Cell encapsulation device with controlled cell bed thickness

Abstract

To provide an implantable containment apparatus for receiving and retaining a biological moiety, including a plurality of cells, for insertion into a patient, such as into a tissue bed.SOLUTION: The device includes a cell encapsulating pouch that forms an interior volume having a reservoir space for receiving cells, where the reservoir space includes first and second interior surfaces and a tensioning member to maintain an average distance between the first and second interior surfaces.SELECTED DRAWING: Figure 3B

Description

Technical Field

[0001] The present invention relates to the field of medical devices and implantable medical devices, and in particular to devices and methods for encapsulating cells for implantation into a patient's body.

Background Art

[0002] Biological therapies are becoming increasingly viable as a way to treat peripheral artery disease, aneurysms, heart disease, Alzheimer's and Parkinson's diseases, autism, blindness, diabetes, and other pathologies.

[0003] For general biological therapies, cells, viruses, viral vectors, bacteria, proteins, antibodies, and other bioactive moieties can be introduced into a patient by surgical or interventional methods that place the bioactive moiety within the patient's tissue bed. In many cases, the bioactive moiety is first placed within a device and then this is inserted into the patient. Alternatively, the device may first be inserted into the patient and the bioactive moiety added later.

Summary of the Invention

Problems to be Solved by the Invention

[0004] In order to maintain a viable and productive population of bioactive moieties (e.g., cells), the bioactive moieties must maintain access to nutrients such as those provided by blood flow through adjacent blood vessels. Such access to nutrients requires that the encapsulated cells, i.e., the cell bed, be in proximity to a membrane that separates the cell bed from the tissue bed into which the cells are implanted. While implantable devices may be designed taking such considerations into account, the devices are often subject to in vivo forces (e.g., compressive forces caused by contact of the patient with another person or object). Such forces distort or destroy the designed desired structure of the device and the cell bed. Thus, an implantable device containing cells (or other bioactive moieties) must not only be configured such that nutrients can reach the encapsulated cells, but must also withstand in vivo forces that have the potential to distort or destroy the designed desired structure of the device and the cell bed. There is still a need for a device that encapsulates cells (or other bioactive moieties, e.g.) and is structured such that the cell bed thickness is controlled and / or the cell bed thickness is restored after deformation.

Means for Solving the Problem

[0005] As used in this specification, the terms "invention", "the invention", "this invention", and "the present invention" are intended to refer broadly to the subject matter of this patent application and to all of the following claims. Descriptions that include these terms should be understood not to limit the subject matter described in this specification or to limit the meaning or scope of the following patent claims. The covered embodiments of the present invention are defined by the claims, not by this summary. This summary is a high-level overview of various aspects of the invention and introduces some of the concepts further described in the section entitled "Detailed Description" below. This summary is not intended to identify key or essential aspects of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. The subject matter should be understood by reference to the appropriate portions of the entire specification, any or all of the drawings, and each claim.

[0006] The present disclosure provides devices and methods for encapsulating cells for insertion into a patient as a biotherapeutic. The device includes a cell encapsulation pouch formed from a membrane or membrane complex that surrounds the cells, through which the cells can receive nutrients from the host body and provide biotherapeutics to the host body. The device further includes a tension member that maintains the designed structure of the cell encapsulation pouch and the cell bed.

[0007] In some embodiments, the cell encapsulation device described herein includes a cell encapsulation pouch, the cell encapsulation pouch including a first layer sealed to a second layer along a portion of the perimeter of the second layer and a portion of the perimeter of the first layer so as to define an internal volume between the first layer and the second layer, the internal volume including a first inner surface and a second inner surface on the opposite side spaced from the first inner surface. The internal volume includes the entire volume inside the cell encapsulation pouch, whether empty or occupied by a structural element. At least one tension member may be disposed inside the internal volume and be able to contact at least two opposing portions around it so as to maintain the average distance between the first inner surface and the second inner surface. The cell encapsulation device further includes a reservoir space for receiving cells inside the internal volume between the first inner surface and the second inner surface and inward from the tension member. The reservoir space is only the portion available for receiving cells and does not include the volume occupied by the structural element. Optionally, the cell encapsulation device may further include at least one port in fluid communication with the reservoir space.

[0008] In some embodiments, the first and second layers of the cell encapsulation pouch include the top and bottom portions of a single tubelike membrane or membrane composite that is at least partially flattened, and the first layer is sealed to the second layer at at least one end of the tubelike membrane or membrane composite. In other embodiments, the first and second layers of the cell encapsulation pouch include two separate membranes or membrane composites.

[0009] In some embodiments, the cell encapsulation device described herein may include at least one cell displacing core inside the internal volume. In other embodiments, the cell encapsulation device described herein may include a plurality of structural spacers inside the internal volume.

[0010] The tension member of the cell encapsulation device described herein may be in fluid communication with the reservoir space or may be isolated from the reservoir space. For example, to isolate the tension member from the reservoir space, the first layer may be sealed to the second layer between the tension member and the reservoir space. The thickness of the seal may define the average thickness between the first inner surface and the second inner surface.

[0011] In some embodiments of the cell encapsulation device described herein, the tension member applies opposing lateral forces in a direction away from the reservoir space. Optionally, the tension member may be a shape memory elastomer or a shape memory polymer. Optionally, the tension member may be a frame including opposing ends that are non-linear and opposing sides that are linear to provide uniform tension over the entire length of the cell encapsulation pouch. The tension member may be adjustable between a deformed state and a non-deformed state such that the distance between at least two opposing sides of the tension member can be adjusted. For example, the distance between at least two opposing sides in the deformed state may be less than the distance between at least two opposing sides in the non-deformed state.

[0012] In some embodiments of the cell encapsulation device described herein, the average distance between the first inner surface and the second inner surface is at least the thickness of the tension member. In other embodiments, the average distance between the first inner surface and the second inner surface is less than the thickness of the tension member.

[0013] Optionally, the cell encapsulation pouch described herein may include an angiogenesis layer. Optionally, the cell encapsulation pouch is a multilayer membrane or membrane composite including an outer angiogenesis layer and an inner cell retention layer adjacent to the outer angiogenesis layer.

[0014] In some embodiments, the cell encapsulation device described herein includes a plurality of interconnected storage tubes, each of the storage tubes including a first end, a second end opposite the first end, and an internal volume or reservoir space disposed within each storage tube for holding cells. The storage tubes may optionally be interconnected by welding, quilting, adhesives, or structural supports. The device further includes a tensioning member disposed about at least a portion of the perimeter of the plurality of storage tubes, the tensioning member maintaining the average thickness of each of the storage tubes. Optionally, the tensioning member may include at least two arcuate portions, the arcuate portions including alternating recesses positioned at the first and second ends of each storage tube. At least a portion of the tensioning member may be attached to one or more of the storage tubes by an adhesive. In addition or alternatively, a portion of the tensioning member may be held at opposite ends of the cell encapsulation device within the interiors of each of the two outermost storage tubes.

[0015] In some embodiments, a method of encapsulating cells includes providing the cell encapsulation device described herein, wherein the tensioning member forms a first deformed configuration that provides tension across the cell encapsulation pouch, deforming the tensioning member from the first deformed configuration to a second deformed configuration that is deformed more than the first deformed configuration, thereby reducing the tension on the cell encapsulation pouch, inserting cells into the reservoir space, and releasing the tensioning member to the first deformed configuration.

[0016] In some embodiments, a method of inserting a cell encapsulation device into a patient includes providing the cell encapsulation device described above, wherein the cell encapsulation device further includes cells disposed within the reservoir space, and wherein the tensioning member forms a first deformed configuration that provides tension across the cell encapsulation pouch, deforming the tensioning member from the first deformed configuration to a second deformed configuration that is deformed more than the first deformed configuration, thereby reducing the tension on the cell encapsulation pouch, implanting the cell encapsulation device into the patient's tissue bed, and releasing the tensioning member to the first deformed configuration.

[0017] The accompanying drawings are included to provide a further understanding of the disclosure, are incorporated in and constitute a part of this specification, illustrate embodiments, and together with the description serve to explain the principles of the disclosure.

Brief Description of the Drawings

[0018]

Figure 1A

Figure 1B

Figure 1C

Figure 2

Figure 3A

Figure 3B

Figure 4

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7

Figure 8

Figure 9

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] It will be readily apparent to those skilled in the art that various aspects of the present disclosure can be realized by any number of methods and apparatuses configured to perform the desired functions. For the sake of redundancy, it should be noted that the accompanying drawings referred to herein are not necessarily drawn to scale and may be exaggerated to illustrate various aspects of the present disclosure, and the drawings should not be construed as limiting in this regard. Directional references, such as, but not limited to, "up", "down", "top", "left", "right", "front", "back" are to be taken to mean the orientation shown and described in the drawings in which the component and direction are referenced.

[0020] This specification describes a therapeutic device that encapsulates biological components. The biological components provide a biological therapy by being implanted within a patient, for example, within a tissue bed. The therapeutic device may include a cell encapsulation device, a drug delivery device, or a gene therapy device. Further described herein are methods of forming the device, methods of introducing the biological components into the device, and methods of introducing the device into a patient in need of biological therapy. In some embodiments, the device is a tensioned cell encapsulation pouch formed from a membrane or membrane composite. The cell encapsulation pouch has two layers spaced apart from each other. These layers form a reservoir space for receiving and holding the biological components. The membrane composite includes a membrane and another biocompatible material, such as a biowoven or non-woven fabric.

[0021] Biological components suitable for encapsulation and implantation using the devices described herein include cells, viruses, viral vectors, gene therapy agents, bacteria, proteins, polysaccharides, antibodies, and other bioactive components. For simplicity, biological components are referred to herein as cells, but nothing in this specification limits biological components to cells or a particular type of cell, and the following description applies to biological components other than cells. Various types of prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, and / or stem cells can be used in conjunction with the cell encapsulation devices of the present invention. In some embodiments, the cells are microencapsulated within a biomaterial of natural or synthetic origin, including, by way of example, a hydrogel biomaterial.

