Giant encapsulation device

Abstract

A method of manufacturing a giant encapsulated device includes aligning one or more membranes of the device with a frame of the device such that a portion of the one or more membranes overlaps a portion of the frame. The method further includes deforming the one or more films and thermoplastically deforming the frame to form a mechanically interlocked region of the films and the frame.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Serial No. 63 / 349,749, filed on June 7, 2022, and entitled “MACROENCAPSULATION DEVICES,” which is incorporated by reference in its entirety for all purposes. Technical Field

[0003] The disclosed embodiments relate to macroencapsulation devices and methods of making the same. Background Art

[0004] Therapeutic devices that deliver biological products can be used to treat metabolic diseases, such as diabetes. Therapeutic devices can be implantable to provide biological products, such as insulin, for a long time. Some of these devices include macroencapsulated devices for containing cells to produce the desired biological product, a matrix including the cells, or other desired therapeutic agents therein. Summary of the invention

[0005] In some embodiments, a method of making a macroencapsulated device may include aligning one or more membranes of the macroencapsulated device with a frame of the macroencapsulated device such that a portion of the one or more membranes may at least partially overlap a portion of the frame. The method may also include deforming the portion of the one or more membranes and thermoplastically deforming the portion of the frame to form a plurality of mechanically interlocked regions of the one or more membranes and the frame.

[0006] In other embodiments, a macroencapsulation device may include: one or more membranes, the one or more membranes comprising a sealed interior volume configured to encapsulate a population of cells. The device may also include a frame. The one or more membranes may be disposed on the frame. The device may also include: a plurality of mechanically interlocking regions of the one or more membranes and the frame, the plurality of mechanically interlocking regions extending around at least a portion of a perimeter of the one or more membranes.

[0007] In another embodiment, a bonding apparatus for manufacturing a macroencapsulated device may include: a holding mechanism configured to selectively hold a frame of the macroencapsulated device and one or more membranes of the macroencapsulated device in an overlapping configuration, wherein at least a portion of the one or more membranes overlaps at least a portion of the frame. The bonding apparatus may also include: a heater configured to heat at least the portion of the frame. The bonding apparatus may also include: one or more molds configured to deform the portion of the one or more membranes and thermoplastically deform the portion of the frame to form a plurality of mechanical interlocking regions of the one or more membranes and the frame, the plurality of mechanical interlocking regions extending around at least a portion of the periphery of the one or more membranes.

[0008] It should be understood that the aforementioned concepts and the additional concepts discussed below can be arranged in any suitable combination, as the present disclosure is not limited in this regard. In addition, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] 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 a like number. For clarity, not every component may be labeled in every drawing. In the drawings:

[0010] Figure 1A is a top view of a membrane of a macroencapsulation device before being mounted to a frame according to one embodiment;

[0011] Figure 1B For example, along the lines of Figure 1A A cross-sectional side view of an embodiment of a membrane of a macroencapsulation device taken along line 1B-1B;

[0012] Figure 1C For example, along the lines of Figure 1A A cross-sectional side view of an embodiment of a portion of a membrane of a macroencapsulation device in a filled configuration, taken along line 1B-1B;

[0013] Figure 1D is a top view of a frame of a macroencapsulation device prior to installation of one or more associated membranes according to one embodiment;

[0014] Figure 1E is a close-up top view of a fill port of a macroencapsulation device prior to installation of one or more associated membranes according to one embodiment;

[0015] Figure 1F For example, along the lines of Figure 1D A cross-sectional side view of a frame of a macroencapsulation device taken along line 1F-1F;

[0016] Figure 2A is a top view of the membrane of the macroencapsulation device mounted to the frame using an adhesive;

[0017] Figure 2B is a top view of a membrane of a macroencapsulation device mounted to a frame using mechanical bonding techniques as disclosed herein according to one embodiment;

[0018] Figure 3A is a close-up top view of a frame / membrane interface of a macroencapsulation device according to one embodiment, wherein the membrane is attached to the frame using an adhesive and subsequently removed;

[0019] Figure 3B is a close-up top view of a frame / membrane interface of a macroencapsulation device according to one embodiment, wherein the membrane is attached to the frame using a mechanical bonding technique as disclosed herein and subsequently removed;

[0020] Figure 4A is a schematic diagram showing one embodiment of a process for creating a mechanical bond between a frame and a membrane at a first step in creating the bond;

[0021] Figure 4B It is shown Figure 4A A schematic diagram of the process at the second step when the binding occurs;

[0022] Figure 4C It is shown Figure 4A A schematic diagram of the process at the third step when a bond is produced;

[0023] Figure 4D It is shown Figure 4A A schematic diagram of the process at the fourth step when a bond is produced;

[0024] Figure 4E It is shown Figure 4A A schematic diagram of the process at the fifth step when a bond is produced;

[0025] Figure 4F It is shown by FIG. 4A to FIG. 4E Schematic diagram of the mechanical bond produced by the process;

[0026] Figure 5A is a schematic diagram of an incorporated apparatus for making a macroencapsulation device according to one embodiment;

[0027] Figure 5B is a schematic diagram of an incorporated apparatus for making a macroencapsulation device according to another embodiment;

[0028] Figure 5C is a schematic diagram of an incorporated apparatus for making a macroencapsulation device according to another embodiment;

[0029] Figure 6 is a schematic diagram of an incorporated apparatus for making a macroencapsulation device according to another embodiment;

[0030] Fig. 7A is a schematic perspective view of a first mold of a bonding apparatus for making a macroencapsulation device according to one embodiment;

[0031] Figure 7B is a schematic perspective view of a second mold of a bonding apparatus for making a macroencapsulation device according to another embodiment;

[0032] Figure 8is a flow chart depicting a method of making a macroencapsulated device according to one embodiment;

[0033] Fig. 9 is a bar graph showing the results of cell viability testing performed on both adhesively bonded macroencapsulated devices and mechanically bonded macroencapsulated devices according to some embodiments;

[0034] Fig.10 is a bar graph showing results of fatigue testing performed on both adhesively bonded macroencapsulated devices and mechanically bonded macroencapsulated devices according to some embodiments;

[0035] Fig.11A is an image of one embodiment of an adhesively bonded macroencapsulated device after fatigue testing;

[0036] Fig. 11B is an image of one embodiment of a mechanically bonded macroencapsulated device after fatigue testing; and

[0037] Fig.12 is a graph showing the results of a macrophage polarization assay performed on both adhesively bonded macroencapsulation devices and mechanically bonded macroencapsulation devices, according to some embodiments. DETAILED DESCRIPTION

[0038] Driven by the growing demand for delivering biological products to treat various diseases (such as diabetes), different types of implantable therapeutic devices have been designed. However, typical methods for manufacturing such devices are often cumbersome, inefficient, and difficult to control. For example, there is a lack of precision and control in forming specific structural features associated with the device (e.g., using an adhesive to mount a membrane to a frame). In addition, it is often difficult to accurately form these devices within acceptable tolerances to prevent mechanical failure of these devices after implantation.

[0039] It has been recognized that several difficulties associated with using adhesive to install the film of macroencapsulation device to the framework. First, such process may require significant manual operation or intervention. These manual processes may introduce undesirable variability and may reduce manufacturing efficiency. In addition, defects and inhomogeneities during the application of adhesive may lead to stress concentration in the film, thereby causing premature fatigue failure and rupture of the film. For example, the viscosity of the adhesive, the application of inhomogeneous adhesive, the contact angle at the application point and the porosity of the film may lead to the variability of the film being installed to the framework. The adhesive may also be absorbed into the holes of the film during application, which may also damage the bonding between the framework and the film, except changing the material properties of the film in the region where absorption has occurred.

[0040] In view of the foregoing, the inventors have recognized and understood the benefits of mechanical bonding between one or more films and the frame of the macroencapsulated device. In some embodiments, this can be achieved in the following manner: the temperature of one or more parts of the frame is raised to a point where the frame can be thermoplastically deformed (e.g., higher than the glass transition temperature or optionally the melting temperature of the frame material), while keeping the temperature of the film lower than the melting temperature of the film material and, in some embodiments, the sintering temperature. It should be understood that thermoplastic deformation of the frame and / or film of the macroencapsulated device may include applying both heat and pressure to achieve the desired deformation. For example, heat may be applied to the frame and / or film to provide the above-mentioned temperature, while applying pressure to one or more parts of the film and frame to be deformed and bonded to each other. Specifically, because the film is flexible, even at a temperature lower than the melting temperature of the film, one or more softened parts of the frame and the corresponding parts of the film may be deformed when pressure is applied to form one or more mechanical bonding parts between the frame and the film. For example, the thermoplastic deformation of the frame and the corresponding deformation of the conforming film can be used to mechanically interlock one or more deformed parts of the frame and the film. Such techniques may allow a strong and / or durable bond to be formed at the interface between the frame and the membrane.In some cases, the bonded portion of the frame and membrane may extend at least partially around the perimeter of one or more membranes.

[0041] In a specific embodiment, a method for manufacturing a macroencapsulated device may include: aligning one or more membranes of the macroencapsulated device with a frame of the macroencapsulated device so that a portion of the one or more membranes overlaps at least partially with a portion of the frame. The method may also include: deforming the portion of the one or more membranes and thermoplastically deforming the portion of the frame to form multiple mechanical interlocking regions of the one or more membranes and the frame. In some embodiments, the frame and / or the membrane may be heated. For example, the frame may be heated to a temperature below the melting temperature or sintering temperature of the membrane so as to promote thermoplastic deformation of the frame. In some embodiments, the deformation may be performed in multiple steps, including a first deformation and a second deformation. In other embodiments, the deformation may be performed in a single step. Multiple mechanical interlocking regions may extend around a portion of the outer periphery of one or more membranes, and in some embodiments, extend at least partially around a sealed internal volume disposed between two opposing layers of one or more membranes.

[0042] As will be described in more detail below, some embodiments of the macroencapsulated device may include one or more membranes comprising a biocompatible polymer, such as polytetrafluoroethylene (PTFE) or expanded polytetrafluoroethylene (ePTFE). Some embodiments may include a frame comprising a thermoplastic material, such as polyetheretherketone (PEEK). In certain embodiments, the macroencapsulated device may include a frame formed by PEEK and one or more membranes formed by ePTFE, but the present disclosure is not limited to any specific combination of these embodiments or materials described herein (and their equivalents). It should be understood that in the context of the macroencapsulated device, there may be significant challenges in producing mechanical bonding between a frame comprising a thermoplastic (such as PEEK) and a membrane comprising a polymer (such as ePTFE), due to the difficulty in welding these materials. For example, this bonding process may result in significant heat and / or pressure being applied to the interface between the frame and the membrane. However, applying too much heat or pressure to the polymer membrane can greatly affect the porosity, permeability or other material properties of the membrane, which can affect the function of the entire device. In this regard, it may be desirable to form mechanically interlocking areas of the frame and membrane rather than simply forming typical welds to facilitate mechanical bonding of difficult-to-bond materials, but the disclosed methods and apparatus may be used with any suitable combination of frame and membrane materials, as the disclosure is not limited in this regard.

