Implantable membrane structure and packaging device including the same

Abstract

An implantable membrane structure is disclosed that includes a maximum aperture (MPS) of less than 2 microns and opposing sides, each side of the structure having a surface roughness (Sa) of greater than about 0.5 microns. When the surface roughness (Sa) of the lumen surface of the implantable membrane structure is greater than about 0.5 microns, mesenchymal cells do not form at the interface of the lumen and the first side, i.e., the lumen interface, so that the mesenchymal cells do not hinder flow of oxygen and nutrients to transplanted cells (when implanted). When implanted, the outermost layer of the implantable membrane structure enables cell penetration, vascularization, and structural anchoring. The implantable membrane structure includes a single layer embodiment and a multi-layer embodiment. Encapsulation devices for encapsulating biological entities (e.g., cells) into a patient using implantable membrane structures are also provided.

Description

Technical Field

[0001] The present disclosure generally relates to the field of implantable medical devices, and more particularly to implantable membrane structures and encapsulation devices incorporating such implantable membrane structures. Background Art

[0002] Biotherapies, including cell-derived therapies, are increasingly becoming a more viable approach for treating chronic and debilitating human diseases.

[0003] For general biotherapies, cells, viruses, viral vectors, bacteria, proteins, antibodies, and other bioactive entities can be introduced into a patient through surgical or interventional methods that place the bioactive entity within the patient's body. Typically, the bioactive entity is first placed within a device and then inserted into the patient. Alternatively, the device can be inserted into the patient first and then the bioactive entity added. The device can be formed from one or more implantable membranes or implantable membrane structures that allow nutrients to pass through the device but prevent cells from exiting the device into the patient.

[0004] To maintain a viable and productive population of bioactive entities (such as cells), the bioactive entity must maintain uptake of nutrients (such as oxygen), which are primarily delivered through the host's blood vessels. To maximize the viability and productivity of implanted, encapsulated cells, it is necessary to ensure that blood vessels form as close as possible to the cells to maximize uptake of oxygen and nutrients, thereby minimizing the diffusion distance and time required to transport oxygen and nutrients to the implanted, encapsulated cells.

[0005] Implanting an external device (such as a cell encapsulation device) into the body elicits a foreign body response from the body, which can lead to adverse biological reactions depending on the material selection and device design. Even if the material / device is intentionally designed to minimize the foreign body response, its payload, such as cells (or other biological components), can be adversely affected by numerous factors. For example, in the case of cell therapy, one possible outcome is that non-functional / non-therapeutic cell populations may be selected / preferred over targeted stem cell therapies, where most of the therapeutic cell populations are present and functional. For example, the formation / selection of non-target cell types (such as mesenchymal cells) within the stem cell population can reduce the total number of cells with therapeutic function (non-mesenchymal), while also increasing the diffusion barrier / distance between the host and the functional / therapeutic cell population. These non-therapeutic functional cells can also occupy physical space within the graft / device, thereby reducing the overall effectiveness of the treatment.

[0006] There is a need in the art for a material that can reduce or even prevent the formation of mesenchymal cells at the lumen interface and throughout the graft to allow encapsulated therapeutic cells to survive and secrete therapeutically active substances. Summary of the Invention

[0007] In one aspect (“Aspect 1”), an implantable membrane structure includes a first layer having a maximum pore size (MPS) of less than about 2 microns and having opposite sides, wherein the surface roughness of each opposite side is at least 0.5 microns.

[0008] According to another aspect of Aspect 1 (“Aspect 2”), the first layer includes a polymer membrane.

[0009] According to another aspect of Aspect 2 (“Aspect 3”), the polymer membrane is a fluoropolymer membrane.

[0010] According to another aspect of Aspect 3 (“Aspect 4”), the fluoropolymer membrane includes expanded polytetrafluoroethylene (ePTFE), modified ePTFE membrane, tetrafluoroethylene (TFE) copolymer membrane, polyvinylidene fluoride (PVDF) membrane, or fluorinated ethylene propylene (FEP) membrane.

[0011] According to another aspect of Aspect 1 (“Aspect 5”), it includes a surface coating at least partially on the first layer, wherein the surface coating includes one or more components selected from the group consisting of: antimicrobial agents, antibodies, drugs, bioactive molecules, and hydrophilic coatings.

[0012] According to another aspect of Aspect 1 (“Aspect 6”), it includes a frame located at the periphery of the first layer.

[0013] According to another aspect of Aspect 1 (“Aspect 7”), it includes a plurality of regions, wherein each region has a microstructure.

[0014] In one aspect (“Aspect 8”), an implantable membrane structure includes a first layer and a second layer having a maximum pore size of less than about 2.0 microns, the second layer being located on the first layer, wherein the first layer has a first outer side and the second layer has a second outer side, and wherein the surface roughness (Sa) of both the first outer side and the second outer side is at least 0.5 microns.

[0015] According to another aspect of Aspect 8 (“Aspect 9”), the first layer is cell-permeable and the second layer is cell-impermeable.

[0016] According to another aspect of Aspect 8 (“Aspect 10”), the total thickness of the membrane structure is about 15 microns to about 150 microns.

[0017] According to another aspect of Aspect 8 (“Aspect 11”), it includes a medium flow average pore size greater than about 0.1 microns.

[0018] According to another aspect of aspect 8 (“aspect 12”), the tensile strength in the weakest direction is greater than about 0.15 N / mm.

[0019] According to another aspect of aspect 13 (“aspect 13”), it includes a reinforcing component.

[0020] According to another aspect of aspect 13 (“aspect 14”), the stiffness of the reinforcing component is from about 0.01 N / cm to about 5 N / cm.

[0021] According to another aspect of aspect 13 (“aspect 15”), the reinforcing component is a woven or non-woven textile.

[0022] According to another aspect of aspect 8 (“aspect 16”), at least one of the first layer and the second layer includes a polymer, a fluoropolymer film, a non-fluoropolymer film, a woven textile, a non-woven textile, a woven or non-woven assembly of fibers or yarns, a fibrous matrix, and combinations thereof.

[0023] According to another aspect of aspect 16 (“aspect 17”), the polymer is a fluoropolymer film selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) film, fluorinated ethylene propylene (FEP) film, and modified ePTFE film.

[0024] According to another aspect of aspect 8 (“aspect 18”), the first layer and the second layer are tightly bonded.

[0025] According to another aspect of aspect 8 (“aspect 19”), the coefficient of variation of the surface roughness (Sa) of the opposite sides in the implantable membrane structure is less than 15%.

[0026] In one aspect (“aspect 20”), an implantable membrane structure includes a first layer having a first outer side, the surface roughness (Sa) of which is at least 0.5 microns, a second layer located on a side opposite to the first outer side on the first layer, and a third layer located on the second layer such that the second layer is between the first layer and the third layer, wherein the surface roughness (Sa) of the second outer side of the third layer is at least 0.5 microns, and wherein the maximum pore size of the implantable membrane is less than about 2.0 microns.

[0027] According to another aspect of aspect 20 (“aspect 21”), the first layer is cell-permeable, and the second layer and the third layer are cell-impermeable.

[0028] According to another aspect of aspect 20 (“aspect 22”), it includes a medium flow average pore size greater than about 0.1 micron.

[0029] According to another aspect of aspect 20 (“aspect 23”), wherein the thickness of the first layer is from about 2 microns to about 100 microns.

[0030] According to another aspect of aspect 20 (“aspect 24”), wherein the coefficient of variation of the surface roughness (Sa) of the first layer and the third layer is less than 15%.

[0031] According to another aspect of aspect 20 (“aspect 25”), wherein the feature spacing in the third layer is greater than about 3 microns.

[0032] According to another aspect of aspect 20 (“aspect 26”), wherein the third layer comprises at least one of a woven fabric, a non-woven fabric, and a non-fluoropolymer film.

[0033] According to another aspect of aspect 20 (“aspect 27”), which includes perforations.

[0034] According to another aspect of aspect 20 (“aspect 28”), including a tensile strength greater than about 0.15 N / mm in the weakest direction.

[0035] According to another aspect of aspect 20 (“aspect 29”), wherein at least two of the first layer, the second layer, and the third layer are tightly bonded.

[0036] According to another aspect of aspect 20 (“aspect 30”), which includes a reinforcing component.

[0037] According to another aspect of aspect 30 (“aspect 31”), wherein the stiffness of the reinforcing component is from about 0.01 N / cm to about 5 N / cm.

[0038] According to another aspect of aspect 30 (“aspect 32”), wherein the reinforcing component comprises a woven or non-woven textile.

[0039] According to another aspect of aspect 20 (“aspect 33”), wherein at least one of the first layer, the second layer, and the third layer comprises a polymer, a fluoropolymer film, a non-fluoropolymer film, a woven textile, a non-woven textile, a woven or non-woven assembly of fibers or yarns, a fibrous matrix, and combinations thereof.

[0040] According to another aspect of aspect 33 (“aspect 34”), wherein the polymer is a fluoropolymer film selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) film, fluorinated ethylene propylene (FEP) film, and modified ePTFE film.

[0041] According to another aspect of aspect 20 (“aspect 35”), wherein the implantable membrane structure has at least partially a surface coating thereon, and wherein the surface coating comprises one or more components selected from the group consisting of: antimicrobial agents, antibodies, drugs, bioactive molecules, and hydrophilic coatings.

[0042] According to another aspect of aspect 20 (“aspect 36”), wherein at least one of the first layer, the second layer, the third layer, or the reinforcing component is formed of a nonwoven fabric.

[0043] In one aspect (“aspect 37”), a cell encapsulation device comprising an implantable membrane structure having a luminal interface with a surface roughness of at least 0.5 microns, an outer surface with a surface roughness of at least 0.5 microns, and a maximum pore size (MPS) of less than about 2 microns.

[0044] According to another aspect of aspect 37 (“aspect 38”), wherein the implantable membrane structure comprises a first layer.

[0045] According to another aspect of aspect 38 (“aspect 39”), wherein the first layer comprises a polymer membrane.

[0046] According to another aspect of aspect 39 (“aspect 40”), wherein the polymer membrane is a fluoropolymer membrane.

[0047] According to another aspect of aspect 40 (“aspect 41”), wherein the fluoropolymer membrane comprises expanded polytetrafluoroethylene (ePTFE), modified ePTFE membrane, tetrafluoroethylene (TFE) copolymer membrane, polyvinylidene fluoride (PVDF) membrane, or fluorinated ethylene propylene (FEP) membrane.

[0048] According to another aspect of aspect 37 (“aspect 42”), comprising at least partially a surface coating on the implantable membrane structure, and wherein the surface coating comprises one or more components selected from the group consisting of: antimicrobial agents, antibodies, drugs, bioactive molecules, and hydrophilic coatings.

[0049] According to another aspect of aspect 37 (“aspect 43”), comprising a hydrophilic coating on the implantable membrane structure.

[0050] According to another aspect of aspect 37 (“aspect 44”), comprising a reinforcing component.

