Macroencapsulation device

Abstract

A method of manufacturing a macroencapsulation device includes 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 overlaps a portion of the frame. The method also includes deforming the one or more membranes and thermoplastically deforming the frame to form a plurality of mechanically coupled regions of the one or more membranes and the frame, thereby forming the mechanically coupled regions of the membranes and the frame.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 349,749, filed on June 7, 2022, entitled "MACROENCAPSULATION DEVICES", which is hereby incorporated by reference in its entirety for all purposes.

[0002] The disclosed embodiments relate to macroencapsulation devices and methods of manufacturing the same.

Background Art

[0003] To treat metabolic disorders such as diabetes, therapeutic devices for delivering biological products can be used. The therapeutic devices can be implantable to supply biological products such as insulin over a long period. Some of these devices include macroencapsulation devices, which are used to contain cells that produce a desired biological product, a matrix containing the cells, or other desired therapeutic agents therein.

Summary of the Invention

Means for Solving the Problems

[0004] In some embodiments, a method of manufacturing a macroencapsulation device can include 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 can at least partially overlap a portion of the frame. The method can further include deforming a portion of the one or more membranes and thermoplastically deforming a portion of the frame to form a plurality of mechanically connected regions of the one or more membranes and the frame.

[0005] In other embodiments, the macroencapsulation device may include one or more membranes that include a sealed internal volume configured to encapsulate a cell population. The device may also include a frame. The one or more membranes may be disposed on the frame. The device may further include a plurality of mechanically connected regions of the one or more membranes and a frame extending around at least a portion of the outer periphery of the one or more membranes.

[0006] In a further embodiment, a bonding apparatus for manufacturing a macroencapsulation device may include a holding mechanism configured to selectively hold 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. The bonding apparatus may further include a heater configured to heat at least a portion of the frame. The bonding apparatus may also include one or more dies configured to deform a portion of the one or more membranes and to thermoplastically deform a portion of the frame so as to form a plurality of mechanically connected regions between the one or more membranes and the frame extending around at least a portion of the outer periphery of the one or more membranes.

[0007] It will be understood that the foregoing concepts, as well as additional concepts discussed below, may be arranged in any suitable combination, and that the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.

[0008] The accompanying drawings are not intended to be drawn to scale. In the drawings, each of the same or substantially same components illustrated in various figures may be represented by like numerals. For clarity, in all of the drawings, not all components may be labeled. The following are the drawings.

Brief Description of the Drawings

[0009]

Figure 1A

[0010]

Figure 1B

[0011]

Figure 1C

[0012]

Figure 1D

[0013]

Figure 1E

[0014]

Figure 1F

[0015]

Figure 2A

[0016]

Figure 2B

[0017]

Figure 3A

[0018]

Figure 3B

[0019]

Figure 4A

[0020]

Figure 4B

[0021]

Figure 4C

[0022]

Figure 4D

[0023]

Figure 4E

[0024]

Figure 4F

[0025]

Figure 5A

[0026]

Figure 5B

[0027]

Figure 5C

[0028]

Figure 6

[0029]

Figure 7A

[0030]

Figure 7B

[0031]

Figure 8

[0032]

Figure 9

[0033]

Figure 10

[0034]

Figure 11A

[0035]

Figure 11B

[0036]

Figure 12

DETAILED DESCRIPTION OF THE INVENTION

[0037] Driven by the increasing need to deliver biological products to treat various diseases such as diabetes, various types of implantable therapeutic devices have been designed. However, typical methods of fabricating such devices are often cumbersome, inefficient, and difficult to control. For example, there is often a lack of precision and control in forming specific structural features associated with the device (e.g., attaching a membrane to a frame using an adhesive). In addition, it is often difficult to accurately form such devices within acceptable tolerances to prevent mechanical breakage of the devices after implantation.

[0038] Several problems associated with using adhesives when attaching a membrane to the frame of a macroencapsulation device have been recognized. First, such processes can require a significant amount of manual operation or intervention. These manual processes can introduce undesirable variability and reduce manufacturing efficiency. Additionally, imperfections and non-uniformities in the adhesive application process can cause stress to concentrate in the membrane, leading to premature fatigue failure and rupture of the membrane. For example, variations in the viscosity of the adhesive, non-uniform application of the adhesive, contact angle at the application point, and porosity of the membrane can result in inconsistent attachment of the membrane to the frame. The adhesive may also be absorbed into the pores of the membrane during application, which can change the material properties of the membrane in the area where absorption occurs and compromise the bond between the frame and the membrane.

[0039] In view of the above, the inventors have recognized and highly appreciated the advantages of creating a mechanical bond between one or more membranes and the frame of the macroencapsulation device. In some embodiments, this can be achieved by maintaining the temperature of the membrane below the melting temperature of the membrane material and, in some embodiments, below the sintering temperature, while raising the temperature of one or more portions of the frame to a level at which the frame can be thermoplastically deformed (e.g., above the glass transition temperature of the frame material or, optionally, the melting temperature). It will be appreciated that thermoplastically deforming the frame and / or membrane of the macroencapsulation device may include applying both heat and pressure to achieve the desired deformation. For example, heat may be applied to the frame and / or membrane to provide the above temperatures, and simultaneously, pressure may be applied to one or more portions of the membrane and frame that will deform and bond to each other. Specifically, because the membrane is flexible, when the pressure is applied even when the temperature is below the melting temperature of the membrane, one or more softened portions of the frame and the corresponding portions of the membrane can deform to form one or more mechanical bonds between the frame and the membrane. For example, the thermoplastic deformation of the frame and the corresponding deformation of the flexible membrane may be used to mechanically connect one or more deformed portions of the frame and the membrane to each other. Such techniques may make it possible to form a strong and / or durable bond at the interface between the frame and the membrane. In some examples, the bonded portions of the frame and the membrane may extend at least partially around the outer periphery of one or more membranes.

[0040] In a particular embodiment, a method of manufacturing a macroencapsulation device may include 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. The method may further include deforming a portion of the one or more membranes and thermoplastically deforming a portion of the frame to form a plurality of mechanically connected regions of the one or more membranes and the frame. In some embodiments, the frame and / or the membrane(s) may be heated. For example, the frame may be heated to a temperature below the melting temperature or sintering temperature of the membrane(s) to facilitate thermoplastic deformation of the frame. In some embodiments, the deformation may be performed in a plurality of steps including a first deformation and a second deformation. In other embodiments, the deformation may be performed in a single step. The plurality of mechanically connected regions may extend around a portion of the outer periphery of the one or more membranes and, in some embodiments, may at least partially extend around a sealed interior volume disposed between two opposing layers of the one or more membranes.

[0041] As described in more detail below, some embodiments of the macroencapsulation device may include one or more membranes including a biocompatible polymer such as polytetrafluoroethylene (PTFE) or expanded polytetrafluoroethylene (ePTFE). Some embodiments may include a frame including a thermoplastic material such as polyetheretherketone (PEEK). In some embodiments, the macroencapsulation device may include a frame formed from PEEK and one or more membranes formed from ePTFE, but the present disclosure is not limited to these embodiments or any particular combination of the materials (and their equivalents) described herein. In the context of the macroencapsulation device, when forming a mechanical bond between a frame including a thermoplastic such as PEEK and a membrane including a polymer such as ePTFE, it will be appreciated that there may be significant challenges due to the difficulty of welding these materials. For example, such a bonding process may involve applying significant heat and / or pressure to the interface between the frame and the membrane. However, if excessive heat or pressure is applied to the polymer membrane, the porosity, permeability, or other material properties of the membrane may be dramatically affected, and thus the functionality of the entire device may be affected. In this regard, rather than simply forming a typical weld, it may be desirable to form a mechanically coupled region of the frame and the membrane to facilitate mechanical bonding in materials where bonding is difficult, but the disclosed methods and devices are not so limited and can be used with any suitable combination of frame and membrane materials.

[0042] Macroencapsulation devices manufactured using the disclosed systems and processes can offer several advantages. For example, the disclosed systems and processes can make it easier to control the dispersion of membrane sag with respect to the support frame because the connecting regions capture and disperse the membrane sag. The disclosed bonding techniques can also improve the uniformity and strength of the bond compared to typical adhesive-based bonds. This can also contribute to an improvement in the fatigue life of the macroencapsulation device. In some embodiments, the mechanically connected regions form strong and / or durable bonds such that the membrane(s) are more likely to undergo fatigue failure or other mechanical failure before the bond is broken, thereby reducing the bond as a potential point of mechanical failure within the device.

[0043] In some embodiments, the macroencapsulation device does not include an adhesive or does not involve the use of adhesive-based bonds. In some embodiments, elimination or reduction of the adhesive can reduce the immune response in a patient during and / or after implantation of the macroencapsulation device. For example, the inflammatory response can be reduced by reducing the amount of adhesive used. Additionally or alternatively, reduction of the adhesive can potentially improve cell viability and / or reduce cytotoxicity in the tissue surrounding the implanted device. In some embodiments, the device does not include an adhesive. In some embodiments, the present disclosure can include a biocompatible adhesive at any suitable location of the device. Thus, in some embodiments, the device comprises both mechanically connected regions and a biocompatible adhesive. For example, some devices can include a combination of an adhesive and a region that mechanically connects at the interface between the membrane(s) and the frame.

[0044] In addition to the above, sag dispersion can be facilitated by one or more manufacturing fixtures during the manufacture of the macroencapsulation device. In some embodiments, the bonding apparatus for manufacturing the macroencapsulation device may include geometric features configured to facilitate sag dispersion of the membrane. For example, in certain embodiments, the die of the bonding apparatus may be configured to evenly disperse the excess surface area of one or more membranes of the macroencapsulation device around the bonding region of the corresponding frame to which the one or more membranes are to be bonded, and may include geometric features such as grooves, ridges, and / or scallops. In such an embodiment, the grooves, ridges, and / or scallops may be evenly dispersed around the outer periphery of the dome or other portion of the bonding apparatus that contacts one or more membranes during the bonding process. Further, the grooves, ridges, and / or scallops may extend radially outward from the central portion or other portion of the dome of the bonding apparatus that contacts one or more membranes during the bonding process. Such geometric features can increase the surface area of the die such that when the membrane is aligned to the die surface (e.g., using the suction force described below), the sag is dispersed in a controlled manner across the entire surface area.

