Large capsule device

Abstract

The present disclosure relates to large capsule devices and related methods of manufacture in which a membrane of the device can be mounted to an associated frame in a loose or relaxed configuration prior to filling of a desired material.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of August 30, 2024, application number 202080029693.0, and invention name “Large Capsule Device”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 828,915, filed April 3, 2019, under 35 U.S.C. 119(e), the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] The disclosed embodiments relate to macrocapsule devices and methods of making the same. Background Art

[0005] Therapeutic devices that deliver biological products can be used to treat metabolic disorders, such as diabetes. Therapeutic devices can be implanted to provide biological products, such as insulin, over an extended period of time. Some of these devices include large capsule devices for containing cells for producing the desired biological product, a matrix containing the cells, or other desired therapeutic agents. Summary of the invention

[0006] In one embodiment, a macrocapsule device for containing a cell population comprises a first membrane and a second membrane disposed on the first membrane. The first membrane and the second membrane are combined 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 are semi-permeable. The device also includes a frame extending along at least a portion of the periphery of the first membrane and the second membrane, and the surface area of ​​the first membrane and / or the second membrane is greater than the cross-sectional area of ​​the frame in which the first membrane and the second membrane are mounted.

[0007] In another embodiment, a macrocapsule device for accommodating a cell population comprises a first membrane and a second membrane disposed on the first membrane. The first membrane and the second membrane are combined 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 are semi-permeable. The device also includes a frame extending along at least a portion of the periphery of the first membrane and the second membrane, and portions of the first membrane and the second membrane connected to the frame are deformed to fit within an area of ​​the frame that is smaller than the area of ​​the portions of the first membrane and the second membrane in an undeformed configuration.

[0008] In another embodiment, a method of forming a large capsule device includes: deforming a first membrane and a portion of a second membrane disposed on the first membrane in a direction out of the plane of the first membrane and the second membrane; and connecting a frame to the second membrane and / or the first membrane while the portions of the first membrane and the second membrane are deformed out of the plane, wherein the frame limits the maximum lateral dimension of the large capsule device, wherein the first membrane and / or the second membrane are semi-permeable.

[0009] In yet another embodiment, a method of forming a large capsule device includes: deforming an outer periphery 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 limit the maximum transverse dimension of the first membrane and the second membrane to the second maximum transverse dimension, wherein the first membrane and / or the second membrane is semi-permeable.

[0010] It should be understood that the aforementioned concepts and the additional concepts discussed below can be arranged in any suitable combination, as the present disclosure is not limited in this regard. In addition, other advantages and novel features of the present disclosure will become apparent through the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.

[0011] In the event that this specification and the documents incorporated by reference include conflicting and / or inconsistent disclosures, this specification shall prevail. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosures, the document with the later effective date shall prevail. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component shown in various figures may be represented by the same number. For clarity, not every component is labeled in every drawing. In the drawings:

[0013] Figure 1A shows a first film and a second film disposed in a fixture during a bonding and cutting process according to one embodiment;

[0014] Figure 1B Show Figure 1A A top view of

[0015] Figure 1C illustrates a process of combining a first film and a portion of a second film in a fixture according to one embodiment;

[0016] Figure 1D shows the membrane in a fixture after bonding according to one embodiment;

[0017] Figure 1E Show Figure 1D A top view of

[0018] Figure 1F shows a process of introducing through holes in a film while positioned in a fixture according to one embodiment;

[0019] Figure 1G Show the obtained Figure 1F A through hole formed in the film;

[0020] Figure 1H illustrates a process of cutting away a portion of a bonding membrane while in a fixture according to one embodiment;

[0021] Fig. 1I illustrates the process of removing a cut-away portion of a film from a fixture according to one embodiment;

[0022] Figure 1J Show Fig. 1I A top view of the removed film;

[0023] Figure 2A illustrates a process of positioning a membrane stack onto a curved support according to one embodiment;

[0024] Figure 2B shows a membrane stack disposed on a curved support according to one embodiment;

[0025] Figure 2C shows a process of positioning a frame on a membrane stack after positioning on a curved support according to one embodiment;

[0026] Figure 2D shows a frame disposed on a surface of a second film after being positioned on a film stack according to one embodiment;

[0027] Figure 2E shows a process of bonding a frame to a second film according to one embodiment;

[0028] Figure 3 showing a frame positioned between a first film and a second film according to one embodiment;

[0029] Figure 4A shows a side view of a large capsule device according to one embodiment before loading;

[0030] Figure 4B Show Figure 4A A top view of a large capsule device;

[0031] Figure 4C Show Figure 4A A side view of a macrocapsule device after loading with a desired material;

[0032] Figure 5A A schematic diagram showing a curved support according to one embodiment;

[0033] Figure 5B Show Figure 5A A top view of a curved support member;

[0034] Figure 5C Show Figure 5A A cross-sectional view of a center plane of a curved support member;

[0035] Figure 5D Show Figure 5A A cross-sectional view of a side plane of a curved support member;

[0036] Fig. 6A An image showing a membrane stack disposed on a curved support according to one embodiment;

[0037] Figure 6B An image showing a frame mounted on a membrane stack arranged on a curved support according to one embodiment;

[0038] Fig. 7A This is a photo of the macrocapsule device before it is loaded with cells;

[0039] Figure 7B yes Fig. 7A A photograph of a portion of the large capsule device;

[0040] Fig. 8A a scanning electron micrograph showing a cross-section of a first macrocapsule device filled with beads and having a first amount of membrane relaxation;

[0041] Figure 8B Scanning electron micrograph showing a cross-section of a second large capsule device filled with beads and having a second amount of membrane relaxation;

[0042] Fig. 9 is a schematic diagram of the relative change of membrane relaxation with the change of frame size;

[0043] Fig. 10A a schematic diagram showing a cross-section of a portion of a first exemplary large capsule device having a first amount of membrane relaxation during installation after filling; and

[0044] Fig. 10B A schematic diagram showing a cross-section of a portion of a second exemplary large capsule having a second amount of relaxation during installation after filling. DETAILED DESCRIPTION

[0045] In the delivery of biological products to treat metabolic disorders (such as diabetes) driven by the growing demand, different types of implantable therapeutic devices have been designed. However, the inventors have recognized that the typical methods for manufacturing such devices are usually cumbersome and difficult to control. For example, when forming specific structural features associated with the device (e.g., compartment height and volume), accuracy and control are often lacking. In addition, the inventors have recognized that it is usually difficult to controllably fill these devices with interested biological entities (e.g., cell groups) to desired density and / or do not cause excessive cell death and / or cell mass formation.

[0046] In view of the above, the inventors have recognized the benefits associated with the following large capsule device, in which the relative size and arrangement of the membrane and frame of the device can be controlled to change one or more parameters of the resulting large capsule device. For example, the relative size of the membrane and the associated frame can provide a simple and easily controlled method for producing large capsule devices with a range of different sizes and / or operating parameters as detailed below. This may include controlling the amount of relaxation of the membrane held in the frame prior to loading a desired therapeutic agent (such as a cell population).

[0047] The above-mentioned general concept of controlling the amount of slack in the membrane during installation with a frame is interchangeably referred to herein as slack installation or installed slack. This concept can refer to installing at least two or more layers of flexible membranes (e.g., a first membrane and a second membrane) under controlled slack tension to form a device including an internal compartment having a defined volume and / or height when filled. By adjusting the membrane slack during the slack installation process, a device with a set of desired geometric properties can be manufactured to accommodate a cell population. For example, in some embodiments, the membrane slack during the slack installation process can be controlled by a combination of the degree of deformation introduced into the membrane during manufacturing and the mechanical constraints applied to the membrane (e.g., using a peripheral frame to limit the maximum lateral dimension of the membrane relative to the total surface area of ​​the membrane), as further described below.

[0048] In some embodiments, during the manufacturing process of the large capsule device, at least one (and in some cases, at least two or more) flexible membrane of the device can be deformed to at least partially fit within a frame and then be coupled to the frame to form the large capsule device. The frame can hold the membrane in a desired configuration, wherein the membrane has a desired amount of slack extending between opposing portions of the frame. For example, in one embodiment, before being coupled to the frame, the outer periphery of the first membrane and the second membrane disposed on the first membrane can be deformed from a first maximum transverse dimension to a second maximum transverse dimension less than the first maximum transverse dimension. This deformation and subsequent retention of the membrane in a deformed configuration can result in the membrane being retained in the frame with a desired amount of slack to accommodate excess material contained within the frame, and can be achieved in a variety of different ways.