[0051] According to another aspect of aspect 43 (“aspect 45”), wherein the reinforcing component comprises a woven or nonwoven textile.

[0052] According to another aspect of aspect 37 (“aspect 46”), it includes a first layer and a second layer located on the first layer, wherein the surface roughness of the lumen interface of the first layer is at least 0.5 micrometers and the outermost surface roughness of the second layer is at least about 0.5 micrometers.

[0053] According to another aspect of aspect 46 (“aspect 47”), wherein the first layer is cell-permeable and the second layer is cell-impermeable.

[0054] According to another aspect of aspect 46 (“aspect 48”), wherein the total thickness of the membrane structure is about 15 micrometers to about 150 micrometers.

[0055] According to another aspect of aspect 46 (“aspect 49”), it includes a medium flow average pore size greater than about 0.1 micrometer.

[0056] According to another aspect of aspect 46 (“aspect 50”), wherein the tensile strength in the weakest direction is greater than about 0.15 N / mm.

[0057] According to another aspect of aspect 46 (“aspect 51”), it includes a reinforcing component.

[0058] According to another aspect of aspect 51 (“aspect 52”), wherein the reinforcing component is a woven or non-woven textile.

[0059] According to another aspect of aspect 46 (“aspect 53”), wherein at least one of the first layer and the second layer includes a polymer, a fluoropolymer membrane, a non-fluoropolymer membrane, a woven textile, a non-woven textile, a woven or non-woven aggregate of fibers or yarns, a fibrous matrix, and combinations thereof.

[0060] According to another aspect of aspect 46 (“aspect 54”), wherein the polymer is a fluoropolymer membrane selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) membrane, fluorinated ethylene propylene (FEP) membrane, and modified ePTFE membrane.

[0061] According to another aspect of aspect 46 (“aspect 55”), wherein the first layer and the second layer are tightly bonded.

[0062] According to another aspect of aspect 46 (“aspect 56”), it includes a first layer, a second layer, and a third layer, wherein the second layer is located between the first layer and the third layer, and wherein the surface roughness of the lumen interface of the first layer is at least 0.5 micrometers and the outermost surface roughness of the third layer is at least 0.5 micrometers.

[0063] According to another aspect of aspect 56 (“aspect 57”), wherein the first layer is cell-impermeable and the second layer and the third layer are cell-permeable.

[0064] According to another aspect of aspect 56 (“aspect 58”), it includes a medium flow average pore size greater than about 0.1 micron.

[0065] According to another aspect of aspect 56 (“aspect 59”), wherein the thickness of the first layer is about 2 microns to about 100 microns.

[0066] According to another aspect of aspect 56 (“aspect 60”), wherein the coefficient of variation of the surface roughness (Sa) on the opposite sides of the implantable membrane structure is less than 15%.

[0067] According to another aspect of aspect 56 (“aspect 61”), wherein the average feature spacing in the third layer is greater than about 3 microns.

[0068] According to another aspect of aspect 56 (“aspect 62”), wherein the third layer includes at least one of a woven fabric, a non-woven fabric, and a non-fluoropolymer membrane.

[0069] According to another aspect of aspect 56 (“aspect 63”), it includes perforations.

[0070] According to another aspect of aspect 56 (“aspect 64”), it includes a tensile strength greater than about 0.15 N / mm in the weakest direction.

[0071] According to another aspect of aspect 56 (“aspect 65”), wherein at least two of the first layer, the second layer, and the third layer are tightly bonded.

[0072] According to another aspect of aspect 56 (“aspect 66”), it includes a reinforcing component.

[0073] According to another aspect of aspect 66 (“aspect 67”), wherein the stiffness of the reinforcing component is about 0.01 N / cm to about 5 N / cm.

[0074] According to another aspect of aspect 66 (“aspect 68”), wherein the reinforcing component includes a woven or non-woven textile.

[0075] According to another aspect of aspect 56 (“aspect 69”), wherein at least one of the first layer, the second layer, and the third layer includes a polymer, a fluoropolymer membrane, a non-fluoropolymer membrane, a woven textile, a non-woven textile, a woven or non-woven aggregate of fibers or yarns, a fibrous matrix, and combinations thereof.

[0076] According to another aspect of aspect 69 (“aspect 70”), wherein the polymer is a fluoropolymer membrane selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) membrane, fluorinated ethylene propylene (FEP) membrane, and modified ePTFE membrane.

[0077] According to another aspect of aspect 56 (“aspect 71”), wherein the implantable membrane structure has at least partially a surface coating thereon, and wherein the surface coating comprises one or more components selected from the group consisting of: an antimicrobial agent, an antibody, a drug, a bioactive molecule, and a hydrophilic coating.

[0078] According to another aspect of aspect 56 (“aspect 72”), wherein at least one of the first layer, the second layer, the third layer, or the reinforcement component is formed of a nonwoven fabric. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to further understand the present disclosure. The drawings illustrate embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.

[0080] Figure 1 is a side schematic view of a single-layer implantable membrane structure according to some embodiments;

[0081] Figure 2 is a side schematic view of a bilayer implantable membrane structure including a mesenchymal alleviation layer and a cell-impermeable layer according to some embodiments;

[0082] Figure 2A is a side schematic view of a bilayer implantable membrane structure including a cell-impermeable layer and a vascularized layer according to some embodiments;

[0083] Figure 3 is a side schematic view of a multi-layer implantable membrane composite according to some embodiments;

[0084] Figure 4A is a top schematic view of a cell encapsulation device according to some embodiments;

[0085] Figure 4B is according to some embodiments of Figure 4A a cross-sectional schematic view of a cell encapsulation device, which shows the orientation of the layers of the biocompatible membrane composite and the cell placement;

[0086] Figure 5 is a schematic view showing the determination of the feature pitch according to some embodiments, wherein three adjacent features represent the corners of a triangle, and there are no additional features inside the circumcircle of the triangle, and the feature pitch is the straight-line distance between two features forming the triangle;

[0087] Figure 6 is a scanning electron micrograph (SEM) of the surface of an ePTFE membrane of Comparative Example 1 according to some embodiments;

[0088] Figure 6Ais a scanning electron microscopic image (SEM) of the cross-section of an ePTFE membrane of Comparative Example 1 according to some embodiments;

[0089] Figure 7 is a representative histological image according to some embodiments, which shows mesenchymal cells arranged on the lumen interface of the implantable membrane structure of Comparative Example 1;

[0090] Figure 8 is a scanning electron microscopic image (SEM) of the lumen-facing side of the implantable membrane structure of Comparative Example 2 according to some embodiments;

[0091] Figure 9 is a scanning electron microscopic image (SEM) of the host-facing side of the implantable membrane structure of Comparative Example 2 according to some embodiments;

[0092] Figure 9A is a scanning electron microscopic image (SEM) of the cross-section of the implantable membrane structure of Comparative Example 2 according to some embodiments;

[0093] Figure 10 is a representative histological image according to some embodiments, which shows mesenchymal cells arranged on the lumen interface of the implantable membrane structure of Comparative Example 2;

[0094] Figure 11 is a scanning electron microscopic image (SEM) of the lumen-facing side of the implantable membrane structure of Example 1 according to some embodiments;

[0095] Figure 12 is a scanning electron microscopic image (SEM) of the host-facing side of the implantable membrane structure of Example 1 according to some embodiments;

[0096] Figure 13 is a scanning electron microscopic image (SEM) of the cross-section of the implantable membrane complex of Example 1 according to some embodiments;

[0097] Figure 14 is a representative histological image according to some embodiments, which shows the presence of living functional cells near the lumen interface of the implantable membrane structure of Example 1;

[0098] Figure 15 is a scanning electron microscopic image (SEM) of the lumen-facing side of the implantable membrane complex of Example 2 according to some embodiments;

[0099] Figure 16 is a scanning electron microscopic image (SEM) of the host-facing side of the implantable membrane complex of Example 2 according to some embodiments;

[0100] Figure 17is a scanning electron microscopy (SEM) image of a cross-section of an implantable membrane structure according to Example 2 of some embodiments;

[0101] Figure 18 is a representative histological image according to some embodiments, showing the presence of living functional cells near the lumen interface of the implantable membrane complex of Example 2;

[0102] Figure 19 is a scanning electron microscopy (SEM) image of the lumen-facing side of an implantable membrane complex according to Example 3 of some embodiments;

[0103] Figure 20 is a scanning electron microscopy (SEM) image of the host-facing side of an implantable membrane complex according to Example 3 of some embodiments;

[0104] Figure 21 is a scanning electron microscopy (SEM) image of a cross-section of an implantable membrane structure according to Example 3 of some embodiments;

[0105] Figure 22 is a representative histological image according to some embodiments, showing the presence of living functional cells near the lumen interface of the implantable membrane complex of Example 3;

[0106] Figure 23 is a scanning electron microscopy (SEM) image of the lumen-facing side of an implantable membrane complex according to Example 4 of some embodiments;

[0107] Figure 24 is a scanning electron microscopy (SEM) image of the host-facing side of an implantable membrane complex according to Example 4 of some embodiments;

[0108] Figure 25 is a scanning electron microscopy (SEM) image of a cross-section of an implantable membrane structure according to Example 4 of some embodiments; and

[0109] Figure 26 is a representative histological image according to some embodiments, showing the presence of living functional cells near the lumen interface of the implantable membrane complex of Example 4.

[0110] Those skilled in the art will readily understand that various aspects of the present disclosure can be implemented by any number of methods and devices configured to perform the intended functions. It should also be noted that the accompanying drawings referred to herein are not necessarily drawn to scale and may be enlarged to illustrate various aspects of the present disclosure. In this regard, the drawings should not be considered restrictive. Detailed Description

[0111] Those skilled in the art will readily appreciate that various aspects of the present disclosure can be implemented by any number of methods and devices configured to perform the intended functions. It should also be noted that the accompanying drawings referred to herein are not necessarily drawn to scale and may be enlarged to illustrate various aspects of the present disclosure, and in this regard, the drawings should not be considered limiting. Directional references such as "upper", "lower", "top", "left", "right", "front", and "rear" are intended to refer to the directions shown and described in the figures to which the components and directions are referenced. It should be noted that all ranges described herein are inherently exemplary and include any and all values therebetween. Additionally, all references cited herein are incorporated herein by reference in their entirety. Further, the terms "implantable membrane structure", "membrane structure", and "structure" are used interchangeably herein and may refer to one or more layers. The terms "cell encapsulation device", "encapsulation device", and "device" are used interchangeably herein..

[0112] The present disclosure relates to an implantable membrane structure and an encapsulation device comprising the implantable membrane structure. The implantable membrane structure includes a maximum pore size (MPS) of less than 2.0 microns and opposing sides, wherein the surface roughness (Sa) of each opposing side is greater than about 0.5 microns. As used herein, the term "implantable membrane structure" includes single-layer and multi-layer embodiments. In both single-layer and multi-layer embodiments, the surface roughness (Sa) of each side of the implantable membrane structure is greater than about 0.5 microns, and the maximum pore size (MPS) of the implantable membrane structure is less than about 2.0 microns. In such embodiments, the first side of the membrane structure can serve as a mesenchymal mitigation layer, and the opposing second side enables cell penetration, vascularization, and structure anchoring (upon implantation). It should be understood that a single-layer membrane structure can have regions of multiple different microstructures throughout the structure.

