, embodiments using supports with different shapes are also contemplated.

[0059] In some embodiments, the support 200 may include one or more raised portions 202 disposed near the edge of the curved surface 206 of the support 200 that support the membrane stacks 102 and 104 thereon. These raised portions are disposed at a plurality of locations around the perimeter of the support such that the first and second membranes 102 and 104 disposed on the curved support 200 flare out near the outer periphery and / or otherwise deform as described above to accommodate the presence of excess membrane material at these locations. Specific examples of the interaction between these raised portions and the membranes disposed thereon will be described in more detail later in connection with FIGS. 5A - 6B. As such, in the illustrated embodiment, the combined membrane stack (including the first and second membranes 102 and 104) is disposed on the support 200. The outer peripheries of the first and second membranes contact the raised portions 202, deforming the portions of the membranes adjacent to the curved surface of the support. In the illustrated embodiment, the raised portions can serve to deform portions of the membranes by forming wrinkles, folds, corrugations, or otherwise deforming the membranes at this location to accommodate the excess material that has been forced into a smaller area when the membrane is deformed from a larger first transverse dimension (e.g., planar configuration) to a smaller second transverse dimension (e.g., deformed configuration disposed on the support).

[0060] Although the use of raised portions is illustrated in the foregoing embodiments, it will of course be possible to use any method of deforming one or more locations around the perimeter of the bonded membranes from a first larger area to a second smaller area.

[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 attached thereto. Thus, in some embodiments, as shown, a vacuum can be applied to one or more non-diffusive portions of the first and second films to hold the first and second films adjacent to the curved support. For example, referring to FIG. 2B, the curved support 200 can include a vacuum chamber 210 connected to a vacuum source (not shown) to apply a negative pressure. The vacuum chamber can be fluidly connected to one or more suction holes 212 disposed on the surface of the curved support 200. The suction holes can be disposed at any desired portion of the surface of the support, but in some embodiments, the suction holes can be disposed on the surface portion of the support where the corresponding non-diffusive portions of the bonding films can be disposed, e.g., the bonded perimeter 122 of the film, the portion of the film disposed radially outward from the bonded perimeter, the bonded portion 124 of the film disposed within the bonded perimeter, and / or any other suitable portion of the film. For example, a plurality of suction holes can be disposed adjacent to or in the raised portion 202 around the perimeter of the curved surface 206 of the support. Of course, other methods can be used to maintain the position and / or orientation of the film with respect to the underlying support. For example, without limitation, mechanical fixation, clamping, temporary adhesives, and / or any other suitable temporary fixation method.

[0062] After deforming the first and second membranes 102 and 104 from a first maximum transverse dimension to a second maximum transverse dimension that is smaller, the frame 220 can be attached to the membranes as shown in FIGS. 2C and 2D. Specifically, while the central portion of the membrane is out-of-plane deformed by the downwardly lying curved support 200, the frame 220 (e.g., a peripheral frame) can be disposed on the laminated membrane. The frame can extend around at least a portion (in some embodiments, around the entire periphery) of the periphery of the bonded membrane. The size and shape of the frame can be selected such that after attachment, the maximum transverse dimension membrane is maintained at a smaller second maximum transverse dimension. The maximum transverse dimension can be measured in the plane in which the planar frame extends. For example, in the illustrated embodiment, the maximum transverse dimension can correspond to the diameter of the circular frame disposed on the bonded membrane. However, embodiments using frames and membranes with different shapes and sizes are also contemplated.

[0063] As described above, in certain embodiments, the frame 220 can 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 in some cases the entire frame, can be aligned with and / or positioned radially outward from the bonded periphery 122 of the membrane. Thereby, it can be avoided that the frame is disposed over the diffusible portion of the bonded membrane and diffusion through the portion of the membrane lying thereunder is blocked. Thus, the frame can have a transverse dimension equal to or slightly larger than the bond extending along the periphery of the membrane and form the internal volume of the membrane. For example, referring to FIG. 2D, the frame 220 only overlaps a portion of the bonded periphery 122 of the membrane. Of course, while in the illustrated embodiment the membrane does not extend past the frame, embodiments where the frame extends past this bond and into the region disposed radially inward from the bonded periphery are also contemplated.