[0045] The macroencapsulation device may include multiple layers of membranes. At least one outer membrane of these multiple layers of membranes may be semipermeable. However, embodiments are also contemplated in which each membrane is semipermeable or at least one of the membranes within the device is substantially impermeable. Further, the device may include two laminated membranes, three laminated membranes, and / or any other suitable number of membranes, although the present disclosure is not limited in this manner. For example, in one embodiment including two membranes, either one of the membranes may be semipermeable and the other impermeable, or both may be semipermeable. Accordingly, it should be understood that the present disclosure is not limited to any particular combination of membranes within the laminated structure.

[0046] In some embodiments, the macroencapsulation device can include at least one cell population disposed within the internal volume of the device. For example, the cell population can be disposed within an internal volume formed between two or more opposing membranes of one or more outer membranes of the device. Here, the outer edge of the internal volume can be defined by one or more bonds that extend at least around a portion of the membrane, and in some cases, around the entire membrane, the outer perimeter of the membrane, or other suitable portions of the membrane. In such embodiments, at least the outer membrane of the device can be configured to block the passage of one or more cell populations out of the device. Thus, one or more cell populations can be retained within the internal volume of the device. Although mainly described for the use of two outer membranes forming a single internal volume, the use of multiple intermediate membranes located between the outer membranes of the device and / or between multiple non-connected internal volumes within the device is also contemplated. Additionally, it is also contemplated to form the internal volume by folding a single membrane and bonding it to itself to obtain two opposing membranes.

[0047] This specification describes the case of mainly using expanded polytetrafluoroethylene (ePTFE) as the membrane material. However, the membrane of the macroencapsulation device can be formed from any suitable biocompatible material. The biocompatible material can be substantially inert to the cells and surrounding tissues contained within the macroencapsulation device. Biocompatible materials can include synthetic polymers or naturally occurring polymers. In some embodiments, the polymer can also be a linear polymer, a cross-linked polymer, a network polymer, an addition polymer, a condensation polymer, an elastomer, a fibrous polymer, a thermoplastic polymer, a non-degradable polymer, a combination of the foregoing, and / or any other suitable type of polymer, although the present disclosure is not limited in this manner. As described above, in one embodiment, the polymer can include expanded polytetrafluoroethylene (ePTFE). Suitable types of polymers can 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-co-glycolic acid) copolymer (PLGA), poly-L-lactide (PLLA), polyacrylonitrile (PAN), electrospun PAN / PVC, any combination of the foregoing, and / or any other suitable polymeric material can also be included. In some embodiments, the membrane used in any of the embodiments disclosed herein can include PVDF. In some embodiments, the membrane used in any of the embodiments disclosed herein can include electrospun PANPVC. In some embodiments, the membrane used in any of the embodiments disclosed herein can include PES. In some embodiments, the membrane used in any of the embodiments disclosed herein can include PS. In some embodiments, the membrane used in any of the embodiments disclosed herein can include PAN.In some embodiments, the membrane used in any of the embodiments disclosed herein may include polycarbonate. In some embodiments, the membrane used in any of the embodiments disclosed herein may include polypropylene. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PVC. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PU. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PET. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PCL. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PLGA. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PLLA. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PMMA. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PEI. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PAN. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PTFE. In some embodiments, the membrane used in any one of the embodiments disclosed herein may include PE. Synthetic methods used to form one or more porous membranes from the above polymer materials include, but are not limited to, the stretching method, the solution casting method, the immersion precipitation and phase separation method, the electrospinning method, a method for obtaining an isotropic network, a method for obtaining a columnar network, or any other suitable method for forming a porous polymer membrane.

[0048] The sintering of a membrane can be used to alter the porosity and flux characteristics of the membrane. For example, sintering can increase the porosity of the membrane while maintaining the pore structure of the membrane. Also, sintering can improve the mechanical stability and diffusional flux of the membrane. In some cases, the melting temperature of the sintered membrane may be lower than that of the non-sintered membrane of the same type. Further, the sintered membrane exhibits the release of different energies during a differential scanning calorimetry scan, which can indicate a more relaxed structure in addition to the thickened porous network exhibited by the sintered material.

[0049] Considering the above, sintering can be used to alter the porosity and / or mechanical properties of a membrane, and thus, sintering can be used to adjust the porosity and flux characteristics of a macroencapsulation device. Accordingly, in some embodiments, any desired combination of sintered membranes or sintered membrane layers and / or non-sintered membranes or non-sintered membrane layers can be used. For example, the two outer membrane layers of a device can be two sintered membranes bonded to each other, two non-sintered membranes bonded to each other, or a sintered membrane and a non-sintered membrane bonded to each other. Further, any number of intermediate membranes located between these outer membranes can be used, and such intermediate membranes may or may not be sintered.

[0050] The membranes of the macroencapsulation devices described herein can be made from a porous membrane material configured to allow substances (such as biological products) having a molecular weight less than about 3000 kDa, less than 2000 kDa, less than 1000 kDa, less than 500 kDa, less than 400 kDa, less than 300 kDa, less than 200 kDa, less than 100 kDa, less than 50 kDa, less than 40 kDa, less than 30 kDa, less than 20 kDa, less than 10 kDa, less than 6 kDa, less than 5 kDa, less than 4 kDa, less than 3 kDa, less than 2 kDa, less than 1 kDa, and / or any other suitable range according to the desired application to be transported through the membrane. The membranes of the macroencapsulation devices described herein can be made from a porous membrane material configured to allow only substances (such as biological products) within a molecular weight range of 1 - 3000 kDa, 1 - 2000 kDa, 1 - 1000 kDa, 1 - 500 kDa, 1 - 400 kDa, 1 - 300 kDa, 1 - 200 kDa, 1 - 100 kDa, 1 - 50 kDa, 1 - 40 kDa, 1 - 30 kDa, 1 - 20 kDa, 1 - 10 kDa, 1 - 6 kDa, 1 - 5 kDa, 1 - 4 kDa, 1 - 3 kDa, or 1 - 2 kDa to be transported through the membrane. For example, one or more membranes of the macroencapsulation device can be configured such that insulin having a molecular weight of about 5.8 kDa can flow through the membrane. In some embodiments, one or more membranes of the macroencapsulation device can be configured to allow the flow of materials such as biological products only within the range of 1 - 10 kDa. In some embodiments, one or more membranes of the macroencapsulation device can be configured to allow the flow of materials such as biological products only within the range of 1 - 6 kDa. In some embodiments, one or more membranes of the macroencapsulation device can be configured to allow the flow of materials such as biological products only within the range of 1 - 5 kDa. In some embodiments, one or more membranes of the macroencapsulation device can be configured to allow the flow of materials such as biological products only within the range of 1 - 4 kDa. In some embodiments, one or more membranes of the macroencapsulation device can be configured to allow the flow of materials such as biological products only within the range of 1 - 3 kDa.In some embodiments, one or more membranes of the macroencapsulation device can be configured to allow the flow of materials, such as biological products, only within the range of 1 to 2 kDa.

[0051] To obtain the desired selectivity, the porous membranes used in the macroencapsulation devices disclosed herein can have a pore structure with an average pore diameter of 1 nm or more, 5 nm or more, 10 nm or more, 15 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, 50 nm or more, 60 nm or more, 70 nm or more, 80 nm or more, 90 nm or more, 100 nm or more, 200 nm or more, 300 nm or more, and / or any other suitable range of sizes. Correspondingly, the average pore diameters of the various membranes described herein can be 2500 nm or less, 2000 nm or less, 1700 nm or less, 1500 nm or less, 1400 nm or less, 1300 nm or less, 1200 nm or less, 1100 nm or less, 1000 nm or less, 900 nm or less, 800 nm or less, 700 nm or less, 600 nm or less, 500 nm or less, 400 nm or less, 300 nm or less, 200 nm or less, 100 nm or less, 90 nm or less, 80 nm or less, 70 nm or less, 60 nm or less, 50 nm or less, 40 nm or less, 30 nm or less, 20 nm or less, and / or any other suitable range of sizes. Combinations of the foregoing are contemplated, including, for example, an average pore diameter of 1 nm or more and 20 nm or less, 1 nm or more and 2500 nm or less, 50 nm or more and 1200 nm or less, and / or any other suitable combination. In some embodiments, the average pore diameters of the various membranes described herein are from 25 nm to 1500 nm. In some embodiments, the average pore diameters of the various membranes described herein are from 50 nm to 1200 nm. In some embodiments, the average pore diameters of the various membranes described herein are from 50 nm to 1000 nm. In some embodiments, the average pore diameter has an upper size limit of 1500 nm. In some embodiments, the average pore diameter has an upper size limit of 1200 nm. In some embodiments, the average pore diameter has an upper size limit of 25 nm. In some embodiments, the average pore diameter has an upper size limit of about 50 nm. While specific average pore diameters have been described above, any suitable average pore diameter may be used for the various membranes described herein, and it should be understood that, for example, both larger and smaller average pore diameters than those described above are contemplated.

[0052] In some embodiments, charge-excluding properties can be included in the membrane. For example, the surface charge of the membrane can be adjusted by an external coating, plasma treatment, or other surface treatment based on the isoelectric point of a desired adjuvant to achieve neutral, positive, negative, or zwitterionic properties. The adjuvant can be a protein, a complex small molecule, and / or any other suitable adjuvant according to the desired application.

[0053] To obtain sufficient strength and / or rigidity of the macroencapsulation device, various membranes and frames can be made from materials of sufficient hardness. The desired rigidity can be obtained by an appropriate combination of the Young's modulus (also called the elastic modulus), thickness, and overall structure of the material that can be balanced with the desired permeability of the device. Suitable Young's moduli for the various membranes and frames described herein are at least 10 5 Pa, 10 6 Pa, 10 7 Pa, 10 8 Pa, 10 9 Pa, and / or 10 10 Pa. Other suitable Young's moduli can be used for the various membranes and frames described herein, for example, both Young's moduli greater than and less than these ranges are included. The above-mentioned range of Young's modulus includes, for example, a Young's modulus of about 10 6 Pa or more and 10 10 Pa or less. In some embodiments, the macroencapsulation device includes at least one hydrophilic membrane.