[0043] Macroencapsulated devices made using the disclosed systems and processes can provide many benefits. For example, the disclosed systems and processes can allow for easier control of the distribution of membrane relaxation relative to the support frame due to the interlocking regions occupying and distributing the membrane relaxation. The disclosed bonding techniques can also improve bonding uniformity and strength compared to typical adhesive-based bonding. This can also help to improve the fatigue life of the macroencapsulated device. In some embodiments, the mechanical interlocking regions can produce a strong and / or durable bond, making it possible for the membrane to experience fatigue failure or other mechanical failure before the bond fails, thereby mitigating the bond as a potential mechanical failure point in the device.

[0044] In some embodiments, the macroencapsulated device does not include the use of an adhesive or a combination based on an adhesive. In some embodiments, the elimination or reduction of an adhesive can reduce the immune response in the patient during the implantation and / or residence of the macroencapsulated device. For example, the inflammatory response can be reduced by reducing the amount of the adhesive used. Additionally or alternatively, the reduction of the adhesive can increase cell viability and / or reduce cytotoxicity in the tissue surrounding the implantable device. In some embodiments, the device does not include an adhesive. In some embodiments, the present disclosure may include a biocompatible adhesive at any appropriate position of the device. Therefore, in some embodiments, the device includes both a mechanical interlocking region and a biocompatible adhesive. For example, some devices may include a combination of an adhesive and a mechanical interlocking region at the interface between the film and the frame.

[0045] In addition to the above, the distribution of relaxation can be promoted by one or more manufacturing fixtures during the manufacture of the macroencapsulation device. In some embodiments, the bonding device for manufacturing the macroencapsulation device may include geometric features configured to promote the distribution of relaxation in the film. For example, in certain embodiments, the mold of the bonding device may include geometric features, such as grooves, ridges and / or serrations, which are configured to uniformly distribute the excess surface area of ​​one or more films of the macroencapsulation device around the bonding area of ​​the corresponding frame to which one or more films will be combined. In one such embodiment, grooves, ridges and / or serrations may be uniformly distributed around the periphery of the vault or other parts of the bonding device that contact one or more films during the bonding process. In addition, grooves, ridges and / or serrations may extend radially outward from the center portion of the vault or other parts of the bonding device that contact one or more films during the bonding process. Such geometric features can increase the surface area of ​​the mold, thereby allowing relaxation to be distributed across the surface area in a controlled manner when the film (e.g., using suction as will be described below) fits the surface of the mold.

[0046] The macroencapsulation device may include multiple membrane layers. At least one outer membrane in these multiple membrane layers may be semi-permeable. However, it is also envisioned that each of the membranes is semi-permeable or at least one of the membranes in the device is substantially impermeable. In addition, the device may include two stacked membranes, three stacked membranes and / or any other appropriate number of membranes, because the present disclosure is not limited in this way. For example, in an embodiment including two membranes, any membrane may be semi-permeable and the other membrane is impermeable, or both may be semi-permeable. Therefore, it should be understood that the present disclosure is not limited to any specific combination of the membranes in the stacked structure.

[0047] In some embodiments, the macroencapsulation device may include at least one cell group disposed in the internal volume of the device. For example, the cell group may be disposed in an internal volume between two or more relative layers of one or more external membranes formed in the device, wherein the outer edge of the internal volume may be limited by one or more joints extending around at least a portion of the membrane, and in some cases the entire periphery or other appropriate portions of the membrane. In such an embodiment, at least the external membrane of the device may be configured to prevent one or more cell groups from leaving the device. Therefore, one or more cell groups may be retained in the internal volume of the device. Although the use of two external membranes forming a single internal volume is mainly described, the use of multiple intermediate membranes positioned between multiple unconnected internal volumes in the external membranes of the device and / or the device is also envisioned. In addition, it is also envisioned that a single membrane is folded and combined with itself to provide two relative membranes to form an internal volume.

[0048] Although expanded polytetrafluoroethylene (ePTFE) is mainly described herein as a membrane material, the membrane of the macroencapsulation device can be formed by any suitable biocompatible material. The biocompatible material can be substantially inert for the cells and surrounding tissues contained in the macroencapsulation device. The biocompatible material can include a synthetic polymer or a naturally occurring polymer. In some embodiments, the polymer can also be a linear polymer, a cross-linked polymer, a mesh polymer, an addition polymer, a condensation polymer, an elastomer, a fiber polymer, a thermoplastic polymer, a non-degradable polymer, a combination of the foregoing items and / or any other suitable type of polymer, because the present disclosure is not limited in this way. As described above, in one embodiment, the polymer can include expanded polytetrafluoroethylene (ePTFE). Suitable types of polymers may also 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), polyacrylonitrile (PAN), electrospun PAN / PVC, any combination of the foregoing items, and / or any other suitable polymer material. In some embodiments, the membrane used with any of the embodiments disclosed herein may include PVDF. In some embodiments, the membrane used with any of the embodiments disclosed herein may include electrospun PAN PVC. In some embodiments, the membrane used with any of the embodiments disclosed herein may include PES. In some embodiments, the membrane used with any of the embodiments disclosed herein may include PS. In some embodiments, the film used with any of the embodiments disclosed herein may include PAN. In some embodiments, the film used with any of the embodiments disclosed herein may include polycarbonate. In some embodiments, the film used with any of the embodiments disclosed herein may include polypropylene. In some embodiments, the film used with any of the embodiments disclosed herein may include PVC. In some embodiments, the film used with any of the embodiments disclosed herein may include PU. In some embodiments, the film used with any of the embodiments disclosed herein may include PET. In some embodiments, the film used with any of the embodiments disclosed herein may include PCL. In some embodiments, the film used with any of the embodiments disclosed herein may include PLGA. In some embodiments, the film used with any of the embodiments disclosed herein may include PLLA.In some embodiments, the membrane used with any of the embodiments disclosed herein may include PMMA. In some embodiments, the membrane used with any of the embodiments disclosed herein may include PEI. In some embodiments, the membrane used with any of the embodiments disclosed herein may include nylon. In some embodiments, the membrane used with any of the embodiments disclosed herein may include PTFE. In some embodiments, the membrane used with any of the embodiments disclosed herein may include PE. The synthetic method for forming one or more of the porous membranes by the above-mentioned polymer materials may include, but is not limited to, expansion, solvent casting, immersion precipitation and phase separation, electrospinning, a method for producing a homomesh network, a method for producing a trabecular network, or any other appropriate method for forming a porous polymer membrane.

[0049] Sintering of membranes can be used to modify the porosity and flux properties of the membrane. For example, sintering can increase the porosity of the membrane while maintaining its pore structure. Sintering can also improve the mechanical stability and diffusion flux of the membrane. In some cases, a sintered membrane can have a lower melting temperature than an unsintered membrane of the same type. In addition, a sintered membrane can exhibit a different energy release during a differential scanning calorimetry scan, indicating a looser structure in addition to the thickened porous network exhibited in the sintered material.

[0050] In view of the above, sintering can be used to change the porosity and / or mechanical properties of the membrane, which in turn can be used to adjust the porosity and flux properties of the macroencapsulation device. Therefore, in some embodiments, any desired combination of sintered and / or unsintered membranes or membrane layers can be used. For example, two outer membrane layers of the device can be combined together, wherein a sintered membrane and an unsintered membrane are combined together, two sintered membranes are combined together, or two unsintered membranes are combined together. In addition, any number of intermediate membranes positioned between these outer membranes can be used, wherein these intermediate membranes can be sintered or unsintered.

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

[0052] To provide the desired selectivity, the porous membrane used with the macroencapsulation device disclosed herein may have an open pore structure having 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 mean pore size of various films described herein can have following mean pore size: be 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. Conceived the combination of aforementioned items, including for example between 1nm and 20nm, 1nm and 2500nm, 50nm and 1200nm or equal to them and / or any other suitable combination of mean pore size. In some embodiments, the mean pore size of various films described herein is between 25nm and 1500nm. In some embodiments, the average pore size of various membranes described herein is between 50nm and 1200nm. In some embodiments, the average pore size of various membranes described herein is between 50nm and 1000nm. In some embodiments, the upper limit of the size of the average pore size is 1500nm. In some embodiments, the upper limit of the size of the average pore size is 1200nm. In some embodiments, the size lower limit of the average pore size is 25nm. In some embodiments, the size lower limit of the average pore size is about 50nm. Although the specific average pore size is described above, it should be understood that any suitable average pore size can be used for various membranes described herein, including an average pore size greater than and less than those average pore sizes mentioned above.

[0053] In some embodiments, charge repulsion properties may be included in the membrane. For example, the surface charge of the membrane may be adjusted with an external coating, plasma treatment or other surface treatment to achieve neutral, positive, negative or zwitterionic properties based on the isoelectric point of the desired adjuvant. Depending on the desired application, the reagent may be a protein, a complex small molecule and / or any other appropriate reagent.

[0054] In order to provide sufficient strength and / or rigidity to the macroencapsulation device, the various membranes and frames can be made of sufficiently rigid materials. The desired stiffness can be provided via an appropriate combination of Young's modulus (also known as elastic modulus), thickness, and overall construction of the material that can be balanced with the desired permeability of the device. An appropriate Young's modulus for the various membranes and frames described herein can be at least 105 Pa, 10 6 Pa, 10 7 Pa, 10 8 Pa, 10 9 Pa and / or 10 10 Pa. Other suitable Young's moduli for the various films and frames described herein may be used, including moduli greater than and less than these ranges. Ranges between the foregoing Young's moduli are contemplated, including, for example, between about 10 6 Pa and 10 10 Pa or equal to their Young's modulus. In some embodiments, the macroencapsulation device comprises at least one hydrophilic membrane.