[0113] The implantable membrane structure can also include multiple layers (i.e., more than one layer). In at least one embodiment, a second layer is located on a first layer. The surface roughness (Sa) of the outermost side of the first layer is greater than about 0.5 microns and the surface roughness of the opposing side of the membrane structure (e.g., the outermost side of the second layer) is also greater than about 0.5 microns. As used herein, the term "outermost side" refers to the outermost portion of a layer of the implantable membrane structure. Upon implantation, the outermost side of the first layer can face the lumen and the outermost side of the second layer can face the host tissue. Either the first layer or the second layer provides cell impermeability to the membrane structure. The maximum pore size (MPS) of the implantable membrane structure is less than about 2.0 microns.

[0114] In certain embodiments, the first layer serves as a mesenchymal mitigation layer and the second layer serves as a cell-impermeable layer. Herein, the terms "first layer" and "mesenchymal mitigation layer" are used interchangeably, and the terms "second layer" and "cell-impermeable layer" are used interchangeably. An additional layer may be present on the cell-impermeable layer (second layer) opposite the first layer (mesenchymal mitigation layer). In some embodiments, the third layer may permit blood vessels to penetrate from the host into the third layer, rapidly anchoring and attaching the implantable membrane structure within the host tissue. Thus, the third layer may be used interchangeably with the "vascularization layer" herein. The second layer, i.e., the cell-impermeable layer, is located inside the implantable membrane structure, e.g., between the first layer and the third layer. The maximum pore size (MPS) of the implantable membrane structure is less than about 2.0 microns. Both the first layer and the third layer have an outer-facing side with a surface roughness greater than about 0.5 microns. In embodiments including three layers, the surface roughness (Sa) of each opposite side of the membrane structure is defined by the outer-facing side of the first layer and the outer-facing side of the third layer. In embodiments including two layers, the surface roughness (Sa) of each opposite side of the membrane structure is defined by the outer-facing side of the first layer and the outer-facing side of the second layer (e.g.). The surface roughness of the outer-facing side is greater than about 0.5 microns. The first layer, the second layer, and the third layer are bonded or otherwise connected to each other. The implantable membrane structure may include a single layer, two layers, three layers, or more layers. As described herein, regardless of the number of layers included in the implantable membrane structure, the surface roughness of the outer-facing side of the implantable membrane structure is at least 0.5 microns. It should be understood that, as used herein, the term "about" means + / - 10% of the specified measurement unit.

[0115] The present disclosure also describes a device for encapsulating a biological entity (e.g., a cell), wherein the encapsulation device is implanted into a patient (e.g., into a tissue bed) to provide a biotherapy. However, it should be understood that the embodiments described herein may be applied to a variety of implantable medical devices, and the encapsulation device described herein is exemplary in nature.

[0116] Biological entities suitable for use with the implantable membrane structure and the implantable membrane include, but are not limited to: cells, viruses, viral vectors, bacteria, proteins, polysaccharides, and antibodies. It should be understood that if a biological entity other than a cell is selected for use, the bioactive component or product of the biological entity (rather than the entity itself) needs to be able to cross the second layer. In short, the biological entity is referred to as a cell herein, but nothing in this specification limits the biological entity to a cell or any particular type of cell, and the following description also applies to non-cell biological entities.

[0117] Prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, and / or stem cells of various types can be used with the implantable membrane structures or implantable membranes described herein. In some embodiments, the cells secrete a therapeutically active substance. Such therapeutically active substances include: hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cell products that provide a therapeutic benefit to the recipient of the device. Examples of such therapeutic cell products include, but are not limited to: insulin and other pancreatic hormones, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, collagen, elastin, tropoelastin, exosomes, vesicles, gene fragments, and factor VIII. Non-limiting examples of suitable growth factors include: vascular endothelial growth factor, platelet-derived growth factor, platelet-activating factor, transforming growth factor, bone morphogenetic protein, activin, inhibin, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, glial cell line-derived neurotrophic factor, growth differentiation factor-9, epidermal growth factor, and combinations thereof. It should be understood that throughout the present disclosure, the terms "cell" or "cells" may be replaced by "biological entity" or "biological entities", respectively. In addition, the terms "mesenchymal cell" and "stromal cell" are used interchangeably herein.

[0118] The first side of the implantable membrane structure forms a suitable environment to minimize, reduce, inhibit, or even prevent the formation of non-target cell types (e.g., mesenchymal-derived cells, including but not limited to fibroblasts, endothelial cells, macrophages), while allowing the encapsulated cells to access oxygen and maintain cellular nutrients. The presence of mesenchymal cells (especially at the luminal interface) is disadvantageous because these non-functional cells may consume oxygen that could otherwise be utilized by the functional cell population. Additionally, mesenchymal cells occupy space within the lumen that could otherwise be utilized by the functional cell population. Further, mesenchymal cells undesirably increase the diffusion barrier distance between the host and the functional cell population. By designing the membrane structure such that the side adjacent to the lumen in the encapsulation device has a minimum surface roughness, the formation of mesenchymal cells at the luminal interface is reduced or even prevented, thereby allowing for maximum mass transport of oxygen and nutrients to the transplanted cell population to achieve its highest therapeutic potential. As shown in the examples, when the surface roughness (Sa) of the luminal surface of the implantable membrane structure is greater than about 0.5 microns, mesenchymal cells do not form at the interface between the lumen and the first side (i.e., the luminal interface), and thus mesenchymal cells do not impede the flow of oxygen and nutrients to the transplanted cells. It is noted that mesenchymal cells may be individually located at the luminal interface, but they do not spread, expand, or impede or prevent the entry of oxygen and nutrients required for the growth of the encapsulated cells. Additionally, in at least one embodiment, the thickness of the first layer (i.e., the mesenchymal mitigation layer) can range from about 2 microns to about 100 microns, from about 2 microns to about 90 microns, from about 2 microns to about 80 microns, from about 2 microns to about 70 microns, from about 3 microns to about 60 microns, from about 3 microns to about 50 microns, from about 3 microns to about 45 microns, from about 5 microns to about 40 microns, from about 5 microns to about 35 microns, from about 5 microns to about 30 microns, from about 5 microns to about 35 microns, or from about 5 microns to about 30 microns.

[0119] As described above, the implantable membrane structure has a maximum pore size (MPS) of less than about 2 microns and opposite sides with a surface roughness (Sa) greater than about 0.5 microns. Each of the opposite sides has a micro-rough surface. As used herein, the term "micro-rough surface" refers to a surface roughness greater than about 0.5 microns but less than about 30 microns. In some embodiments, the surface roughness can be from about 0.5 microns to about 25 microns, about 0.5 microns to about 20 microns, about 0.5 microns to about 15 microns, about 0.5 microns to about 15 microns, about 0.5 microns to about 10 microns, or about 0.5 microns to about 5 microns. This is in contrast to a "macro-rough surface", which refers to a surface roughness visible to the naked eye. Additionally, the surface roughness (Sa) on one side of the implantable membrane structure can be the same as or different from the surface roughness on the opposite side of the implantable membrane structure. Although the outer exposed surface of the implantable membrane structure has a certain surface roughness, it is noted that the outer layer of the implantable membrane structure may be naturally rough or uneven, with a natural surface roughness greater than about 0.5 microns. However, in certain embodiments, the surface roughness of the opposite sides of the implantable membrane structure can be achieved by plasma etching, laser etching, micro-embossing, plasma treatment, 3D printing, deposition, mechanical roughening, or a combination thereof.

[0120] In embodiments where the first layer is the only layer of the implantable membrane structure and in multi-layer embodiments, the maximum pore size MPS of the implantable membrane structure is less than about 2.0 microns. As measured by porosity measurement methods, the range of MPS can be from about 0.05 microns to about 2 microns, about 0.05 microns to about 1.75 microns, about 0.05 microns to about 1.5 microns, about 0.05 microns to about 1.0 microns, about 0.05 microns to about 0.75 microns, about 0.05 microns to about 0.5 microns, or about 0.1 microns to about 1 microns, about 0.1 microns to about 0.75 microns, or about 0.1 microns to 0.5 microns.

[0121] In addition, the surface roughness of the opposite sides of the implantable membrane structure is greater than about 0.5 microns, greater than about 1 micron, greater than about 5 microns, greater than about 10 microns, greater than about 15 microns, greater than about 20 microns, or greater than about 25 microns. In some embodiments, the surface roughness of one or both of the opposite sides of the implantable membrane structure is from about 0.5 microns to about 25 microns, about 0.5 microns to about 20 microns, about 0.5 microns to about 15 microns, about 0.5 microns to about 10 microns, or about 0.5 microns to about 5 microns. Additionally, the surface roughness along the opposite sides can be substantially uniform. In other words, for samples collected at various positions on a sample area no larger than about 0.1 mm 2 the surface roughness (Sa) measured by the coefficient of variation is less than 15%.

[0122] In a multi-layer embodiment, the first layer of the implantable membrane structure includes at least one side having a surface roughness (Sa) greater than about 0.5 microns. When used in an implantable medical device, the side with a surface roughness greater than about 0.5 microns faces the lumen (i.e., the lumen interface) and serves as a mesenchymal mitigation layer.

[0123] The implantable membrane structure may include a second layer located on the first layer. The second layer may be a cell-impermeable layer that serves as a microporous cell isolation barrier, is unaffected by in-growth of blood vessels, and prevents cell contact with the host. The second layer maintains a sufficient porosity to allow molecules (i.e., cell nutrients, oxygen, waste, and therapeutic substances) to pass therethrough. The second layer can be considered a "tight" layer as it restricts or prevents in-growth of blood vessels and / or cells and cell contact between transplanted cells and host cells. As previously described, the membrane structure may be defined by the outer side of the first layer and the outer side of the second layer.