[0022] In some embodiments, the cells secrete therapeutically useful substances. Such substances include hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cell products that provide therapeutic utility to the device recipient. Examples of such therapeutically useful substances include insulin, trophic factors, neurotransmitters, lymphokines, antibodies, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, factor VIII, or other cell products that provide therapeutic utility to the device recipient. Examples of therapeutic cell products include insulin, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, and factor VIII. 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. Needless to say, throughout the present disclosure, the term "cells" in the singular or plural can be replaced by the singular or plural "biological parts", respectively. Needless to say, the term "tension member" shall include one or more tension members.

[0023] Broadly speaking, the cell encapsulation device described herein includes a cell encapsulation pouch and a tension member. The cell encapsulation pouch may be formed from a membrane or a membrane complex. The cell encapsulation pouch forms an internal volume that includes at least one reservoir space for receiving cells. In some embodiments, the internal volume includes a plurality of reservoir spaces for receiving cells. The cell encapsulation pouch may include a top layer and a bottom layer that are formed from two separate membranes or membrane complexes, one membrane or membrane complex folded to form a top layer and a bottom layer, or a single tubular membrane or membrane complex flattened to form a top layer and a bottom layer. In any of these embodiments, the top layer and the bottom layer are sealed along at least a portion of their perimeter, and the cell encapsulation device has at least one internal volume located between the top layer and the bottom layer. In various embodiments, at least a portion of the tension member is disposed within the internal volume. The tension member applies an outward force to the cell encapsulation pouch, thereby applying tension to the top layer and the bottom layer. And the first layer is sealed to the second layer at at least one end of the tubular membrane or membrane complex. In other embodiments, the first layer and the second layer of the cell encapsulation pouch include two separate membranes or membrane complexes.

[0024] In various embodiments, a port extends through the cell encapsulation pouch (e.g., through the sealed perimeter of the pouch) and is in fluid communication with the reservoir space for inserting cells into the reservoir space. In some embodiments, the cell encapsulation devices described herein further include one or more other structural components, such as seals, spacers (e.g., welding spacers or structural spacers), or cell displacement cores. Broadly speaking, a seal is a region where two materials, such as the top layer and the bottom layer of the cell encapsulation pouch, are joined without substantially increasing the thickness of the combined materials. A spacer, such as a welding spacer, can also join two materials, but in addition, it contributes to controlling or maintaining the average distance between the top layer and the bottom layer and can also increase the thickness of the combined materials. In various embodiments, the seal can be useful for defining and / or isolating the reservoir space. A spacer can be useful for defining the thickness of the reservoir space. And the cell displacement core can be useful for improving the movement of nutrients and waste between the cells and the external environment of the device by pushing the cells away from the center of the device towards the cell encapsulation pouch.

[0025] In the cell encapsulation devices described herein, the top layer and the bottom layer are separated from each other by a tension member, or by any spacer, or by any cell displacement core, and the reservoir space for receiving cells is within the internal volume between the inner surfaces of the top layer and the bottom layer. The reservoir space is a part of the internal volume not occupied by the tension member, the spacer (e.g., welding spacer or structural spacer), the cell displacement core, or any other structural component. The thickness of the reservoir space is the distance between the inner surfaces of the top layer and the bottom layer. The distance between the inner surfaces of the top layer and the bottom layer can be defined by the thickness of the tension member or by the thickness of another structural component.

[0026] In some embodiments, the top and bottom layers of the cell encapsulation pouch are flexible, however, the tensioning member, alone or in combination with other structural components, maintains the cell encapsulation device in a generally planar structure. In certain embodiments, the tensioning member applies a force to the cell encapsulation pouch that stretches the cell encapsulation pouch in a tensioned state within the X-Y plane, whereas the reservoir space thickness is in the Z dimension. Thus, even when the thickness of the reservoir space is defined by components other than the tensioning member, the tensioning member maintains its thickness by applying tension to the cell encapsulation pouch. This tension prevents deformation (e.g., crushing or ballooning) of the cell encapsulation pouch and / or, after deformation, restores a defined spacing. Such deformation may occur during cell loading, placement of the cell encapsulation device within the target site, cell growth, and various other uses of the cell encapsulation device.

[0027] The tensioning member is provided to apply a counteracting tension force to the cell encapsulation pouch in a direction away from the reservoir space, thereby maintaining the reservoir space thickness. As a result of being in an elastically deformed or compressed form when the tensioning member is inside the cell encapsulation pouch, the tensioning member can apply tension to the cell encapsulation pouch. Due to the tendency of the tensioning member to return to its non-deformed form, a counteracting force is applied to the cell encapsulation pouch and tension is applied to the top and bottom layers. Since the tensioning member applies tension to the pouch, the material forming the pouch must have the strength necessary to withstand being in a constant state of tension. The tensioning member is elastically deformable by being composed of a material that is essentially elastically deformable, such as an elastomer. Additionally, since the tensioning member can deform the pouch into various different forms, the pouch material needs to be flexible and compliant enough to move and deform with the tensioning member without causing damage or stress (e.g., permanent creases, folds, wrinkles, holes / splits, etc.).

[0028] A non-limiting example of such a tension member is an elastomeric O-ring. Examples of useful elastomers are described herein. The shape of the tension member or a part thereof may contribute to the tension member being elastically deformable. For example, when the frame has a ring shape (e.g., circular or elliptical shape), or forms the shape of a simple polygon having two interior angles of less than 90 degrees (e.g., a parallelogram other than a square, trapezoid, or hexagon), the frame may be deformable. As another example, a frame including one or more non-linear segments, such as arcuate, helical, or serpentine segments, may be elastically deformable.

[0029] In various embodiments, the tension member may be deformable in at least two opposite lateral directions, thereby allowing the distance between opposite sides of the tension member to be adjusted. Thus, the tension member can be deformed by a technician into a narrower form (with a shorter distance between opposite sides) for insertion into the cell encapsulation pouch, and when released by the technician, can expand to a wider, yet still deformed form as enabled by the cell encapsulation pouch. In addition to being adjustable during the assembly of the cell encapsulation device, the tension member is also adjustable during loading of the device and during subsequent use of the device. For example, in some cases, the distance between opposite sides of the tension member can be temporarily increased or decreased during cell loading or during placement of the cell encapsulation device inside a patient. Optionally, reducing (or increasing) the distance can temporarily increase or decrease the thickness of the reservoir space (e.g., to facilitate cell loading), but due to the tendency of the tension member to return to its non-deformed state and the associated forces applied by the tension member to the cell encapsulation pouch, the thickness of the reservoir space is returned to the thickness defined by the structural components.

[0030] In some embodiments, the tension member is between the first and second layers but is isolated from the reservoir space (i.e., not in fluid communication with the reservoir space). In such embodiments, the tension member does not contact the encapsulated cells. Such embodiments can be useful when the tension member is a material that is not compatible with the encapsulated cells, such as various elastomers. In some embodiments, by adding structural elements within the internal volume of the device, a lumen thickness different from the tension member thickness (smaller or larger than the tension member thickness) can be provided, and these structural elements can isolate the tension member from the reservoir space. In other embodiments, the tension member is in fluid communication with the reservoir space. In such embodiments, the tension member will contact the encapsulated cells and must be a material compatible with these cells (such as nitinol). In various embodiments, the material used for the tension member may be selected based on whether the tension member is in fluid communication with the reservoir space or is isolated from the reservoir space, and thus whether the tension member can contact the encapsulated cells.

[0031] In some embodiments, the cell encapsulation pouch may be a porous material and may be a composite layer having two or more pore sizes and / or two or more porosities. For example, the cell encapsulation pouch may have a pore size and / or porosity sufficient to allow cell nutrients, useful cell products, and cell waste to be exchanged through the cell encapsulation pouch between the encapsulated cells and the external environment. As another example, in various embodiments, the pore size of the cell encapsulation pouch can allow or limit in-growth of blood vessels. Such materials are discussed in more detail herein, however, in any cell encapsulation device disclosed herein, the first and second layers of the cell encapsulation pouch can independently be a single porous material or a multi-layer porous material where the pore size and / or porosity of each layer can be different from the pore size and / or porosity of another layer.

[0032] Figures 1A - B illustrate an embodiment of a cell encapsulation device 100. As shown in FIGS. 1A - B, the cell encapsulation device 100 includes a cell encapsulation pouch 102 and a tension member 104. FIG. 1A is a top view of the cell encapsulation device 100 showing a single tension member 104 inside the cell encapsulation pouch 102. FIG. 1B is a cross - sectional view of the cell encapsulation device of FIG. 1A taken along 1B - 1B. FIG. 1C is a top view of the tension member 104 before being inserted into the cell encapsulation pouch 102.

[0033] The cell encapsulation device 100 includes a cell encapsulation pouch 102 as a single membrane formed in a tube shape. This membrane is flattened to form a first layer 106 and a second layer 108. The first layer 106 and the second layer 108 are sealed around their peripheries 110 at one or both ends of the flattened tube. The first layer 106 includes a first inner surface 122, and the second layer 108 includes a second inner surface 124. The second inner surface faces the first inner surface 122 and is spaced apart from the first inner surface 122 to define an internal volume 112. The tension member 104 is disposed inside the internal volume 112, contacts at least two opposing portions of the cell encapsulation pouch 102, and applies tension to the first layer 106 and the second layer 108. FIGS. 1A - B do not show any optional components, but optionally, other components including welding spacers, other seals, structural spacers, cell - pushing - away cores, or other structural elements may be disposed inside the internal volume. A port (not shown) may extend through the cell encapsulation pouch (e.g., through the sealed periphery 110), and the port may be in fluid communication with a reservoir space 120.