[0055] The framework of the macroencapsulation device can be formed by any suitable biocompatible thermoplastic material. As previously mentioned, in some embodiments, suitable materials for the framework may include polyetheretherketone (PEEK). Suitable materials for the framework may also include, but are not limited to, polycarbonate, polyurethane, polyetheretherketone (PEEK), polyvinyl chloride (PVC), poly(formaldehyde), poly(methyl methacrylate) (PMMA), composite materials based on thermoplastic polymers, polypropylene, fluorinated ethylene propylene (FEP), low-density polyethylene (LDPE), high-density polyethylene (HDPE), ultra-high-density polyethylene (UHDPE), polycaprolactone, poly(lactide), poly(glycolic acid), polylactide-co-glycolide, ethylene-vinyl acetate copolymer, polyamide, poly(butylene terephthalate), a combination of the foregoing items and / or any other suitable thermoplastic material. In addition to using thermoplastic materials in the framework, it is also envisioned that the framework includes a thermoplastic part configured to be bonded to the film and an embodiment of another non-thermoplastic part, because the present disclosure is not limited to a framework made entirely of thermoplastic materials. In some embodiments, suitable materials for the frame include polypropylene. In some embodiments, suitable materials for the frame include fluorinated ethylene propylene (FEP). In some embodiments, suitable materials for the frame include ultra high density polyethylene (UHDPE). In some embodiments, suitable materials for the frame include polycarbonate. In some embodiments, suitable materials for the frame include polyurethane. In some embodiments, suitable materials for the frame include PVC. In some embodiments, suitable materials for the frame include poly (formaldehyde). In some embodiments, suitable materials for the frame include poly (methyl methacrylate) (PMMA). In some embodiments, suitable materials for the frame include composite materials based on thermoplastic polymers. In some embodiments, suitable materials for the frame include polypropylene. In some embodiments, suitable materials for the frame include LDPE. In some embodiments, suitable materials for the frame include HDPE. In some embodiments, suitable materials for the frame include polycaprolactone. In some embodiments, suitable materials for the frame include poly (lactide). In some embodiments, suitable materials for the frame include poly (glycolic acid). In some embodiments, suitable materials for the frame include polylactide-co-glycolide. In some embodiments, suitable materials for the frame include ethylene vinyl acetate copolymers. In some embodiments, suitable materials for the frame include polyamides. In some embodiments, suitable materials for the frame include poly(butylene terephthalate). In other embodiments, suitable materials for the frame or portions of the frame may include titanium, graphene, stainless steel, or other suitable biocompatible materials that exhibit sufficient rigidity to serve as a frame for the macroencapsulation device.

[0056] Although the present disclosure relates to a method for bonding one or more membranes of a macroencapsulated device to a frame, it should be understood that the present disclosure is not limited to the use of any specific method for bonding one membrane to another membrane or for bonding two or more membranes together. The membranes described in the various embodiments of the macroencapsulated device described herein can be bonded to each other using any appropriate bonding method, because the present disclosure is not limited in this way. For example, adjacent membranes can be bonded to each other using epoxy resin, welding or other fusion-based techniques (e.g., ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using a frame or a clamp, and / or any other appropriate bonding method. In a specific embodiment, adjacent membranes can be bonded using a heating tool, which is used to press or impact two or more membranes against each other with a predetermined pressure and / or force for a set fusion time.

[0057] As described herein, the macroencapsulation 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 macroencapsulation device may be between 40 μL and 250 μL or equal to them. The width or maximum lateral dimension of the macroencapsulation device may also be between about 20 mm and 80 mm. In addition, in order to provide the desired diffusion of oxygen to the interior of the macroencapsulation device to support the cells contained therein, the maximum oxygen diffusion distance from the outside of the device to the internal part of the device including the cell group may be less than 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm or 500 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal part of the device including the cell group is less than 500 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal part of the device including the cell group is less than 450 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal part of the device including the cell group is less than 400 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is less than 350 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is less than 300 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is less than 250 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is less than 200 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is less than 150 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is 150 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is between 50 μm and 200 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the internal portion of the device including the cell population is between 125 μm and 175 μm.

[0058] Correspondingly, the maximum thickness of the overall device and / or the internal volume located within the device or the dimension perpendicular to the maximum lateral dimension may be less than 25 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm or 500 μm. In some embodiments, the maximum thickness of the overall device and / or the internal volume located within the device or the dimension perpendicular to the maximum lateral dimension is between 250 μm and 700 μm. In some embodiments, the maximum thickness of the overall device and / or the internal volume located within the device or the dimension perpendicular to the maximum lateral dimension is between 250 μm and 500 μm. In some embodiments, the maximum thickness of the overall device and / or the internal volume located within the device or the dimension perpendicular to the maximum lateral dimension is between 400 μm and 500 μm. In some embodiments, the maximum thickness of the overall device and / or the internal volume located within the device or the dimension perpendicular to the maximum lateral dimension is less than 500 μm. In some embodiments, the maximum thickness or dimension perpendicular to the maximum lateral dimension of the overall device and / or the internal volume within the device is 500 μm.

[0059] In some embodiments, the maximum thickness of the frame or the dimension perpendicular to the maximum transverse dimension may be less than or equal to 4mm, 3mm, 2mm, 1mm or any other suitable thickness. In some embodiments, the maximum thickness of the frame or the dimension perpendicular to the maximum transverse dimension may be less than or equal to 4mm. In some embodiments, the maximum thickness of the frame or the dimension perpendicular to the maximum transverse dimension may be less than or equal to 3mm. In some embodiments, the maximum thickness of the frame or the dimension perpendicular to the maximum transverse dimension may be less than or equal to 2mm. In some embodiments, the maximum thickness of the frame or the dimension perpendicular to the maximum transverse dimension may be less than or equal to 1mm. Additionally or alternatively, in some embodiments, the maximum thickness of the frame may be less than or equal to 0.5mm, 1mm, 1.5mm, 2mm or any other suitable thickness. In some embodiments, the maximum thickness of the frame may be greater than or equal to 0.5mm. In some embodiments, the maximum thickness of the frame may be greater than or equal to 1mm. In some embodiments, the maximum thickness of the frame may be greater than or equal to 1.5mm. In some embodiments, the maximum thickness of the frame may be greater than or equal to 2mm. Intermediate values ​​between the aforementioned items and combinations of the aforementioned items and values ​​greater than and / or less than the aforementioned items are also contemplated. For example, in some embodiments, the maximum frame thickness can be greater than or equal to 0.5 mm and less than or equal to 4 mm. In some embodiments, the maximum frame thickness can be greater than or equal to 1.5 mm and less than or equal to 2.5 mm.

[0060] In addition, in some embodiments, the framework may include a framework / membrane interface region that can be configured to be combined with one or more membranes of the device. In some embodiments, the framework / membrane interface region may extend radially inward from the framework and may have a maximum thickness that may be the same or different from the maximum thickness of the overall framework or a size perpendicular to the maximum lateral dimension of the device. In some embodiments, the maximum interface region thickness may be less than the maximum frame thickness. For example, in some embodiments, the maximum interface region thickness may be less than or equal to 2mm, 1.5mm, 1mm, 0.5mm or any other suitable thickness. In some embodiments, the maximum interface region thickness may be less than or equal to 2mm. In some embodiments, the maximum interface region thickness may be less than or equal to 1.5mm. In some embodiments, the maximum interface region thickness may be less than or equal to 1mm. In some embodiments, the maximum interface region thickness may be less than or equal to 0.5mm. Additionally or alternatively, in some embodiments, the maximum interface region thickness may be greater than or equal to 0.3mm, 0.5mm, 1mm, 1.5mm or any other suitable thickness. It is also contemplated that the intermediate value between the aforementioned items and the aforementioned items and the combination of the value greater than and / or less than the aforementioned items. In some embodiments, the maximum interfacial region thickness may be greater than or equal to 0.3 mm. In some embodiments, the maximum interfacial region thickness may be greater than or equal to 0.5 mm. In some embodiments, the maximum interfacial region thickness may be greater than or equal to 1 mm. In some embodiments, the maximum interfacial region thickness may be greater than or equal to 1.5 mm. For example, in some embodiments, the maximum interfacial region thickness may be greater than or equal to 0.3 mm and less than or equal to 2 mm. In some embodiments, the maximum interfacial region thickness may be greater than or equal to 0.3 mm and less than or equal to 0.5 mm.

[0061] As described above, the frame / film interface region may extend from the frame, for example, inwardly (e.g., toward the center of the device, its frame and / or film) in the radial direction, and may have any appropriate width in the radial direction. In some embodiments, the radial interface region width of the frame / film interface region may be less than or equal to 5mm, 4mm, 3mm, 2mm, or any other appropriate width. In some embodiments, the radial interface region width of the frame / film interface region may be less than or equal to 5mm. In some embodiments, the radial interface region width of the frame / film interface region may be less than or equal to 4mm. In some embodiments, the radial interface region width of the frame / film interface region may be less than or equal to 3mm. In some embodiments, the radial interface region width of the frame / film interface region may be less than or equal to 2mm. Additionally or alternatively, in some embodiments, the interface region width may be greater than or equal to 0.75mm, 1mm, 1.5mm, 2mm, or any other appropriate width. In some embodiments, the interface region width may be greater than or equal to 0.75mm. In some embodiments, the interface region width may be greater than or equal to 1mm. In some embodiments, the interface region width may be greater than or equal to 1.5mm. In some embodiments, the interface area width may be greater than or equal to 2mm. Also envisioned are intermediate values ​​between the aforementioned items and combinations of the aforementioned items and values ​​greater than and / or less than the aforementioned items. For example, in some embodiments, the maximum interface area width may be greater than or equal to 0.75mm and less than or equal to 5mm. In some embodiments, the maximum interface area width may be greater than or equal to 1.0mm and less than or equal to 2.0mm. In addition, although radial width is described herein, it should be understood that the above width is not limited to extending in the radial direction because the device is not limited to circular geometry. For example, a device with one or more linear sides may include a frame / membrane interface area with a width extending vertically inward from the linear side.

[0062] Additionally, in some embodiments, the device may have an external surface area to volume ratio of greater than or equal to about 20 cm -1 、40cm -1 , 50cm -1 、60cm -1 、80cm -1 、100cm -1 、120cm -1 、150cm -1 , 200cm -1 、300cm -1 、400cm -1 , 500cm -1 、600cm -1 、700cm -1 、800cm -1 、900cm-1 or 1000cm -1 In some embodiments, the ratio of the external surface area to volume of the device can be 25 cm -1 With 1250cm -1 In some embodiments, the ratio of the external surface area to the volume of the device can be between 50 cm -1 With 1000cm -1 In some embodiments, the ratio of the external surface area to the volume of the device can be between 100 cm -1 With 500cm -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.