[0064] As shown in FIG. 2E, after positioning the frame 220 on the combined membrane laminates 102 and 104, the frame can be bonded to the membrane. In certain embodiments, an adhesive, heat caulking, welding (thermal, ultrasonic, etc.), mechanical fixation, or another suitable method can be used to bond the frame and the membrane at multiple locations around the perimeter of the frame. For example, the frame and the membrane can be bonded to each other at each location where the frame and the membrane contact the raised portion 202 disposed along the perimeter of the curved surface 206 of the support 200. In the illustrated embodiment, the fixing device 230 can be used to form adhesive points between the frame and portions of the first and second membranes at one or more desired locations. The fixing device 230 can correspond to a combination of a port used to dispense a curable adhesive and a light source that can be used to cure the adhesive once it is disposed on the frame and the membrane. The duration of the bonding and the viscosity of the adhesive can be selected to avoid excessive uptake of the adhesive into the diffusive portions of the membrane. Further, while a particular bonding method has been described, other suitable types of bonding can be used as previously described. After bonding the frame to the membrane, the resulting macroencapsulation device including the frame and the attached membrane can be removed from the curved support. In this way, after first securing the membrane to the frame, further processing of the attached frame and membrane can then be performed. For example, a further planar adhesive between the attached frame and the membrane can be added to improve the bond between them, etc.

[0065] In the foregoing embodiment, the frame is connected to the outer surface of the second film 104 on the side opposite to the first film 102 lying on the support 220. However, as shown in FIG. 3, an embodiment in which the frame 220 is disposed between the first film 102 and the second film 104 is also conceivable. In such an embodiment, portions of the first and second films extending radially outward from the bond 122 extending along the periphery of the film may be opened, and the frame may be positioned between the films at a location disposed radially outward from the peripheral bond of the film. And as described above, the first and second films may be coupled to the frame using any suitable bonding method. Although the figure shows a specific angular direction of the frame, the film, and the underlying support, of course, any suitable orientation of these components may be used and the present disclosure is not limited as described above. In any case, the frame can still serve to maintain the desired transverse dimension of the film when removed from the underlying support.

[0066] Figures 4A-4B show an embodiment of a macroencapsulation device after the membranes have been attached to the corresponding frames and before a desired material, such as a cell population, is filled. Specifically, as illustrated in the figures, the macroencapsulation device can include a first membrane 102, a second membrane 104, and a frame 220 extending along at least a portion of the perimeter of the first and second membranes. The device is illustrated in an unfilled and slack state. In this state, the surface area of the first and second membranes is excessive relative to the cross-sectional area of the frame to which the membranes are attached, resulting in slack within the resulting membranes and causing the joined membranes to hang down below the frame. Since the joining portions 122, through-holes 132, and other suitable features disposed within the interior region of the device are already formed on the membranes, a desired material (e.g., a cell population) can be easily filled into the macroencapsulation device with minimal further processing and handling. The internal volume can be filled using ports, openings in the peripheral junctions, and / or any other suitable method. In any 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 and take up the slack within the membranes. This is because the membranes are placed under tension in the filled configuration due to the expansion of the internal volume between the membranes. As a result, the first and second membranes deform and the membranes can generally extend in a direction substantially parallel to the plane of the frame 220 (see Figure 4C). Correspondingly, due to the increase in the internal volume of the filled device in this manner, the first and second membranes can extend outwardly from the opposing faces of the frame by approximately equal distances. In a situation where a portion 132 of the membranes are joined to each other at locations radially inward of the frame, the expanded structure again forms a plurality of interconnected channels 126.