[0054] The frame of the macroencapsulation device may be formed of any suitable biocompatible thermoplastic material. As previously mentioned, in some embodiments, suitable materials for the frame may include polyetheretherketone (PEEK). Suitable materials for the frame include, but are not limited to, polycarbonate, polyurethane, polyetheretherketone (PEEK), polyvinyl chloride (PVC), poly(oxymethylene), poly(methyl methacrylate) (PMMA), thermoplastic polymer-based composite materials, 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, combinations of the foregoing, and / or other suitable thermoplastic materials. Since the present disclosure is not limited to frames made entirely of thermoplastic materials, in addition to using thermoplastic materials for the frame, embodiments of frames are also contemplated that include a thermoplastic portion configured to be bonded to the membrane and another non-thermoplastic portion. In some embodiments, a suitable material for the frame is polypropylene. In some embodiments, a suitable material for the frame is fluorinated ethylene propylene (FEP). In some embodiments, a suitable material for the frame is ultra-high-density polyethylene (UHDPE). In some embodiments, a suitable material for the frame is polycarbonate. In some embodiments, a suitable material for the frame is polyurethane. In some embodiments, a suitable material for the frame is PVC. In some embodiments, a suitable material for the frame is poly(oxymethylene). In some embodiments, a suitable material for the frame is poly(methyl methacrylate) (PMMA). In some embodiments, a suitable material for the frame is a thermoplastic polymer-based composite material.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 copolymer. In some embodiments, suitable materials for the frame include polyamide. In some embodiments, suitable materials for the frame include polybutylene terephthalate. In other embodiments, suitable materials for the frame or a portion of the frame can include titanium, graphene, stainless steel, or other suitable biocompatible materials that exhibit sufficient rigidity to function as the frame of the macroencapsulation device.

[0055] The present disclosure relates to a method of coupling one or more membranes to a frame of a macroencapsulation device, but it should be understood that the present disclosure is not limited to the use of any particular method for coupling one membrane to another or for coupling two or more membranes to each other. The membranes described in various embodiments of the macroencapsulation device described herein can be coupled to each other using any suitable coupling method, but the present disclosure is not limited in this manner. For example, adjacent membranes can be coupled to each other using epoxy resin adhesion, welding or other fusion-based techniques (e.g., ultrasonic bonding, laser bonding, physical bonding, thermal bonding, etc.), mechanical clamping using a frame or fixture, and / or any other suitable coupling method. In a specific embodiment, adjacent membranes can be coupled using a heating tool used to press or strike two or more membranes against each other with a defined pressure and / or force for a set fusion time.

[0056] The macroencapsulation devices described herein can have any suitable combination of internal volume, outer dimensions, and / or other suitable physical parameters. For example, the internal volume encapsulated by the outer membrane of the macroencapsulation device can be from 40 μL to 250 μL. Also, the width, or maximum cross-sectional dimension, of the macroencapsulation device can be from about 20 mm to 80 mm. Additionally, if oxygen is desired to be diffused into the macroencapsulation device to support the cells contained therein, the maximum oxygen diffusion distance from the outside of the device to the inner part of the device containing the cell population can be less than 50 μm, less than 100 μm, less than 150 μm, less than 200 μm, less than 250 μm, less than 300 μm, less than 350 μm, less than 400 μm, less than 450 μm, or less than 500 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 500 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 450 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 400 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 350 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 300 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 250 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is less than 200 μm. In some embodiments, the maximum oxygen diffusion distance from the outside of the device to the inner part of the device containing the cell population is 150 μm or less. In some embodiments, the maximum oxygen diffusion distance from the outside of the device to the inner part of the device containing the cell population is 150 μm. In some embodiments, the maximum diffusion distance from the outside of the device to the inner part of the device containing the cell population is from 50 μm to 200 μm.In some embodiments, the maximum diffusion distance from outside the device to the inner part of the device containing the cell population is from 125 μm to 175 μm.

[0057] Correspondingly, the maximum thickness (or the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the inner volume located within the device can be less than 25 μm, less than 50 μm, less than 100 μm, less than 150 μm, less than 200 μm, less than 250 μm, less than 300 μm, less than 350 μm, less than 400 μm, less than 450 μm, or less than 500 μm. In some embodiments, the maximum thickness (or the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the inner volume located within the device is from 250 μm to 700 μm. In some embodiments, the maximum thickness (or the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the inner volume located within the device is from 250 μm to 500 μm. In some embodiments, the maximum thickness (or the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the inner volume located within the device is from 400 μm to 500 μm. In some embodiments, the maximum thickness (or the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the inner volume located within the device is less than 500 μm. In some embodiments, the maximum thickness (or the dimension perpendicular to the maximum cross-sectional dimension) of the entire device and / or the inner volume located within the device is 500 μm.

[0058] In some embodiments, the maximum thickness of the frame, or the dimension perpendicular to the maximum transverse dimension, may be 4 mm or less, 3 mm or less, 2 mm or less, 1 mm or less, 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 4 mm or less. In some embodiments, the maximum thickness of the frame, or the dimension perpendicular to the maximum transverse dimension, may be 3 mm or less. In some embodiments, the maximum thickness of the frame, or the dimension perpendicular to the maximum transverse dimension, may be 2 mm or less. In some embodiments, the maximum thickness of the frame, or the dimension perpendicular to the maximum transverse dimension, may be 1 mm or less. Additionally or alternatively, in some embodiments, the maximum thickness of the frame may be 0.5 mm or more, 1 mm or more, 1.5 mm or more, 2 mm or more, or any other suitable thickness. In some embodiments, the maximum thickness of the frame may be 0.5 mm or more. In some embodiments, the maximum thickness of the frame may be 1 mm or more. In some embodiments, the maximum thickness of the frame may be 1.5 mm or more. In some embodiments, the maximum thickness of the frame may be 2 mm or more. Intermediate values between the aforementioned values are also contemplated, as well as combinations with values greater than and / or less than the aforementioned values. For example, in some embodiments, the maximum frame thickness may be 0.5 mm or more and 4 mm or less. In some embodiments, the maximum frame thickness may be 1.5 mm or more and 2.5 mm or less.

[0059] Furthermore, in some embodiments, the frame may include a frame / membrane interface region, which may be configured to couple with one or more membranes of the device. In some embodiments, the frame / membrane interface region may extend radially inward from the frame and may have a maximum thickness or a dimension perpendicular to the maximum transverse dimension of the device, which may be the same as or different from the maximum thickness of the entire frame. In some embodiments, the maximum thickness of the interface region may be less than the maximum thickness of the frame. For example, in some embodiments, the maximum thickness of the interface region may be 2 mm or less, 1.5 mm or less, 1 mm or less, 0.5 mm or less, or any other suitable thickness. In some embodiments, the maximum thickness of the interface region may be 2 mm or less. In some embodiments, the maximum thickness of the interface region may be 1.5 mm or less. In some embodiments, the maximum thickness of the interface region may be 1 mm or less. In some embodiments, the maximum thickness of the interface region may be 0.5 mm or less. Further, or alternatively, in some embodiments, the maximum thickness of the interface region may be 0.3 mm or more, 0.5 mm or more, 1 mm or more, 1.5 mm or more, or any other suitable thickness. Intermediate values between the foregoing, combinations of values greater than the foregoing, and / or combinations of values less than the foregoing are also contemplated. In some embodiments, the maximum thickness of the interface region may be 0.3 mm or more. In some embodiments, the maximum thickness of the interface region may be 0.5 mm or more. In some embodiments, the maximum thickness of the interface region may be 1 mm or more. In some embodiments, the maximum thickness of the interface region may be 1.5 mm or more. For example, in some embodiments, the maximum interface region thickness may be from 0.3 mm to 2 mm. In some embodiments, the maximum interface region thickness may be from 0.3 mm to 0.5 mm.

[0060] As described above, the frame / membrane interface region may extend from the frame, for example, radially inwardly (e.g., toward the center of the device, the frame, and / or its membrane(s)), and may have any suitable width in the radial direction. In some embodiments, the frame / membrane interface region may have a width of a radial interface region of 5 mm or less, 4 mm or less, 3 mm or less, 2 mm or less, or any other suitable width. In some embodiments, the frame / membrane interface region may have a radial interface region width of 5 mm or less. In some embodiments, the frame / membrane interface region may have a radial interface region width of 4 mm or less. In some embodiments, the frame / membrane interface region may have a radial interface region width of 3 mm or less. In some embodiments, the frame / membrane interface region may have a radial interface region width of 2 mm or less. Further, or alternatively, in some embodiments, the width of the interface region may be 0.75 mm or more, 1 mm or more, 1.5 mm or more, 2 mm or more, or any other suitable width. In some embodiments, the width of the interface region may be 0.75 mm or more. In some embodiments, the width of the interface region may be 1 mm or more. In some embodiments, the width of the interface region may be 1.5 mm or more. In some embodiments, the width of the interface region may be 2 mm or more. Intermediate values between the foregoing, as well as combinations with values greater than and / or less than the foregoing, are also contemplated. For example, in some embodiments, the maximum interface region width may be 0.75 mm or more and 5 mm or less. In some embodiments, the maximum interface region width may be 1.0 mm or more and 2.0 mm or less. Further, although a radial width is described herein, it will be understood that since the device is not limited to a circular geometric shape, the above widths are not limited to extending in the radial direction. For example, a device having one or more linear sides may include a frame / membrane interface region having a width that extends perpendicularly inward from the linear side(s).

[0061] Further, in some embodiments, the ratio of the outer surface area to the volume of the device is 20 cm -1 , 40 cm -1 , 50 cm-1 , 60 cm -1 , 80 cm -1 , 100 cm -1 , 120 cm -1 , 150 cm -1 , 200 cm -1 , 300 cm -1 , 400 cm -1 , 500 cm -1 , 600 cm -1 , 700 cm -1 , 800 cm -1 , 900 cm -1 , or 1000 cm -1 or more. In some embodiments, the ratio of the outer surface area to the volume of the device is from 25 cm -1 to 1250 cm -1 . In some embodiments, the ratio of the outer surface area to the volume of the device is from 50 cm -1 to 1000 cm -1 . In some embodiments, the ratio of the outer surface area to the volume of the device is from 100 cm -1 to 500 cm -1 . Ranges spanning any values between the aforementioned values for various dimensions and parameters, as well as ranges larger than and smaller than those described above, are also contemplated.