[0034] In the embodiment shown in FIGS. 1A - B, the reservoir space 120 is located between a first inner surface 122 and a second inner surface 124 and inwardly from the tension member 104. The thickness 128 of the reservoir space 120 is the distance from the first inner surface 122 to the second inner surface 124 and is defined by the tension member thickness 138. In this embodiment, the tension on the cell encapsulation pouch 102 provided by the tension member 104 prevents crushing or ballooning of the reservoir space 120 and thus maintains the thickness defined by the tension member 104.

[0035] In the embodiment shown in FIGS. 1A - B, the tension member 104 surrounds the reservoir space 120, however in other embodiments it may only partially surround or enclose the reservoir space 120.

[0036] As shown in FIG. 1B, the tension member 104 may be in fluid communication with the reservoir space 120. Since the tension member 104 is in fluid communication with the reservoir space 120, it must be formed from a material compatible with any cells to be inserted into the device. Biocompatible materials suitable for the tension member are described herein.

[0037] In some embodiments, the tension member of the cell encapsulation device is an insertion frame. In the embodiment shown in FIGS. 1A - C, the tension member 104 is an insertion frame that includes opposing ends 142, 144 that are non - linear and opposing sides 146, 148 that are substantially linear. Needless to say, in some embodiments, the sides 146, 148 may be curved or of any shape that provides uniform tension over the entire length of the cell encapsulation pouch 102 (the length being from one opposing end to the other opposing end). In various embodiments, the non - linear ends 142, 144 may be non - linear in the plane defined by the X - axis line 116 and the Y - axis line 118, as shown in FIG. 1C, and / or may be non - linear in the plane defined by the X - axis line 116 and the Z - axis line (not shown), in the intermediate plane, or in multiple planes. According to various embodiments, the non - linear ends may include one or more S - shaped forms, as shown in FIG. 1C, or may include other non - linear shapes such as curves or spirals. Alternatively, a frame having other shapes described herein may be utilized as the tension member 104.

[0038] As shown in FIGS. 1A - C, the tension member 104 assumes a non - deformed form when separated from the cell encapsulation pouch 102 (FIG. 1C), and assumes a deformed / compressed form when inside the cell encapsulation pouch 102 (FIGS. 1A - B). Thus, the distances 129a, 129c between the opposing sides 146, 148 of the tension member 104 are adjustable, and the distance 129a in the deformed form is smaller than the distance 129c in the non - deformed form. Due to the tendency of the tension member 104 to return to its non - deformed form, opposing lateral forces are applied to the cell encapsulation pouch 102, and tension is applied to the top layer 106 and the bottom layer 108.

[0039] In some embodiments, the cell encapsulation devices described herein further include one or more components, such as one or more seals, one or more spacers (e.g., welding spacers or structural spacers), or a cell displacement core. FIG. 2 is a cross-sectional view showing an embodiment of a cell encapsulation device 200. The cell encapsulation device 200 is similar in shape to the cell encapsulation device 100, but further includes a welding spacer 226 that couples to the first layer 206 and the second layer 208 of the cell encapsulation pouch 202. The welding spacer 226 is positioned between the tension member 204 and the reservoir space 220. The tension member 204 may have a similar shape to the tension members shown in FIGS. 1A - C, but does not necessarily have the same shape and may have an overall different shape (e.g., circular or oval).

[0040] In the embodiment shown in FIG. 2, the reservoir space 220 is located between the first inner surface 222 and the second inner surface 224 and inward from the welding spacer 226. The reservoir space thickness 228 is the distance from the first inner surface 222 to the second inner surface 224, is defined by the thickness of the welding spacer 226, and is independent of the tension member thickness 238. This is because the welding spacer 226 presses the top layer and the bottom layer together inward from the tension member 204. Thus, in the embodiment shown in FIG. 2, the reservoir space thickness 228 is smaller than the tension member thickness 238. As shown in FIG. 2, in some embodiments, the cell encapsulation pouch 202 may be a composite material 240, 241 having an outer porous layer 240 and an inner porous layer 241. In some embodiments, the inner porous layer 241 has a pore size small enough to hold the encapsulated cells and limit in-growth of the tissue. In some embodiments, the outer porous layer 240 allows in-growth of the tissue to anchor the cell encapsulation device 200 when implanted. The composite materials 240, 241 shown in FIG. 2 are optional for the cell encapsulation devices described herein, and thus a cell encapsulation device that otherwise matches FIG. 2 in other respects may include materials different from the cell encapsulation pouch. Further, the embodiments shown in other drawings may include the composite materials 240, 241 shown in FIG. 2.

[0041] The cell encapsulation devices shown in FIGS. 1A - B and FIG. 2 are formed from a flattened tubular membrane, but alternatively may be formed from one membrane folded to form the top and bottom layers, may be formed from separate membranes laminated to form the top and bottom layers, or may be formed from one or more membrane composites.

[0042] Figures 3A - B show an embodiment of a cell encapsulation device 300 including a cell encapsulation pouch 302 and a tension member 304. FIG. 3A is a top view of the cell encapsulation device 300 showing a single ring - shaped tension member 304 inside the cell encapsulation pouch 302. FIG. 3B is a cross - sectional view of FIG. 3A taken along line 3B - 3B.

[0043] In the embodiment shown in FIGS. 3A - B, the cell encapsulation pouch 302 includes a first layer 306 and a second layer 308. The first layer 306 and the second layer 308 are two separate membranes sealed along their perimeter 310. Moving inward from the sealed perimeter 310, the first layer 306 includes a first inner surface 322 and the second layer 308 includes a second inner surface 324. The second inner surface faces the first inner surface 322 and is spaced apart from the first inner surface 322 to define an internal volume 312. The tension member 304 is disposed inside the internal volume, contacts at least two opposing portions of the cell encapsulation pouch 302, and applies tension to the first layer 306 and the second layer 308. FIG. 3B shows a welding spacer 326 disposed inside the internal volume inward from the tension member 304, however, other spacers than the welding spacer may be used instead. FIG. 3A further shows a port 314. The port extends through the sealed perimeter 310 and is in fluid communication with a reservoir space 320. Optionally, a cell - pushing core or other structural element may be disposed inside the internal volume.

[0044] In the embodiment shown in FIGS. 3A - B, the reservoir space 320 is located between a first inner surface 322 and a second inner surface 324 and is positioned inwardly from the welding spacer 326. In this embodiment, the reservoir space thickness 328 is the distance from the first inner surface 322 to the second inner surface 324, is defined by the thickness of the welding spacer 326, and is independent of the tension member thickness 338. This is because the welding spacer 326 presses the top layer and the bottom layer together inwardly from the tension member 304, and the reservoir space thickness 328 is the thickness of the welding spacer 326. Thus, in the embodiment shown in FIGS. 3A - B, the reservoir space thickness 328 is smaller than the tension member thickness 338. However, alternatively, the thickness of the welding spacer may be equal to or greater than the tension member thickness, and in these embodiments, the reservoir space thickness 328 will be equal to or greater than the tension member thickness 338. Regardless of what the reservoir space thickness 328 is, the tension on the cell encapsulation pouch 302 provided by the tension member 304 prevents collapse or ballooning of the reservoir space 320 and thus maintains the thickness defined by the welding spacer 326.

[0045] In the embodiment shown in FIGS. 3A - B, the tension member 304 completely surrounds the reservoir space 320. In other embodiments, the tension member may only partially surround or enclose the reservoir space 320. In the embodiment shown in FIGS. 3A - B, the welding spacer 326 isolates the reservoir space 320 from the tension member 304. Thus, the tension member need not have compatibility with the cells to be encapsulated.

[0046] In the embodiment shown in FIGS. 3A - B, the tension member 304 is a rubber O - ring. In other examples consistent with this embodiment, the tension member may be of a different shape or a different material. When opposing radially inward forces are applied to the tension member 304, the inherent flexibility of the tension member 304 allows the tension member 304 to deform from a substantially circular form to a more elliptical form. When the tension member 304 is inside the cell encapsulation membrane 320, it is in a deformed state. Due to the tendency of the tension member 304 to return to its non - deformed state, opposing lateral forces are applied to the cell encapsulation pouch 302, imparting tension to the top layer 306 and the bottom layer 308. FIG. 3A shows a port 314 in fluid communication with the reservoir space 320.

[0047] FIG. 4 is a cross - sectional view showing another cell encapsulation device 400. The cell encapsulation device 400 is similar to the cell encapsulation device 300 in that the cell encapsulation pouch 402 is formed from two separate membranes, namely a first layer 406 and a second layer 408, and these layers are sealed along at least a portion of the perimeter 410. A tension member 404 is disposed between the first layer 406 and the second layer 408. The tension member 404 contacts at least two opposing portions of the cell encapsulation pouch 420 and applies tension to the first layer 406 and the second layer 408. Instead of a welded spacer, the cell encapsulation device 400 includes a seal 421. The seal joins the first layer 406 and the second layer 408 to each other, inwardly from the tension member 404. Inwardly from the seal 421, a structural spacer 426 separates the first layer 406 and the second layer 408 to form a reservoir space 420 in a portion of the internal volume not occupied by the tension member 404 or the structural spacer 426.

[0048] In this embodiment, the reservoir space thickness 428 is the distance from the first inner surface 422 to the second inner surface 424, defined by the thickness of the structural spacer 426, and is independent of the tension member thickness 438. This is because the seal 410 joins the first layer 406 and the second layer 408 together inward from the tension member 404, and the reservoir space thickness 428 is the thickness of the structural spacer 426 that separates the first layer 406 and the second layer. Although the height of the structural spacer 426 shown in FIG. 4 is smaller than the tension member thickness 438, in some embodiments, the thickness of the structural spacer 426 may be equal to or greater than the tension member thickness 438, and in these embodiments, the reservoir space thickness 428 will also be equal to or greater than the tension member thickness 438. Regardless of the reservoir space thickness 428, the tension on the cell encapsulation pouch 402 provided by the tension member 404 prevents collapse or ballooning of the reservoir space 420, and thus maintains the thickness defined by the weld spacer 426.