[0049] In one embodiment, the frame can be used to limit the maximum transverse dimension of the first and second films to a maximum transverse dimension that is less than the maximum transverse dimension of the film in an undeformed configuration. Specifically, the frame can be connected to the second film and / or the first film when a portion of the first and second films (such as a central portion) is deformed out of plane relative to the plane in which the film extends in a flat configuration. Then, once the force that deforms the film out of the plane is removed, the frame can limit the maximum transverse dimension of the large capsule device. Therefore, the frame can cause the surface area of ​​the first film and / or the second film to be greater than the second maximum transverse dimension, which causes relaxation in the film between the opposing parts of the frame.

[0050] As mentioned above, when the frame is connected to the deformed membrane of the large capsule device during the manufacturing process, the frame can keep the part of the membrane in the deformed configuration to provide the desired relaxation amount in the membrane. For example, the first membrane and the second membrane can be combined along the periphery of the membrane. This combined part of the membrane is deformable to be assembled in the framework, and the framework is combined to at least a part of the periphery of the first membrane and / or the second membrane and extends along it, but the framework can also extend along the entire periphery of the membrane in some embodiments. Specifically, the part of the first membrane and the second membrane connected to the frame is deformable to be assembled in the area of ​​the framework, and the area is less than the area of ​​the part of the first membrane and the second membrane in the undeformed state. Specifically, in order to realize the desired membrane relaxation amount in the device, the frame with a maximum transverse dimension less than the transverse dimension of the membrane in the undeformed state can be connected to the membrane. In this embodiment, the part of the first membrane and the second membrane connected to the frame can include a plurality of positions arranged around the periphery of the frame, and at the plurality of positions, the first membrane and the second membrane are deformed to adapt to the reduction of the area. For example, in some embodiments, the deformed portions of the membrane may include wrinkles, folds, corrugations, plastically deformed or thermally deformed portions, and / or any other suitable type of deformation capable of accommodating a change in area of ​​these portions of the membrane from a first larger area to a second smaller area.

[0051] According to the desired configuration, the framework of the large capsule device can be arranged at different positions of any number of different films relative to the device. For example, in one embodiment, the framework can be connected to the outer surface of one of the outer films of the device. In such an embodiment, the first film can be arranged on the second film, and the framework can be arranged on the outer surface of the second film opposite to the first film and connected thereto. In another embodiment, the framework can be connected to both the first film and the second film, so that the framework is positioned between the films at a part of the film, and the part of the film can be close to at least a part of the periphery of the first film and the second film or otherwise extend along it. Therefore, it should be understood that the present invention is not limited to any specific positioning of the framework relative to the respective films of the device.

[0052] In some embodiments, for a given film size and a corresponding frame size, the volume and height associated with one or more parts of the internal volume of the large capsule device can be controlled by adjusting the film slackness (i.e., relaxation) of the first and second films. The amount of slack present in the film before filling with cells can be related to the difference between the surface area of ​​the first and second films and the corresponding cross-sectional area of ​​the frame to which the film is installed during the installation process (which can also be referred to as the relative mismatch of the area size of the film and the frame). The relative differences in these areas and the resulting slack in the installed film can be controlled by adjusting the size of the frame relative to the size of the film. For example, the cross-sectional area of ​​the frame can be less than the corresponding surface area of ​​the film held in the frame. Therefore, the larger amount of slack in the film can be related to the larger difference in the film surface area relative to the cross-sectional area of ​​the frame in which the film is installed. On the contrary, the smaller amount of slack can be related to the smaller difference in the film surface area relative to the cross-sectional area of ​​the frame.

[0053] In view of the above, the surface area of ​​one or more membranes installed in the frame may be greater than the cross-sectional area of ​​the frame in which the one or more membranes are installed. The surface area of ​​one or more membranes may include the portion of the membrane that is combined together in the inner portion of the membrane, and the inner portion of the membrane is arranged on the radial inner side of the associated frame or otherwise arranged in the associated frame. In addition, the surface area of ​​one or more membranes may be a certain percentage larger than the cross-sectional area of ​​the frame, and the percentage is greater than or equal to 1%, 2%, 3%, 4%, 5%, 10%, 20% and / or any other appropriate percentage. Correspondingly, the surface area of ​​one or more membranes may be a certain percentage larger than the cross-sectional area of ​​the frame, and the percentage is less than or equal to 30%, 20%, 10%, 5% and / or any other appropriate percentage. It is contemplated that the aforementioned combination, including, for example, the surface area of ​​one or more membranes is greater than the cross-sectional area by a percentage between or equal to 1% and 30%. Of course, it is also contemplated that the percentage is greater than and less than those mentioned above, because the present disclosure is not limited in this way.

[0054] Similar to the above, the portion of one or more membranes that is deformed in the direction out of the membrane plane during the process of being mounted to the frame can be deformed by any appropriate amount so as to provide the desired amount of relaxation in the membrane once it is mounted to the frame. In some embodiments, this out-of-plane deformation may correspond to an out-of-plane deformation that will cause the projected two-dimensional area of ​​the membrane to be reduced by a certain percentage relative to the flat planar configuration of the membrane, and the percentage is greater than or equal to 0.3%, 0.5%, 1%, 2%, 3% and / or any other appropriate percentage. Correspondingly, the deformation may cause the projected two-dimensional area of ​​the membrane to be reduced by a certain percentage, and the percentage is less than or equal to 7.5%, 7%, 6%, 5%, 4%, 3% and / or any other appropriate percentage. It is contemplated that the aforementioned combination includes, for example, a range between or equal to 0.3% and 7.5%. In addition, in some embodiments, this deformation may correspond to an out-of-plane deformation between or equal to about 1mm and 10mm in the direction out of the plane of the membrane in a planar flat configuration. Of course, for different frames and membrane sizes, it is expected that the specific deformation range will change. In either case, ranges greater and less than those recited above are contemplated for the percent change in area and / or the absolute amount of deformation, as the present disclosure is not limited in this manner.

[0055] In certain embodiments, the film deformation of the device during the installation of the frame can be assisted by using a support, and the stacked film can be arranged on the support during the frame installation process. The support can extend within at least a portion of the area of ​​the film arranged thereon, and in some cases extend within the entire area. The specific profile of the adjustable support is to control the degree of film deformation. For example, the stacking of two or more films can be arranged on a curved support or other support of suitable shape, and the support can make the film stack arranged thereon deform in a desired manner. The curved support can also have any suitable shape, including but not limited to a sphere, a spherical dome, a cylinder, a partial cylinder, an ovoid, a partial ovoid and / or any other suitable shape that can provide a desired deformation to the film stack arranged thereon or at least partially arranged thereon. In either case, the first film and the second film of the large capsule device are arranged on the support so that a part of the film stack can be deformed in the direction outside the plane of the first film and the second film, so that the film is deformed from the larger first maximum transverse dimension associated with the film in the undeformed planar configuration to the smaller second maximum transverse dimension associated with the film in the deformed state (such as the flexure or bending configuration of the film). The frame may then be mounted to the membrane while maintaining the membrane in the modified configuration.

[0056] Although the above describes the use of curved supports to deform the film stack, the present disclosure is not limited to the use of only curved supports. For example, in some embodiments, the method of deforming the first and second films from a first maximum lateral dimension to a second smaller maximum lateral dimension for mounting a frame thereon may include deforming the films using thermoforming, mechanical deformation, and / or any suitable method that is capable of mounting the frame to the films in a desired configuration while maintaining at least a desired portion of the films extending between the frame in a flexible configuration having a desired amount of slack.

[0057] In certain embodiments, it may be desirable to maintain the stack of two or more films in a desired position and / or orientation on an underlying support. Although this can be done in any appropriate manner, in one embodiment, the support may be configured to apply vacuum suction to one or more portions of the film stack to maintain the film near the support. In order to avoid the diffusion portion of the large capsule device being compacted, a vacuum may be applied to one or more non-diffusion portions of the film. For example, the non-diffusion portion of the first film and the second film may include a bonding area (e.g., the periphery of the bonding of the first film and the second film and / or the internal portion of the bonding) and / or a portion of the film located outside the active area of ​​the device (e.g., at the radially outer side of the bonding portion extending around the periphery of the device forming the internal volume of the device). Therefore, a vacuum may be applied at a position located at the radially outer side of the internal volume between the first film and the second film or other suitable non-diffusion portions of the film.

[0058] As mentioned above, the large capsule device can include multilayer membranes. At least one outer membrane in this multilayer membrane can be semi-permeable. However, it is also envisioned that each film is semi-permeable or at least one film in the device is substantially impermeable. In addition, the device can include two stacked films, three stacked films and / or any other appropriate number of films, because the present disclosure is not limited in this way. For example, in an embodiment comprising two films, either a film can be semi-permeable and another is impermeable, or both films can be semi-permeable. Therefore, it should be understood that the present disclosure is not limited to any specific combination of the film in the stacked structure.