[0067] It can be filled into the macroencapsulation device 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 through the use of a sealable or removable port extending into the internal volume, and / or by the presence of an opening that can be subsequently sealed within the surrounding bond and / or frame of the macroencapsulation device. Materials can be flowed into the internal volume of the device using any suitable inlet to the internal volume, and the flow of this material can be controlled in many different ways to achieve the desired filling of the internal volume. For example, in one embodiment, applying pressure to the internal volume of the macroencapsulation device can correspond to the presence of a desired amount of tension within the membrane of the device in the filling configuration. Thus, filling the device can 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 present disclosure is not limited as described above. This can include the following. For example, control based on the absolute volume of the 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 certain embodiments of a support 200 that can be used during attachment of a frame to a film held on a support. The support can include a curved support surface 206 that is used to support the active diffusible portions of the film laminate during the frame attachment process. In the illustrated embodiment, the support surface is a spherical dome, although other suitable shapes can be used for the support surface as described above. The support surface can be used to support and deform the film disposed thereon as previously described in connection with FIGS. 2A - 2E. The support can also include a corrugated surface that extends along the perimeter of the primary curved support surface. For example, the corrugated surface can include a plurality of alternating ridges 202 and valleys 204 that extend radially outward from adjacent portions of the curved support surface. In some cases, the ridges can extend vertically upward above adjacent portions of the curved support surface, and the valleys can extend vertically downward below adjacent portions of the curved support surface. However, different vertical arrangements of the ridges and valleys with respect to adjacent curved support surfaces are also contemplated. In any case, the corrugated surface, whose height varies along its length, can extend at least partially (entirely in the illustrated embodiment) along the perimeter of the adjacent curved support surface. As will be described in more detail in the following examples, this corrugated surface can guide a portion of the film laminate into a desired folded, pleated, corrugated, or otherwise deformed configuration and can help handle excess material of the film at this location during the frame attachment process.

[0069] In the foregoing embodiment, the vertical direction of the support can be defined as upward with respect to the base of the support that lies beneath the curved support surface.

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

[0071] Example: Manufacture of a Macroencapsulation Device

[0072] FIGS. 6A-6B illustrate the use of a support 200 similar to that described above in connection with FIGS. 5A-5D. Again, in this case, 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 perimeter of the curved support surface. A laminate 214 of the bonding film is disposed on the support surface such that the outer portions of the film extend over the ridges and valleys of the corrugated surface. Since the size of the film at this location 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 outwardly onto the corrugated surface but is deformed to conform to the shape of the ridges and valleys of the corrugated surface and can accommodate the presence of this excess material. The deformation of the film laminate can be performed using a vacuum applied to one or more portions of the film by the vacuum connection 208 of the support, but other fixing methods such as mechanical clamping, temporary adhesives, and other suitable methods can also be used. In any case, the film laminate is deformed into a folded, pleated, wrinkled, corrugated, or otherwise deformed shape to deform the film from a first larger region to a second smaller region within the cross-section of the system and can account for the size mismatch described above. Due to the periodic nature of the corrugated surface, such a deformation of the film laminate into a smaller region can be arranged along the perimeter of the film laminate. Once properly positioned and held in a deformed configuration on the support, a frame 220 can be disposed on the surface in the illustrated embodiment. The frame contacts portions of the film disposed on a plurality of ridges extending around the curved support. The subsequent bonding process as described above can then be performed to bond the frame to the film laminate.

[0073] Figures 7A - 7B are photographs of a macroencapsulation device manufactured using the same processes as described above. The device is in a relaxed state before being filled with cells, and visibly deformed regions (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 includes an array of channels disposed between bonding portions (indicated by indented dots) formed on the first and second membranes. Figure 7B clearly shows channels 126 and bonding portion 124.