[0049] As shown in FIG. 4, the tension member 404 is isolated from the reservoir space 420 by a seal 421. In various embodiments, the seal 421 may be continuous or discontinuous. When the seal 421 is continuous, it isolates the tension member 404 from the reservoir space 420, and the tension member can be formed from any suitable material, whether or not it is compatible with the encapsulated cells. When the seal 421 is discontinuous (not shown), the tension member 404 may be in fluid communication with the reservoir space 420 and needs to be formed from a material compatible with the encapsulated cells.

[0050] Figures 5A - B show embodiments of a cell encapsulation device 500 including a cell displacement core 550. FIG. 5A is a top view of the cell encapsulation device 500, and FIG. 5B is a cross - sectional view of the cell encapsulation device 500 along line 5B - 5B. FIGS. 5A - B show a cell encapsulation pouch 502 formed from a single tubular membrane. This membrane is flattened to form a first layer 506 and a second layer 508. The tube is sealed at the distal end and / or the proximal end. These two ends are called the perimeter 510 of the flattened tube. However, in another embodiment, the cell encapsulation pouch 502 can also be formed from two separate membranes. These membranes are laminated and sealed along at least a portion of their perimeters. Alternatively, the cell encapsulation pouch 502 may be formed from one or more membrane composites.

[0051] In the embodiment shown in FIGS. 5A - B, the cell encapsulation pouch 502 includes a first layer 506 and a second layer 508. The first layer 506 and the second layer 508 are sealed along their perimeter 510. The tension member 504 is disposed inside the internal volume 520, contacts at least two opposing portions of the cell encapsulation pouch 502, and applies tension to the first layer 506 and the second layer 508. FIG. 5B shows a cell displacement core 550 disposed inside the internal volume inward from the tension member 504. FIG. 5A further shows a port 514. The port extends through the sealed perimeter 510 and is in fluid communication with the reservoir space 520.

[0052] In this embodiment, the reservoir space thickness 528 is the distance from the first inner surface 522 to the second inner surface 524, is defined by the thickness of the cell displacement core 550, and is independent of the tension member thickness 538. This is because the cell displacement core 550 is thicker than the tension member thickness. The tension on the cell encapsulation pouch 502 provided by the tension member 504 prevents the collapse or ballooning of the reservoir space 520 and thus maintains the thickness defined by the cell displacement core 550.

[0053] As shown in FIGS. 5A - B, although the tension member 504 is isolated from the reservoir space 502 by the cell - pushing core 550, if the tension member material is compatible with the cells to be inserted, it need not be isolated. Thus, whether the tension member 504 is isolated from the reservoir space 502 is not intended to be a limiting feature of this embodiment.

[0054] The tension member 504 shown in FIGS. 5A - B includes opposing end portions 542, 544 that are non - linear and opposing side portions 546, 548 that are substantially linear, but may be of any shape that provides uniform tension over the entire length (the length from one opposing end to the other opposing end) of the cell - encapsulation pouch 502. According to various embodiments, the non - linear end portions 542, 544 may be non - linear within the plane defined by the X - axis line 516 and the Y - axis line 518, as shown in FIG. 5A, and / or may be non - linear within the plane defined by the X - axis line 516 and the Z - axis line (not shown), within an intermediate plane, or within a plurality of planes. According to various embodiments, the non - linear end portions may include one or more curves, as shown in FIG. 5A, or may include other non - linear shapes such as a meandering shape or a helix. Alternatively, a frame having other shapes described herein can also be utilized as the tension member 504. As such, the exact shape of the tension member 504 should not be considered limiting.

[0055] When opposing inward forces are applied to the side portions 546, 548, the non - linear shape of the end portions 542, 544 allows the tension member 504 to deform from its non - deformed state to a deformed state. The tension member 504 is in a deformed state when it is inside the cell - encapsulation pouch 502. Due to the tendency of the tension member 504 to return to its non - deformed state, opposing lateral forces are applied to the cell - encapsulation pouch 502, and tension is applied to the top layer 506 and the bottom layer 508.

[0056] Figures 6A - B show another embodiment of a cell encapsulation device 600 having a tension member 604 and a cell encapsulation pouch 620. FIG. 6A is a top view of the cell encapsulation device 600. The device is in a plane defined by an X - axis line 616 and a Y - axis line 618. FIG. 6B is a cross - sectional view of the cell encapsulation device 600 taken along 6B - 6B. The cross - sectional view shows a plane defined by the X - axis line 616 and a Z - axis line 619. The cell encapsulation device 600 has a first layer 606 and a second layer 608. These layers are sealed together at an intermediate position 652 so that the reservoir space between the first layer 606 and the second layer 608 is finely divided into a plurality of storage tubes 621. Each storage tube 621 has a separate reservoir space for storing cells. In various examples, each storage tube 621 has a separate port 614 so that cells can be loaded independently into the reservoir space of each storage tube 621. In some embodiments, a filling tube (not shown) can be inserted into the storage tube 621. The filling tube can be pre - filled with cells. In addition, the filling tube can be removed from the storage tube and replenished (and / or reused) as needed.

[0057] As shown in FIGS. 6A - B, the tension member 604 extends around the cell encapsulation device 600. In the embodiment shown in FIGS. 6A - B, the tension member 604 is isolated from the reservoir space (i.e., not in fluid communication), and as a result, the tension member may be formed from any suitable material, regardless of its compatibility with the encapsulated cells. The tension member 604 includes opposing end portions 642, 644 that are non - linear and opposing side portions 646, 648 that are linear. In certain embodiments, at least a portion of the tension member 604 is positioned between the first layer 606 and the second layer 608 (e.g., the opposing linear end portions 646, 648 in FIGS. 6A - B), and another portion is outside the cell encapsulation pouch 602 (e.g., the opposing non - linear end portions 642, 644 in FIGS. 6A - B). According to various embodiments, the non - linear end portions 642, 644 may be non - linear in the plane defined by the X - axis line 616 and the Z - axis line 619, as shown in FIG. 6B, and / or may be non - linear in the plane defined by the X - axis line 616 and the Y - axis line 618, in the intermediate plane, or in multiple planes. In the example shown in FIG. 6B, the non - linear end portions 642, 644 are non - linear in the Z - dimension 619.

[0058] When opposing inward forces are applied to the side portions 646, 648, the non - linear shape of the end portions 642, 644 allows the tension member 604 to deform from its non - deformed state to a deformed state. The tension member 604 is in a deformed state when it is inside the cell encapsulation pouch 602. Due to the tendency of the tension member 604 to return to its non - deformed state, opposing lateral forces are applied to the cell encapsulation pouch 602, tension is applied to the top layer 606 and the bottom layer 608, and the storage tube 621 is stretched, so that the thickness 628 of each storage tube 621 (and thus the reservoir space) is controlled.

[0059] In some embodiments, the cell encapsulation device described herein may include a plurality of tension members. The tension member may be a single tension member that does not completely surround the reservoir space, or may be a plurality of tension members, none of which completely surrounds the reservoir space. The tension members may collectively surround the reservoir space or may not surround it.

[0060] Figures 7A - D illustrate embodiments of an insert 710 for a cell encapsulation device 700 that includes tension members 704a, 704b. Figure 7A is a top view of the insert 710 that includes a cell repelling core 750 coupled to two tension members 704a, 704b. The ends 705a, 705b of the tension members 704a, 704b are embedded within the cell repelling core 750. Figure 7B is an end view of the insert shown in Figure 7A. Figure 7C is a side view of the insert shown in Figure 7A. Figure 7D is a cross - sectional view of the insert shown in Figure 7A taken along line 7D - 7D. Figure 7E is a cross - sectional view of the cell encapsulation device 700 taken along line 7D - 7D when the insert 710 is positioned inside the cell encapsulation pouch 702. The cell encapsulation pouch 702 includes a first porous layer 706 and a second porous layer 708. These layers define an internal volume 712 with the tension members 704a, 704b and the cell repelling core 750 disposed therein. The tension members 704a, 704b contact two opposing portions of the cell encapsulation pouch 702 and apply tension to the first layer 706 and the second layer 708. The cell encapsulation device 700 includes a reservoir space 720 for receiving cells between the first porous layer 706 and the second porous layer 708 and the cell repelling core 750. In other embodiments not shown herein, the cell encapsulation pouch 702 may be a single flattened tubular membrane that forms the first layer 706 and the second layer 708, a single membrane folded to form the first layer 706 and the second layer 708, or two separate membranes laminated and sealed along at least a portion of the perimeter to form the first layer 706 and the second layer 708. Alternatively, the cell encapsulation pouch may be formed from one or more membrane composites.

[0061] In some embodiments of the cell encapsulation devices described herein, the first and second layers of the cell encapsulation pouch are flexible, however, the tension member alone, or in combination with other structural components, maintains the cell encapsulation device as a generally planar structure. The tension member maintains an average distance between the first and second layers under an applied force. As used herein, the expression "average distance" refers to the distance between the first inner surface and the second inner surface over the entire length and / or width of the reservoir of the cell encapsulation device where cells are present, having a substantially uniform thickness over the entire dimension. Maintaining the average distance is advantageous because the structural shape is maintained without damage and deformations that would cause the device to rupture are avoided. Additionally, failure to maintain the average distance can result in undesirable volume changes. The optimal spacing varies depending on the different cell types. Beyond the optimal average distance between the inner surfaces, some of the cells inside the encapsulation device will be located inconveniently far from the device wall, and thus will not be able to receive nutrients and other biomolecules. Cells that do not receive sufficient nutrients and oxygen cannot be healthy and productive, or may even die. In some embodiments, the applied force is an external compressive force, however, in other embodiments, the applied force can be an internal expansive force. In some embodiments, the applied force can be a shear force or a cyclical force. Thus, the tension member, optionally having a structural spacer, can withstand both forces to maintain the average distance.