[0059] In some embodiments, the macrocapsule device may include at least one cell group arranged in the internal volume of the device. For example, the cell group may be arranged in the internal volume between two or more relative external membranes formed in the device, wherein the outer edge of the internal volume may be limited by one or more joints extending around the periphery of the membrane or other appropriate parts of the membrane. In such embodiments, at least the external membrane of the device may be constructed to prevent one or more cell groups from leaving the device. Therefore, one or more cell groups may remain in the internal volume of the device. Of course, although it is pointed out that two external membranes are used to form a single internal volume, it is also envisioned to use multiple intermediate membranes positioned between the external membranes of the device and / or multiple unconnected internal volumes in the device.

[0060] In addition to retaining the cell population inside the device, in some embodiments, the membrane of the device can be configured to protect one or more cell populations disposed inside the device from immune attack while allowing the passage of desired biological products produced by the cells (such as insulin) and waste and nutrients used and produced by the cells. In some embodiments, the membrane is configured to protect the cells from immune attack in the absence of immunosuppressive therapy.

[0061] The membrane of the macrocapsule device can be formed by any suitable biocompatible material. The biocompatible material can be substantially inert to the cells and surrounding tissues contained in the macrocapsule device. The biocompatible material can include synthetic polymers or naturally occurring polymers. In some embodiments, the polymer can also be a linear polymer, a cross-linked polymer, a network polymer, an addition polymer, a condensation polymer, an elastomer, a fiber polymer, a thermoplastic polymer, a non-degradable polymer, a combination of the foregoing and / or any other suitable type of polymer, because the present disclosure is not limited in this manner. Suitable types of polymers may include polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), polystyrene (PS), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyurethane (PU), polyamide (nylon), polyethylene terephthalate (PET), polyethersulfone (PES), polyetherimide (PEI), polyvinylidene fluoride (PVDF), polycaprolactone (PCL), poly (lactic acid-co-glycolic acid) (PLGA), poly-L-lactide (PLLA), any combination of the foregoing and / or any other suitable polymer material. Synthetic methods for forming one or more porous membranes from the above polymer materials may include, but are not limited to, expansion, solvent casting, impregnation precipitation and phase separation, electrospinning, methods for producing iso-reticular networks, methods for producing trabecular networks, or any other suitable methods for forming porous polymer membranes.

[0062] The sintering of film can be used to change the porosity and flux characteristics of film. For example, sintering can increase the porosity of film while maintaining its pore structure. Sintering can also improve the mechanical stability and diffusion flux of film. Therefore, sintering can be used to change the porosity and / or mechanical characteristics of film, which in turn can be used to tune the porosity and flux characteristics of large capsule device. Therefore, in some embodiments, any desired combination of sintered and / or unsintered film can be used. For example, two outer films of device can be combined together, wherein sintered film and unsintered film are combined together, two sintered films are combined together, or two unsintered films are combined together. In addition, any number of intermediate films positioned between these outer films can be used, wherein these intermediate films can be sintered or unsintered.

[0063] The membrane of a macrocapsule device as described herein can be made of a porous membrane material that is configured to allow a material (such as a biological product) to be transported through the membrane, and the molecular weight of the material is less than about 3000kDa, 2000kDa, 1000kDa, 500kDa, 400kDa, 300kDa, 200kDa, 100kDa, 50kDa, 40kDa, 30kDa, 20kDa, 10kDa, 6kDa, 5kDa, 4kDa, 3kDa, 2kDa, 1kDa and / or any other suitable range of molecular weight, depending on the desired application. For example, one or more membranes of a macrocapsule device can be configured to allow an insulin having a molecular weight of about 5.8kDa to flow through the membrane.

[0064] To provide the desired selectivity, the porous membrane used with the macrocapsule devices disclosed herein may have an open porous structure with an average pore size greater than or equal to about 1 nm, 5 nm, 10 nm, 15 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 200 nm, 300 nm and / or any other suitable size range. Correspondingly, the average pore size of various films described herein can have an average pore size less than or equal to 2500nm, 2000nm, 1700nm, 1500nm, 1400nm, 1300nm, 1200nm, 1100nm, 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, 200nm, 100nm, 90nm, 80nm, 70nm, 60nm, 50nm, 40nm, 30nm, 20nm and / or any other suitable size range. Conceive of the aforementioned combination, including, for example, between or equal to 1nm and 20nm, 1nm and 2500nm and / or any other suitable combination of average pore size. Of course, although the above describes a specific average pore size, it should be understood that any suitable average pore size can be used for various films described herein, including an average pore size greater than and less than those mentioned above.

[0065] In order to provide sufficient strength and / or rigidity for the macrocapsule device, the various membranes and frames can be made of sufficiently hard materials. The desired hardness can be provided by an appropriate combination of material Young's modulus, thickness, and overall construction, which can be balanced with the desired permeability of the device. The appropriate Young's modulus of the various membranes and frames described herein can be at least 10 5 Pa, 10 6 Pa, 10 7 Pa, 10 8 Pa, 10 9 Pa, 10 10 Pa, and / or any other suitable modulus greater than and less than these ranges. Of course, ranges between the foregoing Young's moduli are contemplated, including, for example, between or equal to about 10 6 Pa and 10 10 Young's modulus between Pa.

[0066] In some embodiments, it may be desirable that one or more membranes included in the macrocapsule device be hydrophilic to facilitate loading of cells into the macrocapsule device and / or facilitate one or more fluids, biocomplexes, therapeutic agents, cell nutrients, cell waste and / or other materials to flow through the membrane of the device. In addition, when the device is positioned in vivo, the hydrophilic outer membrane can also reduce the occurrence of fibrosis. Therefore, the membrane of the macrocapsule device can be made of a hydrophilic material and / or treated with a hydrophilic coating. Suitable hydrophilic materials can include, but are not limited to, suitable hydrophilic polymers, polyethylene glycol, polyvinyl alcohol, polydopamine, any combination thereof and / or any other suitable hydrophilic material that can form a coating on the membrane or can be made into a membrane.

[0067] The films described in the various embodiments of the large capsule device described herein can be combined with each other using any appropriate bonding method, because the present disclosure is not limited in this way. For example, adhesives, epoxy resins, welding or other technologies based on fusion (e.g., ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using a frame or a fixture, and / or any other appropriate bonding method can be used to combine adjacent films. In a specific embodiment, a heated tool can be used to combine adjacent films, and the heated tool is used to press or impact two or more films against each other with a predetermined pressure and / or force to set the fusion time. In view of the foregoing, it should be understood that the present disclosure is not limited to using any particular method to combine films together.

[0068] In some embodiments, after the films have been combined with each other, and in some cases after the frame has been attached to the film, one or more heat treatments can be applied to the stack of the combined films. For example, the films can be combined together so that the joint extends along the periphery of the film, and / or one or more joints can be formed in the inner area of ​​the film (for example, in the periphery of the combination), and then the film is heat treated. This post-combination heat treatment can enhance the combination of the film at the bonding area. The specific heat treatment temperature and duration for improving the combination between the films can vary according to the specific material used. However, in some embodiments, the heat treatment temperature can be between the glass transition temperature and the melting temperature of the polymer film.

[0069] In certain embodiments, it may be desirable to limit the maximum thickness of the large capsule device in the direction perpendicular to the plane where the maximum transverse dimension of the device is located. Therefore, one or more internal parts of the first film and the second film arranged in the framework can be combined to limit the degree that the film can be displaced relative to each other. These binding parts of the film can be evenly dispersed in the inside of the film located in the framework. These binding parts can have any suitable shape, including for example point, line, curve or any other suitable shape. Although any suitable size for the desired application can be provided in conjunction with the internal part, in an embodiment using a binding point, the diameter of the binding point can be greater than or equal to about 0.5mm, 0.75mm, 1mm, 1.25mm, 1.5mm and / or any other suitable diameter. Correspondingly, the diameter of the point can be less than or equal to about 3mm, 2.75mm, 2.5mm, 2.25mm, 2.0mm and / or any other suitable diameter. It is contemplated that the combination of the above range includes, for example, a diameter between or equal to 0.5mm and 3mm. Although specific shapes and size ranges are provided above, it should be understood that it is contemplated that other shapes and sizes less than and greater than those mentioned above can be provided, because the present invention is not limited in this way.

[0070] In some embodiments, it may be desirable to improve the vascularization of a large capsule device. Thus, in certain embodiments, one or more through holes may be formed in one or more binding portions located within an inner portion of the membrane disposed radially inward of a frame of the device. In addition to growing around the upper and lower surfaces of the device, these through holes may also allow vasculature to grow through the through holes. One or more through holes may be formed in the binding portion of the membrane using laser ablation, mechanical puncture, cutting, or any other suitable method of forming through holes in one or more binding portions of the membrane.