[0062] As described throughout this disclosure, a plurality of coupling portions may be provided in the membrane(s) of the macroencapsulation device. In some embodiments, each coupling portion may be formed in a rounded shape or a circular shape, each having a coupling diameter. In various embodiments, the coupling diameter may be 200 μm or more, 500 μm or more, 1000 μm or more, 1500 μm or more, or any other suitable distance or diameter. In some embodiments, the coupling diameter may be 200 μm or more. In some embodiments, the coupling diameter may be 500 μm or more. In some embodiments, the coupling diameter may be 1000 μm or more. In some embodiments, the coupling diameter may be 1500 μm or more. Additionally or alternatively, in some embodiments, the coupling diameter may be 2000 μm or less, 1500 μm or less, 1000 μm or less, 500 μm or less, or any other suitable distance or diameter. In some embodiments, the coupling diameter may be 2000 μm or less. In some embodiments, the coupling diameter may be 1500 μm or less. In some embodiments, the coupling diameter may be 1000 μm or less. In some embodiments, the coupling diameter may be 500 μm or less. Intermediate values between the foregoing, as well as combinations with values greater than and / or less than the foregoing, are also contemplated. For example, in some embodiments, the coupling diameter may be 200 μm or more and 2000 μm or less. In some embodiments, the coupling diameter may be 700 μm or more and 800 μm or less. Further, although the coupling diameter is described herein, it will be understood that the dimensions of the coupling portion are not limited to the diameter since the coupling portion is not limited to a circular shape. For example, in a coupling portion formed in a linear shape, the above dimensions may apply to the distance between the opposing sides of the linear shape.

[0063] In some embodiments, it may be desirable to improve angiogenesis of the macroencapsulation device. Thus, in certain embodiments, one or more through-holes may be formed within one or more bonding portions located within an inner portion of a membrane disposed radially inwardly from the frame of the device. These through-holes may enable the vascular system 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 can be formed within the bonding portions of the membrane using laser ablation, mechanical puncturing, cutting, or any other suitable method for forming through-holes within one or more bonding portions of the membrane.

[0064] In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 100 μm or more, 125 μm or more, 150 μm or more, 200 μm or more, 300 μm or more, or any other suitable through-hole diameter. In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 100 μm or more. In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 125 μm or more. In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 150 μm or more. In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 200 μm or more. In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 250 μm or more. In some embodiments, the through-hole of the coupling portion may have a diameter dimension, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, of 300 μm or more. Additionally or alternatively, in some embodiments, the diameter of the through-hole, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, may be 700 μm or less, 650 μm or less, 600 μm or less, 500 μm or less, 300 μm or less, or any other suitable through-hole diameter. In some embodiments, the diameter of the through-hole, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, may be 700 μm or less. In some embodiments, the diameter of the through-hole, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, may be 650 μm or less. In some embodiments, the diameter of the through-hole, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, may be 600 μm or less. In some embodiments, the diameter of the through-hole, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, may be 500 μm or less. In some embodiments, the diameter of the through-hole, or another maximum cross-sectional dimension perpendicular to the axis extending through the through-hole, may be 300 μm or less.Similar to the combination of the foregoing with a value greater than or less than the foregoing, intermediate values between the foregoing are also contemplated. For example, in some embodiments, the diameter of the through-hole, or other maximum transverse dimension perpendicular to the axis extending through the through-hole, can be 250 μm or more and 350 μm or less. For example, in some embodiments, the diameter of the through-hole, or other maximum transverse dimension perpendicular to the axis extending through the through-hole, can be 200 μm or more and 400 μm or less.

[0065] Furthermore, in some embodiments, the macroencapsulation device can be formed at any suitable distance or interval (referred to herein as the coupling interval) between two adjacent coupling portions. For example, in some embodiments, the coupling interval can be 1 mm or more, 2 mm or more, 3 mm or more, or any other suitable interval. In some embodiments, the coupling interval can be 1 mm or more. In some embodiments, the coupling interval can be 2 mm or more. In some embodiments, the coupling interval can be 3 mm or more. Additionally or alternatively, the coupling interval can be 5 mm or less, 4 mm or less, 3 mm or less, or any other suitable coupling interval. In some embodiments, the coupling interval can be 5 mm or less. In some embodiments, the coupling interval can be 4 mm or less. In some embodiments, the coupling interval can be 3 mm or less. Similar to the combination of the foregoing with a value greater than or less than the foregoing, intermediate values between the foregoing are also contemplated. For example, in some embodiments, the coupling interval can be 1 mm or more and 5 mm or less. In some embodiments, the coupling interval can be 1 mm or more and 1.5 mm or less.

[0066] Furthermore, in some embodiments, two or more membranes may be joined to each other around the joining perimeter, and the joined portion may be located inside the joining perimeter. In various embodiments, the joining perimeter may be formed in any suitable shape, including any suitable circular, elongated, straight, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), and / or any other suitable regular or irregular shape. In some embodiments, the joining perimeter may generally be formed as a circle having a diameter. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 1 cm or more, 1.5 cm or more, 2 cm or more, 2.5 cm or more, or any other suitable distance or diameter. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 1 cm or more. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 1.5 cm or more. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 2 cm or more. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 2.5 cm or more. Additionally or alternatively, in some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 7 cm or less, 6.5 cm or less, 6 cm or less, 5 cm or less, or any other suitable distance or diameter. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 7 cm or less. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 6.5 cm or less. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 6 cm or less. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 5 cm or less. Intermediate values between the foregoing are also contemplated, as well as combinations of the foregoing with values greater than or less than the foregoing. For example, in some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 1 cm or more and 6.5 cm or less. In some embodiments, the diameter dimension of the joining perimeter, or other maximum transverse dimension, may be 1.5 cm or more and 6.5 cm or less.Furthermore, although the diameter around the bond is described herein, it will be understood that since the area around the bond is not limited to a circular shape, the dimensions of the bond area described above are not limited to the diameter. For example, in the case of a bond area formed in a linear shape, the above dimensions can be applied to the distance between the opposing sides of the linear shape.

[0067] In some embodiments, after the membranes are bonded to each other (e.g., bonding of the outer and / or inner portions of the first and second membranes), the first and second membranes can be coated with a hydrophilic material and / or subjected to other processes that may not be compatible with the bonding process. In some embodiments, in order to facilitate filling the macroencapsulation device with cells and / or to facilitate the flow of one or more fluids, biological compounds, therapeutic agents, cell nutrients, cell waste products, and / or other substances through the membranes of the device, it may be desirable for one or more of the membranes included in the macroencapsulation device to be hydrophilic. Additionally, when the device is located in vivo, the occurrence of fibrosis can also be reduced if the outer membrane is hydrophilic. Thus, the membranes of the macroencapsulation device may be made of a hydrophilic material and / or treated with a hydrophilic coating agent. Suitable hydrophilic materials may include, but are not limited to, the following. Suitable hydrophilic polymers, polyethylene glycol, polyvinyl alcohol, polydopamine, any combination thereof, and / or any other suitable hydrophilic material that can form a coating on or form the membrane.

[0068] In some embodiments, the root mean square (RMS) surface roughness of the bonding surface of the membrane and the frame may be 5 μm or greater, 10 μm or greater, 15 μm or greater, 20 μm or greater, 30 μm or greater, and / or any other suitable RMS surface roughness. The RMS surface roughness may also be 50 μm or less, 40 μm or less, 30 μm or less, 20 μm or less, 10 μm or less, and / or any other suitable surface roughness. For example, combinations including an RMS surface roughness between 5 μm and 50 μm or equal thereto are contemplated. 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 may be measured using a light tomography-based technique, image analysis of a cross-section of the bonding region, and / or any other suitable technique.

[0069] Specific dimensions, parameters, and relationships related to the macroencapsulation device and the materials used as raw materials for the macroencapsulation device have been described above, but dimensions, parameters, and relationships larger and smaller than those described above are also conceivable. However, it should be understood that the present disclosure is not limited in this manner. Accordingly, any suitable combination of size, configuration, material properties, and / or relative performance parameters may be used for the device depending on the desired application.

[0070] Depending on the specific application and desired duration of use, when implanted in a subject's body, the macroencapsulation device can be configured to have any suitable fatigue life. For example, in some embodiments, the macroencapsulation device can be configured to be implanted within the abdominal tissue of a subject. Within such abdominal tissue, the macroencapsulation device may be affected by abdominal contractions during use. Thus, in some embodiments, the fatigue life of the macroencapsulation device can be 50,000 cycles or more, 60,000 cycles or more, 70,000 cycles or more, and / or 80,000 cycles or more. In some embodiments, the fatigue life of the macroencapsulation device can be 50,000 cycles or more. In some embodiments, the fatigue life of the macroencapsulation device can be 60,000 cycles or more. In some embodiments, the fatigue life of the macroencapsulation device can be 70,000 cycles or more. In some embodiments, the fatigue life of the macroencapsulation device can be 80,000 cycles or more. In some embodiments, the fatigue life can also be 1,000,000 cycles or less, 500,000 cycles or less, 200,000 cycles or less, 100,000 cycles or less, and / or 80,000 cycles or less. In some embodiments, the fatigue life can also be 1,000,000 cycles or less. In some embodiments, the fatigue life can also be 500,000 cycles or less. In some embodiments, the fatigue life can also be 200,000 cycles or less. In some embodiments, the fatigue life can also be 100,000 cycles or less. In some embodiments, the fatigue life can also be 80,000 cycles or less. Combinations of the foregoing ranges are contemplated, for example, a fatigue life of 50,000 cycles or more and 200,000 cycles or less. Also contemplated are both devices having a fatigue life longer than the above and devices having a fatigue life shorter than the above, but the present disclosure is not limited in this manner.For the purposes of this application, the fatigue life of the macroencapsulation device can be determined using a fatigue cycle test with a periodically applied load of 12 N, similar to the forces experienced by the device implanted in vivo within the abdominal tissue of interest. In some embodiments, the fatigue life of a device that measures biphasic center mesh fatigue using a periodically applied load of 45 N is between 1,000 cycles and 500,000 cycles. In some embodiments, the fatigue life of a device that measures biphasic center mesh fatigue using a periodically applied load of 45 N is between 10,000 cycles and 80,000 cycles. In some embodiments, the fatigue life of a device that measures biphasic center mesh fatigue using a periodically applied load of 45 N is between 40,000 cycles and 1,000,000 cycles.