[0062] In some embodiments, the applied force can be an external compressive force. The external compressive force tends to crush the reservoir space between the first and second layers in the absence of the tension member. For example, the surrounding tissue may apply a compressive force to the in vivo device, or a clinician may apply a compressive force to the outside of the device before or during insertion. When the external compressive force shortens the distance between the first inner surface and the second inner surface, the encapsulated device may be subjected to undesirable mechanical stimulation, and as a result, cell function may be minimized or cells may die. In some examples, the device is intended for subcutaneous implantation, and thus, when the device is implanted within a patient, the compressive force may be caused by contact with the patient, such as a hug, a gentle tap on the back, or a fall.

[0063] Alternatively, the applied force can be an internal expansive force. The internal expansive force tends to expand the reservoir space between the first and second layers into a rounded balloon-like structure in the absence of the tension member. For example, pressure may be required to inject cells into the reservoir space. In one example, the pressure can be caused by overexpansion during insertion, for example due to operator error. In another example, the pressure can be caused by an increase in cells due to cell growth.

[0064] In some embodiments, the tension member is an elastically deformable material. For example, the tension member may be an elastically deformable polymer, polymer blend, or metal alloy. For example, the elastically deformable material may be a polymeric elastomer such as natural or synthetic polyisoprene, polybutadiene, styrene-butadiene rubber, nitrile rubber, ethylene propylene rubber, ethylene propylene diene rubber, or ethylene vinyl acetate. In some embodiments, the devices described herein require only a small amount of deflection of the tension member and thus do not require high elastic behavior and superelastic behavior. Thus, in some embodiments, the tension member may be a spring temper type stainless steel such as spring temper type 316 SST, a spring temper type cobalt-chromium alloy such as Co-28Cr-6Mo or Co-35Ni-20Cr-10Mo, or a spring temper type titanium-based alloy such as Ti-6Al-4V. In other embodiments, the tension member may be a material having high elasticity. Thus, in some embodiments, the tension member may be a spring temper type nickel-titanium alloy such as Nitinol. The tension member can be pre-formed into a desired shape to conform to the patient's biological structure. In addition, the tension member can be delivered to a desired site via a catheter or trocar.

[0065] In some embodiments, the tension member may be formed from or include a shape memory material. The above-described Nitinol is a shape memory alloy. Non-limiting examples of useful shape memory alloys include, for example, copper-aluminum-nickel, copper-zinc-aluminum, and iron-manganese-silicon alloys.

[0066] Other non-limiting examples of shape memory materials include shape memory polymers such as polyetheretherketone (PEEK), polymethylmethacrylate, polyethylmethacrylate, polyacrylate, poly-alpha-hydroxy acid, polycaprolactone, polydioxanone, polyester, polyglycolic acid, polyglycol, polylactide, polyorthoester, polyphosphate, polyoxaester, polyphosphoester, polyphosphonate, polysaccharide, polythyrosine carbonate, polyurethane, polyurethane having an ionic or mesogenic component formed by a prepolymer method, and copolymers or polymer blends thereof. Some block copolymers, such as block copolymers of polyethylene terephthalate (PET) and polyethylene oxide (PEO), block copolymers containing polystyrene and poly(1,4-butadiene), and ABA triblock copolymers formed from poly(2-methyl-2-oxazoline) and polytetrahydrofuran also exhibit a shape memory effect.

[0067] Broadly speaking, the tension members described herein should be operable to impart tension to the cell encapsulation pouch over the lifetime of the implanted cell encapsulation device. Thus, in some embodiments, shape memory polymers useful as tension members are not biodegradable. However, in other embodiments, shape memory polymers having at least some degree of biodegradability (such as polyglycolic acid and some polyurethanes in the presence of certain enzymes) may also be useful as tension members if they impart tension to the cell encapsulation pouch over the desired time.

[0068] In embodiments where the tension member must have biocompatibility with the encapsulated cells, the tension member may be or may be formed from a material that is essentially biocompatible, or may be a material that does not have essential biocompatibility but is made biocompatible, for example, by a biocompatible coating. Non-limiting examples of essentially biocompatible tension member materials include nitinol and Ti-6Al-4V. Non-limiting examples of materials that can be used as biocompatible coatings include polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), and parylene. Fluoropolymers that can be solvent-applied may also be useful as biocompatible coatings.

[0069] In any of the embodiments described herein, the first and second layers of the cell encapsulation pouch may optionally be composite layers. An example of a composite layer is shown in FIG. 2, but any of the embodiments described herein may optionally include a composite layer. In various examples, the composite layer includes at least two layers and may include three or more layers. For example, the composite layer may include at least an outer porous layer and an inner porous layer disposed adjacent to the outer porous layer. In some embodiments, both the first and second layers of the cell encapsulation pouch may be composite materials each having an outer porous layer and an inner porous layer. The outer porous layers of the first and second layers may be the same material or different materials. Similarly, the inner porous layers of the first and second layers may be the same material or different materials. In certain embodiments, the pore size of the inner porous layer is smaller than the pore size of the outer porous layer. In certain embodiments, the porosity of the inner porous layer is smaller than the porosity of the outer porous layer. In various embodiments, the portion of the inner porous layer forms the first and second inner surfaces of the cell encapsulation device.

[0070] When both the first and second layers of the cell encapsulation pouch are composite layers, in some embodiments, the average pore size of both inner porous layers is small enough to prevent in-growth of blood vessels. In this specification, a layer that limits or prevents in-growth of blood vessels may be referred to as a "tight" layer. As one non-limiting example, the average pore size of the inner porous layer, measured by porometry, may be less than about 5 microns, less than about 1 micron, less than about 0.8 microns, less than about 0.5 microns, less than about 0.3 microns, or less than about 0.1 microns. In some further examples, the average pore size of the inner porous layer, measured by porometry, may be from about 0.05 to about 0.4 microns. The small pore size allows the inner porous layer to function as a cell retention layer, keeping the cells within the reservoir space inside the encapsulation device, while also allowing nutrients and other biomolecules to enter and cellular waste products and therapeutic products to exit. Thus, this layer may be referred to in this specification as the cell retention layer. In some embodiments, the pores resist in-growth of cells, but can selectively pass certain macromolecules.

[0071] When both the first and second layers of the cell encapsulation pouch are composite layers, in some embodiments, the average pore size of both outer porous layers is large enough to allow vascular tissue to grow inside the pores of the outer porous layer from the patient. In this specification, a layer having an opening wide enough to allow in-growth of blood vessels may be referred to as an "open" layer or an "angiogenic" layer. In some non-limiting examples, the pore size of the outer porous layer, measured by porometry, is greater than about 5.0 microns, greater than about 6.0 microns, greater than about 7.0 microns, or greater than about 10 microns. In-growth of vascular tissue through the outer porous layer facilitates the movement of nutrients and biomolecules from the body to the cells encapsulated within the device.

[0072] Various cell types can grow within the angiogenic layer composed of the porous material of the cell encapsulation device described herein. The major cell types that grow within a particular porous material primarily depend on the implantation site, the composition and permeability of the material, and biological factors such as cytokines and / or cell adhesion molecules that can be incorporated into the material or introduced through the porous material. In some embodiments, vascular endothelium is the major cell type that grows into the porous material for use within the cell encapsulation device. Angiogenesis of the porous material by a well-established collection of vascular endothelial cells forming a capillary network promotes development as a result of the material neo-angiogenizing into and across the thickness of the cell encapsulation device's inner surface, very close to the patient's tissue, but not across the cell retention layer.

[0073] In some embodiments, only one of the first layer and the second layer is a composite layer. For example, the first layer may be a composite layer including an outer porous layer that is an angiogenic layer and an inner porous layer that is a cell retention layer, whereas the second layer may only include a cell retention layer.

[0074] In another embodiment, neither the first layer nor the second layer is a composite layer, and both are cell retention layers. Thus, the device does not include an angiogenic layer. In such an embodiment, the cell encapsulation device can optionally also be used with a housing. The housing can be placed within or can be placed in the patient, and since it is formed from angiogenic material, the housing allows for ingrowth of vascular tissue from the patient. In some embodiments, the housing may be implanted in the patient for a time sufficient to allow angiogenesis before the device is inserted into the housing. In other embodiments, the device and the housing may be inserted together into the patient.

[0075] In a further embodiment, neither the first layer nor the second layer is a composite layer. Instead, both are angiogenesis layers. Thus, the device does not include a cell retention layer. In such an embodiment, the cells to be inserted into the cell encapsulation device may be microencapsulated. This can isolate the cells from the host immune response. In some embodiments, the cells can be microencapsulated within a biomaterial of natural or synthetic origin, including, for example, a hydrogel or alginate biomaterial. As a result, a separate cell retention layer can be omitted from the cell encapsulation device.

[0076] Examples of materials useful as an outer porous angiogenesis layer and an inner cell retention layer include alginate, cellulose acetate, polyalkylene glycols such as polyethylene glycol and polypropylene glycol, panvinyl polymers such as polyvinyl alcohol, chitosan, polyacrylates such as polyhydroxyethyl methacrylate, agarose, hydrolyzed polyacrylonitrile, polyacrylonitrile copolymers, polyvinyl acrylates such as polyethylene-co-acrylic acid, porous tetrafluoroethylene (TFE) polymers such as porous polytetrafluoroethylene (PTFE) (e.g., expanded PTFE (ePTFE)), porous modified PTFE, and porous TFE copolymers, porous polyalkylenes such as porous polypropylene, porous polyethylene, porous polyvinylidene fluoride, porous polyester sulfone (PES), porous polyurethane, porous polyester, porous PPX (ePPX), porous ultra-high molecular weight polyethylene (eUHMWPE), porous ethylene tetrafluoroethylene (eETFE), porous polylactic acid (ePLLA), and copolymers and combinations thereof, as well as woven or non-woven aggregates of fibers or threads, can be mentioned alone or in combination. In some embodiments, materials useful as the porous layer include biomaterial textiles including woven and non-woven fabrics.