[0071] In some embodiments, the above-mentioned bonding portions and corresponding through holes within the interior region of the device can be formed before the frame is mounted on the device while the membrane is positioned in a flat planar configuration. This can simplify the manufacturing process when dealing with a flexible membrane that is mounted to the frame with a desired amount of slack that can complicate the formation of other features after mounting on the frame.

[0072] As described in detail below, in some embodiments, one or more portions of adjacent membranes can be joined together so that the internal volume within the device is subdivided into a plurality of interconnected channels, which in some embodiments can be shaped similar to a lumen, although any suitable shape or configuration of the channel can also be used. The channel can have an internal maximum transverse dimension greater than or equal to 40 μm, 50 μm, 100 μm, 200 μm, 300 μm, 400 μm, and / or any other suitable size, such as an inner diameter. Correspondingly, the channel can have an internal maximum transverse dimension less than or equal to 800 μm, 700 μm, 600 μm, 500 μm, 400 μm, and / or any other suitable size. Combinations of the foregoing are contemplated, including, for example, internal maximum transverse dimensions of multiple channels between or equal to 40 μm and 800 μm. In addition, the density of the interconnected channels forming the various compartments of the device can have greater than or equal to about 10 channels / cm in the transverse plane of the device. 2 , 15 channels / cm 2 , 20 channels / cm 2 , 25 channels / cm 2 , 30 channels / cm 2 , 35 channels / cm 2 , 40 channels / cm 2 , 45 channels / cm 2 , 50 channels / cm 2 , 60 channels / cm 2 , 70 channels / cm 2 , 80 channels / cm 2 , 90 channels / cm 2 , 100 channels / cm 2 , 110 channels / cm 2 , 120 channels / cm 2 , 130 channels / cm 2 , 140 channels / cm 2 , 150 channels / cm 2 , 175 channels / cm2 or 200 channels / cm 2 Also contemplated are ranges extending between any of the above channel densities, including, for example, between or equal to about 10 channels / cm 2 and 200 channels / cm 2 Although densities greater and less than the above ranges are also contemplated.

[0073] As described herein, the macrocapsule device may have any suitable combination of internal volume, external dimensions, and / or other suitable physical parameters. For example, the internal volume surrounded by the outer membrane of the macrocapsule device may be between or equal to 40 μL and 250 μL. The width or maximum lateral dimension of the macrocapsule device may also be between about 20 mm and 80 mm. In addition, in order to provide the desired oxygen diffusion to the interior of the macrocapsule device to support the cells contained therein, the maximum oxygen diffusion distance from the outside of the device to the internal portion of the device including the cell population may be less than 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm. Correspondingly, the maximum thickness or dimension perpendicular to the maximum lateral dimension of the entire device and / or the internal volume located within the device may be less than 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm. In addition, in some embodiments, the ratio of the external surface area to the volume of the device may be greater than or equal to about 20 cm -1 、40cm -1 、60cm -1 、80cm -1 、100cm -1 、120cm -1 or 150cm -1 Ranges extending between any of the foregoing values ​​of the various dimensions and parameters, as well as ranges greater and less than those recited above, are also contemplated.

[0074] Although specific dimensions, parameters, and relationships related to the macrocapsule device and its manufacturing materials are described above, it should be understood that dimensions, parameters, and relationships greater than and less than those described above are contemplated, as the present disclosure is not limited in this manner. Thus, any suitable combination of dimensions, configurations, material properties, and / or relative performance parameters may be used for the device, depending on the desired application.

[0075] In some embodiments, the cell group contained in the internal volume of the large capsule device can be an insulin secreting cell group. In some embodiments, the cell group includes at least one cell derived from stem cell derived cells. In some embodiments, at least one cell is a genetically modified cell. In some cases, compared with comparable cells that are not genetically engineered, at least one cell is genetically engineered to reduce the immune response of the subject after the device is implanted. In some embodiments, the cell group is a stem cell derived cell that can perform glucose-stimulated insulin secretion (GSIS). For example, a suitable cell group may include pancreatic progenitor cells, endocrine cells, beta cells, a matrix comprising one or more of the aforementioned cells, or any combination thereof. In addition, the matrix may include isolated islet cells, isolated cells from the pancreas, isolated cells from tissues, stem cells, stem cell derived cells, induced pluripotent cells, differentiated cells, transformed cells or expression systems, which can synthesize one or more biological products. Optionally, in some embodiments, the matrix may include a second type of cell that supports the synthesis of one or more biological products. In some embodiments, the cell can be encapsulated and then placed in the matrix. In this embodiment, the cell can be encapsulated in a microcapsule, or the cell can be conformably coated. However, naked (ie, unencapsulated) cells may also be used.

[0076] According to a specific embodiment, the cells of the effective density of treatment can be loaded into the internal volume of the large capsule device. The suitable cell density arranged in the internal volume can be greater than or equal to about 1000 cells / μL, 10,000 cells / μL, 50,000 cells / μL, 100,000 cells / μL, 500,000 and / or any other suitable cell density. The suitable cell density arranged in the compartment can also be less than or equal to about 1,000,000 cells / μL, 500,000 cells / μL, 100,000 cells / μL, 50,000 cells / μL, 10,000 cells / μL and / or any other suitable cell density. It is contemplated that the above-mentioned combination includes the cell density between about 1000 cells / μL and 1,000,000 cells / μL. Of course, it is also possible to use a cell density greater than and less than those mentioned above, depending on the desired application and the cell type used.

[0077] The large capsule device described herein can be implanted in different parts of the subject's body. In one example, the device can be implanted in the subject's body by extraperitoneal or retrorectus implantation. In other examples, the device can be placed by intraomental implantation. In another example, the device can be placed by subcutaneous implantation. In another example, the device can be placed by supra-liver implantation. In some cases, any appropriate fixation method (including, for example, applying a tissue adhesive) can be used to fix the large capsule device described herein to the implantation site in the body. Suitable tissue adhesives may include, but are not limited to, fibrin, cyanoacrylate, polyethylene glycol, albumin-based adhesives, polymer-based adhesives, and / or any other appropriate adhesives. In another example, platelet-rich plasma and / or any other appropriate fixation method can be used to fix the device, because the present disclosure is not limited in this way.

[0078] Turning to the drawings, specific non-limiting embodiments are described in further detail. It should be understood that the various systems, components, features, and methods described with respect to these embodiments may be used individually and / or in any desired combination, as the present disclosure is not limited to only the specific embodiments described herein. For clarity, the drawings are described with respect to methods and devices that include only a first outer film and a second outer film that are bonded to each other. However, it should be understood that the methods and devices described with respect to the drawings may include any number of intermediate films disposed between these outer films, as the present disclosure is not limited in this manner.

[0079] Figures 1A to 1H One embodiment of a process for bonding two or more membranes together and forming various other features on the membranes prior to mounting a frame on the membranes is depicted.

[0080] like Figure 1A to Figure 1B As shown, the first film 102 is disposed on the lower portion 106 of the fixture so that the first film 102 is directly or indirectly disposed on the surface of the lower portion of the fixture. The second film 104 is disposed on the surface of the first film 102 opposite to the lower portion of the fixture. In some embodiments, the lower portion of the fixture may include one or more sensors 110, which are distributed across the surface of the lower portion of the fixture on which the film is disposed. These sensors can be configured to sense the force, pressure and / or temperature applied to the corresponding portions of the first and second films.

[0081] Once the first film 102 and the second film 104 are properly positioned on the lower portion 106 of the fixture, the upper portion 108 of the fixture can be brought into contact with one or more portions of the second film so that both the first film 102 and the second film 104 are clamped between the upper and lower portions of the fixture or otherwise held in position therebetween. In the depicted embodiment, the first and second films are held on the flat surface of the lower fixture in a substantially flat configuration. However, embodiments are also contemplated in which the films are held in different configurations during the initial forming step. Also as shown, the upper portion 108 of the fixture includes an opening or other arrangement that leaves a central portion of the stacked first and second films uncovered or otherwise exposed for further processing. Thus, the lower and upper portions of the fixture can be configured to clamp one or more peripheral portions of the first and second films that are located radially outward of a central uncovered portion of the film that is intended to form part of a large capsule device. This arrangement of the exposed central portion of the film is Figure 1B Although a circular opening in the top portion of the clamp has been shown in the drawings, it should be understood that the present disclosure is not limited to any particular shape of the exposed portion of the membrane and / or manner of holding the membrane in place during the bonding and initial forming process.