[0074] Example: Device Filling

[0075] Figures 8A - 8B are scanning electron micrographs of two cross - sectioned macroencapsulation devices with different amounts of membrane slack (i.e., the frame undersize is 5% and 10% relative to the corresponding size of the membrane). The devices were filled with 150 - μm beads. The size of the beads represents the average diameter of human pancreatic islets, and the chamber height of the filled devices was measured. As shown, the first device shown in Figure 8A, corresponding to a 5% frame undersize, contained fewer beads than the second device shown in Figure 8B, corresponding to a 10% frame undersize. Also, the first device corresponded to a smaller chamber height compared to the second device. Thus, both the chamber height and the fill volume are larger for devices with a greater degree of frame undersize relative to the corresponding attached membrane. Additionally, an attempt was made to fill a device with 0% membrane slack. The device could not be filled, and it was confirmed that if the membrane is attached in a relaxed configuration with some slack, it may be easier to fill the device with cells or other materials.

[0076] Example: Various Frame Sizes

[0077] FIG. 9 is an explanatory diagram of the concept of film slack, where a film of a predetermined size is mounted on frames of different diameters. As shown, the diameter of the paired films joined (for example, joining the first and second films around their perimeter) is 42.3 mm, and it is mounted on frames of various sizes (for example, diameters of 42.3 mm, 40.2 mm, 38.3 mm). The degree of undersizing of the frame was calculated as the ratio of the difference in diameter between the film and the surrounding frame to the diameter of the film laminate. Undersizing of the frame by degrees of 0%, 5%, and 10% corresponded to surrounding frames of 42.3 mm, 40.3 mm, and 38.3 mm, respectively. In order to accommodate the excessive surface area of the membrane module when mounting the membrane on the undersized frame, an increase in the degree of film slack (i.e., sagging of the film) was observed as the degree of undersizing of the frame increased relative to the size of the film.

[0078] Example: Internal Volume Dimension 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, the macroencapsulation device 300A of Figure 10A was modeled using a smaller amount of undersizing compared to the macroencapsulation device 300B of Figure 10B. Similar to the previous embodiments, the device may include a first membrane 104 and a second membrane 104, which are joined along their perimeter to form an internal volume 250 between the membranes. The illustrated device also includes a joining portion 124, and a through hole 132 is disposed within the central portion of the membrane disposed within a frame (not shown). Mathematical modeling was used to determine the membrane structure when filled to a membrane of a predetermined tension under equilibrium conditions. The determined chamber height H associated with 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 generally located, as illustrated. It was observed that the device 300A of Figure 10A with a smaller degree of frame undersizing has a smaller chamber height after filling compared to the device 300B of Figure 10B with a larger degree of undersizing and correspondingly a larger amount of membrane slack or sag.

[0080] Example: Control of Device Structure

[0081] Although not bound by theory, by controlling the degree of undersize of the frame relative to the size of the corresponding membrane, the chamber height and the total internal volume of the channels formed within the device can be controlled. Similarly to the foregoing, a membrane with a diameter of 42.3 mm can be mounted on frames with various diameters, and channels with a 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 characteristics of the channels (e.g., channel spacing, channel diameter). And the internal volume and chamber height were predicted at filling equilibrium. The prediction was made by the difference in surface area when a bound membrane mounted under tension was compared to a loose mounting state obtained by reducing the surface area corresponding to the dimensions of the frame. As shown in the table below, both the chamber height and the total internal volume increased with a decrease in the diameter of the frame. This corresponds to an increase in the mismatch between the areas of the membrane and the frame and an increase in the amount of sagging of the membrane before filling.

Table 1

[0082] Although the present teachings have been described in connection with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings include various alternatives, modifications, and equivalents, as will be apparent to those skilled in the art. Accordingly, the foregoing description and drawings are merely illustrative.

Claims

1. A macroencapsulation device for containing a cell population, wherein the macroencapsulation device comprises: a first membrane; a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along the periphery of the first membrane and the second membrane to form an internal volume therebetween, and the first membrane and / or the second membrane is semi-permeable; a frame extending along at least a part of the periphery of the first membrane and the second membrane, wherein the surface area of the first membrane and / or the second membrane is larger than the cross-sectional area of the frame to which the first membrane and the second membrane are attached; and a part of the first membrane and the second membrane connected to the frame includes a plurality of locations disposed around the frame, and at the plurality of locations, the first membrane and the second membrane are deformed from a first larger area to a second smaller area.