[0124] Further, the implantable membrane structure may also include a third layer. The third layer is located on the second layer on the opposite side of the first layer. The surface roughness (Sa) of the outer side of the third layer is greater than about 0.5 microns. The third layer may be a vascularized layer that allows blood vessels to penetrate from the host, thereby allowing the implantable membrane structure to rapidly anchor and attach within the host tissue. The vascularized layer is considered an "open" layer. In this regard, the vascularized layer can be designed to have a feature spacing (e.g., the spacing between adjacent features) to achieve host integration and attachment. The nodal feature spacing increases the pore size to facilitate faster tissue growth into the vascular layer (i.e., the third layer). It is noted that the first side of the membrane structure may be defined by the first layer, and the second side of the membrane structure may be defined by the third layer. The average feature spacing (i.e., the spacing between adjacent features) may be greater than about 3 microns, greater than about 5 microns, greater than about 10 microns, greater than about 25 microns, greater than about 50 microns, greater than about 75 microns, greater than about 100 microns, greater than about 125 microns, greater than about 150 microns, greater than about 175 microns, greater than about 200 microns, greater than about 225 microns, greater than about 250 microns, or greater than about 275 microns. Additionally, the average feature spacing may be from about 3 microns to about 300 microns, from about 3 microns to about 275 microns, from about 3 microns to about 250 microns, from about 3 microns to about 225 microns, from about 3 microns to about 200 microns, from about 10 microns to about 175 microns, from about 10 microns to about 150 microns, from about 10 microns to about 125 microns, from about 10 microns to 100 microns, or from about 10 microns to about 50 microns. In some embodiments, the third layer may include a biocompatible textile, which includes woven and non-woven fabrics (e.g., spunbond non-woven fabric, meltblown fiber material, electrospun nanofibers, etc.), non-fluoropolymer membranes (e.g., nanofibers, polysulfone, polyethersulfone, polyarylsulfone, polyetheretherketone (PEEK), polyethylene, polypropylene, and polyimide)

[0125] It should be understood that additional layers may alternatively or additionally be present in the implantable membrane structure. For example, an enhancement component may be provided to the implantable membrane structure to minimize in vivo deformation and thus maintain the cell bed thickness (e.g., in an encapsulation device). This additional, optional enhancement component provides a greater stiffness to the implantable membrane structure than the implantable membrane structure itself to provide mechanical support. The optional enhancement component may be continuous in nature or it may be present in discrete layers on the implantable membrane structure, such as forming a pattern over the entire surface of the implantable membrane structure or located at specific locations, such as the perimeter (e.g., frame) of the implantable membrane structure. Non-limiting patterns suitable for the enhancement component on the surface of the implantable membrane structure include dots, straight lines, diagonal lines, curves, dashed lines, grids, etc. The patterns forming the enhancement component may be used alone or in combination. Additionally, the enhancement component may be temporary in nature (e.g., formed from a bioabsorbable material) or may be permanent in nature (e.g., polyethylene terephthalate (PET) mesh or nitinol). One of ordinary skill in the art should understand that the effect of the component stiffness depends not only on the stiffness of the individual component but also on the location and restraint of the enhancement component in the final device form. In order for a component (e.g., an enhancement component) to be practically useful for increasing the stiffness of the implantable membrane structure, the enhancement component should have a stiffness greater than about 0.01 N / cm, although the ultimately determined required stiffness will depend on the location and restraint in the finished cell encapsulation device. In some embodiments, the stiffness of the enhancement component may be from about 0.01 N / cm to about 5 N / cm, about 0.05 N / cm to about 4 N / cm, about 0.1 N / cm to about 3 N / cm, about 0.3 N / cm to about 2 N / cm.

[0126] In at least one embodiment, an enhancement component may be provided on the outer surface of the outermost layer (e.g., the vascularized layer) to strengthen the implantable membrane structure against environmental forces. In this direction, the enhancement component has a sufficiently large pore size to allow blood vessels to grow inwards. Materials that can be used as the enhancement component include materials that are significantly stiffer than the implantable membrane structure. Such materials include, but are not limited to: open mesh biomaterial textiles, woven textiles, non-woven textiles (e.g., a collection of fibers or yarns), and fibrous matrices, which are used alone or in combination. In another embodiment, a patterned grid, screen, wire, or rod may be used as the enhancement component. Additionally, the enhancement component may be oriented within or between the first, second, and third layers of the discrete layer or within the composite layer itself. It should be understood that the enhancement component may be located outside, inside (e.g., between layers), within a layer, or a combination thereof, of the implantable membrane structure.

[0127] As an alternative to or in addition to the reinforcing component, the implantable membrane structure may be surrounded by a frame to improve operability and stiffness. In some embodiments, the frame is located around the implantable membrane structure. The material forming the frame is not particularly limited as long as it meets the basic requirements of being compatible with the implantation environment and having the necessary stiffness. Polymer materials such as polyetheretherketone (PEEK), polyethylene terephthalate (PET), polypropylene, polyethylene, polymethyl methacrylate, polyethyl methacrylate, polyacrylate, poly(α-hydroxy acid), polycaprolactone, polydioxanone, polyester, polyglycolic acid, polyethylene glycol, polylactide, polyorthoester, polyphosphate, polyoxaester, polyphosphonate, polyphosphonite, polysaccharide, poly(tyrosine carbonate), silicone, polyurethane, polyurethane having ionic or mesogenic components prepared by a prepolymer method, block copolymers of polyethylene terephthalate (PET) and polyethylene oxide (PEO), block copolymers comprising polystyrene and poly(1,4-butadiene), and ABA triblock copolymers made from poly(2-methyl-2-oxazoline) and polytetrahydrofuran, and their copolymers or polymer blends. Metal frames may also be incorporated using materials such as spring-tempered 316SST; spring-tempered cobalt-chromium alloys such as Co-28Cr-6Mo or Co-35Ni-20Cr-10Mo; spring-tempered titanium-based alloys such as Ti-6Al-4V or spring-tempered nickel-titanium alloys such as Nitinol or copper-aluminum-nickel, copper-zinc-aluminum, and iron-manganese-silicon alloys. The frame material may be a material that is inherently biocompatible or a material that lacks inherent biocompatibility but is rendered biocompatible, such as having a biocompatible coating. Non-limiting examples of inherently biocompatible frame materials include PEEK, Nitinol, or Ti-6Al-4V. Non-limiting examples of materials that may be used as biocompatible coatings include PTFE, FEP, and parylene. Solvent-based fluoropolymers may also be used as biocompatible coatings.

[0128] In some embodiments, the implantable membrane structure is perforated to allow host cells and the vasculature to directly contact the transplanted cells contained within the lumen of the encapsulation device. The size, number, and location of the perforations can be selected to optimize the function and therapeutic potential of the graft. The size of the perforations should be large enough to allow host vascular tissue (e.g., capillaries) to enter the device lumen to support the contained biological entities. Perforations that allow vascular structures to grow into the device lumen contribute to the long-term health and function of the transplanted cells as they are directly perfused by the host circulatory system. Although penetration of the device by some host tissues improves the therapeutic function of the biological components (e.g., vascular structures and capillaries), other host tissue populations can be detrimental to the encapsulated biological components by occupying space and volume within the lumen that could otherwise be utilized by therapeutically functional entities. Since the perforations also allow immune cells to contact the transplanted cells, the transplanted cells are no longer protected from immune rejection unless the host is immunocompromised, receiving immunosuppressive drugs, or the transplanted cells have low immunogenicity or are immunologically matched to the host.

[0129] In one embodiment of a perforated device, the membrane structure can also prevent the presence and proliferation of certain harmful host cell populations that can enter the lumen of the device and spread and expand therein. These host cell populations can also deprive the functional therapeutic cells in the lumen of valuable space. One such host cell population can be fibroblasts. Another host population can be other mesenchymal cells, and / or any other cells that can reduce the overall function or available volume of the therapeutic cells.

[0130] The implantable membrane structure has a total thickness. As used herein, "total thickness" refers to the thickness of the implantable membrane structure, i.e., the total thickness of the layers present in the membrane composite in the z-direction. In some embodiments, the thickness of the composite can range from about 15 microns to about 200 microns, from about 15 microns to about 175 microns, from about 15 microns to about 150 microns, from about 15 microns to about 125 microns, from about 15 microns to about 100 microns, from about 15 microns to about 75 microns, or from about 15 microns to about 50 microns.

[0131] In addition, the median flow mean pore size of the implantable membrane structure is greater than about 0.10 microns. The median flow mean pore size can be greater than about 0.5 microns, greater than about 1.0 microns, greater than about 1.5 microns, or greater than about 2.0 microns. In addition, the range of the median flow mean pore size can be from about 0.1 microns to about 3.0 microns, from about 0.1 microns to about 2.75 microns, from about 0.1 microns to about 2.5 microns, from about 0.1 microns to about 2.0 microns, or from about 0.1 microns to about 1.5 microns. The median flow mean pore size ensures that the pore size is large enough to allow for substantial transport and diffusion.

[0132] A trade-off needs to be made between two competing properties: strength and diffusional resistance. Strength is important for the ability to handle, fabricate the encapsulation device, and ensure the integrity of the device in the body. The tensile strength in the weakest direction of the implantable membrane structure is greater than about 0.15 N / mm, greater than about 0.25 N / mm, greater than about 0.50 N / mm, greater than about 0.75 N / mm, greater than about 1 N / mm, greater than about 1.15 N / mm, or greater than about 1.25 N / mm. Additionally, the range of the maximum tensile strength in the weakest direction can be from about 0.15 N / mm to about 1.5 N / mm, from about 0.15 N / mm to about 1.25 N / mm, from about 0.15 N / mm to about 1 N / mm, from about 0.25 N / mm to about 0.75 N / mm, or from about 0.3 N / mm to about 0.5 N / mm.

[0133] The implantable membrane structure also has a z-strength. The z-strength is sufficient to prevent delamination of the membrane structure in the body. In some embodiments, the layers are tightly bound to each other or otherwise connected to form the implantable membrane structure. As used herein, "tightly bound" means that the layers of the implantable membrane structure do not readily separate or split at any point on their surfaces. In a two-layer structure, the first layer and the second layer are tightly bound. In a three-(or more)-layer structure, at least two of the first, second, and third layers are tightly bound.

[0134] The porosity of the implantable membrane structure is sufficient to allow cell nutrients, cell wastes, and therapeutic substances to flow through, but not sufficient to allow cells to pass through. In certain embodiments, the porosity of the implantable membrane structure is greater than about 50%, greater than about 60%, greater than about 70%, or greater than about 80%. Additionally, the range of the porosity of the implantable membrane structure can be from about 50% to about 98%, from about 50% to about 90%, from about 50% to about 80%, or from about 60% to about 90%.

[0135] The implantable membrane composite can have a surface coating at least partially thereon, such as a zwitterionic antifouling coating, a hydrophilic coating, or / heparin coating (available from W.L. Gore & Associates, Inc.). The surface coating can also contain or alternatively contain antibacterial agents, antibodies [such as anti-CD47 antibodies (anti-fibrotic)], drugs, and other bioactive molecules (such as angiogenesis stimulants, such as FGF, VEGF, endoglin, PDGF, angiopoietin, and integrin; anti-fibrotic agents, such as TGFb inhibitors, sirolimus, CSF1R inhibitors, and anti-CD47 antibodies; anti-inflammatory / immunomodulators, such as CXCL12 and corticosteroids) and combinations thereof.