[0082] After positioning the first film 102 and the second film 104 in the fixture, the films may undergo a number of different processes, including bonding at one or more locations. Figure 1C to Figure 1E An embodiment of a process of bonding a first film and a second film to each other is shown. Figure 1C , using a bonding tool 120 to bond the first film and the second film together in a desired position. In a specific embodiment, the bonding tool may include a heated tip, which is positioned at a desired position on the top surface of the second film and is pressed in a downward direction at a predetermined temperature and force for a predetermined duration to form a bond between the two films. The one or more sensors 110 previously mentioned and distributed around the surface of the lower portion of the clamp 106 can transmit signals to an associated processor (not described) to achieve feedback control of the bonding process. Once a bond is formed in the desired position, the bonding tool can be moved to an adjacent portion of the film that at least partially overlaps the portion of the bond that has been formed until the desired shape and size of the specific bond is formed, but different bonding methods may also be used as described above. The tool can then continue to move according to the specific application to form any number of other bonds between the two films in any number of desired positions and in any number of desired patterns. For example, as Figure 1D and Figure 1E As shown, the first and second membranes may be joined along a perimeter 122 of the active portion of the membranes intended to form an internal volume therebetween.

[0083] As in Figure 1E In some embodiments, a bonding tool may also be used to bond one or more portions 124 of the membrane that are radially inward of the resulting bonding perimeter 122. In this particular embodiment, these bonded portions that are positioned within the bonding perimeter 122 may take the form of bonding points distributed across the surface area of ​​the membrane. However, any suitable shape and / or configuration of these bonded regions may also be used. Due to the presence of these bonded regions that are radially inward of the bonding perimeter of the membrane, the internal volume formed between the membrane, once in a filtration configuration, may take the form of a plurality of interconnected channels 126 that extend between these bonded portions corresponding to the unbonded regions of the membrane.

[0084] In some cases, due to the bonding process, the bonded portions of the membranes 102 and 104 may have a substantially lower membrane permeability, so that they may be considered as non-diffusive portions of the membrane. This may include a bonded perimeter 122 and an internal bonded portion 124 of the membrane located radially inward of the bonded perimeter. In contrast, the unbonded portion of the membrane, such as the channel 126 in the depicted embodiment, may be considered as a diffuse portion of the membrane, wherein the permeability of the membrane may be significantly higher than the non-diffusive portion, and in some embodiments, may be substantially the same as the parent membrane material. In addition to the bonded portion of the membrane being considered as the non-diffusive portion of the membrane, for the purposes of this specification, the portion of the membrane located radially outward of the bonded perimeter 122 and not being directly fluidically connected to the resulting internal volume formed between the membranes may also be considered as the non-diffusive portion of the membrane.

[0085] In some embodiments, after portions of the first and second films 102 and 104 are bonded together, one or more through holes 132 may be formed in one or more bonded portions 122 and 124. For example, referring to Figure 1F to Figure 1G , a device such as a laser, a punch, a cutter, or other suitable device may be used to form a through hole 132 in one or more bonded portions of the first film 102 and the second film 104. In one particular embodiment, the through hole may be formed by laser ablation, wherein the laser removes the bonded portions of the first and second films while leaving the surrounding bonded portions of the films to act as a seal between the interior volume formed by the films and the exterior of the device.

[0086] In the case where the outer shape and size of the binding membrane are already in the final desired configuration, the binding membrane can simply move to the next step of the manufacturing process. Alternatively, in some embodiments, one or more peripheral portions of the membrane can be cut off from the membrane to provide the desired size and / or shape of the binding membrane. Figure 1H, wherein a blade 140 or other cutting device may be used to form an incision extending around the bonding perimeter 122 of the membrane. In the depicted embodiment, the blade extends through the first and second membranes and then moves relative to the membranes along any desired cutting profile around the bonding perimeter of the membranes to cut off one or more peripheral portions of the membranes held in the fixture and located radially outward of the bonding perimeter. Of course, while the figures have depicted the blade moving relative to the membranes held in the fixture, any suitable method of cutting off the peripheral area of ​​the bonding membrane to provide the desired size and shape of the bonding membrane may be used, as the invention is not limited in this manner.

[0087] Regardless of whether the cutting process is performed, after the respective desired portions of the films 102 and 104 are bonded together, the bonded films may be removed from the clamps corresponding to the upper clamp portion 108 and the lower clamp portion 106, as shown. Fig. 1I As shown. This can be done in a variety of ways, including simply opening the fixture and manually removing the binding film. Alternatively, the system can automatically pick up the film and remove it from the fixture. For example, the system can apply a vacuum to one or more non-diffusing portions of the binding film to lift it from the surface of the fixture. However, any suitable method of removing the binding film from the fixture or other device can be used, as the present disclosure is not limited in this manner.

[0088] Figure 1J , a top view of the resulting combined membrane stack is shown in . In this figure, the top surface of the second membrane 104 is shown, wherein the combined perimeter 122 of the membrane (e.g., where the first membrane and the second membrane are combined) extends around the periphery of the combined membrane. Although the combined perimeter has been shown to extend all the way to the outer edge of the membrane, it is also conceivable that an embodiment in which the combined portion extending along the periphery of the membrane is inserted from the outer edge of the membrane. The combined membrane also includes one or more combined portions 124 located radially inward of the combined perimeter. In addition, a through hole 132 may be formed in one or more combined portions, wherein the through hole extends from the outer surface of the first membrane to the relative outer surface of the second membrane. Due to the presence of a combined portion of the membrane located radially inward of the peripheral combined portion, the internal volume formed between the first membrane and the second membrane may be formed as a plurality of interconnected channels 126 corresponding to the uncombined portion of the membrane.

[0089] In some embodiments, after the membranes are bonded together (e.g., bonding the perimeter and / or interior portions of the first and second membranes), the first and second membranes may be coated with a hydrophilic material and / or subjected to other treatments that may be incompatible with the bonding process. In some embodiments, this may include various high temperature treatments, wherein the bonded membranes may be subjected to various heat treatments, which may enhance the bonding of the membranes.

[0090] In some embodiments, a pre-bonded film stack (such as the bonded first and second films described above) can be mounted to the frame. Alternatively, in some embodiments, the perimeter of the film stack can be bonded together and attached to the frame simultaneously. In either case, a method for mounting the film to the frame can be used to provide a desired amount of slack in the film once mounted. FIG. 2A to FIG. 2E One such embodiment is described in further detail.

[0091] FIG. 2A to FIG. 2B The first and second films 102 and 104 are shown as being moved from a first maximum lateral dimension prior to installation (e.g., where the films are in Figure 2A to a second maximum lateral dimension after installation (e.g., wherein the membrane is deformed to conform to the relatively flat planar configuration in FIG. Figure 2B Specifically, the surface of the first film opposite to the second film can be placed on the curved surface 206 of the support 200 and conform to its shape, so that a portion of the first film and the second film are deformed in a direction out of the plane of the first film and the second film. For example, since the central portion of the film is deformed in a direction out of the plane of the film due to the underlying curved surface of the support, the outer periphery of the first film and the second film is deformed from Figure 2A The first transverse dimension in the plane configuration in the deformation to Figure 2B In some embodiments, the curved surface of the support member is a spherical dome, such as FIG. 2A to FIG. 2E However, embodiments using support members having different shapes are also conceivable.

[0092] In some embodiments, the support 200 may include one or more ridges 202 disposed near the edge of the curved surface 206 of the support 200 on which the stack of films 102 and 104 is supported. These ridges may be disposed at multiple locations around the perimeter of the support so that the first film 102 and the second film 104 disposed on the curved support 200 are flared near the outer perimeter and / or otherwise deformed as described above to accommodate the presence of excess film material at these locations. FIG. 5A to FIG. 6BSpecific examples of these ridges and their interaction with the films disposed thereon are described in further detail. That is, in the depicted embodiment, a combined stack of films (including first and second films 102 and 104) is disposed on a support 200, wherein the outer perimeters of the first and second films contact the ridges 202 to deform portions of the films adjacent to the curved surface of the support. In the depicted embodiment, these ridges can help deform portions of the film by wrinkling, folding, corrugating, folding, or otherwise deforming the film in this location to accommodate excess material that is forced into a smaller area as the film deforms from a larger first transverse dimension (e.g., a planar configuration) to a smaller second transverse dimension (e.g., a deformed configuration disposed on a support).

[0093] While the use of raised ridges has been shown in the above described embodiments, it should be understood that any method of deforming one or more locations around the perimeter of the binding membrane from a first, larger area to a second, smaller area may be used.