[0063] As described throughout the present disclosure, multiple binding moieties may be provided in the membrane of the macroencapsulation device. In some embodiments, each binding moiety may be formed in a rounded or circular shape, each having a binding diameter. In various embodiments, the binding diameter may be greater than or equal to 200 μm, 500 μm, 1000 μm, 1500 μm, or any other appropriate distance or diameter. In some embodiments, the binding diameter may be greater than or equal to 200 μm. In some embodiments, the binding diameter may be greater than or equal to 500 μm. In some embodiments, the binding diameter may be greater than or equal to 1000 μm. In some embodiments, the binding diameter may be greater than or equal to 1500 μm. Additionally or alternatively, in some embodiments, the binding diameter may be less than or equal to 2000 μm, 1500 μm, 1000 μm, 500 μm, or any other appropriate distance or diameter. In some embodiments, the binding diameter may be less than or equal to 2000 μm. In some embodiments, the binding diameter may be less than or equal to 1500 μm. In some embodiments, the binding diameter may be less than or equal to 1000 μm. In some embodiments, the binding diameter may be less than or equal to 500 μm. Intermediate values ​​between the aforementioned items and combinations of the aforementioned items and values ​​greater than and / or less than the aforementioned items are also envisioned. For example, in some embodiments, the binding diameter may be greater than or equal to 200 μm and less than or equal to 2000 μm. In some embodiments, the binding diameter may be greater than or equal to 700 μm and less than or equal to 800 μm. In addition, although the binding diameter is described herein, it should be understood that the size of the above-mentioned binding portion is not limited to the diameter because the binding portion is not limited to a circular geometry. For example, in a binding portion formed in a straight line shape, the above-mentioned dimensions may be applicable to the distance between the opposite sides of the straight line shape.

[0064] In some embodiments, it may be desirable to improve vascularization of the macroencapsulated device. Thus, in certain embodiments, one or more through holes may be formed in one or more binding portions located within an interior portion of the membrane disposed radially inward from the frame of the device. These through holes may permit vasculature to grow through the through holes in addition to growing around the upper and lower surfaces of the device. The 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.

[0065] In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimension perpendicular to the axis extending through the through hole may be greater than or equal to 100 μm, 125 μm, 150 μm, 200 μm, 300 μm, or any other suitable through hole diameter. In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimension perpendicular to the axis extending through the through hole may be greater than or equal to 100 μm. In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimension perpendicular to the axis extending through the through hole may be greater than or equal to 125 μm. In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimension perpendicular to the axis extending through the through hole may be greater than or equal to 150 μm. In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimension perpendicular to the axis extending through the through hole may be greater than or equal to 200 μm. In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimension perpendicular to the axis extending through the through hole may be greater than or equal to 250 μm. In some embodiments, the diameter of the through hole of the binding portion or other maximum lateral dimensions perpendicular to the axis extending through the through hole may be greater than or equal to 300 μm. Additionally or alternatively, in some embodiments, the through hole diameter or other maximum lateral dimensions perpendicular to the axis extending through the through hole may be less than or equal to 700 μm, 650 μm, 600 μm, 500 μm, 300 μm, or any other suitable through hole diameter. In some embodiments, the through hole diameter or other maximum lateral dimensions perpendicular to the axis extending through the through hole may be less than or equal to 700 μm. In some embodiments, the through hole diameter or other maximum lateral dimensions perpendicular to the axis extending through the through hole may be less than or equal to 650 μm. In some embodiments, the through hole diameter or other maximum lateral dimensions perpendicular to the axis extending through the through hole may be less than or equal to 600 μm. In some embodiments, the through hole diameter or other maximum lateral dimensions perpendicular to the axis extending through the through hole may be less than or equal to 500 μm. In some embodiments, the through-hole diameter or other maximum lateral dimension perpendicular to the axis extending through the through-hole may be less than or equal to 300 μm. Intermediate values ​​between the foregoing items and combinations of the foregoing items and values ​​greater than or less than the foregoing items are also contemplated. For example, in some embodiments, the through-hole diameter or other maximum lateral dimension perpendicular to the axis extending through the through-hole may be greater than or equal to 250 μm and less than or equal to 350 μm. In some embodiments, the through-hole diameter or other maximum lateral dimension perpendicular to the axis extending through the through-hole may be greater than or equal to 200 μm and less than or equal to 400 μm.

[0066] In addition, in some embodiments, the macroencapsulation device can be formed to have any appropriate distance or spacing (referred to herein as bonding spacing) between two adjacent binding parts. For example, in some embodiments, the bonding spacing may be greater than or equal to 1mm, 2mm, 3mm or any other appropriate spacing. In some embodiments, the bonding spacing may be greater than or equal to 1mm. In some embodiments, the bonding spacing may be greater than or equal to 2mm. In some embodiments, the bonding spacing may be greater than or equal to 3mm. Additionally or alternatively, the bonding spacing may be less than or equal to 5mm, 4mm, 3mm or any other appropriate bonding spacing. In some embodiments, the bonding spacing may be less than or equal to 5mm. In some embodiments, the bonding spacing may be less than or equal to 4mm. In some embodiments, the bonding spacing may be less than or equal to 3mm. It is also envisioned that the intermediate value between the aforementioned items and the aforementioned items and the combination of values ​​greater than or less than the aforementioned items. For example, in some embodiments, the bonding spacing may be greater than or equal to 1mm and less than or equal to 5mm. In some embodiments, the bonding spacing may be greater than or equal to 1mm and less than or equal to 1.5mm.

[0067] In addition, in some embodiments, two or more films can be combined together at the binding periphery, and the binding portion can be located in the binding periphery. In various embodiments, the binding periphery can be formed in any appropriate shape, and any appropriate shape includes any appropriate circular shape, elongated shape, linear shape, polygonal (e.g., pentagon, hexagon, octagon, etc.) shape and / or any other appropriate regular or irregular shape. In some embodiments, the binding periphery can be generally formed as a circle with a diameter. In some embodiments, the diameter or other maximum transverse dimension of the binding periphery can be greater than or equal to 1cm, 1.5cm, 2cm, 2.5cm or any other appropriate distance or diameter. In some embodiments, the diameter or other maximum transverse dimension of the binding periphery can be greater than or equal to 1cm. In some embodiments, the diameter or other maximum transverse dimension of the binding periphery can be greater than or equal to 1.5cm. In some embodiments, the diameter or other maximum transverse dimension of the binding periphery can be greater than or equal to 2cm. In some embodiments, the diameter or other maximum transverse dimension of the binding periphery can be greater than or equal to 2.5cm. Additionally or alternatively, in some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be less than or equal to 7cm, 6.5cm, 6cm, 5cm or any other appropriate distance or diameter. In some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be less than or equal to 7cm. In some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be less than or equal to 6.5cm. In some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be less than or equal to 6cm. In some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be less than or equal to 5cm. It is also envisioned that the intermediate value between the aforementioned items and the combination of the aforementioned items and the value greater than or less than the aforementioned items. For example, in some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be greater than or equal to 1cm and less than or equal to 6.5cm. In some embodiments, the diameter or other maximum transverse dimension of the combined periphery may be greater than or equal to 1.5cm and less than or equal to 6.5cm. In addition, although the diameter of the combined periphery is described herein, it should be understood that the size of the combined periphery is not limited to the diameter because the combined periphery is not limited to a circular geometry. For example, in a bonding perimeter formed in a linear shape, the above dimensions may apply to the distance between opposite sides of the linear shape.

[0068] In some embodiments, after the membranes are combined together (e.g., the periphery and / or the inner part of the first and second membranes are combined), the first and second membranes may be coated with hydrophilic materials and / or subjected to other treatments that may be incompatible with the combining process. In some embodiments, it may be desirable that one or more of the membranes included in the macroencapsulation device are hydrophilic to facilitate the loading of cells into the macroencapsulation device and / or to facilitate one or more fluids, biocompounds, 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 macroencapsulation device can be made of hydrophilic materials and / or treated with hydrophilic coatings. Suitable hydrophilic materials may include, but are not limited to, suitable hydrophilic polymers, polyethylene glycol, polyvinyl alcohol, polydopamine, any combination thereof and / or any other suitable hydrophilic materials that can form a coating on the membrane or can be made of the membrane.

[0069] In some embodiments, the root mean square (RMS) surface roughness of the bonding surface of the film and the frame may be greater than or equal to 5 μm, 10 μm, 15 μm, 20 μm, 30 μm and / or any other suitable RMS surface roughness. The RMS surface roughness may also be less than or equal to 50 μm, 40 μm, 30 μm, 20 μm, 10 μm and / or any other suitable surface roughness. Combinations of the foregoing are contemplated, including, for example, between 5 μm and 50 μm or equal to their RMS surface roughness. In some embodiments, the surface roughness may more preferably be between 5 μm and 10 μm. The RMS surface roughness value of the bonding surface can be measured using a technique based on optical tomography, image analysis of the cross-sectional bonding area and / or using any other suitable technique.

[0070] Although specific dimensions, parameters, and relationships related to the macroencapsulation device and the materials from which it is made 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 size, configuration, material properties, and / or related performance parameters may be used for the device, depending on the desired application.

[0071] Depending on the specific application and the desired duration of use, the macroencapsulated device may be configured to have any appropriate fatigue life when implanted in a subject. For example, in some embodiments, the macroencapsulated device may be configured for implantation in the abdominal tissue of a subject, where the macroencapsulated device may be subjected to abdominal contractions during use. Therefore, in some embodiments, the fatigue life of the macroencapsulated device may be greater than or equal to 50,000 cycles, 60,000 cycles, 70,000 cycles, and / or 80,000 cycles. In some embodiments, the fatigue life of the macroencapsulated device may be greater than or equal to 50,000 cycles. In some embodiments, the fatigue life of the macroencapsulated device may be greater than or equal to 60,000 cycles. In some embodiments, the fatigue life of the macroencapsulated device may be greater than or equal to 70,000 cycles. In some embodiments, the fatigue life of the macroencapsulated device may be greater than or equal to 80,000 cycles. In some embodiments, the fatigue life may also be less than or equal to 1,000,000 cycles, 500,000 cycles, 200,000 cycles, 100,000 cycles, and / or 80,000 cycles. In some embodiments, the fatigue life may also be less than or equal to 1,000,000 cycles. In some embodiments, the fatigue life may also be less than or equal to 500,000 cycles. In some embodiments, the fatigue life may also be less than or equal to 200,000 cycles. In some embodiments, the fatigue life may also be less than or equal to 100,000 cycles. In some embodiments, the fatigue life may also be less than or equal to 80,000 cycles. Combinations of the foregoing ranges are contemplated, including, for example, fatigue lives between 50,000 cycles and 200,000 cycles or equal to them. Devices having fatigue lives greater than and less than those described above are also contemplated, as the present disclosure is not limited in this manner. For the purposes of this application, the fatigue life of the macroencapsulated device can be determined using a fatigue cycle test at a cyclic applied load of 12N, which is similar to the force that the device may experience when implanted in the abdominal tissue of a subject in vivo. In some embodiments, the fatigue life of the device achieved by measuring the fatigue of the dual-phase central grid using a cyclic applied load of 45N is between 1,000 cycles and 500,000 cycles. In some embodiments, the fatigue life of the device achieved by measuring the fatigue of the dual-phase central grid using a cyclic applied load of 45N is between 10,000 cycles and 80,000 cycles. In some embodiments, the fatigue life of the device achieved by measuring the fatigue of the dual-phase central grid using a cyclic applied load of 45N is between 40,000 cycles and 1,000,000 cycles.

