Cell encapsulation device

Abstract

To provide therapeutic devices.SOLUTION: A therapeutic device includes a tubular body including a lumen extending therethrough, where a wall of the tubular body includes a first composite layer, a second composite layer, and a reservoir between the first and second composite layers, the reservoir being configured to receive and contain a biological moiety. In another embodiment, a therapeutic device includes a toroidal therapeutic device having a first opening therein and a hollow interior, where the toroidal therapeutic device has a wall including a first permeable composite layer, a second permeable composite layer, and a reservoir between the first and second composite layers, the reservoir being configured to receive and contain a biological moiety.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention generally relates to the field of medical devices, and more particularly to therapeutic devices for encapsulating cells for implantation treatment of patients.

Background Art

[0002] Biological therapies are increasingly viable methods for treating peripheral arterial disease, aneurysms, heart disease, Alzheimer's and Parkinson's diseases, autism, blindness, diabetes, and other medical conditions. For common 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 into the patient's tissue bed. Conventionally, the bioactive moiety is first placed in a device and then the device is inserted into the patient. Alternatively, the device can be first inserted into the patient and the bioactive moiety added later.

[0003] Often, the device has a core (such as silicone), such that angiogenesis can only occur from the outer periphery of the device. The distance between the bioactive moiety introduced into these devices and the oxygen supply and nutrient source presents a problem for cell encapsulation. This is because cells begin to die without an adequate supply of oxygen and nutrients within a relatively short period of time. Accordingly, there is a need for a device that encapsulates cells and / or other biological moieties while ensuring cell survival and growth.

Summary of the Invention

[0004] This summary is a high-level overview of various aspects of the invention and introduces some of the concepts that are further described in detail in the following detailed description section. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used alone to determine the scope of the claimed subject matter. The subject matter should be understood by reference to the entire specification, part or all of the drawings, and the appropriate portions of each claim.

[0005] Embodiments of the present disclosure relate to a therapeutic device including a tubular member (e.g., a tubular body) and a lumen extending therethrough. The wall of the therapeutic device includes a first permeable composite layer, a second permeable composite layer, and a reservoir between the first composite layer and the second composite layer. The reservoir is configured to receive and contain biological moieties.

[0006] In some embodiments, the first composite layer includes a first cell-permeable layer and a first cell-impermeable layer, and the second composite layer includes a second cell-permeable layer and a second cell-impermeable layer.

[0007] In some embodiments, the therapeutic device has a first end and a second end. Each of the first end and the second end is open to the lumen, such that angiogenesis occurs from the first cell-permeable layer of the first composite layer and the second cell-permeable layer of the second composite layer.

[0008] In some embodiments, the reservoir has a thickness of 50 microns to 200 microns.

[0009] In some embodiments, the biological moiety is a plurality of cells.

[0010] In some embodiments, the plurality of cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof.

[0011] In some embodiments, the device further includes a port in fluid communication with the reservoir.

[0012] Embodiments of the present disclosure also relate to an article comprising a plurality of treatment devices, each including a tubular member (e.g., a tubular body). The treatment devices are connected by a connecting member. Each treatment device includes a lumen extending therethrough. Each treatment device has a first end and a second end. Each of the first end and the second end is open to the lumen. Each treatment device has a wall including a first permeable composite layer, a second permeable composite layer, and a reservoir between the first and second composite layers. The reservoir is configured to receive and contain a biological portion.

[0013] In some embodiments, the treatment devices are interconnected by a connecting member at a first end or a second end of the treatment device.

[0014] In some embodiments, the treatment devices are movable independently of each other.

[0015] In some embodiments, the treatment devices are fluidly interconnected by a connecting member.

[0016] In some embodiments, the reservoir has a thickness of 50 microns to 200 microns.

[0017] Embodiments of the present disclosure also relate to a device comprising a toroidal treatment device having a first opening and a hollow interior therein. The toroidal treatment device has a wall including a first permeable composite layer, a second permeable composite layer, and a reservoir between the first and second composite layers. The reservoir is configured to receive and contain a biological portion.

[0018] In some embodiments, the toroidal treatment device has a second opening on the side opposite and substantially aligned with the first opening.

[0019] In some embodiments, the device further includes a second toroidal treatment device having a third opening disposed adjacent to the second opening.

[0020] In some embodiments, the first toroidal treatment device and the second toroidal treatment device are fluidly interconnected by the second opening and the third opening.

[0021] In some embodiments, the biological portion is a plurality of cells.

[0022] In some embodiments, the plurality of cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof.

[0023] In some embodiments, the first composite layer and the second composite layer each include a cell-permeable layer and a cell-impermeable layer.

[0024] In some embodiments, the device further includes a port in fluid communication with the reservoir. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings, which are included to provide a further understanding of the disclosure and 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.