[0094] In some cases, it may be desirable to maintain the orientation and / or position of the membrane stack on the support during mounting of the frame to the membrane stack. Thus, in some embodiments, and as shown, a vacuum may be applied to one or more non-diffusing portions of the first and second membranes to maintain the first and second membranes close to the curved support. For example, referring to Figure 2B , the curved support 200 may include a vacuum compartment 210, which is connected to a vacuum source not shown to provide negative pressure. The vacuum compartment may be fluidly connected to one or more vacuum holes 212 disposed on the surface of the curved support 200. Although the vacuum holes may be located at any desired portion of the support surface, in some embodiments, the vacuum holes may be located on a portion of the support surface where a corresponding non-diffusing portion of the bonding film may be located, the corresponding non-diffusing portion including, for example, a bonding perimeter 122 of the film, a portion of the film located radially outside the bonding perimeter, a bonding portion 124 of the film located within the bonding perimeter, and / or any other appropriate portion of the film. For example, a plurality of vacuum holes may be located near or at the ridge 202 surrounding the perimeter of the curved surface 206 of the support. Of course, other methods of maintaining the position and / or orientation of the film relative to the underlying support may be used, including but not limited to mechanical fixing, clamping, temporary adhesives, and / or any other appropriate temporary fixing methods.

[0095] After deforming the first and second membranes 102 and 104 from the first maximum transverse dimension to the smaller second maximum transverse dimension, the frame 220 may be mounted to the membranes, such as Figure 2C and Figure 2DAs shown. Specifically, a frame 220 (e.g., a peripheral frame) can be placed on the stacked film while the central portion of the film is deformed out of plane by the underlying curved support 200. The frame can extend around at least a portion of the periphery of the bonded film, and in some embodiments, around the entire periphery of the bonded film. The size and shape of the frame can be selected to maintain the maximum lateral dimension of the film at a smaller second maximum lateral dimension after installation, wherein the maximum lateral dimension can be measured in the plane in which the planar frame extends. For example, the maximum lateral dimension in the depicted embodiment can correspond to the diameter of a circular frame placed on the bonded film. However, it is also conceivable to use embodiments with frames and films of different shapes and sizes.

[0096] As described above, in certain embodiments, the frame 220 may extend along at least a portion of the perimeter of the bonded membranes 102 and 104. To avoid reducing the effective diffusion area of ​​the bonded membrane, at least a portion of the frame, and in some cases, the entire frame may be aligned with and / or positioned radially outward of the bonded perimeter 122 of the membrane. This may avoid placing the frame on top of the diffusion portion of the bonded membrane, which would prevent diffusion through the underlying portion of the membrane. Thus, the frame may have a lateral dimension that is equal to or slightly larger than the bond that extends along the perimeter of the membrane to form the internal volume of the membrane. For example, referring to Figure 2D , the frame 220 overlaps only a portion of the membrane's bonded perimeter 122. Of course, while the membrane does not extend over the frame in the depicted embodiment, embodiments are also contemplated where the frame extends over this bond into an area radially inward of the bonded perimeter.

[0097] like Figure 2EAs shown, after framework 220 is positioned on the combination stack of films 102 and 104, framework can be bonded to film.In certain embodiments, adhesive, hot melt, welding (heat, ultrasound, etc.), mechanical fixing or other appropriate methods can be used to combine framework and film at multiple positions around the framework circumference.For example, framework and film can be combined together at each position of the ridge 202 that the frame and film contact the circumference of the curved surface 206 around the support 200.In the embodiment depicted, fixture 230 can be used to form bonding points between a part of framework and the first film and the second film at one or more desired positions.Fixture 230 can correspond to the combination of the port for distributing curable adhesive and the light source that can be used for curing adhesive once positioned on framework and film.The bonding duration and viscosity of adhesive can be selected to avoid excessive wicking of adhesive into the diffusion part of film.In addition, although specific bonding methods have been described, other appropriate types of bonding can be used as described above.After framework is bonded to film, the resulting large capsule device including framework and the film installed can be removed from the curved support. After the membrane is initially secured to the frame, the mounted frame and membrane may then be subjected to additional processing including, for example, placing additional adhesive between the mounted frame and membrane to improve the bond therebetween.

[0098] In the above-described embodiment, the frame is connected to the outer surface of the second membrane 104 opposite to the first membrane 102 resting on the support 220. However, as Figure 3 As shown, it is also contemplated that the frame 220 is disposed between the first film 102 and the second film 104. In this embodiment, the portion of the first film and the second film extending radially outward from the joint 122 extending along the periphery of the film can be opened, and the frame is positioned between the films at a position radially outside the peripheral joint of the film. Then, the first film and the second film can be bonded to the frame using any suitable bonding method as described above. Although the specific angular orientation of the frame, the film and the underlying support has been depicted in the accompanying drawings, it should be understood that any suitable orientation of these components can be used because the present disclosure is not limited in this manner. In either case, once removed from the underlying support, the frame can still be used to maintain the desired lateral dimensions of the film.

[0099] FIG. 4A to FIG. 4BDescribe an embodiment of the large capsule device after film has been mounted on the corresponding framework and before filling with desired materials such as cell groups. Specifically, as shown in the figure, the large capsule device may include a first film 102, a second film 104 and a frame 220 extending along at least a portion of the periphery of the first film and the second film. The device is shown as being in an unfilled loose state, wherein the first film and the second film are mounted relative to the extra surface area of ​​the cross-sectional area of ​​the frame within the film due to the relaxation produced in the film and causing the combined film to be suspended below the framework. Due to the binding portion 122, through hole 132 and other suitable features formed on the film that are located in the internal area of ​​the device, now the large capsule device can be easily filled with desired materials such as cell groups by minimal additional processing and manipulation. The internal volume can be filled using the opening in the port, the peripheral joint and / or any other appropriate method. In either case, after filling the large capsule device with desired materials, the internal volume included between the first film 102 and the second film 104 can expand, which can tighten the relaxation in the film, because the film is under tension due to the internal volume expansion between the film in the filling configuration. This can cause the first and second membranes to deform so that the membranes generally extend in a direction generally parallel to the plane of the frame 220, see Figure 4C Correspondingly, due to this increase in the internal volume of the now filled device, the first and second membranes may now extend outwardly from the opposing surfaces of the frame by approximately equal distances. With the portions 132 of the membranes having been joined together at a location radially inward of the frame, the expanded structure may again form a plurality of interconnected channels 126.

[0100] Any suitable filling method can be used to fill the large capsule device. For example, a cell group or other desired material can be flowed into the internal volume formed between the outer membrane of the device of the large capsule device. This can be achieved by using a sealable or removable port extending into the internal volume, and / or there may be a subsequently sealable opening in the peripheral joint and / or frame of the large capsule device. Although any suitable inlet of the internal volume can be used to make the material flow into the internal volume of the device, the flow of this material can be controlled in a variety of different ways to provide the desired filling of the internal volume. For example, in one embodiment, the pressure applied to the internal volume of the large capsule device can correspond to the desired tension amount present in the film of the device in the filling configuration. Therefore, the filling of the device can continue until a predetermined pressure and / or membrane tension threshold has been reached. However, any suitable method for controlling the amount of material flowing into the internal volume can also be used, because the present disclosure is not limited in this way. This can include, for example, control based on the absolute volume of the material flowing into the internal volume, the duration at a given flow rate, and / or any other suitable control method.

[0101] FIG. 5A to FIG. 5DA specific embodiment of a support 200 is depicted that can be used during the installation of a frame to a membrane held on the support. The support can include a curved support surface 206 that is used to support the active diffusion portion of the membrane stack during the frame installation process. In the depicted embodiment, the support surface is a spherical dome, but as previously discussed, other suitable shapes for the support surface can be used. The support surface can be used to support and deform the membrane placed thereon, as described above with respect to Figures 2A to 2E The support member may also include a corrugated surface extending around the periphery of the main curved support surface. For example, the corrugated surface may include a plurality of alternating ridges 202 and grooves 204 extending radially outward from adjacent portions of the curved support surface. In some cases, the ridges may extend vertically upward above the adjacent portions of the curved support surface, and the grooves may extend vertically downward below the adjacent portions of the curved support surface. However, different vertical arrangements of ridges and grooves relative to adjacent curved support surfaces are also contemplated. In either case, the corrugated surface including a height variation along its length may at least partially surround, and in the depicted embodiment completely extend around the periphery of adjacent curved support surfaces. As described in further detail below in the embodiments, this corrugated surface may help guide the portion of the membrane stack to a desired fold, wrinkle, corrugation or otherwise deformed configuration to handle excess material of the membrane in this position during the frame installation process.

[0102] In the above embodiments, the vertical direction of the support member may be defined as vertically upward relative to the base of the support member below the curved support surface.