2. The macroencapsulation device according to claim 1, wherein the frame extends entirely around the first membrane and the second membrane.

3. The macroencapsulation device according to any one of claims 1 or 2, wherein the first membrane and the second membrane are configured to block the movement of the cell population out of the device.

4. The macroencapsulation device according to claim 3, further comprising the cell population disposed within the internal volume.

5. The macroencapsulation device according to any one of claims 1 to 4, wherein the internal volume includes a plurality of channels.

6. The macroencapsulation device according to claim 5, further comprising a plurality of connecting portions of the first membrane and the second membrane disposed radially inward from the frame, the plurality of connecting portions forming the plurality of channels, and at least some of the plurality of connecting portions having through holes therethrough.

7. The macroencapsulation device according to any one of claims 1 to 6, wherein the first membrane and / or the second membrane is sintered.

8. The macroencapsulation device according to any one of claims 1 to 7, wherein the first membrane and / or the second membrane includes a hydrophilic coating.

9. A macroencapsulation device for containing a cell population, wherein the macroencapsulation device comprises: a first membrane; a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along the periphery of the first membrane and the second membrane to form an internal volume therebetween, and the first membrane and / or the second membrane is semi-permeable; a frame extending along at least a portion of the periphery of the first membrane and the second membrane, 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 a region of the portion of the first membrane and the second membrane in an undeformed configuration; comprising; a portion of the first membrane and the second membrane connected to the frame includes a plurality of locations disposed around the frame, at which locations the first membrane and the second membrane are deformed from a first, larger region to a second, smaller region. **Claim 10** The macroencapsulation device according to claim 9, wherein a surface area of the first membrane and / or the second membrane is larger than a cross-sectional area of the frame to which the first membrane and the second membrane are attached. **Claim 11** The macroencapsulation device according to any one of claims 9 to 10, wherein the frame extends entirely around the first membrane and the second membrane. **Claim 12** The macroencapsulation device according to any one of claims 9 to 11, wherein the first membrane and the second membrane are configured to prevent movement of the cell population out of the device. **Claim 13** The macroencapsulation device according to claim 12, further comprising the cell population disposed within the internal volume. **Claim 14** The macroencapsulation device according to any one of claims 9 to 13, wherein the internal volume includes a plurality of channels. **Claim 15** The macroencapsulation device according to claim 14, further comprising a plurality of joining portions of the first membrane and the second membrane disposed radially inward of the frame, the plurality of joining portions forming the plurality of channels, and at least some of the plurality of joining portions including through-holes therethrough. **Claim 16** The macroencapsulation device according to any one of claims 9 to 15, wherein the first membrane and / or the second membrane is sintered.

17. The macroencapsulation device according to any one of claims 9 to 16, wherein the first membrane and / or the second membrane comprises a hydrophilic coating.

18. A method of forming a macroencapsulation device, the macroencapsulation device being for containing a cell population, the method comprising: deforming a first membrane and a part of a second membrane disposed on the first membrane in a direction out of the plane of the first membrane and the second membrane; deforming the first membrane and the second membrane from a first larger region to a second smaller region at a plurality of locations disposed around the first membrane and / or the second membrane; connecting a frame to the second membrane and / or the first membrane while the part of the first membrane and the second membrane is deformed out of the plane, the frame restricting the maximum transverse dimension of the macroencapsulation device, and the first membrane and / or the second membrane being semi-permeable; A method comprising.