[0071] In some embodiments, the cell population contained within the compartment of the macroencapsulation device can be a population of insulin-secreting cells. In some embodiments, the cell population contained within the compartment of the macroencapsulation device includes a heterogeneous population of cells. In some embodiments, the cell population includes at least one cell obtained from a stem cell-derived cell. In some embodiments, at least one cell is a genetically engineered cell. Optionally, at least one cell is genetically engineered such that the immune response in the subject at the time of device implantation is reduced compared to an equivalent non-genetically engineered cell. In some embodiments, the cell population is a stem cell-derived cell capable of glucose-responsive insulin secretion (GSIS). For example, suitable cell populations can include pancreatic progenitor cells, endocrine cells, beta cells, a matrix comprising one or more of the foregoing, or combinations thereof. Further, the matrix can include isolated pancreatic islet cells, isolated cells from the pancreas, isolated cells from a tissue, stem cells, stem cell-derived cells (e.g., stem cell-derived pancreatic islet cells), induced pluripotent cells, differentiated cells, transformed cells, or an expression system capable of synthesizing one or more biological products. In some embodiments, the macroencapsulation device includes a population of stem cell-derived pancreatic islet cells. In some embodiments, the stem cell-derived pancreatic islet cells include stem cell-derived beta cells, stem cell-derived alpha cells, and / or stem cell-derived delta cells.

[0072] Depending on a particular embodiment, a therapeutically effective density of cells can be filled within one or more compartments of the macroencapsulation device. Suitable cell densities disposed within the compartments can be about 1,000 cells / μL or more, 10,000 cells / μL or more, 50,000 cells / μL or more, 100,000 cells / μL or more, 500,000 cells / μL or more, 750,000 cells / μL or more, 1,000,000 cells / μL or more, and / or any other suitable cell density. Also, suitable cell densities disposed within the compartments can be about 1,000,000 cells / μL or less, 500,000 cells / μL or less, 100,000 cells / μL or less, 50,000 cells / μL or less, 10,000 cells / μL or less, and / or any other suitable cell density. Combinations of the foregoing are contemplated, for example, cell densities of about 1000 cells / μL to 1,000,000 cells / μL are contemplated. In some embodiments, the cell density disposed within the compartment is from 100,000 cells / μL to 1,000,000 cells / μL. In some embodiments, the cell density disposed within the compartment is from 75,000 cells / μL to 500,000 cells / μL. In some embodiments, the cell density disposed within the compartment is from 500,000 cells / μL to 1,000,000 cells / μL. In some embodiments, the cell density disposed within the compartment is from 750,000 cells / μL to 1,000,000 cells / μL. In some embodiments, the cell density disposed within the compartment is from 750,000 cells / μL to 1,250,000 cells / μL. Of course, cell densities can also be used that are greater than and less than those described above, depending on the desired application and the cell type being used.

[0073] Referring to the figures, certain non-limiting embodiments are described in more detail. Since the present disclosure is not limited to only the particular embodiments described herein, it should be understood that the various systems, components, features, and methods described in connection with these embodiments can be used individually and / or in any desired combination.

[0074] Figures 1A - 1C show embodiments of the macroencapsulation device membrane before attachment to a frame. As shown in the figures, the membrane can 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 can include a polymeric material such as ePTFE. In various embodiments, each of the first membrane layer 102 and the second membrane layer 104 can be either sintered or unsintered. Each of the first membrane layer and the second membrane layer can also include a single layer or multiple layers.

[0075] The first membrane layer 102 and the second membrane layer 104 can be joined to each other at a bonding perimeter 122 and a bonding portion 124 located within the bonding perimeter. In Figure 1A, the upper surface of the second membrane layer 104 is shown, and the bonding perimeter 122 of the membrane (e.g., where the first and second membrane layers are joined) extends around the outer perimeter of the membrane. The bonding perimeter 122 can form an internal volume disposed between the first and second membranes configured to encapsulate a cell population. In some embodiments, the bonding perimeter 122 can extend across the entire outer perimeter of the membrane, but as shown in Figure 1A, the bonding perimeter can have, for example, a fill port (not shown) that can accommodate introducing a cell population into the internal volume of the device and / or a non - bonding portion 135 for communicating with the outside. As will be understood, the dimensions of the bonding perimeter 122 can at least partially define the size of the internal volume. For example, in embodiments where the membrane(s) and / or the device has a substantially circular shape, the bonding perimeter 122 has a diameter 128, which can at least partially define the size of the internal volume between the first and second membrane layers.

[0076] In some embodiments, the internal volume between the first membrane layer and the second membrane layer can include a network of continuous interconnected volumes formed by various bonding portions of the membranes and / or between them. For example, as shown in FIG. 1C, the internal volume between the first membrane layer 102 and the second membrane layer 104 can include a network of volumes (e.g., channels 126) formed between the bonding portions 124. In some embodiments, the internal volume can have a volume thickness 136, which can be the maximum distance between the first and second membrane layers in a direction perpendicular to the maximum transverse dimension of the device. As will be appreciated, the total thickness of the membrane (e.g., total thickness 140) can depend at least in part on the internal volume thickness 136, as well as the membrane layer thicknesses 138 for each membrane layer. As described herein, the thickness can be measured in a direction perpendicular to the maximum transverse dimension of the device.

[0077] As shown, the bonding perimeter can be disposed radially inward from the outer perimeter 150 of the membrane. The bonding portions 124 can take the form of bonding points dispersed in a hexagonal array across the surface area of the membrane. However, any suitable shape, arrangement, configuration, and / or spacing of such bonding regions can also be used. For example, as shown in FIG. 1C, the bonding spacing 142 can be the distance between adjacent bonding portions 124. Further, in some embodiments, one or more of the bonding portions 124 can include through-holes 132 formed therein. Each through-hole can have a through-hole diameter 144. Due to the presence of these bonding regions located radially inward from the bonding perimeter of the membrane, the internal volume formed between the membranes can, when in a filled configuration (e.g., as shown in FIG. 1C), take the form of a plurality of interconnected channels 126 corresponding to non-bonded regions of the membrane that extend between these bonding portions.

[0078] In some embodiments, when the membrane layer is connected to the frame, the unbonded portion 135 may be disposed around and sealed around the filling port of the frame such that the filling port remains in fluid communication with the internal volume. In some embodiments, the filling port may be included within the frame to allow for at least one-way fluid communication between the external environment and the internal volume of the device. For example, the filling port may be configured to allow a cell population to be introduced into the volume between the first and second membrane layers. FIGS. 1D-1F show non-limiting examples of filling ports 250 included on a frame 202 of a macroencapsulation device 200 according to one embodiment. The filling port includes a through-hole (not shown) that extends through the filling port to the internal volume of the macroencapsulation device formed by the first membrane layer 102 and the second membrane layer 104 shown in FIGS. 1A-1C.

[0079] In various embodiments, the frame 202 may be formed in any suitable shape, including any suitable circular, elongated, linear, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), and / or any other suitable regular or irregular shape. For example, in the illustrated embodiment, the frame 202 may be formed in a generally circular shape having a frame diameter 214 and / or a frame thickness 220. The frame thickness may 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 may be measured in a direction perpendicular to the maximum transverse dimension of the frame 202 and / or the device 200.

[0080] Furthermore, in some embodiments, device 200 may include a frame / membrane interface region 206 that may extend inwardly (e.g., radially inwardly) from frame 202 and may be configured to couple to one or more membranes of the device. For example, as shown in the cross-sectional view of FIG. 1F (along line 1F-1F of FIG. 1D), the frame / membrane interface region 206 may extend from frame 202 to provide one or more surfaces that can adhere, mechanically couple, fasten, secure, and / or join the membrane. The frame / membrane interface region may have an interface region width 216 where the frame and the membrane(s) may have the same extent with respect to each other, which may be the distance between the innermost portion of frame 202 and the innermost portion of the frame / membrane interface region 206. Further, 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 cross-sectional dimension of frame 202 and / or device 200j.

[0081] FIGS. 2A and 2B each show a macroencapsulation device 200. Each macroencapsulation device 200 includes a frame 202, a membrane 204, and a frame / membrane interface region 206 with an adhesively (FIG. 2A) and mechanically coupled region (FIG. 2B) that couples them together. The frame / membrane interface region 206 shown in the figures may be the region of the macroencapsulation device 200 where membrane 204 and frame 202 overlap each other. In some embodiments, as shown, the frame / membrane interface region 206 may be disposed around at least a portion of the outer perimeter of membrane 204. For example, the frame / membrane interface region 206 may be disposed radially outward from a bonding perimeter 207 that surrounds the sealed internal volume of the device. Membrane 204 and frame 202 may be joined to each other at the frame / membrane interface region 206.

[0082] In some embodiments, the membrane may be attached to the frame leaving slack in the membrane relative to the frame before being filled with the desired cell population. When the membrane 204 is attached to the frame 202, slack may accumulate in certain regions along the interface between the frame and the membrane. For example, as shown in FIG. 2A, significant membrane slack accumulation 208 may form during the adhesive attachment process. The slack accumulation 208 may be a region where the membranes 204 are gathered together or a region where the membranes are folded over themselves. It will be appreciated that when the macroencapsulation device 200 bends or flexes as may occur during use or implantation, stress concentrations may occur in the membrane 204 in the regions containing these slack accumulations 208, potentially leading to premature failure of the macroencapsulation device 200.

[0083] Note that in the macroencapsulation device 200 of FIG. 2B, the slack can be more uniformly distributed and no visible slack accumulation may be seen. As will be described later, a uniform distribution of the slack in the membrane 204 can be achieved by forming regions that are mechanically coupled to the frame / membrane interface region 206. In some embodiments, each mechanically coupled region may include connections, overlaps, folds, or crimps in the membrane 204 that are mechanically locked within plastically deformed or thermoplastically deformed portions of the frame 202. In such embodiments, each mechanically coupled region may take up a portion of the slack in the membrane 204 along the interface between the frame 202 and the membrane 204. In embodiments where each mechanically coupled region is of substantially uniform size, the substantially uniform mechanically coupled regions may provide a substantially uniform distribution of slack along the frame / membrane interface region 206. Without wishing to be bound by theory, this may be due to deformation of one or more membranes within the mechanically coupled regions that take up at least a portion of the slack along the frame / membrane interface.