[0077] In some embodiments, the porous angiogenesis layer may be a bioabsorbable material. Alternatively, the porous angiogenesis polymer material may be coated with a bioabsorbable material, or the bioabsorbable material may be incorporated in the form of a powder into or onto the porous angiogenesis polymer material. The coated material can promote reduction of the infection site, angiogenesis, and favorable type I collagen deposition. The porous polymer materials described herein may include any bioabsorbable material known to those skilled in the art. Non-limiting examples of bioabsorbable materials include polyglycolide:trimethylene carbonate (PGA:TMC), polyalpha 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), and copolymers and blends thereof.

[0078] In some embodiments, the structural spacer is formed from a porous material. The pore size of the porous material precludes ingrowth of cells within the structural spacer material. In some embodiments, the porous material includes porous (e.g., ePTFE), porous polypropylene, porous polyethylene, polyester sulfone (PES), polyurethane, polyester, and polyvinylidene fluoride (PVDF) alone or in any combination.

[0079] In another embodiment, the structural spacer is formed from a non-porous material. In some embodiments, the non-porous material includes polytetrafluoroethylene (PTFE), polyurethane, polypropylene, polyethylene, polyether amide, polyether ether ketone, polyphenyl sulfone, polysulfone, silicone polycarbonate urethane, polyether urethane, polycarbonate urethane, silicone polyether urethane, polyester, polyethylene terephthalate, a melt processable fluoropolymer such as fluorinated ethylene propylene (FEP), tetrafluoroethylene-(perfluoroalkyl) vinyl ether (PFA), ethylene / TFE alternating copolymer (ETFE), tetrafluoroethylene (TFE) / hexafluoropropylene (HFP) / vinylidene fluoride (VDF) terpolymer (THV), polyvinylidene fluoride (PVDF), and combinations thereof.

[0080] In some embodiments, the structural spacer of the cell encapsulation device described herein is attached to one or both of the inner surfaces of the first and second layers. In some embodiments, the structural spacers are attached to at least one inner surface, but they do not necessarily have to be attached. For example, in other embodiments, the structural spacers may freely float within the reservoir space. In some embodiments, both the first and second layers are composite materials having an inner dense porous layer, and the structural spacers are attached to both of the inner dense porous layers. The structural spacers may penetrate through a portion of the pores of the inner dense porous layer. In some embodiments, the spacers do not penetrate the outer angiogenic porous layer, so the outer angiogenic porous layer remains unhindered in allowing intracellular growth.

[0081] In some embodiments, the structural spacer can be formed by depositing a fluoropolymer powder onto the cell retention layer so as to form at least a portion of the structural spacer. A useful powder coating method is taught in Bacino's U.S. Patent No. 8,808,848, which is hereby incorporated by reference in its entirety.

[0082] Any material that acts to push cells away from the center of the device is suitable for use as the material of the cell-pushing core. For example, as an example of a suitable core material, there may be mentioned polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polydimethylsiloxane, polyurethane, polyester, polyamide, or a hydrogel, alginate, hydrolyzed polyacrylonitrile, and combinations thereof derived from polysaccharides. In some embodiments, the core is a flexible polymer or elastomer. In other embodiments, the core may be made of a polysaccharide, a hydrophilic copolymer of polyacrylonitrile, a copolymer of polyacrylonitrile and acrylamide, and / or other non-porous polymers.

[0083] Methods of sealing the top and bottom layers include thermal welding, staking, ultrasonic sealing, and impulse heat sealing. For example, as an example of a device useful for sealing the top and bottom layers to form a sealed perimeter, impulse heat sealing is one. In certain embodiments, an impulse heat seal-based fixture includes a silicone die plate and a conforming impulse heat band geometry. The membrane or membrane composite to be sealed can be placed between the base fixture and a compression top fixture having a mirror-image silicone die plate, and by compressing and heating the impulse heat band between the silicone die plates, the membrane or membrane composite is sealed and a cell encapsulation pouch is formed.

[0084] In some examples, the distance between the first inner surface and the second inner surface, which is also the thickness of the reservoir space, is at least about 50 microns (0.05 mm) (e.g., at least 0.1 mm, at least 0.15 mm, at least 0.2 mm, or at least 0.5 mm). In some examples, the distance between the first inner surface and the second inner surface, which is also the thickness of the reservoir space, is 0.05 mm to 0.25 mm (e.g., 0.05 mm to 0.15 mm, 0.05 mm to 0.10 mm, 0.10 mm to 0.20 mm, 0.10 mm to 0.15 mm, 0.15 mm to 0.25 mm, 0.15 mm to 0.20 mm, or 0.20 mm to 0.25 mm). In some embodiments, the cell encapsulation device does not include a cell displacement core, and the distance between its first inner surface and the second inner surface is 0.05 mm to 0.25 mm. In some embodiments, the cell encapsulation device includes a cell displacement core, and the distance between its first inner surface and the second inner surface, including the cell displacement core, is 0.5 mm to 4.0 mm (e.g., 1.0 mm to 3.0 mm, 1.0 mm to 2.0 mm, 2.0 mm to 4.0 mm, 2.0 mm to 3.0 mm, 3.0 mm to 4.0 mm). In some embodiments, the thickness of the reservoir space (from the surface of the cell displacement core or other structural element to the pouch) is about 0.05 to about 0.25 mm. In one embodiment, by maintaining the average distance, the first layer can be placed in a substantially parallel relationship with the second layer. It is important that the materials used within the composite layer, such as ePTFE, have sufficient tensile strength to maintain the integrity of the cell encapsulation device both during implantation and in vivo.

[0085] In certain embodiments, the overall thickness of the cell encapsulation device (the distance between the opposing outer surfaces of the cell encapsulation pouch) is less than about 5 mm, such as less than about 4 mm, less than about 3 mm, less than about 2 mm, or less than about 1 mm. In some embodiments, the overall thickness of the cell encapsulation device is from about 0.3 mm to about 4 mm, such as from about 0.3 mm to about 1.0 mm, from about 0.3 to about 0.5 mm, or from about 0.5 mm to about 1.0 mm, from about 1 mm to about 4 mm, from about 1 mm to about 3 mm, or from about 2 mm to about 4 mm. In some embodiments, the overall thickness of the device including the cell displacement core may be from about 1 mm to about 4 mm. In some embodiments, the overall thickness of the device without the cell displacement core may be from about 0.3 mm to about 0.5 mm.

[0086] In one non-limiting example, the distance between the opposing sides of the tension member in its non-deformed configuration is from about 5 mm to about 50 mm (e.g., about 20 mm), and the distance between the opposing sides of the same tension member when the tension member is in its deformed configuration and disposed within the cell encapsulation pouch is from about 5 mm to about 50 mm (e.g., about 15 mm).

[0087] The cell encapsulation devices described herein are useful for providing biological therapy to a patient by retaining cells or other biological moieties at a predetermined location within a tissue bed in the patient. In some embodiments, the cells are introduced in the form of a suspension or slurry in a medium. The cells may be individual cells, cell aggregates, or cell clusters. By way of example, the medium may be a cell culture medium or cell growth medium optionally containing the desired nutrients. In some embodiments, insertion of the cells through the port can be accomplished using a syringe. In some embodiments, pressure is applied to the device upon insertion of the cells, but the device retains its overall cross-sectional shape based on the tension member.

[0088] In some embodiments, when the tension member of the cell encapsulation device is in a first deformed configuration that provides tension across the entire cell encapsulation pouch of the cell encapsulation device, cells or other biological moieties are introduced into the reservoir space. In various embodiments, when the tension member is in a second deformed configuration that is deformed more (e.g., made narrower) than the first deformed configuration such that the tension on the cell encapsulation pouch is reduced, cells or other biological moieties are introduced into the reservoir. In some embodiments, while the tension member is in the second deformed configuration, cells or other biological moieties are introduced into the reservoir space of the device through one or more ports. In some embodiments, the ports extend through the sealed perimeter between the first and second layers of the sealed cell encapsulation pouch, such that cells are introduced into the reservoir of the pouch through the edge of the pouch. In various embodiments, after inserting the cells into the reservoir space, the tension member is released from the second deformed configuration, whereby the tension member returns to the first deformed configuration.

[0089] The encapsulation devices described herein can be implanted into a patient before or after insertion of cells. For example, by inserting the device into a patient to enable angiogenesis, vascular tissue can grow into the angiogenesis layer of the device. Then, cells can be added while the device is in vivo. Alternatively, cells can be added to the device before inserting the device into the tissue bed of a patient. For example, in some embodiments, a cell encapsulation device containing cells can be provided with the tension member in a first deformed configuration that provides tension across the entire cell encapsulation pouch. The tension member can be deformed from the first deformed configuration to a second deformed configuration that is deformed more (e.g., made narrower) than the first deformed configuration such that the tension on the cell encapsulation pouch is reduced. The cell encapsulation device can be inserted into the tissue bed of a patient, and then by releasing the tension member from the second deformed configuration, the tension member can return to the first deformed configuration.

[0090] In some embodiments, the materials used for the tension members described herein are substantially radiopaque. Device materials that are not substantially radiopaque can be modified to be radiopaque, for example, by impregnating the material with barium. Other useful methods for making materials radiopaque are known to those of ordinary skill in the art. The radiopacity of the materials used to construct the devices described herein is primarily used to facilitate the surgical placement of the cell encapsulation device or to locate the cell encapsulation device within a patient following implantation.