[0026]

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Figure 12

[0038] Those skilled in the art will readily appreciate that various aspects of the present disclosure can be realized by any number of methods and apparatuses configured to perform the intended functions. The accompanying drawings referred to herein are not necessarily drawn to scale and may be exaggerated in order to illustrate various aspects of the present disclosure, and in that regard, the drawings should not be construed as limiting. The terms "treatment device" and "device" may be used interchangeably herein. The terms "permeable composite layer", "porous composite layer", and "composite layer" may be used interchangeably herein. Further, the terms "tubular member" and "tubular body" can be interchangeable within the present disclosure.

[0039] Described herein is a treatment device for encapsulating a biological moiety, where the treatment device containing the biological moiety is implanted into a patient, such as a tissue bed, to provide a biological treatment. Also described herein are methods for forming the treatment device and methods for introducing the biological moiety into the device. In some embodiments, the treatment device is in a tubular or substantially tubular shape, which allows for angiogenesis not only from the outside of the treatment device but also from within the lumen. In some embodiments, the treatment device includes a tubular member (e.g., a tubular body) formed from a composite layer, each composite layer having a cell-impermeable layer and a cell-permeable layer, which allows for angiogenesis and intracellular growth. In some embodiments, the composite layers are spaced apart from each other to define a reservoir space for holding the biological moiety.

[0040] In some embodiments, biological moieties suitable for encapsulation and implant procedures using the devices described herein include cells, viruses, viral vectors, gene therapy, bacteria, proteins, polysaccharides, antibodies, and other bioactive moieties. For simplicity, biological moieties are referred to herein as cells, but this description is not intended to limit biological moieties to cells or any particular type of cell, and the following description applies to biological moieties that are not cells. In some embodiments, various types of prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, and / or stem cells can be used with the cell encapsulation devices of the present invention. In some embodiments, the cells are microencapsulated within a biomaterial of natural or synthetic origin that includes a hydrogel material.

[0041] In some embodiments, the cells secrete therapeutically useful substances. In some embodiments, such substances include hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cell products that provide a therapeutic benefit to the device recipient. Examples of such therapeutic cell products include, but are not limited to, insulin, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, and factor VIII. Non-limiting examples of suitable growth factors include vascular endothelial growth factor, platelet-derived growth factor, platelet-activating factor, transforming growth factor, bone morphogenetic protein, activin, inhibin, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, glial cell line-derived neurotrophic factor, growth differentiation factor-9, epidermal growth factor, and combinations thereof. Throughout the present disclosure, it should be understood that the terms "cell" or "cells" can be replaced, respectively, with "biological moiety" or "biological moieties".

[0042] I. Therapeutic Device with Angiogenically Generated Lumens One embodiment of a therapeutic device for encapsulating cells is shown in FIGS. 1-5. According to one embodiment, the therapeutic device 100 includes a tubular body 102 (e.g., a tubular member) having an open first end 130 and an open second end 132. The body 102 is defined by a first permeable composite layer 104 and a second permeable composite layer 106 and is sealed along at least a portion of its perimeter 110. A reservoir 108 for receiving cells is formed between the first permeable composite layer and the second permeable composite layer 104, 106. At least one port 107 is in fluid communication with the reservoir 108 and provides a path for accessing the reservoir 108 to fill, flush, or drain the reservoir. The port 107 can be located anywhere on the body 102 as long as it provides a path from the outside of the therapeutic device 100 to the reservoir 108. A lumen 112 extends through the tubular body 102 and defines the inner diameter ID of the therapeutic device 100, while the outer surface of the first composite layer 104 defines the outer diameter OD of the therapeutic device 100, as shown in FIG. 1. The inner diameter can be in the range of about 100 microns to about 5 mm, about 150 microns to about 4.5 mm, about 200 microns to about 4 mm, or about 250 microns to about 3.5 mm. In some embodiments, the lumen 112 extends through the entire tubular body 102. In some embodiments, the lumen 112 is substantially centrally located within the tubular body 102. The first composite layer 104, the second composite layer 106, and the reservoir 108 therebetween define the wall of the tubular body 102. As described in more detail below, the lumen 112 of the therapeutic device 100 allows for the internal growth of vascular tissue from the inner diameter ID such that the distance between the cells contained in the reservoir and the vascular tissue (i.e., the nutrient source) is sufficient to maintain cell proliferation and growth.

[0043] As shown in FIG. 2, the first composite layer 104 includes a cell-permeable layer 116 and a cell-impermeable layer 118 disposed adjacent to the cell-permeable layer 116. The second composite layer 106 includes a cell-permeable layer 120 and a cell-impermeable layer 122. The cell-permeable layers 116, 120 of the first and second composite layers 104, 106, respectively, can be formed from the same or different materials.