[0136] In at least one embodiment, layers (such as a first and second layer or a first, second, and third layer) are joined together by one or more biocompatible adhesives to form an implantable membrane structure. The adhesive can be applied to the surface of one or more layers to form a bond between the layers. Non-limiting examples of suitable biocompatible adhesives include fluorinated ethylene propylene (FEP), (polycarbonate polyurethane), polycarbonate polyurethane, a thermoplastic fluoropolymer composed of TFE and PAVE, EFEP (ethylene fluorinated ethylene propylene), PEBAX (polyetheramide), PVDF (polyvinylidene fluoride), Carb- (AB silicone polycarbonate polyurethane), Elasthane TM (polyether polyurethane), (silicone polyether polyurethane), polyethylene, high density polyethylene (HDPE), ethylene chlorotrifluoroethylene (ECTFE), perfluoroalkoxy (PFA), polypropylene, polyethylene, polyethylene terephthalate (PET), and combinations thereof.

[0137] The membrane structure (such as one or more of the first, second, and third layers) includes at least a fluoropolymer membrane, such as expanded polytetrafluoroethylene, a modified ePTFE membrane, a tetrafluoroethylene (TFE) copolymer membrane, a polyvinylidene fluoride (PVDF) membrane, or a fluorinated ethylene propylene (FEP) membrane. Expanded polytetrafluoroethylene (ePTFE) (and other fibrillated polymers) has a node and fibril microstructure, where the nodes are interconnected by fibrils and the pores are the spaces between the nodes and fibrils throughout the membrane. As used herein, the term "node" refers to a feature consisting primarily of polymeric material. The expanded polytetrafluoroethylene membranes used herein are, for example but not limited to, those prepared according to the methods described in U.S. Patent No. 3,953,566 to Gore, U.S. Patent No. 7,306,729 to Bacino et al., U.S. Patent No. 5,476,589 to Bacino, WO 94 / 13469 to Bacino, U.S. Patent No. 5,814,405 to Branca et al., or U.S. Patent No. 5,183,545 to Branca et al. In some embodiments, the membrane structure can include a non-fluoropolymer membrane, such as but not limited to a polyethylene membrane.

[0138] In some embodiments, at least one of the first layer, the second layer, the third layer, or the reinforcement component is formed of a nonwoven fabric. There are a wide variety of nonwoven fabrics, each of which may vary in the tightness of the weave and the thickness of the sheet. Nonwoven fabrics can be bonded fabrics, formed fabrics, or engineered fabrics made by methods other than weaving or knitting. In some embodiments, the nonwoven fabric is a porous, textile-like material, typically in the form of a flat sheet, formed mainly or entirely of fibers, such as staple fibers assembled into a net, sheet, or batting. The structure of the nonwoven fabric is based on, for example, the arrangement of staple fibers, which is usually more or less random. In addition, nonwoven fabrics can be manufactured by a variety of techniques known in the textile industry. Various methods can form carded, wet-laid, meltblown, spunbond, electrospun, or air-laid nonwoven materials. Exemplary methods and substrates are described, for example, in U.S. Patent Publication No. 2010 / 0151575 to Colter et al. In some embodiments, the nonwoven fabric is biocompatible and / or bioabsorbable.

[0139] In some embodiments, it may be desirable for one or more of the third layer (i.e., the vascularized layer) and / or the reinforcement component to be non-permeable (e.g., biodegradable). In such cases, biodegradable materials can be used to form the third layer and / or the reinforcement component. Non-limiting examples of suitable bioabsorbable materials include, but are not limited to: polyglycolide: trimethylene carbonate (PGA:TMC), poly-α-hydroxy acids, such as polylactic acid, polyglycolic acid, poly(glycolide), and poly(lactide-co-caprolactone), poly(caprolactone), poly(carbonate), poly(dioxanone), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate-co-valerate), expanded poly(l-lactic acid) (ePLLA), as taught, for example, in U.S. Patent No. 9,732,184 to Sbriglia, and their copolymers and blends. Alternatively, the third layer can be coated with a bioabsorbable material, or the bioabsorbable material can be incorporated into the third layer or applied to the third layer in powder form. The coating material can promote reduction of the infection site, vascularization, and facilitate type I collagen deposition.

[0140] The maximum pore size (MPS) of the simplest structure of the implantable membrane structure 10 is less than about 2 microns and has two opposite sides 20, 30, where the surface roughness of each opposite side is at least 0.5 microns (as Figure 1 shown). The implantable membrane structure 10 is formed of a single layer 40, which, when placed over the lumen in a cell encapsulation device, is used to mitigate the formation of mesenchymal cells at the lumen interface. In some embodiments, the membrane structure is formed of a fluoropolymer membrane, such as, but not limited to, an expanded polytetrafluoroethylene membrane.

[0141] See Figure 2, shows a two - layer implantable membrane structure 200. The implantable membrane structure 200 includes a first layer 210 and a second layer 220 located on the first layer 210. When the implantable membrane structure is in a cell encapsulation device, the surface roughness (Sa) of the surface of the side of the first layer opposite to the side of the second layer (i.e., side 230) is at least about 0.5 microns, and it is located next to the lumen to form a lumen interface. The first layer 210 and the second layer 220 are adhered or otherwise fixed together. It should be understood that in an embodiment such as Figure 1 shown, the surface roughness of the outer sides 230, 240 is at least 0.5 microns, and the maximum pore size (MPS) of the implantable membrane structure 100 is less than about 2 microns.

[0142] Figure 2A shows another two - layer embodiment of the implantable membrane structure 200A. As shown, the implantable membrane structure 200A includes a first layer 210A (which may be the same as the single - layer membrane as shown in Figure 1 in some embodiments) and a second layer 220A. The two sides 210A, 220A can be adhered to each other or otherwise fixed together. Figure 2A In the embodiment shown, the surface roughness of the outer surfaces 230A, 240A of the structure 200A is at least 0.5 microns. The first layer 210A provides the function of a mesenchymal alleviation layer, while the second layer 220A provides the function of vascularization. The maximum pore size (MPS) of the implantable membrane structure 200A is less than about 2 microns. When the implantable membrane structure 300 is in the cell encapsulation device, the side of the first layer 210A is located next to the lumen to form a lumen interface.

[0143] Figure 3 shows an embodiment in which the implantable membrane structure 300 has a first layer 310, a second layer 320, and a third layer 350. The third layer 350 is located on the side of the second layer 320 opposite to the first layer 310. In other words, the second layer 320 is located between the first layer 310 and the third layer 350. As described herein, the first layer 310 is a mesenchymal alleviation layer (e.g., an open layer), the second layer 320 is a cell - impermeable layer (e.g., a tight layer), and the third layer 350 is a vascularization layer (e.g., an open layer). When the implantable membrane structure 300 is in the cell encapsulation device, the first layer 310 is located on the lumen to form a lumen interface. The surface roughness (Sa) of the first side and the second side of the implantable membrane structure 400 is greater than about 0.5 microns. In addition, the maximum pore size of the implantable membrane structure 300 is less than about 2.0 microns.

[0144] The implantable membrane structure can be fabricated in various forms, including but not limited to a housing, a chamber, a pouch, a tube, or a cap. In some embodiments, a cell encapsulation device can be implemented to provide a therapeutic substance to an individual in need of treatment. In one embodiment, the implantable membrane structure forms a cell encapsulation device (such as Figure 4A as shown). Figure 4A is a top view of an exemplary cell encapsulation device 400 formed by two implantable membrane structures. The two implantable membrane structures are sealed along at least a portion of their perimeter 410. Figure 4A Only the outer layer of one of the two implantable membrane structures 420 is shown in

[0145] Figure 4B The cell encapsulation device 400 includes an inner cavity (not shown) for accommodating cells and a port 430 that extends into the inner cavity and is in fluid communication therewith. Figure 4A is a cross-sectional view of the cell encapsulation device Figure 4B No optional reinforcing components are shown in

[0146] although they can be used in this embodiment. The lumen 560 is located between the two membrane complexes 500, 600 for placement and retention of cells (and / or other biological entities).

[0147] Having provided a general description of the present disclosure, a further understanding can be obtained by reference to certain specific examples described below, which are for illustrative purposes only and are not intended to encompass all or limit all, unless otherwise specified.

[0148] Test method

[0149] Surface roughness (Sa)

[0150] The surface roughness was measured using a Keyence VK-X1000 laser scanning confocal microscope and the accompanying Multi File Analyzer Software. Unless otherwise stated, the materials were tested after applying any coatings. The samples were fixed to 5-mm metal studs using a carbon tape adhesive. The opposite side of the side to be imaged was placed on top of the adhesive, and then the sample was cut to the stud diameter. Then, photos were taken with the VK-X1000 at magnifications ranging from 20x to 150x. The surface area used for analyzing the surface roughness was 0.01–0.1 mm 2 . This range ensures sufficient resolution and a representative analysis of the layer.

[0151] Then, the images were processed in the Multi File Analyzer Software by performing surface shape correction to eliminate any wavy surfaces or large curvatures. For the height data of the entire image, surface shape correction was performed using waveform removal with a correction intensity of 5. After preprocessing the images, the areas to be analyzed and the parameters to be calculated were set. The Multi File Analyzer Software performed the calculations automatically.

[0152] Maximum pore size (MPS)

[0153] The maximum pore size was measured using a Quantachrome 3Gzh porosimeter from Anton Paar according to ASTM F316, and silicone oil (20.1 dynes / cm) was used as the wetting solution.

[0154] Mid-flow average pore size

[0155] The mid-flow average pore size test was conducted using ASTM F316 as the standard test method.

[0156] Porosity

[0157] In this article, the porosity of the layer is defined as the ratio of the layer volume composed of pore spaces to the total volume of the layer. The porosity was calculated by comparing the volume density of the porous structure composed of solid and void parts with the density of the solid part, using the following formula:

[0158]

[0159] Tensile strength, weakest direction

[0160] The maximum tensile load of the materials was tested using a 5500 series electromechanical test system. Unless otherwise stated, the materials were tested after applying any coatings. The samples were cut using a laser cutting system along the longitudinal and transverse axes of the material to form D412F dog-bone-shaped samples. Then, the samples were loaded into The tester fixture is used to conduct tests at a constant rate of 20 inches per minute until the sample fails. The maximum load endured during the test is normalized by the nominal width of the sample (6.35 mm for D412F samples) to define the maximum tensile load. The lower of the two results defines the tensile strength in the weakest direction.

[0161] Z strength

[0162] Use the 5500 series The composite bond strength of the material is tested using a 5500 series electromechanical test system. Unless otherwise stated, the tensile strength of the material is tested before any coating is applied. The sample is fixed to a 1” x 1” steel platen using 3M 9500PC double-sided tape and loaded into which is opposite to a 1” x 1” steel platen with 3M 9500PC double-sided tape on the surface. A characteristic pressure load of 1001 N is applied for 60 s to allow the adhesive to partially penetrate the structure. After this bonding, the platens are separated at a constant rate of 20 inches per second until failure. The maximum load is normalized by the test area (defined as a 1” x 1” test area) to define the composite bond strength.

[0163] Thickness

[0164] The sample for thickness measurement is cut and placed in a thin-bottom imaging petri dish with a glass coverslip on top. Then the sample is wetted with DI water and placed on a laser scanning confocal microscope equipped with a photomultiplier tube (PMD) detector. The thickness of the sample is obtained by capturing the difference in refractive index with a laser of a fixed wavelength.