Example

[0091] Example 1: A cell-containing pouch was formed from two multilayer membrane layers by welding two layers together using a fluoropolymer thermoplastic film. The multilayer membrane consisted of a multilayer expanded PTFE (ePTFE) membrane. This membrane was produced by combining layers of different membranes bonded together with a discontinuous fluoropolymer layer consisting of fluorinated ethylene propylene (FEP). The inner layer (dense layer) consisted of a membrane having a smaller pore size and the material properties listed in Table 3, formed generally in accordance with the teachings of Gore U.S. Patent No. 3,953,566, which is hereby incorporated by reference in its entirety. Using the Gore method, a liquid lubricant was mixed with commercially available PTFE powder and the mixture was extruded by a ram extruder or other type of extruder. The liquid lubricant was then removed and the material was stretched by rapid extension in a uniaxial, biaxial, or multiaxial direction. The outer layer (open layer) consisted of a membrane having a larger pore size, formed generally in accordance with the teachings of Branca et al. U.S. Patent No. 5,814,405, which is hereby incorporated by reference in its entirety. Here, with the substrate left air permeable, a discontinuous FEP layer was incorporated onto the layer of this membrane generally in accordance with the process teachings of Bacino WO 94 / 13469 pamphlet, which is hereby incorporated by reference in its entirety. The properties of this open layer are listed in Table 1. The inner layer (dense layer) was then brought into contact with the outer layer (open layer). A bonded multilayer membrane having the final properties specified in Table 1 was formed by placing the discontinuous FEP surface between two PTFE layers while heating to a temperature above the melting temperature of the two PFEP. The ePTFE multilayer membrane was hydrophilically treated.

[0092]

Table 1

[0093] The cell-containing pouch was welded on three sides and the fourth side was left open for access to cell loading. The welding film was 125 μm THV500 (available from Dyneon). The welding film was open in the center where cells were intended to be placed. Both membrane layers and the welding film extended about 1 cm beyond the weld on the outer edge of this part. Two slits were formed on one layer of the membrane, extending outward from the weld at two locations at the open end of the active region. A silicone rubber O-ring was placed outside the welds on the three sides where the membrane layers were welded to each other and above both membrane layers that were left open for later cell filling. The O-ring was forced into contact with the welds on the two long sides of the pouch and was fixed in place by welding the membranes to each other outside the O-ring. This enabled the silicone O-ring to act as a tensioning member and keep the active region in tension. The excess membrane and welding film were trimmed and removed. Inserting a filling needle between the layers facilitated cell loading into the device. After aseptic filling, the needle was intended to be removed, the open end of the pouch was welded shut, and the excess membrane was removed to complete cell encapsulation. In this example, the tensioning member is isolated from the cells contained inside the pouch.

[0094] Example 2: A device containing a cell-containing pouch was formed from two multilayer membrane layers by welding two layers together using a fluorinated thermoplastic film. FIG. 8 shows an example of a device 800 having a cell encapsulation pouch 802 surrounding a tension member 804. The therapeutic cells can be loaded through the open end, and then the end can be sealed / and the excess membrane removed to complete the combined device. In this example, the multilayer membrane was the same composite membrane as used in Example 1. The welding film was 125 μm THV500 (available from Dyneon). The cell-containing pouch was welded on three sides and the fourth side was left open for access to load the cells. The welding film was open in the center where the cells were intended to be placed. Excess membrane was trimmed and removed from the three sides where the membranes were welded together. A nitinol wire (0.27 mm) was bent into an elliptical shape and heat treated at 470 °C for 7 minutes and then rapidly quenched in a water bath to form the tension member. Excess nitinol wire was trimmed and removed and the ends were welded together by laser welding. The inner diameter of the pouch was about 8 mm from the inside of the weld. The non-deformed form of the tension member was about 9 mm outside the long edge. The long edges of the tension member were pressed together by a pair of tweezers to a distance of about 6 mm and the tension member was placed inside the pouch. The tension member was released and the tweezers were removed.

[0095] Example 3: A first porous expanded polytetrafluoroethylene (ePTFE) membrane was formed generally in accordance with the teachings of Gore's U.S. Patent No. 3,953,566. The specification is hereby incorporated by reference in its entirety. Using Gore's method, a liquid lubricant was mixed with commercially available PTFE powder and the mixture was extruded by a ram extruder or other type of extruder. The liquid lubricant was then removed therefrom and the material was stretched by rapid stretching in a uniaxial, biaxial, or multiaxial direction. The mass per unit area of the membrane was about 2.43 g / m 2and had a thickness of approximately 8.9 μm, a density of approximately 0.27 g / cc, a longitudinal matrix tensile strength of approximately 663 MPa, a transverse matrix tensile strength of approximately 14.3 MPa, and an IPA bubble point of approximately 4.83 kPA.

[0096] The second porous expanded polytetrafluoroethylene (ePTFE) membrane was formed generally in accordance with the teachings of Bacino U.S. Patent No. 5,476,589, which is hereby incorporated by reference in its entirety. The mass per unit area of the film was approximately 1.46 g / m 2 and had a thickness of approximately 0.00012 inches [approximately 3.05 μm], a density of approximately 0.48 g / cc, a longitudinal matrix tensile strength of approximately 101,321 psi (approximately 699 MPa), a transverse matrix tensile strength of approximately 9288 psi (approximately 64.04 MPa), and an IPA bubble point of approximately 35.27 psi (approximately 243.2 kPa).

[0097] The third porous expanded polytetrafluoroethylene (ePTFE) membrane was formed generally in accordance with the teachings of Branca U.S. Patent No. 5,814,405, which is hereby incorporated by reference in its entirety. The mass per unit area of the film was 6.23 grams / m 2 and had a thickness of 0.0017 inches (approximately 43.2 μm). The IPA bubble point was 0.41 psi (approximately 2.83 kPA), the longitudinal tensile strength was approximately 27974 psi (approximately 192.87 MPa), and the transverse matrix tensile strength was approximately 5792 psi (approximately 39.93 MPa).

[0098] In accordance generally with Newman's U.S. Patent No. 6,617,151 (FIG. 9, steps 902-910 and corresponding text), a multi-tube cell-containing structure was fabricated by forming a continuous length of a first ePTFE membrane into a tube having an inner diameter of approximately 13 mm. The said specification is hereby incorporated by reference in its entirety. A cell storage tube was formed to have one longitudinal wrap made of a first ePTFE membrane, six overlapping helical wraps made of a second ePTFE membrane, and one overlapping wrap made of a third ePTFE membrane. The tube was treated with a hydrophilic coating and removed from the core. The tube was trimmed to a predetermined length and one end was sealed closed by fluorothermoplastic (THV 500) welding.

[0099] A tension member was formed from a 0.5 mm nitinol wire and bent around a jig to form a shape having two parallel sides and two "M"-shaped sides, thereby controlling deflection when the parallel sides were deformed. The formed nitinol was heated to 470 °C over 7 minutes and quenched by quenching in water. The formed nitinol was removed from the jig and the ends were welded to each other with a laser welder. The parallel sides were approximately 22 mm apart.

[0100] The tension member was deformed by moving the parallel sides towards each other by approximately 15 mm with a pair of tweezers, and the tension member was inserted into the ePTFE tube with one "M"-shaped end of the tension member in contact with the end sealed by welding of the ePTFE tube.

[0101] The device was prepared for loading by adding a storage tube and an end seal to the open end of the tube. It was observed that the center of the lumen opened when the parallel edges of the tension member were pressed towards each other. When the external force pressing the parallel edges together was released, the device returned to a state having a lumen thickness dimension determined by the thickness of the tension member.

[0102] Example 4: An ePTFE tube was assembled as described in Example 3. A Nitinol tension frame was formed by bending a 0.37 mm Nitinol wire around a jig. The wire was formed into a shape having two edges parallel to each other and two edges having multiple wavy ends. The Nitinol was heated to 470° C. over 7 minutes and then quenched in a room temperature water bath. The formed Nitinol was removed from the jig and the ends were welded to each other with a laser welder. The edges of the tension member parallel to each other were approximately 23 mm apart.

[0103] A cell displacement core was formed from a thermoplastic fluoropolymer (polymerized from Gore, TFE, HFP, VDF) in a compression mold. By cutting the mold from aluminum, a negative shape of a generally elliptical insert was provided. A space was left at one end of the ellipse to facilitate cell loading. The edges of the insert were approximately 0.25 mm thicker than the center to provide a controlled lumen thickness when the membrane was stretched over the thicker edge.

[0104] The tension member was inserted into the tube as described in Example 3, and then the cell displacement core was placed into the tube. FIG. 9 shows a partially assembled device 900. Needless to say, the core and the tension member can be placed together into a cell encapsulation pouch 902 without affecting the intent of this patent. Needless to say further, the core and the tension member can be pre-assembled, or the core can hold the tension member in a predetermined position, and these tension members are not continuous and are attached to the core to provide the desired force. The device can be finished as described in Example 3.