[0072] In some embodiments, the cell group contained in the compartment of the macroencapsulation device may be an insulin secreting cell group. In some embodiments, the cell group contained in the compartment of the macroencapsulation device includes a heterogeneous cell group. In some embodiments, the cell group includes at least one cell derived from a stem cell-derived cell. In some embodiments, at least one cell is a genetically modified cell. In some cases, at least one cell is genetically engineered to reduce the immune response in the subject after implantation of the device compared to comparable cells that are not genetically engineered. In some embodiments, the cell group is a stem cell-derived cell capable of glucose-stimulated insulin secretion (GSIS). For example, a suitable cell group may include pancreatic progenitor cells, endocrine cells, β cells, a matrix including one or more of the foregoing items, or any combination thereof. In addition, the matrix may include isolated islet cells that can synthesize one or more biological products, isolated cells from the pancreas, isolated cells from tissues, stem cells, stem cell-derived cells (e.g., stem cell-derived islet cells), induced pluripotent cells, differentiated cells, transformed cells, or expression systems. In some embodiments, the macroencapsulation device includes a stem cell-derived islet cell group. In some embodiments, the stem cell-derived islet cells include stem cell-derived β cells, stem cell-derived α cells, and / or stem cell-derived δ cells.

[0073] According to a specific embodiment, cells of a therapeutically effective density can be loaded into one or more compartments of a macroencapsulation device. Suitable cell densities disposed in a compartment may be greater than or equal to about 1,000 cells / μL, 10,000 cells / μL, 50,000 cells / μL, 100,000 cells / μL, 500,000 cells / μL, 750,000 cells / μL, 1,000,000 cells / μL, and / or any other suitable cell density. Suitable cell densities disposed in a compartment may 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. Combinations of the foregoing are contemplated, including cell densities between about 1000 cells / μL and 1,000,000 cells / μL. In some embodiments, the cell density disposed in the compartment is between 100,000 cells / μL and 1,000,000 cells / μL. In some embodiments, the cell density disposed in the compartment is between 75,000 cells / μL and 500,000 cells / μL. In some embodiments, the cell density disposed in the compartment is between 500,000 cells / μL and 1,000,000 cells / μL. In some embodiments, the cell density disposed in the compartment is between 750,000 cells / μL and 1,000,000 cells / μL. In some embodiments, the cell density disposed in the compartment is between 750,000 cells / μL and 1,250,000 cells / μL. Of course, cell densities greater and less than those recited above may also be used, depending upon the desired application and cell type used.

[0074] Turning to the drawings, specific non-limiting embodiments are described in more detail. It should be understood that the various systems, components, features, and methods described with respect to these embodiments may be used alone and / or in any desired combination, as the present disclosure is not limited to the specific embodiments described herein.

[0075] Figures 1A to 1C An embodiment of a membrane of a macroencapsulation device before being mounted to a frame is shown. As shown, the membrane may include a first membrane layer 102 and a second membrane layer 104. In some embodiments, the first membrane layer and / or the second membrane layer may include a polymer material, such as ePTFE. In various embodiments, each of the first membrane layer 102 and the second membrane layer 104 may be sintered or unsintered. Each of the first membrane layer and the second membrane layer may also include a single layer or multiple layers.

[0076] The first film layer 102 and the second film layer 104 may be bonded together at a bonded perimeter 122 and a bonded portion 124 located within the bonded perimeter. Figure 1A , the top surface of the second membrane layer 104 is shown as having a bonding perimeter 122 of the membrane extending around the perimeter of the membrane (e.g., where the first membrane layer and the second membrane layer are bonded). The bonding perimeter 122 can form an interior volume disposed between the first membrane layer and the second membrane layer, the interior volume being configured to encapsulate a cell population. In some embodiments, the bonding perimeter 122 can extend completely around the perimeter of the membrane; however, as Figure 1A As shown, the binding perimeter may have an unbound portion 135, for example to receive and / or cooperate with a filling port through which a cell population can be introduced into the internal volume of the device. As will be appreciated, the size of the binding perimeter 122 can at least partially define the size of the internal volume. For example, in embodiments in which the membrane and / or device has a generally circular shape, the binding perimeter 122 can have a diameter 128 that can at least partially define the size of the internal volume between the first membrane layer and the second membrane layer.

[0077] In some embodiments, the internal volume between the first membrane layer and the second membrane layer may include a network of continuous interconnected volumes formed by and / or between the various bonded portions of the membrane. Figure 1C As shown, the internal volume between the first film layer 102 and the second film layer 104 may include a network of volumes (e.g., channels 126) formed between the bonding portions 124. In some embodiments, the internal volume may have a volume thickness 136, which may be the maximum distance between the first film layer and the second film layer in a direction perpendicular to the maximum lateral dimension of the device. As will be appreciated, the total thickness of the film (e.g., total thickness 140) may depend at least in part on the internal volume thickness 136 and the film layer thickness 138 of each film layer. As described herein, the thickness may be measured in a direction perpendicular to the maximum lateral dimension of the device.

[0078] As shown, the binding perimeter can be arranged radially inward from the outer perimeter 150 of the film. The binding portion 124 can take the form of binding points distributed in the surface area of ​​the cross-film in a hexagonal array. However, any suitable shape, arrangement, configuration and / or spacing of these binding areas can also be used. For example, Figure 1C As shown, the bonding spacing 142 can be the distance between adjacent bonding portions 124. In addition, in some embodiments, one or more bonding portions 124 can include a through hole 132 formed therein. Each through hole can have a through hole diameter 144. Due to the presence of these bonding areas located radially inward from the bonding perimeter of the membrane, the internal volume formed between the membranes once in a filled configuration (e.g., as Figure 1CThe bonding portion 124 may take the form of a plurality of interconnecting channels 126 corresponding to unbonded areas of the membrane extending between the bonded portions.

[0079] In some embodiments, when the membrane layer is connected to the frame, the unbound portion 135 can be positioned and sealed around a fill port of the frame so that the fill port is in fluid communication with the internal volume. In some embodiments, a fill port can be included in the frame to allow fluid communication between the external environment and the internal volume of the device in at least one direction. For example, the fill port can be configured to allow the introduction of a cell population into the volume between the first membrane layer and the second membrane layer. Figures 1D to 1F A non-limiting example of a fill port 250 included on the frame 202 of the macroencapsulation device 200 is shown according to one embodiment. The fill port includes a portion of the macroencapsulation device extending through the fill port to the macroencapsulation device. Figures 1A to 1C The first membrane layer 102 and the second membrane layer 104 are shown to form a through hole (not depicted) in the internal volume.

[0080] In various embodiments, the frame 202 can be formed in any suitable shape, including any suitable circular shape, elongated shape, rectilinear shape, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.) shape, and / or any other suitable regular or irregular shape. For example, in the illustrated embodiment, the frame 202 can be formed in a generally circular shape having a frame diameter 214 and / or a frame thickness 220. The frame thickness can be the maximum thickness between any two opposing surfaces or points of a cross-section of the frame. In some embodiments, the frame thickness 220 can be measured in a direction perpendicular to the maximum lateral dimension of the frame 202 and / or the device 200.

[0081] Additionally, in some embodiments, the device 200 may include a frame / membrane interface region 206 that may extend inwardly (e.g., radially inwardly) from the frame 202 and may be configured to bond with one or more membranes of the device. Figure 1D The line 1F-1F is intercepted) Figure 1F As shown in the cross-sectional view of , the frame / membrane interface region 206 may extend from the frame 202 to provide one or more surfaces to which the film may be adhered, mechanically interlocked, fastened, fixed and / or bonded. The frame / membrane interface region may have an interface region width 216 in which the frame and the film may extend together, which may be the distance between the innermost portion of the frame 202 and the innermost portion of the frame / membrane interface region 206. In addition, the frame / membrane interface region may have an interface region thickness 218, which may be the thickness of the frame / membrane interface region in a direction perpendicular to the maximum lateral dimension of the frame 202 and / or the device 200j.

[0082] Figure 2A and Figure 2B Each macroencapsulation device 200 is shown. Each macroencapsulation device 200 includes an adhesive ( Figure 2A ) and mechanical bonding area ( Figure 2B ) is a frame 202, a membrane 204, and a frame / membrane interface region 206 that are bonded together. The frame / membrane interface region 206 as shown can be a region of the macroencapsulated device 200 where the membrane 204 and the frame 202 overlap each other. In some embodiments and as shown, the frame / membrane interface region 206 can be disposed around at least a portion of the outer perimeter of the membrane 204. For example, the frame / membrane interface region 206 can be disposed radially outward from a bonded perimeter 207 around the sealed interior volume of the device. The membrane 204 and the frame 202 can be joined together at the frame / membrane interface region 206.

[0083] In some embodiments, the membrane can be mounted to the frame with some slack in the membrane relative to the frame before being filled with the desired cell population. When the membrane 204 is mounted to the frame 202, slack can accumulate in certain regions along the interface between the frame and the membrane. For example and as Figure 2A As shown, significant membrane slack accumulations 208 may form during the adhesive installation process. Slack accumulations 208 may be areas where the membrane 204 bunches together or folds over itself. It should be appreciated that when the macroencapsulated device 200 flexes or bends, as may occur during use or implantation, stress concentrations may occur in the membrane 204, in areas including these slack accumulations 208, which may lead to premature failure of the macroencapsulated device 200.

[0084] It can be noted that Figure 2B The macroencapsulation device 200 may have a more uniform distribution of relaxation and may not show any visible relaxation accumulation. As will be described below, the uniform distribution of relaxation in the film 204 can be achieved by forming a mechanical interlocking region at the frame / film interface region 206. In some embodiments, each mechanical interlocking region may include an interlocking portion, an overlap, a folding portion or a curling portion in the film 204, and the interlocking portion, the overlap, the folding portion or the curling portion mechanically locks in the plastic or thermoplastic deformation portion of the framework 202. In such embodiments, each mechanical interlocking region may occupy a part of relaxation in the film 204 along the interface between the framework 202 and the film 204. In the embodiment where each mechanical interlocking region is substantially uniform in size, substantially uniform mechanical interlocking regions can provide substantially uniform relaxation distribution along the frame / film interface region 206. Do not wish to be bound by theory, this can be attributed to the deformation of one or more films in the mechanical interlocking region, and the mechanical interlocking region occupies at least a part of relaxation along the frame / film interface.