[0084] Figures 3A-3B each show an enlarged view of the frame / membrane interface region after the membrane has been removed from the frame 202. Since the membranes of each device have been removed, neither Figure 3A nor Figure 3B shows the complete membrane. However, removing the membrane from Figures 3A-3B allows for a clearer depiction of the frame / membrane interface region in each device. Figure 3A shows a frame / membrane interface region 206 where the membrane is joined to the frame 202 using an adhesive 210. Figure 3B shows a frame / membrane interface region 206 where the membrane is coupled to the frame 202 using the mechanical coupling techniques disclosed herein.

[0085] As shown in Figure 3A, in the adhesive 210, there may be a tendency to be discretely or dispersedly non-uniform across the entire frame / membrane interface region 206. In some embodiments, this may lead to a non-uniform strength of the adhesive bond between the membrane and the frame 202, and as a result, as described above, there may be an early breakage of the macroencapsulation device.

[0086] As shown in Figure 3B, a plurality of mechanically coupled regions 212 may be formed in the frame / membrane interface region 206. Each mechanically coupled region 212 may form a mechanically locking interface between the membrane and the frame. As shown in the figure, the mechanical coupling techniques disclosed herein may produce a more uniform bond in the frame / membrane interface region 206 with respect to position, size, and strength, as compared to the non-uniform adhesive bond shown in Figure 3A.

[0087] Figures 4A - 4F show cross - sections of the frame / membrane interface region 206 that can be seen along a portion of the length of the frame / membrane interface region of the macro - encapsulation device. As shown in Figures 4A - 4F, it will be understood that a plurality of mechanically connected regions can be formed so as to extend around at least a portion of the outer periphery of the membrane of the macro - encapsulation device, or along any other suitable shaped interface between the membrane and the frame. In some embodiments, the plurality of mechanically connected regions can form a sealed internal volume of the macro - encapsulation device disposed between two opposing membrane layers of the macro - encapsulation device. For example, the plurality of mechanically connected regions can form a compartment in which a cell population can be encapsulated.

[0088] In Figure 4A, a first membrane layer 102 and a second membrane layer 104 are stacked on the frame 202. In some embodiments, an intermediate material layer 210 may be disposed between one or more membranes and the frame of the device. This intermediate material layer can include a material having a melting temperature that is between the melting temperature of the frame and the melting temperature of the one or more membranes. The illustrated embodiment shows a device having two membrane layers, but it is again understood that the macro - encapsulation devices described herein are not limited in that regard and may have any suitable number of membrane layers.

[0089] In some embodiments of the manufacturing method, the first membrane layer 102, the second membrane layer 104, the frame 202, and the optional intermediate layer 210 may be disposed between a first die 414 and a second die 418. In some embodiments, the first die 414 can include a support surface 432 that can be disposed relative to a corresponding surface of the frame 202. In the illustrated embodiment, the support surface 432 and the corresponding surface of the frame are shown as flat for ease of explanation. However, of course, the frame can be formed in any suitable shape, and the die can be formed in any suitable shape or configuration corresponding to or supporting the frame.

[0090] In some embodiments, the system may include a heater configured to heat an interface region between the membrane and the frame. For example, the first die 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 die 414 or other suitable part 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 radiant 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 particular heater used, the heater 416 can heat the frame 202 to a temperature sufficient to promote plastic deformation of the frame 202 while maintaining the temperatures of the membrane layers 102 and 104 below the melting temperature and / or sintering temperature of the membrane layers. In this regard, the frame 202 can be plastically deformed without changing or impairing the material properties of one or more portions of the membrane adjacent to the bonding region.

[0091] In some embodiments, a second die 418 may also be disposed within the system such that the membrane layers 102 and 104 are disposed between the first die 202 and the second die. For example, as shown, the second die 418 may be disposed in contact with the first membrane layer 102 on the side of the membrane layer opposite the first die. The second die 418 may be configured to deform a portion of the flexible membrane layer and plastically deform the portion beneath the frame. The deformation of the membrane layer and the frame may enable the formation of one or more mechanically coupled regions, as described below.

[0092] In some embodiments, the formation of a plurality of mechanically coupled regions can be facilitated by forming alternating raised and recessed regions along the length of the membrane / frame interface. Thus, the second die 418 may include one or more corrugations 420 or other protrusions configured to form the desired recessed and raised regions. In the specifically illustrated embodiment, each corrugation 420 may be configured to deform a portion of the membrane(s) and frame when the corrugation 420 is pressed against the membrane and frame at a desired molding temperature that exceeds the melting temperature of the frame. In the illustrated embodiment, a second die 418 having a plurality of corrugations 420 for simultaneously forming a plurality of deformations is shown, but in other embodiments, a single corrugation, or a set of corrugations, may be alternately pushed in and moved along the length of the membrane / frame interface such that different portions of the bonding interface are formed sequentially. Further, it will be understood that including corrugations only in the second die 418 of the illustrated embodiment does not limit the placement of corrugations in other embodiments. For example, in some embodiments, corrugations may be included in the first die 414, either in addition to or as an alternative to, the corrugations shown on the second die 418.

[0093] FIG. 4B shows the second die 418 being moved relative to the first die 414 to compress and deform the first film layer 102, the second film layer 104, and the frame 202 between the dies. In embodiments where the second die 418 includes the scallations 420, each scallation 420 or other protrusion forms a plurality of depressions 426 and raised regions 427 in the first film layer 102, the second film layer 104, and the frame 202 such that the raised and depressed regions alternate along at least a portion of the length of the interface. Again, this deformation may be performed at a temperature at which the frame is thermoplastically deformable, 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 may be higher than the glass transition temperature, and in some cases, the melting temperature of the frame material. The temperature may also be less than at least the melting temperature of one or more films, and in some cases, less than the sintering temperature or the glass transition temperature. Again, this may enable the frame to be deformed without significantly altering the material properties of the films within and / or adjacent to the bonding region.

[0094] As shown in FIG. 4C, a third die 422 may also be used. In some embodiments, the second die 418 may be changed to the third die 422. In some embodiments, after the second die 418 has completed the first deformation (e.g., by creating the recesses 426 in the frame 202 and the film layers 102, 104 as shown), the third die 422 may be used to create a second deformation. In some embodiments, the third die 422 may have a different shape than the second die 418 to create a second deformation that is different from the first deformation created by the second die. For example, the third die 422 may include a flat surface 424 or other suitable shaped surface configured to deform the raised regions 427 of the deformed film / frame interface.

[0095] As shown in FIG. 4D, the first die 414 and / or the third die 422 can be displaced to compress the frame 202 and the film layers 102, 104 therebetween. When a flat surface 424 or a surface of other suitable shape is compressed against the raised portions of the frame 202 and the film layers 102, 104, the raised region 427 can begin to fold into and over the recess 426 formed by the second die 418. Thus, the raised region can be deformed to at least partially overlap the recessed region of the interface. It will be appreciated that the air within the recess can be released during the deformation process, such that the recess and the raised region can be deformed without forming voids.

[0096] As shown in FIG. 4E, as the first die 414 and the third die 422 continue to be compressed against each other, the frame 202 and the film layers 102, 104 are deformed and a portion of the film is folded and compressed between the recess 426 and the corresponding overlapping portion of the deformed raised region, forming a mechanically connected region 428. For example, as shown in the figure, the first portions 102A and 104A of the first film layer and the second film layers 102 and 104 may be compressed between a first portion 202A of the frame 202 corresponding to the recessed region of the frame 202 and a second portion 202B of the frame 202 corresponding to the raised region of the frame that at least partially overlaps the recessed region. Due to their flexibility, one or more films, such as film layers 102 and 104, extend from and between these continuously arranged mechanically connected regions.

[0097] It should be understood that in the above embodiments, the relative movement of the various dies can be adjusted in any suitable manner. For example, the dies shown in the various process steps may be moved together or individually to provide the desired relative movement for compressing the frame and the film therebetween.

[0098] FIG. 4F shows the frame / membrane interface region 206 of the macroencapsulation device after the frame and the membrane are coupled to each other. The interface region 206 can include a plurality of mechanically coupled regions 428, as shown and described above. The interface region 206 can further include the outer surface 230 of one or more membranes that are substantially flat as a result of the second deformation by the third die 422 described above. However, embodiments are also contemplated where the outer surface of the membrane located on the opposite side of the frame is not flat along the membrane / interface region.

[0099] Comparing FIG. 4F with FIG. 4A, it will be appreciated that the mechanically coupled regions 428 can promote the dispersion of the sagging of the membrane layers 102, 104 across the frame / membrane interface region 206. Specifically, in each mechanically coupled region 428, the membrane layers 102, 104 may be deformed from the flat configuration shown in FIG. 4A to the coupled configuration of FIG. 4F, in which a portion of the flexible membrane is folded in a T-shape, and the cross-sectional length of the membrane in this region is shorter than the cross-sectional length of the mechanically coupled region along the membrane / frame interface. In other words, for a given linear length 430 along the frame / membrane interface region 206, the path length of the interface 434 between the membrane and the frame may be longer in the coupled configuration than in the flat configuration. Thus, the coupled configuration can utilize a membrane of a length longer than the flat configuration for a given linear length 430, thereby dispersing the excess membrane sag across the entire frame / membrane interface.

[0100] Figures 5A - 5C show schematic diagrams of various embodiments of a bonding apparatus 600 for manufacturing a macro - encapsulation device 200 according to the methods disclosed herein. As shown in each of Figures 5A - 5C, the bonding apparatus 600 may comprise a plurality of dies including a first die 414. The first die 414 may be configured to hold the frame 202 and / or one or more membranes 204 of the macro - encapsulation device. In some embodiments, the first die 414 may include a holding mechanism configured to hold the frame 202 and / or the membrane(s) 204 relative to the first die. The first die 414 or the holding mechanism may be configured to hold the frame 202 and the membrane 204 in a configuration where at least a portion of the membrane 204 overlaps at least a portion of the frame 202, as shown. For example, in the illustrated embodiment, the first die 414 may include a plurality of vacuum ports 602 for applying a holding suction force to one or more portions of the macro - encapsulation device 200. Each of the vacuum ports 602 may be coupled to a vacuum source (e.g., a pump, a vacuum line, or other suitable vacuum source). The vacuum ports 602 may be disposed at positions on the first die 414 corresponding to desired holding positions of the membrane 204, whereby the first die 414 is configured to hold the membrane 204 in the desired position and configuration. In various embodiments, suction force may be used to hold the membrane 204, the frame 202, or both the membrane and the frame. The illustrated embodiment includes a holding mechanism that includes vacuum ports, but it will be understood that in some embodiments, other holding mechanisms including clips, detents, snap - fit fittings, friction - fit fittings, screw - type arrangements, magnetic - type arrangements, fasteners, and / or any other suitable holding mechanism may be additionally or alternatively included.