[0165] The confocal function of the microscope allows scanning of the sample structure at different depths. The total thickness of the sample or sample area is obtained by stitching together optical sections (individual images at each z position).

[0166] SEM sample preparation

[0167] When preparing SEM samples, first fix the membrane composite or membrane composite layer to an adhesive for handling, with the side opposite to the side to be imaged facing the adhesive. Then cut the film into an area of approximately 3 mm x 3 mm for imaging. Then sputter coat the sample using an Emitech K550X sputter coater with a platinum target. Subsequently, take images using a Thermo Fisher Scientific FEI Quanta 400 scanning electron microscope and / or a Hitachi SU-8230 scanning electron microscope, with magnifications and resolutions that allow sufficient features to be seen for reliable analysis while ensuring that the minimum size of each analyzed feature is at least five pixel lengths.

[0168] Feature spacing

[0169] The feature spacing was determined by analyzing SEM images in NIH ImageJ 1.51h. The image scale was set based on the scale provided by the SEM image. As used herein, "feature" is defined as a three-dimensional component within a layer that is generally immobile and resistant to deformation when exposed to environmental forces [such as but not limited to cell movement (e.g., cell migration and ingrowth, host vascularization / endothelial angiogenesis)]. Features were resolved and separated by combining size / shadow-based thresholding and / or manual identification. In cases where the structure consists of a continuous structure (e.g., nonwoven or etched surface) rather than discrete solid features, the solid feature is defined as the structural portion surrounding a void, and its corresponding spacing extends from one side of the void to the opposite side. After isolating these features, Delaunay triangulation was performed to identify adjacent features. Triangulations whose circumcircles extend beyond the image edge were excluded from the analysis. Lines were drawn between the nearest edges of adjacent features, and the lengths were measured to define the spacing between adjacent features (see, for example Figure 5 ). As Figure 5 shown, the designated feature (P) is connected to the adjacent feature (N) to form a triangle 700, within which no solid feature is included in the circumcircle 710. The solid feature (X) represents the solid feature of a non-adjacent feature. Thus, in Figure 5 the case shown, the feature spacing 730 is the straight-line distance between the designated features (P) and (N).

[0170] Stiffness

[0171] The stiffness of un-reinforced and reinforced plastics and electrical insulating materials was tested according to the ASTM D790-17 standard test method. This method was used for the reinforcing layer and / or the final film structure.

[0172] Following Procedure B, including a strain >5% and a Type 1 crosshead position for deflection. The fixture dimensions were adjusted so that the span was 16 mm and the radius of the supports and nose was 1.6 mm. The test parameters used were a deflection of 3.14 mm and a test speed of 96.8 mm / min. In cases where the sample width differed from the standard 1 cm, the force was normalized to a 1 cm sample width by linear scaling.

[0173] Integrating the implantable membrane structure into a device form

[0174] To evaluate in vivo utility, various implantable membrane structures were fabricated into a device form suitable for use as an implantable encapsulation device for cell therapy delivery. In this test form, two identical membrane complexes were sealed in the peripheral region to form an open internal lumen space, which was accessed through a perfusion tube or port for loading cells.

[0175] In the welding operation, the thermoplastic film acts as the adhesive component to form a peripheral seal around the device. The film used is a polycarbonate polyurethane film. The outer diameter of the extrusion tube is 1.60 mm and the inner diameter is 0.889 mm.

[0176] In addition, a reinforcing mechanical support with appropriate stiffness is added outside the encapsulation device. In particular, a polyester monofilament woven mesh with fibers of 120 microns and a fiber spacing of approximately 300 microns is placed on the outer side of the two composite films (i.e., outside the device). The stiffness of this layer is 0.097 N / cm.

[0177] All layers are cut to an elliptical outer dimension of approximately 22 x 11 mm using a laser cutting table. The film is cut into an elliptical annular profile 2 mm wide and placed on both sides of the implantable membrane structure and around the mesh (reinforcing layer) in an inserted stack manner. This inserted stack manner of the components causes the molten film to adhere at the peripheral positions of each composite layer and the mesh. The layers of the implantable membrane structure are symmetrically stacked opposite the perfusion tube, such that the cell-impermeable tight layer of the implantable membrane structure faces inward towards the inner lumen.

[0178] An integral peripheral seal is formed around the device by using an ultrasonic welding machine (Herrmann Ultrasonics) or a hot riveting welding machine. In both processes, heat or vibrational energy and force are applied to the layer stack, causing the thermoplastic film to melt and flow above its softening temperature, thereby welding all layers together. The device is constructed using a two-step welding process, where energy or heat is applied from one side such that the first composite film is integrated into one side of the device, and subsequently the second composite film is integrated into the other side of the device. The integrity of the device is tested by performing a pressure decay test using a USON Sprint iQ leak tester at a test pressure of 5 psi to evaluate the final suitability of the welding.

[0179] In Vivo Studies in Nude Mice and Explant Histology

[0180] The encapsulation device is loaded in vitro with 6 - 7x10 6A number of pancreatic progenitor cells (or approximately 20 μL), as described at least according to the teachings of U.S. Patent No. 8,278,106 to Martinson et al. After being stored in the culture medium for less than 24 - 96 hours, two devices were subcutaneously implanted into each male immunodeficient athymic nude mouse. The pancreatic progenitor cells can develop and mature in vivo. At the designated time points after implantation, the nude mice were euthanized and the devices were removed. Excess tissue was removed, and the devices were placed in neutral buffered 10% formalin for 6 - 30 hours. The fixed devices were processed for paraffin embedding in a Leica Biosystems ASP300S tissue processor. The processed devices were cut into 4 - 6 slices, each about 5 mm, and embedded together in a paraffin block. Multiple cross - sectional slices of 3 - 10 microns were cut from each block, placed on glass slides, and stained with hematoxylin and eosin (H&E). The glass slide images were captured using a Hamamatsu Nanozoomer 2.0 - HT digital slide scanner.

[0181] Example

[0182] Comparative Example 1

[0183] Manufacture of the Membrane

[0184] Obtained from Millipore (Cork, Ireland) under the trade name A commercially available hydrophilic expanded polytetrafluoroethylene (ePTFE) sold, with a maximum pore size (MPS) of 0.43 microns. This single - layer membrane provides a tight, cell - impermeable interface while still allowing for substantial transport of oxygen and nutrients through it. The surface roughness (Sa) of both sides of the ePTFE membrane is approximately 0.4 microns. A representative scanning electron micrograph (SEM) of the membrane surface is as shown in Figure 6 shown. Since it is a one - piece single - layer membrane, it represents both sides of the membrane. A representative scanning electron micrograph (SEM) of the membrane cross - section is as shown in Figure 6A shown.

[0185] Characterization of the Membrane

[0186] The relevant parameters required for the intended function of the membrane were evaluated and characterized. If the parameter is not relevant to a specific function, it is marked as "None". If the parameter is actually not obtainable due to the way the layers of the structure are processed, it is marked as "--". The methods for characterizing the relevant parameters were carried out according to the methods described in the "Testing Methods" section above. The results of Comparative Example 1 are summarized in Table 1.

[0187] Table 1

[0188] Relevant performance Unit Measured value Surface roughness (Sa), lumen side μm 0.38 Surface roughness (Sa), host side μm 0.38 Maximum pore size (MPS) μm 0.43 Thickness, mesenchymal mitigation layer μm None Average pore size μm 0.2 Tensile strength N / mm 0.4 Total thickness μm 26.6 Z strength kPa None Porosity ％ 63.6 Characteristic spacing, lumen side μm None Characteristic spacing, host side μm None

[0189] In Vivo Evaluation of the Membrane

[0190] The ePTFE membrane was ultrasonically welded into a device form according to "Integrating the biocompatible membrane into the device form" described in the test method section. The device was evaluated in vivo according to "In vivo nude mouse study" described in the test method section.

[0191] The presence of mesenchymal cells was observed at the cell-impermeable layer within the encapsulated device, thereby forming an additional diffusion barrier and reducing the functional cell population within the graft. Figure 7 It shows that at the time point of the 19th week, mesenchymal cells 810 are arranged on the luminal interface 820 of the implantable membrane complex 800.

[0192] Comparative Example 2

[0193] Manufacture of the implantable membrane structure

[0194] The implantable membrane structure was manufactured in the same manner as the cell encapsulation device described in International Patent Publication WO 2020 / 243663A1 by Bruhn et al., and then made hydrophilic according to the teachings of U.S. Patent No. 5,902,745 by Butler et al. The membrane structure is a two-layer composite consisting of a tight cell-impermeable layer and an open cell-permeable layer. The maximum pore size (MPS) of the membrane structure is 0.41 microns, providing cell impermeability while maintaining the transport of oxygen and nutrients. The open cell-permeable layer of the membrane structure faces the outside, and the side facing the host tissue allows tissue ingrowth and vascularization through the cell-impermeable surface. Representative scanning electron micrographs (SEM) of each side of the membrane structure are shown in Figure 8 (luminal side) and Figure 9 (host side). Representative scanning electron micrographs (SEM) of the cross-section of the membrane structure are shown in Figure 9A as shown.

[0195] Characterization of the implantable membrane structure

[0196] The relevant parameters required for the expected function of the membrane structure were evaluated and characterized. If the parameter is not related to a specific function, it is marked as "none". If the parameter is actually unobtainable due to the way the layers of the structure are processed, it is marked as "--". The characterization method of the relevant parameters was carried out according to the method described in the "Test method" section. The results of Comparative Example 2 are summarized in Table 2.

[0197] Table 2

[0198] Relevant performance Unit Measured value Surface roughness (Sa), lumen side μm 0.41 Surface roughness (Sa), host side μm 3.88 Maximum pore size (MPS) μm 0.36 Thickness, mesenchymal mitigation layer μm None Average pore size μm 0.18 Tensile strength N / mm 0.20 Total thickness μm 23.3 Z strength kPa 307 Porosity ％ 97.0 Characteristic spacing, lumen side μm None Characteristic spacing, host side μm 33

[0199] Evaluation of the implantable membrane structure

[0200] The implantable membrane structure was thermally welded into a device form according to "Integrating the biocompatible membrane into a device form" described in the test method section and evaluated in vivo. The device was evaluated according to "Nude mouse study in vivo" described in the test method section.

[0201] The presence of mesenchymal cells was observed on the surface of the cell-impermeable layer facing the transplanted cell population. The mesenchymal cells in this layer increased the diffusion barrier / distance between the host and the functional cell population and consumed the space within the lumen of the device that was originally available for the functional cell population. This led to a reduction in the functional cell population within the transplanted group. Figure 10 is a representative histological image showing that at the 28-week time point, mesenchymal cells 1010 are arranged on the luminal surface 1020 of the implantable membrane structure 1000.