[0085] FIG. 3A to FIG. 3BEach shows a close-up of the frame / membrane interface region after the membrane has been removed from the frame 202. Since the membrane of each device has been removed, Figure 3A and Figure 3B None of them depicts the complete membrane. However, FIG. 3A to FIG. 3B Removal of the middle membrane allowed for clearer delineation of the frame / membrane interface region in each device. Figure 3A A frame / membrane interface region 206 is shown where the membrane has been bonded to the frame 202 using an adhesive 210 . Figure 3B A frame / membrane interface region 206 is shown where the membrane has been joined to the frame 202 using mechanical bonding techniques as disclosed herein.

[0086] like Figure 3A As shown, the adhesive 210 may tend to be unevenly dispersed or distributed across the frame / membrane interface region 206. In some embodiments, this may result in uneven strength of the adhesive bond between the membrane and the frame 202, leading to premature failure of the macroencapsulated device as described above.

[0087] like Figure 3B As shown, a plurality of mechanical interlocking regions 212 may be formed at the frame / membrane interface region 206. Each mechanical interlocking region 212 may form a mechanical locking interface between the membrane and the frame. Figure 3A The mechanical bonding techniques disclosed herein may produce a more uniform bond in position, size, and strength at the frame / membrane interface region 206 compared to the uneven adhesive bond shown.

[0088] 4A to 4F Depicted is a cross section of a frame / membrane interface region 206 as seen along a portion of the length of the frame / membrane interface region of a macroencapsulated device. It should be appreciated that multiple mechanical interlocking regions may be as shown. 4A to 4F The plurality of mechanical interlocking regions may be formed to extend around at least a portion of the outer periphery of the membrane of the macroencapsulation device or along any other appropriately shaped interface between the membrane and the frame. In some embodiments, the plurality of mechanical interlocking regions may form a sealed interior volume of the macroencapsulation device disposed between two opposing membrane layers of the macroencapsulation device. For example, the plurality of mechanical interlocking regions may form a compartment within which a cell population may be encapsulated.

[0089] exist Figure 4A , a first film layer 102 and a second film layer 104 are overlaid on a frame 202. In some embodiments, an intermediate material layer 210 may be disposed between the one or more films of the device and the frame. The intermediate material layer may include a material having a melting temperature between the melting temperature of the frame and the melting temperature of the one or more films. Although the illustrated embodiments depict a device having two film layers, it should again be understood that the macroencapsulated device as described herein may have any suitable number of film layers, as the present disclosure is not limited in this regard.

[0090] In some embodiments of the manufacturing method, the first film layer 102, the second film layer 104, the frame 202, and the optional intermediate layer 210 can be placed between the first mold 414 and the second mold 418. In some embodiments, the first mold 414 can include a support surface 432, which can be placed against a corresponding surface of the frame 202. In the illustrated embodiment, for ease of illustration, the support surface 432 and the corresponding surface of the frame are depicted as flat. However, it should be understood that the frame can be formed in any suitable geometric structure, and the mold can be formed in any suitable shape or configuration to correspond to or otherwise support the frame.

[0091] In some embodiments, the system may include a heater configured to heat the interface region between the film and the frame. For example, the first mold 414 may be associated with one or more heaters 416. The heater 416 may be configured to provide heat to the frame 202 through the first mold 414 or other appropriate parts of the system. In some embodiments, the heater 416 may be one or more resistive heaters. In some embodiments, the heater 416 may be one or more electric heater cartridges. In some embodiments, the heater 416 may be one or more laser heaters. In some embodiments, the heater 416 may be one or more radiation heaters. In some embodiments, the heater 416 may be one or more induction heaters. In some embodiments, the heater 416 may be one or more ultrasonic horns. Regardless of the specific heater used, the heater 416 may heat the frame 202 to a temperature sufficient to promote plastic deformation of the frame 202, while keeping the temperature of the film layers 102 and 104 at a temperature lower than the melting temperature and / or sintering temperature of the film layers. In this regard, the frame 202 can be thermoplastically deformed without changing or damaging the material properties of the portion adjacent to the bonding area of ​​one or more films.

[0092] In some embodiments, the second mold 418 may also be positioned in the system so that the membrane layers 102 and 104 are disposed between the first mold 202 and the second mold. For example and as shown, the second mold 418 may be placed opposite the first mold to contact the first membrane layer 102 on one side of the membrane layer. The second mold 418 may be configured to deform a portion of the flexible membrane layer and thermoplastically deform the lower portion of the frame. The deformation of the membrane layer and the frame may allow one or more mechanical interlocking regions to be formed, as will be described below.

[0093] In some embodiments, the formation of multiple mechanical interlocking regions can be promoted by forming alternating raised areas and recessed areas along the length of the film / frame interface. Therefore, the second mold 418 may include one or more serrations 420 or other protrusions configured to form desired recessed portions and raised areas. In the embodiment specifically depicted, each serration 420 may be configured to deform a portion of the film and frame when the serration 420 is pressed into the film and frame at a desired forming temperature higher than the melting temperature of the frame. It should be understood that although the illustrated embodiment depicts the second mold 418 with multiple serrations 420 to simultaneously form multiple deformations, in other embodiments, a single serration or a group of serrations may be alternately pressed into the film / frame interface and moved along the length of the film / frame interface to orderly form different parts of the bonding interface. In addition, it should be understood that the depicted embodiment only includes serrations in the second mold 418 and does not limit the placement of serrations in other embodiments. For example, in some embodiments, serrations may be included in first die 414 in addition to or in lieu of the serrations shown on second die 418 .

[0094] Figure 4B It is shown that the second mold 418 moves relative to the first mold 414 to compress the first film layer 102, the second film layer 104 and the frame 202 between the molds and deform them. In the embodiment where the second mold 418 includes a sawtooth 420, each sawtooth 420 or other protrusion can form a plurality of recessed portions 426 and raised areas 427 in the first film layer 102, the second film layer 104 and the frame 202, so that there are alternate raised areas and recessed areas along at least a portion of the length of the interface. Again, this deformation can be carried out at a temperature where the frame can be thermoplastically deformed and one or more films maintain their structural integrity during the deformation process. For example, the temperature of at least a portion of the frame material and the film can be greater than the glass transition temperature of the frame material and in some cases the melting temperature. The temperature can also be at least less than the melting temperature of one or more films and in some cases the sintering temperature or the glass transition temperature. Again, this can allow the frame to deform without significantly changing the material properties of the film in and / or adjacent to the bonding area in the bonding area.

[0095] like Figure 4CAs shown, a third mold 422 may also be used. In some embodiments, the second mold 418 may be replaced with a third mold 422. In some embodiments, after the second mold 418 has completed the first deformation (e.g., by forming a recessed portion 426 in the frame 202 and the film layer 102, 104 as shown in the figure), the third mold 422 may be used to produce a second deformation. In some embodiments, the third mold 422 may have a different geometry from the second mold 418 so as to produce a second deformation different from the first deformation produced by the second mold. For example, the third mold 422 may include a flat surface 424 or other appropriately shaped surface configured to deform a raised area 427 of the deformed film / frame interface.

[0096] like Figure 4D As shown, the first mold 414 and / or the third mold 422 can be displaced to compress the frame 202 and the film layers 102, 104 therebetween. When the flat surface 424 or other appropriately shaped surface is compressed against the raised portions of the frame 202 and the film layers 102, 104, the raised area 427 can begin to fold into the recessed portion 426 formed by the second mold 418 and on top of the recessed portion. Thus, the raised area can be deformed to at least partially overlap with the recessed area of ​​the interface. It should be understood that the recessed portion and the raised area can be deformed without forming a gap because any air within the recessed portion can be allowed to escape during the deformation process.

[0097] like Figure 4E As shown, when the first mold 414 and the third mold 422 continue to be compressed toward each other, the frame 202 and the film layers 102, 104 can be deformed so that the portion of the film is folded and compressed between the corresponding overlapping portions of the recessed portion 426 and the deformed raised area to form a mechanical interlocking area 428. For example and as shown, the first portion 102A of the first film layer 102 and the first portion 104A of the second film layer 104 can be compressed between the first portion 202A of the frame 202 corresponding to the recessed area and the second portion 202B of the frame 202 corresponding to the raised area of ​​the frame, and the raised area overlaps at least partially with the recessed area. Due to its flexibility, one or more films (e.g., film layers 102 and 104) extend out from these orderly arranged mechanical interlocking areas and extend between them.

[0098] It should be understood that in the above embodiments, the relative movement of each mold can be coordinated in any suitable manner. For example, the molds depicted can be moved together or individually in various processing steps to provide the desired relative movement in order to compress the frame and film between the molds.

[0099] Figure 4FDescribe the frame / film interface region 206 of the macroencapsulation device after the frame and the film have been combined together. The interface region 206 may include multiple mechanical interlocking regions 428, as shown and described above. The interface region 206 may also include an outer surface 230 of one or more films, which is substantially flat due to the second deformation performed by the third mold 422. However, embodiments in which the outer surface of the film located opposite to the frame is uneven along the film / interface region are also envisioned.

[0100] Compare Figure 4F and Figure 4A It should be appreciated that the mechanical interlocking regions 428 can promote the distribution of relaxation in the film layers 102, 104 throughout the frame / film interface region 206. Specifically, in each mechanical interlocking region 428, the film layers 102, 104 can be relaxed from Figure 4A The flat configuration shown is deformed into Figure 4F The interlocking configuration of the flexible film has been folded into a T-shape in the interlocking configuration so that the cross-sectional length of the film in this region is less than the cross-sectional length of the mechanical bonding region along the film / frame interface. In other words, for a given linear length 430 along the frame / film interface region 206, the path length of the interface 434 between the film and the frame can be greater in the interlocking configuration than in the flat configuration. Therefore, for a given linear length 430, the interlocking configuration can utilize a greater length of the film compared to the flat configuration, thereby distributing excess film slack throughout the frame / film interface.