[0103] In some embodiments, and as previously described, the support 200 can be configured to apply vacuum to the film stack disposed thereon. For example, as shown, a vacuum connector 208 can be fluidly connected to a central vacuum compartment 210 formed in the support. This central vacuum compartment can also be fluidly connected to a vacuum hole 212, which extends upward to the curved support surface 206 of the support where the film stack can be located. These vacuum holes can be distributed around the periphery of the support surface, although the vacuum holes can also be located in other suitable positions. For example, as shown, the vacuum holes can be distributed so that at least one vacuum hole is located on each ridge 202 and groove 204 of the corrugated surface extending around the curved support surface 206. However, it should be understood that any suitable arrangement of vacuum holes can be used, because the present invention is not limited to using vacuum holes only in these positions. In addition, in some embodiments, the vacuum holes can be positioned so that they can be applied to the non-diffusing portion of the film disposed thereon during the frame installation process. In any case, the vacuum holes can apply vacuum suction from the vacuum connector to one or more parts of the film stack disposed on the support surface, which can help maintain the orientation and / or position of the film stack on the support.

[0104] Example: Fabrication of a large capsule device

[0105] FIG. 6A to FIG. 6B Show similar to the above about FIG. 5A to FIG. 5D The use of the support member 200 described. Similarly, the support member may include a curved support surface 206 and a corrugated surface, wherein the corrugated surface includes a plurality of alternating ridges 202 and grooves 204 extending at least partially around the periphery of the curved support surface. The stack of bonding membranes 214 is arranged on the support surface, wherein the outer portion of the membrane extends to the ridges and grooves of the corrugated surface. Due to the size mismatch between the diameter of the curved support surface adjacent to the corrugated surface and the undeformed planar configuration of the membrane, the size of the membrane in this position is greater than the diameter of the curved support member. The resulting excess material extending outwardly onto the corrugated surface of the membrane can be deformed to conform to the shape of the ridges and grooves of the corrugated surface, thereby adapting to the presence of such excess material. The vacuum applied to one or more parts of the membrane by the vacuum connector 208 of the support member can be used to deform the membrane stack, but other fixing methods including mechanical clamping, temporary adhesives and other appropriate methods can also be used. In either case, the film stack can be deformed into a folded, pleated, wrinkled, corrugated or otherwise deformed shape, which deforms the film from a first larger area to a second smaller area in the transverse plane of the system to resolve the noted size mismatch. Due to the periodic nature of the corrugated surface, these deformations of the film stack to a smaller area can be arranged around the periphery of the film stack. Once properly positioned and maintained on the support member in a deformed configuration, in the depicted embodiment, a frame 220 can be placed on the surface, the frame contacting the portion of the film located at a plurality of ridges extending around the curved support member. Then, a subsequent bonding process as previously described can be implemented to bond the frame to the film stack.

[0106] FIG. 7A to FIG. 7B is a photograph of a macrocapsule device made using a process similar to that described above. The device is in a relaxed state prior to filling with cells, and visible areas of deformation (i.e., wrinkles) in the mounting membrane are distributed around the circumference of the device due to the slack in the membrane. The device includes an array of channels located between the bonding portions (as indicated by the recessed dots) formed on the first and second membranes. Figure 7B The channel 126 and the joining portion 124 are clearly shown.

[0107] Example: Device filling

[0108] FIG. 8A to FIG. 8B are scanning electron micrographs of two cross-sectional macrocapsule devices with different amounts of membrane slack (i.e., 5% and 10% undersizing of the frame relative to a correspondingly sized membrane). The height of the compartments of the filled devices was measured by filling the devices with 150 μm beads, the size of which represents the average diameter of human islets. As shown in the figure, Fig. 8AThe first device shown in FIG. 1 corresponds to a 5% undersizing of the frame with Figure 8B The second device corresponding to 10% undersizing of the frame shown in FIG. 1 contained fewer beads than the second device and was associated with a smaller compartment height than the second device. Thus, the compartment height and fill volume were both greater for devices with an increased degree of undersizing of the frame relative to the associated mounted membrane. Additionally, attempts to fill a device with 0% membrane slack failed to fill, demonstrating that a membrane mounted in a slack configuration with a certain amount of slack enables easier filling of the device with cells or other materials.

[0109] Example: Changing the frame size

[0110] Fig. 9 is an illustration of the concept of membrane slack, where membranes of predetermined size are mounted to frames having different diameters. As shown, a pair of bonded membranes (e.g., a first membrane and a second membrane bonded at their periphery) have a diameter of 42.3 mm and are mounted to frames of different sizes (e.g., diameters of 42.3 mm, 40.2 mm, and 38.3 mm). The undersizing of the frame is calculated as a percentage of the diameter difference between the peripheral frame and the membrane relative to the diameter of the membrane stack. The undersizing of the frame is 0%, 5%, and 10% and is associated with peripheral frames of 42.3 mm, 40.3 mm, and 38.3 mm, respectively. In order to accommodate the excess surface area of ​​the membrane module when the membrane is mounted to an undersized frame, it is observed that the membrane slack (i.e., membrane relaxation) increases with the increase in the undersizing of the frame relative to the size of the membrane.

[0111] Example: Internal Volume Dimensions and Relaxation

[0112] Fig. 10A and Fig. 10B Figures showing large capsule devices that have been submitted, where two devices have different amounts of undersizing of the frame relative to the undeformed dimensions of the associated membrane. Fig. 10B Compared with the large capsule device 300B, Fig. 10AThe large capsule device 300A is modeled as having a smaller amount of undersizing. Similar to the above-described embodiments, the device may include a first membrane 104 and a second membrane 104, which are combined along their peripheries to form an internal volume 250 between the membranes. The depicted device also includes a bonding portion 124 having a through hole 132 located within a central portion of the membrane disposed within a frame (not shown). Mathematical modeling is used to determine the membrane structure when filled to a predetermined tension of the membrane under equilibrium conditions. The determined compartment height H associated with the channels forming the internal volume 250 and depicted in the figure can be measured in a direction perpendicular to the plane in which the membrane and the associated frame are generally positioned. It was observed that the larger the compartment height H associated with having a greater degree of undersizing and a correspondingly greater amount of membrane slack or relaxation. Fig. 10B Compared with the device 300B, it has a lesser degree of frame undersizing. Fig. 10A The device 300A results in a smaller compartment height after filling.

[0113] Embodiment: Control device structure

[0114] Do not wish to be bound by theory, the chamber height and the total internal volume of the channel formed in the device can be controlled by the undersize degree of the control framework relative to the size of the associated film.Similar to the above, a film with a diameter of 42.3mm can be installed to a frame of different diameters, and a channel with fixed channel spacing and diameter can be formed in the film.Mathematical modeling is used to estimate the chamber height and volume by the geometric characteristics (such as channel spacing, channel diameter) of the fixed channel, and then the internal volume and chamber height are predicted by the surface area difference between the combined membrane installed under tension compared to the loose installation state provided by the reduced surface area associated with the size of the framework when filling balance.As shown in the table below, both chamber height and total internal volume increase with the reduction of frame diameter, and the reduction of frame diameter corresponds to the increase of the mismatch between the area of ​​the film and the framework before filling and the increase of the film relaxation amount.

[0115] Table I

[0116] Peripheral frame diameter (mm) Internal volume when balanced filling Maximum chamber height 42.3mm 0μL 0μm 40.3mm 58μL 160μm 38.3mm 100μL 322μm

[0117] Although the teachings of the present invention have been described in conjunction with various embodiments and examples, the teachings of the present invention are not intended to be limited to these embodiments or examples. On the contrary, the teachings of the present invention include various substitutions, modifications and equivalents, as will be understood by those skilled in the art. Therefore, the foregoing description and accompanying drawings are only examples.

[0118] This application also includes the following specific implementation schemes:

[0119] 1. A macrocapsule device for accommodating a cell population, comprising:

[0120] First film;

[0121] a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along perimeters of the first membrane and the second membrane to form an interior volume therebetween, wherein the first membrane and / or the second membrane are semi-permeable; and

[0122] A frame extending along at least a portion of the perimeter of the first and second membranes, and wherein the surface area of ​​the first and / or second membranes is greater than the cross-sectional area of ​​the frame within which the first and second membranes are mounted.

[0123] 2. The large capsule device of embodiment 1, wherein the frame extends completely around the periphery of the first membrane and the second membrane.

[0124] 3. The macrocapsule device of any one of embodiments 1 or 2, wherein the first membrane and the second membrane are configured to prevent the cell population from leaving the device.

[0125] 4. The large capsule device of embodiment 3, further comprising the cell population disposed in the internal volume.

[0126] 5. The large capsule device of any one of Embodiments 1 to 4, wherein the interior volume comprises a plurality of channels.

[0127] 6. The large capsule device as described in specific embodiment 5 also includes a plurality of combining portions of the first membrane and the second membrane arranged on the radial inner side of the frame, the plurality of combining portions forming the plurality of channels, and wherein at least some of the combining portions include through holes passing therethrough.