[0202] Example 1

[0203] Manufacture of the implantable membrane structure

[0204] The implantable membrane structure was manufactured in the same manner as the cell encapsulation device described in International Patent Publication WO 2020 / 243663A1 by Bruhn et al., except that the third layer was not added. The implantable membrane composite has two layers. One layer (mesenchymal mitigation layer) is an open, cell-permeable layer. The other layer (cell-impermeable layer) consists of a tight, cell-impermeable layer. The MPS of the membrane structure is 1.78 microns, providing cell impermeability while maintaining the transport of oxygen and nutrients. The open layer of the membrane structure faces the host tissue side of the device and contains a cell-permeable surface that allows tissue ingrowth and vascularization through the cell-impermeable surface. The surface roughness of the surface facing the host side is approximately 0.9 microns. The luminal side of the membrane structure is provided by a tight, cell-impermeable layer, and its surface roughness is approximately 0.6 microns. Representative scanning electron micrographs (SEM) of the membrane are shown in Figure 11 (luminal side) and Figure 12 (host side). Representative scanning electron micrographs (SEM) of the cross-section of the membrane structure are shown in Figure 13 as shown.

[0205] Characterization of the implantable membrane structure

[0206] The relevant parameters required for the expected function of the membrane structure were evaluated and characterized. If the parameter is not relevant to a specific function, it is marked as "None". If the parameter cannot actually be obtained due to the way the layers of the structure are processed, it is marked as "—". The characterization method for the relevant parameters was carried out according to the method described in the "Test method" section. The results are summarized in Table 3.

[0207] Table 3

[0208]

[0209]

[0210] Evaluation of implantable membrane structure

[0211] The implantable membrane structure is thermally welded into a device form according to "Integrating the biocompatible membrane into a device form" described in the test method section. The device is evaluated in vivo according to "In vivo nude mouse study" described in the test method section.

[0212] The presence of mesenchymal cells was not observed on the surface of the cell-impermeable layer facing the transplanted cell population (i.e., the lumen interface). Figure 14 It is a representative histological image, which shows viable functional cells 1410 near the lumen surface 1420 of the implantable membrane structure 1400 at the 25-week time point.

[0213] Example 2

[0214] Manufacture of implantable membrane structure

[0215] An implantable membrane structure having two different layers was constructed. Specifically, a bilayer composite was prepared by laminating, drying, co-expanding and then heat-treating a first expanded polytetrafluoroethylene (ePTFE) layer and a second polytetrafluoroethylene (PTFE) layer. The first expanded polytetrafluoroethylene is composed of a dried and expanded tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (mesenchymal mitigation layer), and the second polytetrafluoroethylene (PTFE) layer is composed of a paste-extruded, calendered and expanded tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (cell-impermeable layer). The MPS of the membrane structure is 0.65 microns, providing cell impermeability while maintaining the transport of oxygen and nutrients. The cell-impermeable tight layer faces the host side of the device and its surface roughness is 0.64 microns. The open first layer of the membrane structure has a cell-permeable surface with a surface roughness of 0.97 microns, which faces the lumen and prevents the formation and spread of mesenchymal cells at the lumen interface. Representative scanning electron micrograph (SEM) images of the surface of the membrane are shown in Figure 15 (lumen side) and Figure 16 (host side). Representative scanning electron micrograph (SEM) images of the cross-section of the membrane structure are shown in Figure 17 as shown.

[0216] Characterization of biocompatible membrane structure

[0217] The relevant parameters required for the intended functions of the membrane structure were evaluated and characterized. If a parameter is not relevant to a specific function, it is marked as "None". If a parameter is actually not obtainable due to the way the layers of the structure are processed, it is marked as "--". The method for characterizing the relevant parameters was carried out according to the method described in the "Test Methods" section. The results are summarized in Table 4.

[0218] Table 4

[0219] Relevant performance Unit Measured value Surface roughness (Sa), lumen side μm 0.97 Surface roughness (Sa), host side μm 0.64 Maximum pore size (MPS) μm 0.65 Thickness, mesenchymal mitigation layer μm 27.3 Average pore size μm 0.16 Tensile strength N / mm 0.33 Total thickness μm 48.9 Z strength kPa 330 Porosity ％ 88.0 Characteristic spacing, lumen side μm 9.7 Characteristic spacing, host side μm None

[0220] Evaluation of Biocompatible Membrane Structures

[0221] The implantable membrane complex was thermally welded into a device form according to "Integrating the biocompatible membrane into a device form" described in the Test Methods section.

[0222] The device was evaluated in vivo according to "In vivo nude mouse study" described in the Test Methods section.

[0223] Figure 18 The histological images shown in show the implantable membrane structure, where the cell-impermeable surface (second layer) faces the host tissue and the cell-permeable (first layer) surface faces the transplanted cell population. The presence of mesenchymal cells was not observed at the transplanted cell population interface (i.e., the lumen interface).

[0224] Figure 18 Shown is the viable functional cell 1820 near the lumen interface 1810 of the implantable membrane structure 1800 at the 25-week time point.

[0225] Example 3

[0226] Manufacture of Implantable Membrane Structures

[0227] An implantable membrane structure having three different layers was constructed. A three-layer composite was prepared by laminating, drying, co-expanding and then heat-treating a first PTFE layer, a second ePTFE layer and a third PTFE layer. The first PTFE layer consists of a paste-extruded and calendered tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (mesenchymal mitigation layer), the second ePTFE layer consists of a dry biaxially expanded membrane prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (cell-impermeable layer), and the third PTFE layer consists of a paste-extruded and calendered tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (vascularization layer).

[0228] The implantable membrane structure is a three - layer composite, which consists of a tight, cell - permeable second layer and two open, cell - impermeable layers (i.e., the first and third layers) on opposite sides of the second layer. The MPS of the membrane structure is 0.26 microns, providing cell impermeability while maintaining the transport of oxygen and nutrients. The third layer of the membrane structure has a cell - permeable surface, which enables the vascularization of the device towards the host side, and its surface roughness is 3.9 microns. The first layer of the membrane structure has a cell - permeable surface towards the luminal side of the device, which prevents the formation and spread of mesenchymal cells at the luminal interface, and its surface roughness is 2.5 microns.

[0229] Representative scanning electron micrograph (SEM) images of the surface of the membrane are as shown in Figure 19 (luminal side) and Figure 20 (host side). Representative scanning electron micrograph (SEM) images of the cross - section of the membrane structure are as shown in Figure 21 shown.

[0230] Characterization of the biocompatible membrane structure

[0231] The relevant parameters required for the expected functions of the membrane structure were evaluated and characterized. If the parameter is not relevant to a specific function, it is marked as "none". If the parameter is actually not obtainable due to the way the layers of the structure are processed, it is marked as "—". The characterization method of the relevant parameters was carried out according to the methods described in the test methods section. The results are summarized in Table 5.

[0232] Table 5

[0233] Relevant performance Unit Measured value Surface roughness (Sa), lumen side μm 2.5 Surface roughness (Sa), host side μm 3.9 Maximum pore size (MPS) μm 0.26 Thickness, mesenchymal mitigation layer μm 11.9 Average pore size μm 0.13 Tensile strength N / mm 0.33 Total thickness μm 30.4 Z strength kPa 500 Porosity ％ 85.3 Characteristic spacing, lumen side μm 16.0 Characteristic spacing, host side μm 19.8

[0234] Evaluation of the biocompatible membrane structure

[0235] The implantable membrane structure was thermally welded into a device form according to "Integrating the biocompatible membrane into a device form" described in the test methods section.

[0236] The device was evaluated in vivo according to "In - vivo nude mouse study" described in the test methods section.

[0237] Figure 22 The histological image 2000 shown in shows the implantable membrane structure 2200, where the first cell - permeable (open layer) surface faces the transplanted cell population. The presence of mesenchymal cells was not observed at the luminal interface 2220. Figure 22 Shows viable functional cells 2210 near the luminal interface 2220 of the implantable membrane structure 2200 at the 28 - week time point.

[0238] Example 4

[0239] Manufacture of Implantable Membrane Structure

[0240] An implantable membrane structure with three different layers was constructed. A three-layer composite was prepared by laminating, drying, co-expanding, and then heat-treating a first ePTFE layer, a second PTFE layer, and a third PTFE layer. The first ePTFE layer consists of a dried and expanded tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (mesenchymal mitigation layer), the second PTFE layer consists of a paste-extruded, calendered, and expanded tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (cell-impermeable layer), and the third PTFE layer consists of a dried and expanded tape prepared according to the teachings of U.S. Patent No. 3,953,566 of Gore (vascularization layer). The implantable membrane structure is a three-layer composite consisting of a tight, cell-permeable second layer and two open, cell-impermeable layers (i.e., the first and third layers) on opposite sides of the second layer. The MPS of the membrane structure is 0.79 microns, providing cell impermeability while maintaining the transport of oxygen and nutrients. The third layer of the membrane structure has a cell-permeable surface with a surface roughness of 1.12, which prevents the formation and spread of mesenchymal cells at the lumen interface.

[0241] Representative scanning electron micrographs (SEM) of the surface of the membrane are shown as Figure 23 (lumen side) and Figure 24 (host side). Representative scanning electron micrographs (SEM) of the cross-section of the membrane structure are shown as Figure 25 shown.

[0242] Characterization of Biocompatible Membrane Structure

[0243] The relevant parameters required for the intended function of the membrane structure were evaluated and characterized. If the parameter is not relevant to a specific function, it is marked as "None". If the parameter is actually not obtainable due to the way the layers of the structure are processed, it is marked as "—". The characterization method of the relevant parameters was carried out according to the methods described in the test method section. The results are summarized in Table 6.

[0244] Table 6

[0245]

[0246]

[0247] Evaluation of Biocompatible Membrane Structure

[0248] The implantable membrane structure was thermally welded into a device form according to "Integrating the biocompatible membrane into a device form" described in the test method section.

[0249] The device was evaluated in vivo according to the "in vivo nude mouse study" described in the test method section.

[0250] Figure 26 The histological images shown in illustrate the implantable membrane structure 2600, where the first cell-permeable (open layer) surface faces the transplanted cell population. The presence of mesenchymal cells was not observed at the luminal interface 2620. Figure 26 Shown is the viable functional cell 2610 near the luminal interface 2620 of the implantable membrane structure 2600 at the 28-week time point.

[0251] The invention of the present application has been generally described above and in connection with specific embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments described herein without departing from the spirit and scope of the invention. Accordingly, the embodiments are intended to cover such modifications and variations of the invention as long as they come within the scope of the appended claims and their equivalents.

Claims

1. An implantable membrane structure, comprising: A first layer and opposite sides with a maximum pore size (MPS) of less than about 2 microns, wherein the surface roughness of each of the opposite sides is at least 0.5 microns.