[0101] FIG. 5A to FIG. 5C Schematic diagrams of various embodiments of a bonding apparatus 600 for making a macroencapsulation device 200 according to the methods disclosed herein are depicted. FIG. 5A to FIG. 5CAs shown in each of the above, the combined device 600 may include a plurality of molds, including a first mold 414. The first mold 414 may be configured to hold the frame 202 and / or one or more films 204 of the macroencapsulation device. In some embodiments, the first mold 414 may include a holding mechanism configured to hold the frame 202 and / or the film 204 against the first mold. The first mold 414 or the holding mechanism may be configured to hold the frame 202 and the film 204 in an overlapping configuration, in which at least a portion of the film 204 overlaps with at least a portion of the frame 202, as shown. For example, in the depicted embodiment, the first mold 414 may include a plurality of vacuum ports 602 for applying a holding suction force to one or more portions of the macroencapsulation device 200. Each of the vacuum ports 602 may be connected to a vacuum source (e.g., a pump, a vacuum line, or other appropriate vacuum source). The vacuum port 602 may be disposed at a position corresponding to the desired holding position of the film 204 on the first mold 414, so that the first mold 414 is configured to hold the film 204 in a desired position and configuration. In various embodiments, suction may be used to hold the membrane 204, the frame 202, or both. Although the depicted embodiments include a holding mechanism that includes a vacuum port, it should be appreciated that some embodiments may additionally or alternatively include other holding mechanisms, including clips, detents, snap fittings, friction fittings, threaded arrangements, magnetic arrangements, fasteners, and / or any other suitable holding mechanisms.

[0102] The bonding apparatus 600 may also include one or more heaters 416. For example, one or more heaters may be incorporated into the first mold 414 or other suitable portion of the bonding apparatus to apply heat to the frame. Specifically, the one or more heaters 416 may heat the first mold 414, which may transfer heat to the frame 202 to raise the temperature of the frame to a desired processing temperature. Of course, it should be understood that the one or more heaters may be incorporated into another portion of the bonding apparatus and / or any suitable type of heating may be used to heat the frame, as the present disclosure is not limited in this manner.

[0103] In some applications, it may be desirable to maintain the temperature of the active portion of one or more membranes (i.e., the portion of the one or more membranes that encapsulates the cell population and through which material flows) below the temperature of the portion of one or more adjacent portions of the membrane that are being bonded during the formation of the plurality of mechanical interlocking regions. For example, in some embodiments, it may be desirable to prevent overheating of the active portion of the one or more membranes 204 of the macroencapsulation device so as to substantially prevent the properties of the active portion of the one or more membranes from changing. Thus, in some embodiments, the bonding apparatus 600 may be configured to cool one or more portions of the one or more membranes 204 and / or thermally isolate the one or more portions from heat applied to the frame 202. For example, in the depicted embodiment, the first mold 414 may include one or more thermal shields 604, which may correspond to insulating material, an air gap, or other suitable insulating configuration disposed between the one or more heaters and the active portion of the one or more membranes.

[0104] In one such embodiment and as shown, one or more thermal shields 604 (e.g., air gaps as depicted) may be positioned between portions of the first mold 414 against which the frame 202 is disposed during formation and portions of the first mold against which the film 204 is disposed during formation. As described above, in other embodiments, active and / or passive coolers may be thermally coupled to one or more portions of one or more films (e.g., active portions of one or more films) to remove heat from the one or more films during the formation process so as to maintain the temperature of the corresponding portions of the films below the desired operating temperature. Such coolers may include, but are not limited to, cooling channels formed in the structure, heat sinks, thermoelectric coolers, liquid cooling devices, forced ambient air cooling devices, forced cold air cooling devices, chemical cooling devices (utilizing, for example, liquid nitrogen, dry ice, or other coolant chemicals), passive cooling devices (utilizing, for example, cooling fins, thermally conductive materials, and / or specialized geometric structures), Peltier modules, and / or any other suitable type of cooler. Of course, embodiments are also contemplated in which thermal shields and / or coolers are not used to thermally isolate a portion of one or more films.

[0105] In some embodiments, the first mold 414 can optionally be configured to deform a portion of the film 204 to promote uniform distribution of slack in the film throughout the frame / film interface. The plane of the film 204 can be defined when the film 204 is laid flat, such as Figure 1B As shown and FIG. 5A to FIG. 5C In some embodiments, the dome 606 may be included in the first mold 414 to deform the film in a direction out of the plane of the film 204 and the frame 202, see FIG. 5A to FIG. 5B . If through Figure 5A Implementation plan and Figure 5BAs will be appreciated from a comparison of the embodiments of FIG. 6A and FIG. 6B , the dome 606 (if included) may have any desired geometry or curvature, depending on the embodiment. For example, increasing the amount of membrane relaxation associated with a larger macroencapsulation volume may be associated with a larger dome and out-of-plane deformation of one or more membrane layers during the bonding process, see FIG. Figure 5A and Figure 5B In some embodiments, FIG. 5A to FIG. 5C The dome 606 of various embodiments may include grooves, ridges and / or serrations as described above. In some embodiments, FIG. 5A to FIG. 5C The dome 606 of various embodiments may include grooves, such as radial grooves. In some embodiments, FIG. 5A to FIG. 5C The vault 606 of various embodiments may include ridges. In some embodiments, FIG. 5A to FIG. 5C The dome 606 of various embodiments may include serrations. In other embodiments, the serrations may be included on a fixture (not shown) that may be configured to cooperate with the bonding apparatus 600 or a mold component thereof to produce deformations in the macroencapsulation device.

[0106] In some embodiments, the first mold 414 may not include the dome 606. For example, in Figure 5C In the embodiment shown, instead of Figure 5A and Figure 5B As shown in the dome, the first mold 414 may include a flat surface 608. In such embodiments, grooves, ridges, and / or serrations may still be included on the first mold 414. Thus, it should be appreciated that the first mold 414 may include any desired geometry, as the present disclosure is not limited in this regard.

[0107] The plurality of molds of the combined apparatus 600 may further include at least a second mold (not shown; see FIG. 4A to FIG. 4B or Fig. 7A ) and a third mold 422. Each of the second mold, the third mold, and any additional molds can be configured to produce a different deformation in the macroencapsulation device. For example, the second mold can be configured to produce a first deformation (e.g., FIG. 4A to FIG. 4C The concave portion 426), and the third mold can be configured to produce a second deformation (for example, the above FIG. 4E to FIG. 4F Mechanical interlocking area 428). FIG. 5A to FIG. 5CIn an embodiment of the present invention, the third mold 422 may include a flat surface 424 configured to produce a mechanical interlocking area 428 as described above. Multiple molds of the bonding apparatus 600 may be interchangeable within the bonding apparatus 600, so that the first deformation and the second deformation can be produced in a single macroencapsulated device 200 without removing the macroencapsulated device 200 from the bonding apparatus 600. However, embodiments are also contemplated in which separate forming processes are performed sequentially on different bonding apparatuses with different molds.

[0108] In operation, the macroencapsulation device 200 can be positioned against the first mold 414 as shown. The vacuum source can be activated to hold the film 204 and the frame 202 against the first mold 424. The heater 416 can be activated to provide heat to the frame 202, while the heat shield 604 can prevent the heat from the heater 406 from passing through the dome 606 and excessively heating adjacent portions of the film 204. The third mold 422 can be pressed in the direction of arrow A to produce the desired deformation in the frame 202 and the film 204. Using a single mold or multiple molds as described above, a series of deformations can be produced that can form multiple mechanical interlocking areas that secure the film 204 to the frame 202.

[0109] As part of the forming and bonding process, it may be desirable to seal adjacent membrane layers together to form a sealed interior cavity into which a cell population may be introduced. Figure 6 A modification of the bonding apparatus 600 for making the macroencapsulation device 200 is shown. This embodiment is substantially similar to that of FIGS. Figure 5C However, the sealing mold 436 can be configured to bond adjacent layers of one or more membranes 204 in an area disposed radially inward from the frame 202. For example, such an embodiment can be used as described with respect to Figure 1A to Figure 1B The described formation of bonding portions between the layers of the membrane includes a bonding perimeter that extends at least partially around the perimeter of the sealed interior volume of the macroencapsulation device to form one or more compartments within the membrane 204 for housing a cell population.

[0110] In the illustrated embodiment, a heater such as the ultrasonic horn 702 shown or other suitable heater may be operably coupled to the sealing mold 436 and / or the first mold 414. During operation, the heater may heat the portion of the film compressed between the first mold and the sealing mold to facilitate bonding of one or more layers of the film 204 when the film layers are compressed between the first mold and the sealing mold. The use of the ultrasonic horn in this embodiment may allow energy to be applied with sufficient precision to allow bonding to be formed in the desired area of ​​the film 204 without compromising the material properties of the film 204 in other areas. However, it should be understood that heat may be applied using any suitable heater to bond the film layers.

[0111] FIG. 7A to FIG. 7B Two embodiments of molds according to the present disclosure are depicted. In some embodiments, the size and shape of the mold can be designed to receive a portion of the corresponding mold when pressed toward the corresponding mold. For example, in the embodiments shown above, the size and shape of the first mold 418 and the second mold 422 can be designed to receive a portion of the first mold such as FIG. 5A to FIG. 6 The top surface of each mold oriented toward the macroencapsulated device during formation can be configured to produce a desired deformation in the frame and / or membrane of the macroencapsulated device. In some embodiments, the first mold 418 may include a top surface having a plurality of serrations 420 to produce a plurality of recesses in the macroencapsulated device as described above, see Fig. 7A In some embodiments, the second mold 422 may include a flat surface 424 to further create a mechanical interlocking region as described above, see Figure 7B .

[0112] Although certain embodiments described herein contemplate the use of multiple molds, it should be understood that, depending on the desired deformation in the macroencapsulation device, only a single mold may be used to achieve the desired deformation. For example, the position and / or orientation of the mold (which may correspond to any structure for deforming the frame and membrane) may be controlled to produce multiple sets of desired deformations in order to produce a bond between the frame and one or more membranes.

[0113] Figure 8 A flow chart showing an embodiment of a method for manufacturing a macroencapsulated device according to the present disclosure is depicted. At step 802, the membrane may be aligned so that the membrane overlaps at least partially with a corresponding portion of the frame of the macroencapsulated device. The overlapping portion of one or more membranes and the frame may include a desired frame / membrane interface region to be combined. At step 804, the macroencapsulated device or a portion thereof may be heated to facilitate deformation. For example, the frame of the macroencapsulated device may be directly or indirectly heated to a temperature greater than the glass transition temperature of the frame and, in some embodiments, the melting temperature. As previously described, this temperature may be less than the melting temperature of one or more membranes, and in some cases less than the sintering temperature. At step 806, one or more flexible membranes may be deformed, and the frame may be thermoplastically deformed so as to form a plurality of alternating concave and convex regions along at least a portion of the membrane / frame interface and, in some cases, the entire length. The convex regions of the frame and one or more membranes may be deformed to overlap at least partially with the concave regions and compress a portion of one or more membranes between the relative portions of the deformed frame to form a plurality of mechanical interlocking regions disposed along the length of the membrane / frame interface.