[0105] The invention of this application has been described generally and in relation to specific embodiments. As will be apparent to those skilled in the art, various modifications and changes can be made to the embodiments without departing from the scope of the disclosure. Accordingly, the embodiments are intended to cover modifications and variations of the invention provided they fall within the scope of the appended claims and equivalents thereof.The following are embodiments of the present invention. [Embodiment 1] A cell encapsulation device comprising a cell encapsulation pouch, at least one tension member, and a reservoir space, the cell encapsulation pouch is configured to define an internal volume between the first layer and the second layer by sealing a part of the periphery of the first layer to a part of the periphery of the second layer, and the internal volume further includes a first inner surface and a second inner surface spaced apart from and facing the first inner surface, the at least one tension member is disposed inside the internal volume so as to maintain an average distance between the first inner surface and the second inner surface, and is in contact with at least two opposing portions of the cell encapsulation pouch, and the reservoir space is for receiving cells within the internal volume between the first inner surface and the second inner surface. Cell encapsulation device. [Embodiment 2] The cell encapsulation device according to Embodiment 1, wherein the first layer and the second layer include a top portion and a bottom portion of a single tubular membrane or membrane composite that is at least partially flattened, and the first layer and the second layer are sealed along the part of the periphery of the first layer and the second layer at at least one end of the tubular membrane or membrane composite. [Embodiment 3] The cell encapsulation device according to Embodiment 1, wherein the first layer and the second layer include two separate membranes or membrane composites. [Embodiment 4] The cell encapsulation device according to Embodiment 1, further comprising at least one cell displacement core inside the internal volume. [Embodiment 5] The cell encapsulation device according to Embodiment 4, wherein the cell displacement core defines an average thickness between the first inner surface and the second inner surface. [Embodiment 6] The cell encapsulation device according to Embodiment 1, further comprising a plurality of structural spacers inside the internal volume. [Embodiment 7] The cell encapsulation device according to Embodiment 6, wherein the first layer is sealed to the second layer between the tension member and the structural spacer, and the structural spacer defines an average thickness between the first inner surface and the second inner surface. [Embodiment 8] The cell encapsulation device according to Embodiment 1, wherein the at least one tension member is isolated from the reservoir space. [Embodiment 9] The cell encapsulation device according to aspect 1, wherein the first layer is sealed to the second layer between the tension member and the reservoir space in order to isolate the tension member from the reservoir space. [Aspect 10] The cell encapsulation device according to aspect 9, wherein the thickness of the seal defines an average thickness between the first inner surface and the second inner surface. [Aspect 11] The cell encapsulation device according to aspect 1, wherein the at least one tension member applies opposing lateral forces in a direction away from the reservoir space. [Aspect 12] The cell encapsulation device according to aspect 1, wherein the at least one tension member comprises a shape memory alloy or an elastomer. [Aspect 13] The cell encapsulation device according to aspect 1, wherein the at least one tension member is a frame including opposing end portions that are non-linear and opposing side portions that are linear to provide uniform tension over the entire length of the cell encapsulation pouch. [Aspect 14] The cell encapsulation device according to aspect 1, wherein the device includes at least two tension members. [Aspect 15] The at least one tension member can be adjusted between a deformed state and a non-deformed state such that the distance between at least two opposing side portions of the at least one tension member can be adjusted, and the distance between at least two opposing side portions in the deformed state is smaller than the distance between at least two opposing side portions in the non-deformed state. The cell encapsulation device according to aspect 1. [Aspect 16] The cell encapsulation device according to aspect 1, wherein the average distance is at least the thickness of the at least one tension member. [Aspect 17] The cell encapsulation device according to aspect 1, wherein the average distance is smaller than the thickness of the at least one tension member. [Aspect 18] The cell encapsulation device according to aspect 1, wherein the cell encapsulation pouch includes an angiogenesis layer. [Aspect 19] The cell encapsulation device according to aspect 1, wherein the cell encapsulation pouch is a membrane composite including an outer porous layer and an inner porous layer adjacent to the outer porous layer, and the porosity of the inner porous layer is lower than the porosity of the outer porous layer. [Aspect 20] The cell encapsulation device according to aspect 1, further including a plurality of biological parts disposed inside the reservoir space. [Aspect 21] The cell encapsulation device according to aspect 1, further comprising at least one port in fluid communication with the reservoir space. [Aspect 22] A plurality of interconnected storage tubes including a first end portion, a second end portion opposite to the first end portion, and an internal reservoir space, and a tension member disposed around at least a part of the periphery of the plurality of storage tubes, wherein the tension member maintains the average thickness of each of the storage tubes, a cell encapsulation device. [Aspect 23] The cell encapsulation device according to aspect 22, wherein the storage tubes are arranged substantially parallel to each other with the first end portions aligned and the second end portions aligned. [Aspect 24] The cell encapsulation device according to aspect 22, wherein the storage tubes are interconnected by welding, quilting, an adhesive, or a structural support. [Aspect 25] The cell encapsulation device according to aspect 22, wherein the tension member includes at least two arcuate portions, and the arcuate portions include alternating recesses positioned at the first end portion and the second end portion of each of the storage tubes. [Aspect 26] The cell encapsulation device according to aspect 22, wherein at least a part of the tension member is attached to one or two or more storage tubes by an adhesive. [Aspect 27] The cell encapsulation device according to aspect 22, wherein a part of the tension member is held at opposite ends of the cell encapsulation device inside each of the two outermost storage tubes of the plurality of storage tubes. [Aspect 28] A method for encapsulating cells, comprising: providing the cell encapsulation device according to aspect 1, wherein the tension member forms a first deformed state that provides tension across the entire cell encapsulation pouch, deforming the tension member from the first deformed state to a second deformed state that is deformed more than the first deformed state, thereby reducing the tension on the cell encapsulation pouch, inserting cells into the reservoir space, and releasing the tension member to the first deformed state A method for encapsulating cells. [Aspect 29] A method for inserting a cell encapsulation device into a patient, comprising: providing the cell encapsulation device according to aspect 1, wherein the cell encapsulation device further includes cells disposed in the reservoir space, and The tension member assumes a first deformed state that provides tension across the entire cell encapsulation pouch. The tension member is deformed from the first deformed state to a second deformed state that is more deformed than the first deformed state, thereby reducing the tension on the cell encapsulation pouch. The cell encapsulation device is implanted into the tissue bed of a patient. And the tension member is released to the first deformed state. A method of inserting a cell encapsulation device into a patient, including the above. [Aspect 30] A cell encapsulation device comprising a cell encapsulation pouch, a tension member, and a reservoir space, The cell encapsulation pouch is configured to define an internal volume between the first layer and the second layer by sealing a part of the periphery of the first layer to a part of the periphery of the second layer. Further, the internal volume includes a first inner surface and a second inner surface spaced apart from and facing the first inner surface. The tension member is disposed inside the internal volume so as to maintain an average distance between the first inner surface and the second inner surface, and is in contact with at least two opposing portions of the cell encapsulation pouch. Further, the tension member is a frame including opposing end portions that are non-linear and opposing side portions that are linear so as to provide uniform tension over the entire length of the cell encapsulation pouch. The reservoir space is for receiving cells within the internal volume between the first inner surface and the second inner surface, and is in fluid communication with the tension member. Cell encapsulation device. [Aspect 31] A cell encapsulation device comprising a cell encapsulation pouch, at least one tension member, and a reservoir space, The cell encapsulation pouch is configured to define an internal volume between the first layer and the second layer by sealing a part of the periphery of the first layer to a part of the periphery of the second layer. Further, the internal volume includes a first inner surface and a second inner surface spaced apart from and facing the first inner surface. The at least one tension member is disposed inside the internal volume so as to maintain an average distance between the first inner surface and the second inner surface, and is in contact with at least two opposing portions of the cell encapsulation pouch, and The reservoir space is for receiving cells within the internal volume between the first inner surface and the second inner surface, and further To isolate the tension member from the reservoir space, the first layer is sealed to the second layer between the tension member and the reservoir space. Cell encapsulation device. [Aspect 32] The cell encapsulation device according to aspect 31, wherein the thickness of the seal defines an average thickness between the first inner surface and the second inner surface. [Aspect 33] Furthermore, the cell encapsulation device according to aspect 31, further comprising a plurality of structural spacers inside the internal volume toward the inside from the seal, and the structural spacers define the average thickness between the first inner surface and the second inner surface. [Aspect 34] A cell encapsulation device comprising a cell encapsulation pouch, at least one tension member, a cell pushing core, and a reservoir space, The cell encapsulation pouch is configured to define an internal volume between the first layer and the second layer by sealing a part of the periphery of the first layer to a part of the periphery of the second layer. Further, the internal volume includes a first inner surface and a second inner surface spaced apart from and facing the first inner surface. The at least one tension member is disposed inside the internal volume so as to maintain an average distance between the first inner surface and the second inner surface, and is in contact with at least two opposing portions of the cell encapsulation pouch. The cell pushing core is disposed inside the internal volume, defines an average thickness between the first inner surface and the second inner surface, and The reservoir space is for receiving cells adjacent to at least a part of the cell pushing core within the internal volume between the first inner surface and the second inner surface. Cell encapsulation device. [Aspect 35] The cell encapsulation device according to aspect 34, wherein the at least one tension member includes two tension members embedded in opposing side portions of the cell pushing core.

Claims

1. A method of manufacturing a storage device comprising: a plurality of interconnected storage tubes, each storage tube including a first end, a second end opposite the first end, and an internal reservoir space; a tensioning member extending circumferentially around the plurality of containment tubes, the tensioning members maintain an average thickness of each of the storage tubes; the tensioning members include opposed non-linear ends exterior to the cell encapsulation device and opposed linear sides interior to the cell encapsulation device. Cell encapsulation device.

2. 10. The cell encapsulation device of claim 1, wherein the storage tubes are positioned substantially parallel to one another with first ends aligned and with the second ends aligned.

3. 10. The cell encapsulation device of claim 1, wherein the containment tubes are interconnected by welding, quilting, adhesives, or structural supports.

4. 2. The cell encapsulation device of claim 1, wherein the tensioning member comprises at least two arcuate portions, the arcuate portions comprising alternating recesses positioned at one or both of the first end and the second end.

5. 10. The cell encapsulation device of claim 1, wherein at least a portion of the tensioning members are attached to one or more containment tubes by an adhesive.

6. 2. The cell encapsulation device of claim 1, wherein at least a portion of the tensioning member is disposed between first and second layers of the opposing non-linear ends.

7. A cell encapsulation device as described in claim 1, wherein the tensioning member is isolated from the internal reservoir space.

8. The cell encapsulation device of claim 1, wherein deformation of the tensioning member applies tension to the opposing non-linear ends and stretches the storage tubes, such that the thickness of each storage tube is controlled.

9. 1. A method for encapsulating cells, comprising:

2. A cell encapsulation device as claimed in claim 1, wherein the tensioning member is in a first configuration providing tension across the cell encapsulation pouch; deforming the tensioning members from the first deformation configuration to a second deformation configuration that is more deformed than the first deformation configuration, thereby reducing tension on the cell encapsulation pouch; Inserting cells into the reservoir space, and Releasing the tensioning members to the first deformation configuration.

16. A method for encapsulating cells, comprising:

Images