[0101] The bonding device 600 may further include one or more heaters 416. For example, one or more heaters may be incorporated into the first die 414 or other suitable part of the bonding device to apply heat to the frame. Specifically, one or more heaters 416 can heat the first die 414, and the first die 414 can transfer that heat to the frame 202 to raise the temperature of the frame to a desired processing temperature. Of course, the present disclosure is not limited to this, and it should be understood that one or more heaters may be incorporated into other parts of the bonding device and / or any suitable type of heating may be used to heat the frame.

[0102] In some applications, during the formation of a plurality of mechanically connected regions, it may be desirable to maintain the temperature of the active portion of one or more membranes (i.e., the portion of one or more membranes that encapsulates a cell population and through which substances flow out) lower than the temperature of one or more adjacent portions of the membranes being joined. For example, in some embodiments, it may be desirable to prevent excessive heating of the active portions of one or more membranes 204 of a macroencapsulation device in order to substantially prevent changes in the properties at the active portions of the one or more membranes. Thus, in some embodiments, the bonding device 600 may be configured to cool and / or thermally insulate one or more portions of one or more membranes 204 from the heat applied to the frame 202. For example, in the illustrated embodiment, the first die 414 may include one or more thermal shields 604 that may correspond to an insulating material, void, or other suitable insulating configuration disposed between one or more heaters and the active portions of one or more membranes.

[0103] In one such embodiment, as shown in the figure, one or more thermal shields 604 (e.g., the illustrated voids) may be disposed between a portion of the first die 414 where the frame 202 is disposed during formation and a portion of the first die where the membrane 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 membranes (e.g., the active portions of one or more membranes) to remove heat from the one or more membranes during the formation process and maintain the temperature of the corresponding portions of the membranes below a desired operating temperature. Such cooling devices may include, but are not limited to, cooling channels formed within the structure, heat sinks, thermoelectric cooling devices, liquid cooling devices, forced ambient air cooling devices, forced cold air cooling devices, chemical cooling devices (e.g., using liquid nitrogen, dry ice, or other cooling chemicals), passive cooling devices (e.g., using cooling fins, thermally conductive materials, and / or special shapes), Peltier modules, and / or any other suitable type of cooling device. Of course, embodiments are also contemplated in which no thermal shields and / or cooling devices are used to thermally isolate a portion of one or more membranes.

[0104] In some embodiments, the first die 414 can optionally be configured to deform a portion of the membrane 204 to promote uniform distribution of membrane sag across the frame / membrane interface. The plane of the membrane 204 can be defined when the membrane 204 is laid flat, as shown in FIG. 1B and represented by line M-M in FIGS. 5A-5C. In some embodiments, a dome 606 can be included in the first die 414 to deform the membrane in a direction out of the plane of the membrane 204 and the frame 202 (see FIGS. 5A-5B). As can be appreciated by comparing the embodiment of FIG. 5A with the embodiment of FIG. 5B, the dome 606, if included, can have any desired geometric shape or curvature depending on the embodiment. For example, an increase in the amount of membrane sag associated with an increase in the macroencapsulation volume may be related to the dome growing larger or out-of-plane deformation of one or more membrane layers occurring during the bonding process. See the different dome sizes in FIGS. 5A and 5B. In some embodiments, the dome 606 of the different embodiments of FIGS. 5A-5C may include grooves, ridges, and / or scallinations as described above. In some embodiments, the dome 606 of the different embodiments of FIGS. 5A-5C may include grooves such as radial grooves. In some embodiments, the dome 606 of the different embodiments of FIGS. 5A-5C may include ridges. In some embodiments, the dome 606 of the different embodiments of FIGS. 5A-5C may include scallinations. In a further embodiment, the scallinations may be included in a clamp (not shown), which may be configured to cooperate with the bonding device 600 or its die components to cause deformation in the macroencapsulation device.

[0105] In some embodiments, the first die 414 may not include the dome 606. For example, in the embodiment shown in FIG. 5C, the first die 414 may include a flat surface 608 instead of the domes shown in FIGS. 5A and 5B. In such embodiments, grooves, ridges, and / or crevations may be further included on the first die 414. Thus, it will be understood that the first die 414 may include any desired geometric shape, as the present disclosure is not limited in this regard.

[0106] The plurality of dies of the coupling device 600 may further include at least a second die (not shown, see FIGS. 4A-4B or 7A) and a third die 422. Each of the second die, the third die, and any additional die may be configured to cause a different deformation in the macroencapsulation device. For example, the second die may be configured to generate a first deformation (e.g., the recess 426 of FIGS. 4A-4C above), and the third die may be configured to generate a second deformation (e.g., the mechanically coupled region 428 of FIGS. 4E-4F above). In the embodiments of FIGS. 5A-5C, the third die 422 can include a flat surface 424 configured to generate the mechanically coupled region 428 as described above. The plurality of dies of the coupling device 600 may be interchangeable within the coupling device 600, such that the first and second deformations can be caused within a single macroencapsulation device 200 without the need to remove the macroencapsulation device 200 from the coupling device 600. However, embodiments are also contemplated where separate forming processes are sequentially performed on different coupling devices having different dies.

[0107] During operation, the macroencapsulation device 200 may be positioned relative to the first die 414, as illustrated. A vacuum source may be activated to hold the membrane 204 and the frame 202 relative to the first die 424. The heater 416 may be activated to provide heat to the frame 202, while the heat shield 604 may prevent heat from the heater 406 from overheating adjacent portions of the membrane 204 through the dome 606. To cause a desired deformation in the frame 202 and the membrane 204, the third die 422 may be pressed in the direction of arrow A. As described above, a series of deformations may be caused using either a single die or multiple dies, which may form a plurality of mechanically coupled regions that secure the membrane 204 to the frame 202.

[0108] As part of the formation and bonding process, it may be desirable to seal adjacent membrane layers together to form a sealed internal cavity into which a cell population can be introduced. FIG. 6 shows a variant of the bonding apparatus 600 for manufacturing the macroencapsulation device 200. This embodiment is substantially similar to the embodiments of FIGS. 5A-5C. However, the sealing die 436 may be configured to bond adjacent layers of one or more membranes 204 in a region disposed radially inward from the frame 202. For example, such an embodiment can be used to form a bonding portion that includes a bonding perimeter between layers of the membrane, as described with respect to FIGS. 1A-1B, which at least partially extends around the sealed internal volume of the macroencapsulation device to form one or more compartments within the membrane 204 for housing a cell population.

[0109] In the illustrated embodiment, a heater such as the illustrated ultrasonic horn 702 or other suitable heater may be operably coupled to the sealing die 436 and / or the first die 414. During operation, the heater may heat a portion of the membrane compressed between the first die and the sealing die to facilitate bonding of one or more layers of the membrane 204 when the membrane layer is compressed between the first die and the sealing die. Using an ultrasonic horn in this embodiment may enable energy to be applied with sufficient precision to form bonds in the desired regions of the membrane 204 without degrading the material properties of other regions of the membrane 204. On the other hand, it will be appreciated that heat may be applied using any suitable heater to bond the membrane layers.

[0110] Figures 7A - 7B illustrate two embodiments of dies according to the present disclosure. In some embodiments, the die may have a size and shape that accommodates a portion of the corresponding die when pressed towards the corresponding die. For example, in the embodiments shown above, the first die 418 and the second die 422 may be sized and shaped to conform to a dome or other shape of the first die that extends at least partially within the die, as shown in FIGS. 5A - 6. In some embodiments, this may correspond to a die having a tubular shape with channels that extend at least partially axially through the die. The upper surface of each die oriented towards the macroencapsulation device during formation may be configured to cause a desired deformation in the frame and / or membrane of the macroencapsulation device. In some embodiments, the first die 418 may have an upper surface with a plurality of scallops 420 for forming a plurality of recesses in the macroencapsulation device as described above, as shown in FIG. 7A. In some embodiments, the second die 422 may include a flat surface 424 for further manufacturing regions for mechanical connection as described above (see FIG. 7B).

[0111] While the specific embodiments described herein contemplate the use of multiple dies, it will be appreciated that the desired variations in the macroencapsulation device can be achieved using only a single die, depending on the desired variation. For example, the position and / or orientation of the die (which may correspond to any structure used to deform the frame and membrane) may be controlled to produce a set of desired variations to create a bond between the frame and one or more membranes.

[0112] FIG. 8 shows a flowchart illustrating one embodiment of a method of manufacturing a macroencapsulation device according to the present disclosure. At step 802, the membrane can be aligned so as to at least partially overlap a corresponding portion of the frame of the macroencapsulation device. The overlapping portion of the one or more membranes and the frame may include a desired frame / membrane interface region that is to be bonded. At step 804, the macroencapsulation device or a portion thereof can be heated to facilitate deformation. For example, the frame of the macroencapsulation device may be heated directly or indirectly to a temperature above the glass transition temperature of the frame and, in some embodiments, above the melting temperature. As described above, this temperature may be below the melting temperature of the one or more membranes and, in some cases, below the sintering temperature. At step 806, one or more flexible membranes are deformed and the frame is plastically deformed to alternately form a plurality of recessed regions and raised regions along at least a portion, and in some cases the entire length, of the membrane / frame interface. The raised regions of the frame and the one or more membranes are deformed so as to at least partially overlap the recessed regions, and a portion of the one or more membranes is compressed between opposite portions of the deformed frame to form a plurality of mechanically connected regions disposed along the length of the membrane / frame interface.

[0113] Example: Good implantation and explant durability tests with reduced bond interface breakage and no reduction in cell viability

[0114] As described above, by the mechanically coupled bonds described herein, a strong, safe, and / or durable bond can be achieved between the membrane and the frame that does not significantly affect the viability of surrounding tissue cells or, on the contrary, has a positive effect on cell viability. For example, macroencapsulation devices manufactured using mechanically coupled regions were implanted into mini-pigs together with similar devices manufactured using adhesive bonds instead of mechanical coupling. After a six-month residence period, all devices were removed. It was observed that all devices remained intact, demonstrating the in vivo durability of the mechanically coupled regions described herein. Next, the viability of the surrounding tissue cells was determined and each device was subjected to additional fatigue testing.