[0114] Example: Favorable implantation and explant durability testing with reduced interface failure and no reduction in cell viability

[0115] As mentioned above, the strong, firm and / or durable combination between film and framework can be realized by mechanical interlocking combination described herein, and can not significantly affect the vigor of surrounding tissue cells, or even have a positive impact on cell viability.For example, the macroencapsulated device made using the mechanical interlocking region is implanted in miniature pigs together with a similar device made by using adhesion combination instead of mechanical combination.After 6 months of residence time, all devices are removed.Observe that all devices remain intact, thereby confirm the in vivo durability of mechanical interlocking region described herein.Then measure the vigor of surrounding tissue cells, and make each device stand additional fatigue test.

[0116] like Fig. 9 As shown, the cell viability of the mechanical binding device was similar to that of the adhesion binding device, with a slight improvement noted in the mechanical binding device. Fig.10 As shown in Figure 2, the durability of the mechanical bonded device was significantly improved compared to the adhesive bonded device, and significantly higher failure cycles were observed. FIG. 11A to FIG. 11B , the failure in the mechanical bonding device 200B was limited to the membrane 204B, as shown by the membrane failure 204F. The mechanical interlocking interface between the membrane 204B and the frame 202B withstood the fatigue test. In contrast, the adhesive bonding device 200A failed at both the membrane 204A and the interface region 206A between the membrane 204A and the frame 202A, as shown by the membrane failure 204F and the interface failure 206F, respectively. At the interface failure 206F, it was observed that the adhesive 210A had detached from the interface region 206A.

[0117] In view of the above, it should be appreciated that the mechanical interlocking regions described herein can significantly mitigate failure modes that may exist in other bonding technologies. Specifically, the mechanical interlocking bonds described herein can mitigate failures such as detachment at the interface between the membrane and the frame. Additionally, these benefits can be obtained without a significant adverse effect on cell viability within the device or with a positive effect on cell viability.

[0118] Example: Reduced immune response

[0119] In addition, as described above, the mechanical interlocking regions described herein can result in a reduced immune response compared to similar devices that are adhesively bonded. For example, the mechanically bonded devices and adhesively bonded devices were each evaluated in a macrophage polarization assay to determine the level of pro-inflammatory cytokine secretion caused by each device. THP-1 macrophages were seeded on each device, and the levels of 20 different pro-inflammatory cytokines secreted by the macrophages were measured after 6 days. Fig.12As shown, reduced expression was observed in most cytokines in response to the mechanical binding device compared to the adhesive binding device, with the majority of cytokines showing significantly reduced expression for the mechanical binding device. This suggests that the mechanical binding device results in a reduced immune response compared to a similar device that is adhesively bound.

[0120] Although the present teaching has been described in conjunction with various embodiments and examples, it is not intended that the present teaching be limited to such embodiments or examples. On the contrary, as will be appreciated by those skilled in the art, the present teaching encompasses various alternatives, modifications and equivalents. Therefore, the foregoing description and accompanying drawings are intended only as examples.

Claims

1. A method for manufacturing a macroencapsulation device, the method comprising: aligning one or more membranes of the macroencapsulation device with a frame of the macroencapsulation device such that a portion of the one or more membranes at least partially overlaps a portion of the frame; as well as The portion of the one or more membranes is deformed and the portion of the frame is thermoplastically deformed to form a plurality of mechanically interlocking regions of the one or more membranes and the frame.

2. The method of claim 1, wherein the plurality of mechanical interlocking regions extend around at least a portion of a perimeter of the one or more films.

3. The method of any one of the preceding claims, wherein the plurality of mechanically interlocking regions extend at least partially around a sealed interior volume disposed between two layers of the one or more films.

4. The method of claim 3, wherein the sealed interior volume is configured to encapsulate a population of cells.

5. The method according to any one of the preceding claims, further comprising: At least one of the one or more films and the frame is heated.

6. The method of any one of the preceding claims, wherein deforming the portion of the one or more films and thermoplastically deforming the portion of the frame comprises: forming alternating concave and convex portions of the one or more membranes and the frame; as well as The raised portions of the one or more films and the frame are deformed to at least partially overlap with the recessed portions of the one or more films and the frame to form the plurality of mechanical interlocking regions.

7. A method as described in any of the preceding claims, wherein the one or more membranes comprise one or more materials selected from the group consisting of 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-co-glycolic acid) (PLGA), poly-L-lactide (PLLA), polyacrylonitrile (PAN) and electrospun PAN / PVC.

8. The method of any of the preceding claims, wherein at least one of the one or more membranes comprises ePTFE.

9. A method as claimed in any preceding claim, wherein the frame comprises a thermoplastic material.

10. The method of claim 9, wherein the frame comprises one or more materials selected from the group consisting of polycarbonate, polyurethane, polyetheretherketone (PEEK), polyvinyl chloride (PVC), poly(formaldehyde), poly(methyl methacrylate) (PMMA), composite materials based on thermoplastic polymers, polypropylene, fluorinated ethylene propylene (FEP), low density polyethylene (LDPE), high density polyethylene (HDPE), ultra high density polyethylene (UHDPE), polycaprolactone, poly(lactide), poly(glycolic acid), polylactide-co-glycolide, ethylene vinyl acetate copolymer, polyamide, poly(butylene terephthalate), titanium, graphene, and stainless steel.

11. The method of any one of the preceding claims, wherein the frame comprises polyetheretherketone (PEEK).

12. The method of claim 9, wherein the frame comprises fluorinated ethylene propylene (FEP).

13. The method of any one of the preceding claims, wherein the one or more films comprises a first film and a second film disposed on the first film. The method of claim 13 , wherein the first film is sintered. The method of claim 14 , wherein the second film is unsintered.

16. The method of claim 14, wherein the second film is sintered.

17. The method of any one of the preceding claims, wherein the method does not include an adhesive.

18. The method of any preceding claim, wherein the macroencapsulation device comprises a filling port.

19. A macroencapsulation device, comprising: one or more membranes comprising a sealed interior volume configured to encapsulate a population of cells; a frame, wherein the one or more membranes are disposed on the frame; as well as A plurality of mechanical interlocking areas of the one or more membranes and the frame, the plurality of mechanical interlocking areas extending around at least a portion of a perimeter of the one or more membranes.

20. The device of claim 19, wherein the plurality of interlocking regions comprise alternating recessed and raised portions of the one or more membranes and the frame, wherein the raised portions of the one or more membranes and the frame at least partially overlap with the recessed portions of the one or more membranes and the frame.

21. A device as described in any of claims 19 to 20, wherein the one or more membranes comprise one or more materials selected from the following items: 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-co-glycolic acid) (PLGA), poly-L-lactide (PLLA), polyacrylonitrile (PAN) and electrospun PAN / PVC.

22. The device of any one of claims 19 to 21, wherein at least one of the one or more membranes comprises ePTFE.

23. The device of any one of claims 19 to 22, wherein the frame comprises a thermoplastic material.

24. The device of claim 23, wherein the frame comprises one or more materials selected from the group consisting of polycarbonate, polyurethane, polyetheretherketone (PEEK), polyvinyl chloride (PVC), poly(formaldehyde), poly(methyl methacrylate) (PMMA), thermoplastic polymer-based composites, polypropylene, fluorinated ethylene propylene (FEP), low-density polyethylene (LDPE), high-density polyethylene (HDPE), ultra-high-density polyethylene (UHDPE), polycaprolactone, poly(lactide), poly(glycolic acid), polylactide-co-glycolide, ethylene-vinyl acetate copolymer, polyamide, poly(butylene terephthalate), titanium, graphene, and stainless steel.

25. The device of claim 24, wherein the frame comprises polyetheretherketone (PEEK).

26. The device of claim 24, wherein the frame comprises fluorinated ethylene propylene (FEP).

27. The device of any one of claims 19 to 26, wherein the one or more membranes include a first membrane and a second membrane disposed on the first membrane.

28. The device of claim 27, wherein the first film is sintered.

29. The device of claim 28, wherein the second film is unsintered.

30. The device of claim 28, wherein the second film is sintered.

31. The device of any one of claims 29 to 30, wherein the device does not include an adhesive.

32. The device of any one of claims 19 to 31 , wherein the device comprises a filling port.

33. A combined apparatus for manufacturing a macroencapsulation device, the combined apparatus comprising: a retaining mechanism configured to selectively retain a frame of the macroencapsulation device and one or more membranes of the macroencapsulation device in an overlapping configuration in which at least a portion of the one or more membranes overlaps at least a portion of the frame; a heater configured to heat at least the portion of the frame; as well as One or more molds configured to deform the portion of the one or more membranes and thermoplastically deform the portion of the frame to form a plurality of mechanical interlocking regions of the one or more membranes and the frame, the plurality of mechanical interlocking regions extending around at least a portion of the periphery of the one or more membranes.

34. The bonding apparatus of claim 33, wherein the retaining mechanism is configured to retain the frame and the one or more films against a first mold of the one or more molds.

35. The bonding apparatus of claim 34, wherein the first mold is configured to deform an interior portion of the one or more films in an out-of-plane direction of the one or more films.

36. The bonding apparatus of claim 35, wherein the first mold includes a dome configured to deform the interior portion of the one or more films in the out-of-plane direction.

37. The bonding apparatus of claim 36, wherein the dome includes radial grooves configured to distribute slack in the one or more membranes.

38. The bonding apparatus of any one of claims 34 to 37, wherein the first mold is configured to be coupled to a vacuum source to hold the one or more films against the first mold via suction.

39. A combining device as described in any one of claims 34 to 38, wherein the one or more molds include a second mold having a serrated surface, the second mold being configured to deform the portion of the one or more films and to thermoplastically deform the portion of the frame against the first mold to form alternating concave and convex portions of the one or more films and the frame.

40. A combining device as described in claim 39, wherein the one or more molds include a third mold, which is configured to deform the raised portions of the one or more membranes and the frame to at least partially overlap with the recessed portions of the one or more membranes and the frame so as to form the multiple mechanical interlocking areas.

41. The bonding apparatus of any one of claims 33 to 40, wherein the heater is at least one selected from the group consisting of a resistive heater, an ultrasonic horn, an electric heater cartridge, a laser heater, a radiant heater, or an induction heater.

42. The bonding device of any one of claims 33 to 41, further comprising: A thermal shield and / or a cooler configured to maintain a temperature of an active portion of the one or more membranes below a temperature of the portion of the one or more membranes during formation of the plurality of mechanical interlock regions.

43. The bonding apparatus of any one of claims 33 to 42, wherein the plurality of mechanically interlocking regions form a sealed interior volume.

44. The binding device of claim 43, wherein the sealed interior volume is configured to encapsulate a population of cells.

Images