[0128] 7. The large capsule device of any one of embodiments 1 to 6, wherein the first membrane and / or the second membrane is sintered.

[0129] 8. The large capsule device of any one of embodiments 1 to 7, wherein the first membrane and / or the second membrane comprises a hydrophilic coating.

[0130] 9. A macrocapsule device for containing a cell population, comprising:

[0131] First film;

[0132] a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along perimeters of the first membrane and the second membrane to form an interior volume therebetween, wherein the first membrane and / or the second membrane are semi-permeable; and

[0133] A frame extending along at least a portion of the perimeter of the first membrane and the second membrane, and wherein the portions of the first membrane and the second membrane connected to the frame are deformed to fit within an area of ​​the frame that is smaller than the area of ​​the portions of the first membrane and the second membrane in an undeformed configuration.

[0134] 10. A large capsule device as described in specific embodiment 9, wherein the portions of the first membrane and the second membrane connected to the frame include a plurality of positions arranged around the periphery of the frame, at which the first membrane and the second membrane are deformed from a first larger area to a second smaller area.

[0135] 11. A large capsule device as described in any one of specific embodiments 9 or 10, wherein the surface area of ​​the first membrane and / or the second membrane is larger than the cross-sectional area of ​​the frame in which the first membrane and the second membrane are installed.

[0136] 12. The large capsule device of any one of Embodiments 9 to 11, wherein the frame extends completely around the perimeter of the first and second membranes.

[0137] 13. The macrocapsule device of any one of embodiments 9 to 12, wherein the first membrane and the second membrane are configured to prevent the cell population from leaving the device.

[0138] 14. The macrocapsule device of embodiment 13, further comprising the cell population disposed in the internal volume.

[0139] 15. The large capsule device of any one of Embodiments 9 to 14, wherein the interior volume comprises a plurality of channels.

[0140] 16. The large capsule device as described in specific embodiment 15 also includes a plurality of combining portions of the first membrane and the second membrane arranged on the radial inner side of the frame, the plurality of combining portions forming the plurality of channels, and wherein at least some of the combining portions include through holes passing therethrough.

[0141] 17. The large capsule device of any one of embodiments 9 to 16, wherein the first membrane and / or the second membrane is sintered.

[0142] 18. The large capsule device of any one of embodiments 9 to 17, wherein the first membrane and / or the second membrane comprises a hydrophilic coating.

[0143] 19. A method of forming a macrocapsule device, the method comprising:

[0144] deforming a first film and a portion of a second film disposed on the first film in a direction out of the plane of the first film and the second film; and

[0145] A frame is connected to the second membrane and / or the first membrane while the portions of the first membrane and the second membrane are deformed out of plane, wherein the frame limits the maximum lateral dimension of the large capsule device, wherein the first membrane and / or the second membrane are semi-permeable.

[0146] 20. The method of embodiment 19, wherein the surface area of ​​the first membrane and / or the second membrane is larger than the cross-sectional area of ​​the frame in which the first membrane and the second membrane are mounted.

[0147] 21. The method of embodiment 19 or 20, wherein the first membrane and the second membrane are configured to prevent the cell population from leaving the device.

[0148] 22. The method of embodiment 21 further comprises: filling the internal volume of the device with the cell population.

[0149] 23. The method of any one of embodiments 19 to 22, wherein the first film and / or the second film is sintered.

[0150] 24. The method of any one of embodiments 19 to 23, further comprising: coating the first membrane and / or the second membrane with a hydrophilic material.

[0151] 25. The method of any one of embodiments 19 to 24, wherein deforming the portions of the first and second films out of plane comprises positioning a surface of the first film opposite the second permeable film on a curved support.

[0152] 26. The method of embodiment 25, wherein the curved support comprises a spherical dome.

[0153] 27. The method of any one of embodiments 25 or 26, further comprising: applying a vacuum to one or more non-diffusing portions of the first membrane and the second membrane to maintain the first membrane and the second membrane close to the curved support.

[0154] 28. The method of embodiment 27, wherein the non-diffusing portion is located radially outside of an interior volume disposed between the first membrane and the second membrane.

[0155] 29. The method of any one of embodiments 19 to 28, further comprising: before connecting the frame to the second membrane, combining one or more portions of the first membrane and the second membrane to form a plurality of channels therebetween.

[0156] 30. The method of embodiment 29, further comprising: forming one or more through holes in the one or more bonding portions before connecting the frame to the second film.

[0157] 31. A method of forming a macrocapsule device, the method comprising:

[0158] deforming an outer perimeter of a first film and a second film disposed on the first film from a first maximum transverse dimension to a second maximum transverse dimension that is less than the first maximum transverse dimension; and

[0159] A frame is connected to the second membrane and / or the first membrane to limit the maximum transverse dimension of the first membrane and the second membrane to the second maximum transverse dimension, wherein the first membrane and / or the second membrane is semi-permeable.

[0160] 32. The method of embodiment 31, wherein the surface area of ​​the first membrane and / or the second membrane is larger than the cross-sectional area of ​​the frame in which the first membrane and the second membrane are mounted.

[0161] 33. A method as described in any of embodiments 31 to 32, wherein the first membrane and the second membrane are constructed to prevent the cell population from leaving the device.

[0162] 34. The method of any one of embodiments 31 to 33, further comprising: filling the internal volume of the device with the cell population.

[0163] 35. The method of any one of embodiments 31 to 34, wherein the first film and / or the second film is sintered.

[0164] 36. The method of any one of embodiments 31 to 35, further comprising: coating the first membrane and / or the second membrane with a hydrophilic material.

[0165] 37. A method as described in any one of specific embodiments 31 to 36, wherein deforming the outer periphery of the first membrane and the second membrane from a first maximum lateral dimension to a second maximum lateral dimension smaller than the first maximum lateral dimension includes: placing the surface of the first membrane opposite to the second permeable membrane on the curved support member.

[0166] 38. The method of embodiment 37, wherein the curved support comprises a spherical dome.

[0167] 39. The method of any one of embodiments 37 or 38, further comprising: applying a vacuum to one or more non-diffusing portions of the first membrane and the second membrane to maintain the first membrane and the second membrane close to the curved support member.

[0168] 40. The method of embodiment 39, wherein the non-diffusing portion is located radially outward of an interior volume disposed between the first membrane and the second membrane.

[0169] 41. The method of any one of embodiments 31 to 40, further comprising: before connecting the frame to the second membrane, combining one or more portions of the first membrane and the second membrane to form a plurality of channels therebetween.

[0170] 42. The method of embodiment 41, further comprising: forming one or more through holes in the one or more bonding portions before connecting the frame to the second film.

Claims

1. A macrocapsule device for accommodating a cell population, comprising: First film; a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along perimeters of the first membrane and the second membrane to form an interior volume therebetween, wherein the first membrane and / or the second membrane are semi-permeable; as well as A frame extending along at least a portion of the perimeter of the first and second membranes, and wherein the surface area of ​​the first and / or second membranes is greater than the cross-sectional area of ​​the frame within which the first and second membranes are mounted.

2. The large capsule device of claim 1, wherein the frame extends completely around the perimeter of the first membrane and the second membrane.

3. The macrocapsule device of any one of claims 1 or 2, wherein the first membrane and the second membrane are configured to prevent the cell population from leaving the device.

4. The macrocapsule device of claim 3, further comprising the cell population disposed in the interior volume.

5. The large capsule device of any one of claims 1 to 4, wherein the interior volume comprises a plurality of channels.

6. The large capsule device of claim 5, further comprising a plurality of combining portions of the first membrane and the second membrane disposed radially inwardly of the frame, the plurality of combining portions forming the plurality of channels, and wherein at least some of the combining portions include through holes passing therethrough.

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

8. The large capsule device of any one of claims 1 to 7, wherein the first membrane and / or the second membrane comprises a hydrophilic coating.

9. A macrocapsule device for containing a cell population, comprising: First film; a second membrane disposed on the first membrane, wherein the first membrane and the second membrane are joined along perimeters of the first membrane and the second membrane to form an interior volume therebetween, wherein the first membrane and / or the second membrane are semi-permeable; as well as A frame extending along at least a portion of the perimeter of the first membrane and the second membrane, and wherein the portions of the first membrane and the second membrane connected to the frame are deformed to fit within an area of ​​the frame that is smaller than the area of ​​the portions of the first membrane and the second membrane in an undeformed configuration.

10. The large capsule device of claim 9, wherein the portions of the first and second membranes connected to the frame include a plurality of locations disposed around a periphery of the frame at which the first and second membranes deform from a first larger area to a second smaller area.

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