[0115] As shown in FIG. 9, the cell viability of the mechanically coupled devices was similar to that of the adhesively coupled devices, but a slight improvement was observed in the mechanically coupled devices. As shown in FIG. 10, the durability of the mechanically coupled devices was significantly improved compared to the adhesively coupled devices, and it was observed that the number of cycles until failure was significantly higher. Further, referring to FIGS. 11A-11B, the failure of the mechanically coupled device 200B was limited to the membrane 204B, as indicated by the membrane failure 204F. The mechanically coupled interface between the membrane 204B and the frame 202B withstood the fatigue testing. In contrast, the adhesively coupled device 200A failed at both the membrane 204A and the interface region 206A between the membrane 204A and the frame 202A, indicated by the membrane failure 204F and the interface failure 206F, respectively. In the interface failure 206F, it was observed that the adhesive 210A peeled off from the interface region 206A.

[0116] Considering the above, it will be appreciated that the mechanically coupled regions described herein can significantly reduce failure modes that may exist in other joining techniques. In particular, the mechanical coupling bonds described herein can reduce failures such as delamination at the interface between the membrane and the frame. Furthermore, these advantages can potentially be obtained without significantly negatively impacting the viability of cells within the device or while having a positive impact on cell viability.

[0117] Example: Reduction of Immune Response

[0118] Furthermore, as described above, the mechanically coupled regions described herein can result in a reduction of the immune response as compared to similar devices that are adhesively bonded. For example, a mechanically bonded device and an adhesively bonded device were each evaluated in a macrophage polarization assay to measure the secretion levels of inflammatory cytokines induced by each device. THP-1 macrophages were seeded onto each device, and the levels of 20 different inflammatory cytokines secreted by the macrophages were measured after 6 days. As shown in FIG. 12, it was observed that the expression of most cytokines was reduced for the mechanically bonded device as compared to the adhesively bonded device, and it was shown that the expression was significantly reduced for a substantial percentage of the cytokines in the mechanically bonded device. This indicates that the mechanically bonded device results in a reduction of the immune response as compared to a similar adhesively bonded device.

[0119] Although the present teachings have been described with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings include various alternatives, modifications, and equivalents, as will be apparent to those skilled in the art. Accordingly, the foregoing description and drawings are merely illustrative.

Claims

1. A method for manufacturing a macroencapsulation device, wherein the method is Align one or more films of the macroencapsulation device with the frame of the macroencapsulation device so that a portion of the one or more films overlaps at least partially with a portion of the frame, Deform a portion of the one or more membranes and a portion of the frame in a thermoplastic manner so as to form a plurality of mechanically connected regions of the one or more membranes and the frame. Methods that include...

2. The method according to claim 1, wherein the plurality of mechanically connected regions extend around at least a portion of the outer periphery of one or more membranes.

3. The method according to claim 1, wherein the plurality of mechanically connected regions extend at least partially around a sealed internal volume located between two layers of the one or more membranes.

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

5. The method according to claim 1, further comprising heating at least one of the one or more membranes and the frame.

6. Deforming a portion of one or more of the aforementioned membranes and thermoplastically deforming a portion of the aforementioned frame is, To form alternating recessed and raised portions of one or more of the aforementioned membranes and the aforementioned frame, Deform the raised portion of one or more membranes and the frame to form the plurality of mechanically connected regions, and overlap the recessed portion of one or more membranes and the frame at least partially. The method according to any one of claims 1 to 5, including the method described in any one of claims 1 to 5.

7. The method according to any one of claims 1 to 5, wherein the one or more membranes comprises one or more materials selected from polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), polystyrene (PS), polytetrafluoroethylene (PTFE), ePTFE, polyurethane (PU), polyamide (nylon), polyethylene terephthalate (PET), polyethersulfone (PES), polyetherimide (PEI), polyvinylidene fluoride (PVDF), polycaprolactone (PCL), polylactic acid / glycolic acid copolymer (PLGA), poly-L-lactide (PLLA), polyacrylonitrile (PAN), and electrospun PAN / PVC.

8. The method according to claim 7, wherein at least one of the one or more membranes comprises ePTFE.

9. The method according to any one of claims 1 to 5, wherein the frame comprises a thermoplastic material.

10. The method according to claim 9, wherein the frame comprises one or more materials selected from polycarbonate, polyurethane, polyetheretherketone (PEEK), polyvinyl chloride (PVC), poly(oxymethylene), poly(methyl methacrylate) (PMMA), thermoplastic polymer-based composite materials, 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 according to claim 10, wherein the frame comprises polyetheretherketone (PEEK) or fluorinated ethylene propylene (FEP).

12. The method according to any one of claims 1 to 5, wherein the one or more membranes include a first membrane and a second membrane disposed on the first membrane.

13. The method according to claim 12, wherein the first film is sintered.

14. The method according to claim 13, wherein the second film is either not sintered or is sintered.

15. The method according to any one of claims 1 to 5, wherein the method does not involve joining one or more films to the frame using an adhesive.

16. The method according to any one of claims 1 to 5, wherein the macroencapsulation device includes a filling port.

17. The method according to any one of claims 1 to 5, wherein one or more membranes are mechanically connected to the frame in each of the mechanically connected regions of the plurality of mechanically connected regions.

18. A macroencapsulation device, One or more membranes containing a sealed internal volume configured to encapsulate a population of cells, A frame, wherein the one or more films are arranged on the frame, A plurality of mechanically connected regions of the one or more membranes and the frame, wherein the plurality of mechanically connected regions extend around at least a portion of the outer circumference of the one or more membranes. A device that includes this.

19. The device according to claim 18, wherein the plurality of mechanically connected regions include alternating recessed and raised portions of the one or more membranes and the frame, and 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.

20. The device according to claim 19, wherein the one or more membranes comprise one or more materials selected from polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA), polystyrene (PS), polytetrafluoroethylene (PTFE), ePTFE, polyurethane (PU), polyamide (nylon), polyethylene terephthalate (PET), polyethersulfone (PES), polyetherimide (PEI), polyvinylidene fluoride (PVDF), polycaprolactone (PCL), polylactic acid / glycolic acid copolymer (PLGA), poly-L-lactide (PLLA), polyacrylonitrile (PAN), and electrospun PAN / PVC.

21. The device according to claim 20, wherein at least one of the one or more films comprises ePTFE.

22. The device according to any one of claims 18 to 21, wherein the frame comprises a thermoplastic material.

23. The device according to claim 22, wherein the frame comprises one or more materials selected from polycarbonate, polyurethane, polyetheretherketone (PEEK), polyvinyl chloride (PVC), poly(oxymethylene), poly(methyl methacrylate) (PMMA), thermoplastic polymer-based composite materials, 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.

24. The device according to claim 23, wherein the frame comprises polyetheretherketone (PEEK) or fluorinated ethylene propylene (FEP).

25. The device according to any one of claims 18 to 21, wherein the one or more films include a first film and a second film disposed on the first film.

26. The device according to claim 25, wherein the first film is sintered.

27. The device according to claim 26, wherein the second film is either not sintered or is sintered.

28. The device according to any one of claims 18 to 21, wherein the device does not include an adhesive for joining the one or more films to the frame.

29. The device according to any one of claims 18 to 21, wherein the device includes a filling port.

30. The device according to any one of claims 18 to 21, wherein one or more membranes are mechanically connected to the frame in each of the mechanically connected regions of the plurality of mechanically connected regions.

31. A coupling apparatus for manufacturing a macroencapsulation device, wherein the coupling apparatus is A holding mechanism configured to selectively hold the frame of the macroencapsulation device and one or more films of the macroencapsulation device in an overlapping configuration in which at least a portion of the one or more films overlaps with at least a portion of the frame, A heater configured to heat at least a portion of the frame, One or more dies are configured to deform a portion of the one or more membranes and thermoplastically deform a portion of the frame so as to form a plurality of mechanically connected regions between the one or more membranes and the frame, extending around at least a portion of the outer circumference of the one or more membranes. A coupling device, including a coupling device.

32. The coupling device according to claim 31, wherein the holding mechanism is configured to hold the frame and the one or more membranes with respect to the first die among the one or more dies.

33. The coupling apparatus according to claim 32, wherein the first die is configured to deform the inner portion of the one or more films in the out-of-plane direction of the one or more films.

34. The coupling apparatus according to claim 33, wherein the first die includes a dome configured to deform the inner portion of one or more films in the out-of-plane direction.

35. The coupling device according to claim 34, wherein the dome includes radial grooves configured to disperse the slack of one or more membranes.

36. The coupling apparatus according to any one of claims 31 to 35, wherein the first die is coupled to a vacuum source and configured to hold one or more membranes to the first die by suction force.

37. The coupling apparatus according to any one of claims 31 to 35, wherein the one or more dies include a second die having a crenelous surface, configured to deform a portion of the one or more films and thermoplastically deform a portion of the frame relative to the first die, thereby forming alternating recessed and raised portions of the one or more films and the frame.

38. The coupling apparatus according to claim 37, wherein the one or more dies include a third die configured to deform the raised portions of the one or more films and the frame so as to form the plurality of mechanically connected regions, thereby at least partially overlapping the recessed portions of the one or more films and the frame.

39. The coupling device according to any one of claims 31 to 35, wherein the heater is at least one selected from a resistance heater, an ultrasonic horn, an electric heater cartridge, a laser heater, a radiation heater, or an induction heater.

40. The coupling apparatus according to claim 39, further comprising a heat shield and / or cooling device configured to maintain the temperature of the active portion of one or more films lower than the temperature of the portion of the one or more films during the formation of the plurality of mechanically connected regions.

41. The coupling device according to any one of claims 31 to 35, wherein the plurality of mechanically connected regions form a sealed internal volume.

42. The binding device according to claim 41, wherein the sealed internal volume is configured to encapsulate a population of cells.

43. The coupling device according to any one of claims 31 to 35, wherein one or more membranes are mechanically connected to the frame in each of the mechanically connected regions of the plurality of mechanically connected regions.

Images