19. A method of forming a macroencapsulation device, the macroencapsulation device being for containing a cell population, the method comprising: deforming a first membrane and a part of a second membrane disposed on the first membrane in a direction out of the plane of the first membrane and the second membrane; connecting a frame to the second membrane and / or the first membrane while the part of the first membrane and the second membrane is deformed out of the plane, the frame restricting the maximum transverse dimension of the macroencapsulation device, and the first membrane and / or the second membrane being semi-permeable; comprising, wherein deforming the part of the first membrane and the second membrane out of the plane comprises disposing the surface of the first membrane on the side opposite the second membrane on a curved support.

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

21. The method according to any one of claims 18 to 20, wherein the first membrane and the second membrane are configured to block the movement of the cell population out of the device.

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

23. The method according to any one of claims 18 to 22, wherein the first membrane and / or the second membrane is sintered.

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

25. The method according to claim 19, wherein the curved support includes a spherical dome.

26. The method according to any one of claims 19 or 25, further comprising maintaining the first membrane and the second membrane adjacent to the curved support by applying a vacuum to one or more non-diffusive portions of the first membrane and the second membrane.

27. The method according to claim 26, wherein the non-diffusive portion is disposed radially outward from an internal volume disposed between the first membrane and the second membrane.

28. The method according to any one of claims 18 to 27, further comprising forming a plurality of channels therebetween by joining one or more portions of the first membrane and the second membrane before connecting the frame to the second membrane.

29. The method according to claim 28, further comprising forming one or more through-holes in the one or more joined portions before connecting the frame to the second membrane.

30. A method of forming a macroencapsulation device, the macroencapsulation device being for accommodating a cell population, the method comprising: deforming an outer peripheral portion of a first membrane and a second membrane disposed 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; deforming the first membrane and the second membrane from a first larger region to a second smaller region at a plurality of locations disposed around the first membrane and / or the second membrane; limiting the maximum cross-sectional dimension of the first membrane and the second membrane to the second maximum cross-sectional dimension by connecting a frame to the second membrane and / or the first membrane, wherein the first membrane and / or the second membrane is semipermeable; and including.

31. A method of forming a macroencapsulation device, the macroencapsulation device being for accommodating a cell population, the method comprising: deforming an outer periphery of a first membrane and a second membrane disposed 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; limiting the maximum cross-sectional dimensions of the first membrane and the second membrane to the second maximum cross-sectional dimension by connecting a frame to the second membrane and / or the first membrane, wherein the first membrane and / or the second membrane is semi-permeable; comprising: Deforming the outer periphery of the first membrane and the second membrane from a first maximum cross-sectional dimension to a second maximum cross-sectional dimension smaller than the first maximum cross-sectional dimension includes disposing a surface of the first membrane on the side opposite to the second membrane on a curved support. The method.

32. The method according to claim 30 or 31, wherein a surface area of the first membrane and / or the second membrane is larger than a cross-sectional area of a frame to which the first membrane and the second membrane are attached.

33. The method according to any one of claims 30 to 32, wherein the first membrane and the second membrane are configured to block movement of the cell population out of the device.

34. The method according to any one of claims 30 to 33, further comprising filling the internal volume of the device with the cell population.

35. The method according to any one of claims 30 to 34, wherein the first membrane and / or the second membrane is sintered.

36. The method according to any one of claims 30 to 35, further comprising coating the first membrane and / or the second membrane with a hydrophilic material.

37. The method according to claim 31, wherein the curved support includes a spherical dome.

38. The method according to any one of claims 31 or 37, further comprising maintaining the first membrane and the second membrane adjacent to the curved support by applying a vacuum to one or more non-diffusive portions of the first membrane and the second membrane.

39. The method according to claim 38, wherein the non-diffusive portion is disposed radially outward from an internal volume disposed between the first membrane and the second membrane.

40. The method according to any one of claims 30 to 39, further comprising forming a plurality of channels therebetween by bonding one or more portions of the first membrane and the second membrane before connecting the frame to the second membrane. **Claim 41** The method according to claim 40, further comprising forming one or more through holes in the one or more bonding portions before connecting the frame to the second membrane.

Images