2. The implantable membrane structure according to claim 1, wherein the first layer comprises a polymer membrane.

3. The implantable membrane structure according to claim 2, wherein the polymer membrane is a fluoropolymer membrane.

4. The implantable membrane structure according to claim 3, wherein the fluoropolymer membrane comprises expanded polytetrafluoroethylene (ePTFE), modified ePTFE membrane, tetrafluoroethylene (TFE) copolymer membrane, polyvinylidene fluoride (PVDF) membrane, or fluorinated ethylene propylene (FEP) membrane.

5. The implantable membrane structure according to claim 1, comprising a surface coating at least partially on the first layer, wherein the surface coating comprises one or more components selected from the group consisting of: antimicrobial agents, antibodies, drugs, bioactive molecules, and hydrophilic coatings.

6. The implantable membrane structure according to claim 1, comprising a frame at the periphery of the first layer.

7. The implantable membrane structure according to claim 1, comprising a plurality of regions, each region having a microstructure.

8. An implantable membrane structure, comprising: A first layer; and A second layer with a maximum pore size (MPS) of less than about 2.0 microns, wherein the second layer is located on the first layer, wherein the first layer has a first outer-facing side, the second layer has a second outer-facing side, and the surface roughness (Sa) of both the first outer-facing side and the second outer-facing side is at least 0.5 microns.

9. The implantable membrane structure according to claim 8, wherein the first layer is cell-permeable and the second layer is cell-impermeable.

10. The implantable membrane structure according to claim 8, wherein the total thickness of the membrane structure is from about 15 microns to about 150 microns.

11. The implantable membrane structure according to claim 8, comprising a mid-flow average pore size greater than about 0.1 micron.

12. The implantable membrane structure according to claim 8, wherein the tensile strength in the weakest direction is greater than about 0.15 N / mm.

13. The implantable membrane structure according to claim 8, comprising a reinforcing component.

14. The implantable membrane structure according to claim 13, wherein the stiffness of the reinforcing component is from about 0.01 N / cm to about 5 N / cm.

15. The biocompatible membrane structure according to claim 13, wherein the reinforcing component is a woven or non-woven textile.

16. The implantable membrane structure according to claim 8, wherein at least one of the first layer and the second layer comprises a polymer, a fluoropolymer membrane, a non-fluoropolymer membrane, a woven textile, a non-woven textile, a woven or non-woven assembly of fibers or yarns, a fibrous matrix, and combinations thereof.

17. The implantable membrane structure according to claim 16, wherein the polymer is a fluoropolymer membrane selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) membrane, fluorinated ethylene propylene (FEP) membrane, and modified ePTFE membrane.

18. The implantable membrane structure according to claim 8, wherein the first layer and the second layer are tightly bonded.

19. The implantable membrane structure according to claim 8, wherein the coefficient of variation of the surface roughness (Sa) of the opposite sides of the implantable membrane structure is less than 15%.

20. An implantable membrane structure, comprising: A first layer having a first outer-facing side with a surface roughness (Sa) of at least 0.5 microns, A second layer located on a side of the first layer opposite to the first outer-facing side, and A third layer located on the second layer such that the second layer is between the first layer and the third layer, wherein the third layer has a second outer-facing side with a surface roughness (Sa) of at least 0.5 microns, wherein the maximum pore size of the implantable membrane is less than about 2.0 microns.

21. The implantable membrane structure according to claim 20, wherein the first layer is cell-permeable, and the second layer and the third layer are cell-impermeable.

22. The implantable membrane structure according to claim 20, which comprises a median flow mean pore size greater than about 0.1 micron.

23. The implantable membrane structure according to claim 20, wherein the thickness of the first layer is about 2 microns to about 100 microns.

24. The implantable membrane structure according to claim 20, wherein the coefficient of variation of the surface roughness (Sa) of the first layer and the third layer is less than 15%.

25. The implantable membrane structure according to claim 20, wherein the feature spacing in the third layer is greater than about 3 microns.

26. The implantable membrane structure according to claim 20, wherein the third layer comprises at least one of a woven fabric, a non-woven fabric, and a non-fluoropolymer membrane.

27. The implantable membrane structure according to claim 20, which comprises perforations.

28. The implantable membrane structure according to claim 20, which comprises a tensile strength greater than about 0.15 N / mm in the weakest direction.

29. The implantable membrane structure according to claim 20, wherein at least two of the first layer, the second layer, and the third layer are tightly bonded.

30. The implantable membrane structure according to claim 20, which includes a reinforcing component.

31. The implantable membrane structure according to claim 30, wherein the stiffness of the reinforcing component is from about 0.01 N / cm to about 5 N / cm.

32. The biocompatible membrane structure according to claim 30, wherein the reinforcing component includes a woven or non-woven textile.

33. The implantable membrane structure according to claim 20, wherein at least one of the first layer, the second layer, and the third layer includes a polymer, a fluoropolymer membrane, a non-fluoropolymer membrane, a woven textile, a non-woven textile, a woven or non-woven assembly of fibers or yarns, a fibrous matrix, and combinations thereof.

34. The implantable membrane structure according to claim 33, wherein the polymer is a fluoropolymer membrane selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) membrane, fluorinated ethylene propylene (FEP) membrane, and modified ePTFE membrane.

35. The implantable membrane structure according to claim 20, wherein the implantable membrane structure has at least partially a surface coating thereon, and the surface coating includes one or more components selected from the group consisting of an antimicrobial agent, an antibody, a drug, a bioactive molecule, and a hydrophilic coating.

36. The implantable membrane structure according to claim 20, wherein at least one of the first layer, the second layer, the third layer, or the reinforcing component is formed of a non-woven fabric.

37. A cell encapsulation device, comprising: An implantable membrane structure having a lumen interface with a surface roughness of at least 0.5 microns, an outer surface with a surface roughness of at least 0.5 microns, and a maximum pore size (MPS) of less than about 2 microns.

38. The cell encapsulation device according to claim 37, wherein the implantable membrane structure includes a first layer.

39. The cell encapsulation device according to claim 38, wherein the first layer includes a polymer membrane.

40. The cell encapsulation device according to claim 39, wherein the polymer membrane is a fluoropolymer membrane.

41. The cell encapsulation device according to claim 40, wherein the fluoropolymer membrane includes an expanded polytetrafluoroethylene (ePTFE) membrane, a modified ePTFE membrane, a tetrafluoroethylene (TFE) copolymer membrane, a polyvinylidene fluoride (PVDF) membrane, or a fluorinated ethylene propylene (FEP) membrane.

42. The cell encapsulation device according to claim 37, which includes at least partially a surface coating on the implantable membrane structure, and the surface coating includes one or more components selected from the group consisting of an antimicrobial agent, an antibody, a drug, a bioactive molecule, and a hydrophilic coating.

43. The cell encapsulation device according to claim 37, which comprises a hydrophilic coating on the implantable membrane structure.

44. The cell encapsulation device according to claim 37, which comprises a reinforcing component.

45. The cell encapsulation device according to claim 43, wherein the reinforcing component comprises a woven or non-woven textile.

46. The cell encapsulation device according to claim 37, which comprises a first layer and a second layer located on the first layer, wherein the surface roughness of the lumen interface of the first layer is at least 0.5 microns and the surface roughness of the outer-facing side of the second layer is at least about 0.5 microns.

47. The cell encapsulation device according to claim 46, wherein the first layer is cell-permeable and the second layer is cell-impermeable.

48. The cell encapsulation device according to claim 46, wherein the total thickness of the membrane structure is about 15 microns to about 150 microns.

49. The cell encapsulation device according to claim 46, which comprises a median flow mean pore size greater than about 0.1 micron.

50. The cell encapsulation device according to claim 46, wherein the tensile strength in the weakest direction is greater than about 0.15 N / mm.

51. The cell encapsulation device according to claim 46, which comprises a reinforcing component.

52. The cell encapsulation device according to claim 51, wherein the reinforcing component is a woven or non-woven textile.

53. The cell encapsulation device according to claim 46, wherein at least one of the first layer and the second layer comprises a polymer, a fluoropolymer membrane, a non-fluoropolymer membrane, a woven textile, a non-woven textile, an assembly of woven or non-woven fibers or yarns, a fibrous matrix, and combinations thereof.

54. The cell encapsulation device according to claim 46, wherein the polymer is a fluoropolymer membrane selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) membrane, fluorinated ethylene propylene (FEP) membrane, and modified ePTFE membrane.

55. The cell encapsulation device according to claim 46, wherein the first layer and the second layer are tightly bonded.

56. The cell encapsulation device according to claim 46, which comprises a first layer, a second layer, and a third layer, wherein the second layer is located between the first layer and the third layer, and wherein the surface roughness of the lumen interface of the first layer is at least 0.5 microns and the surface roughness of the outer-facing side of the third layer is at least 0.5 microns.

57. The cell encapsulation device according to claim 56, wherein the first layer is impermeable to cells, and the second and third layers are permeable to cells.

58. The cell encapsulation device according to claim 56, which comprises a median flow mean pore size greater than about 0.1 micron.

59. The cell encapsulation device according to claim 56, wherein the thickness of the first layer is from about 2 microns to about 100 microns.

60. The cell encapsulation device according to claim 56, wherein the coefficient of variation of the surface roughness (Sa) on opposite sides of the implantable membrane structure is less than 15%.

61. The cell encapsulation device according to claim 56, wherein the average feature spacing in the third layer is greater than about 3 microns.

62. The cell encapsulation device according to claim 56, wherein the third layer comprises at least one of a woven fabric, a non-woven fabric, and a non-fluoropolymer membrane.

63. The cell encapsulation device according to claim 56, which comprises perforations.

64. The cell encapsulation device according to claim 56, which comprises a tensile strength greater than about 0.15 N / mm in the weakest direction.

65. The cell encapsulation device according to claim 56, wherein at least two of the first, second, and third layers are tightly bonded.

66. The cell encapsulation device according to claim 56, which comprises a reinforcing component.

67. The cell encapsulation device according to claim 66, wherein the stiffness of the reinforcing component is from about 0.01 N / cm to about 5 N / cm.

68. The cell encapsulation device according to claim 66, wherein the reinforcing component comprises a woven or non-woven textile.

69. The cell encapsulation device according to claim 56, wherein at least one of the first, second, and third layers comprises a polymer, a fluoropolymer membrane, a non-fluoropolymer membrane, a woven textile, a non-woven textile, a woven or non-woven assembly of fibers or yarns, a fibrous matrix, and combinations thereof.

70. The cell encapsulation device according to claim 69, wherein the polymer is a fluoropolymer membrane selected from the group consisting of expanded polytetrafluoroethylene (ePTFE) membrane, fluorinated ethylene propylene (FEP) membrane, and modified ePTFE membrane.

71. The cell encapsulation device according to claim 56, wherein the implantable membrane structure has at least partially thereon a surface coating, wherein the surface coating comprises one or more components selected from the group consisting of an antimicrobial agent, an antibody, a drug, a bioactive molecule, and a hydrophilic coating.

72. The cell encapsulation device according to claim 56, wherein at least one of the first layer, the second layer, the third layer or the reinforcing component is formed of a nonwoven fabric.

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