[0044] In some embodiments, the cell-permeable layers 116, 120 have a pore size large enough to allow for the in-growth of capillary networks 137, as shown in FIG. 2. As used herein, a layer having an opening large enough to allow for in-growth of blood vessels may sometimes be referred to as an “in-cell growth” layer. In some embodiments, the pore size of the cell-permeable layers 116, 120, as measured by porometry, is greater than about 5.0 microns. In-growth of blood vessel tissue through both of the cell-permeable layers 116, 120 (e.g., through the cell-permeable layer 120 facing the lumen 112 and through the cell-permeable layer 116 facing the external environment surrounding the body 102) promotes the migration of nutrients and biomolecules from the patient through the cell-permeable layer 116, but stops at the cell-impermeable layer 118 and does not cross the cell-impermeable layer 118.

[0045] Various cell types can grow within the internal cell growth layers (i.e., cell-permeable layers 116, 120) of the treatment device 100 as described herein. The main cell types that grow within the porous material depend primarily on the implant treatment site, the composition and permeability of the material, and biological factors such as cytokines and / or cell adhesion molecules that may be incorporated into the material or introduced through the porous material. In some embodiments, vascular endothelium is the main cell type that grows within the porous material for use in cell encapsulation devices. As shown in FIGS. 3-4, angiogenesis of the cell-permeable layers 116, 120 by a well-established population of vascular endothelial cells in the form of capillary network 137 is promoted to occur as a result of angiogenesis within and across the thickness of the cell-permeable layers 116, 120 from the patient's tissue. FIG. 4 shows an enlarged view of angiogenesis of a portion of the treatment device of FIG. 3.

[0046] The cell-impermeable layers 118, 122 are impermeable to angiogenesis and internal cell growth and are thus cell retention layers. For example, in some embodiments, both cell-impermeable layers 118, 122 have a pore size small enough to prevent internal growth of blood vessels. However, the cell-impermeable layers 118, 122 have a pore size large enough to allow nutrients from the patient and products produced by cells to pass therethrough. In some embodiments, the pore size of the cell-impermeable layers 118, 122 is less than about 5 microns, less than about 1 micron, or less than about 0.5 microns as measured by porometry.

[0047] In some embodiments, the outer cell-permeable layers 116, 120 and / or the inner cell-impermeable layers 118, 122 can be made of, either alone or in combination, polyalkylene glycols such as alginate, cellulose acetate, polyethylene glycol and polypropylene glycol, polyvinyl polymers such as polyvinyl alcohol, chitosan, polyacrylates such as polyhydroxyethyl methacrylate, agarose, hydrolyzed polyacrylonitrile, polyacrylonitrile copolymer, polyvinyl acrylate such as polyethylene-co-acrylic acid, porous polytetrafluoroethylene (PTFE), porous modified polytetrafluoroethylene polymer, porous tetrafluoroethylene (TFE) copolymer, porous polyalkylenes such as porous polypropylene and 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 vinylidene fluoride (eVDF), porous polylactic acid (ePLLA), and their copolymers and combinations, and can be formed from a collection of fibers or yarns or woven or non-woven fabrics of fiber matrices. In some embodiments, the cell-permeable layers 116, 120 are porous expanded polytetrafluoroethylene membranes (e.g., ePTFE membranes).

[0048] In embodiments where the treatment device 100 includes only a cell retention layer (e.g., a cell-impermeable layer) and does not include a cell ingrowth layer (e.g., a cell-permeable layer), the treatment device 100 can optionally be implanted or can be capable of being implanted in a patient and used with a housing made of an angiogenic material that allows for ingrowth of vascular tissue. In some embodiments, the housing can be implanted in the patient for a period of time sufficient to allow for angiogenesis before inserting the treatment device 100 into the housing. In other embodiments, the treatment device 100 and the housing can be inserted into the patient together.

[0049] As described above, the reservoir 108 is formed between the first composite layer 104 and the second composite layer 106 of the treatment device 100. As used herein, the term "reservoir" means defining the total area within the treatment device 100 between the cell-impermeable layer 118 and the cell-impermeable layer 122 and the area within the treatment device 100 where cells and other biological moieties are disposed (and where cells or other biological moieties are present). In some embodiments, the reservoir 108 can include a plurality of reservoir subsections (not shown) for disposing cells. In some embodiments, the reservoir 108 includes two or more reservoir subsections interconnected to allow for the flow of cells into and / or through the reservoir subsections. The reservoir 108 can take on a number of configurations, such as, but not limited to, geometric shapes (e.g., common forms such as rectangles, circles, squares, semi-circles, semi-elliptical shapes, tubes, etc.).

[0050] As used herein, the "width" of the reservoir 108 means the distance between the cell-impermeable layer 118 of the first composite layer 104 and the cell-impermeable layer 122 of the second composite layer 106 as shown in FIG. 2, across the length of the treatment device 100 where cells are present. In some embodiments, the reservoir 108 has a thickness of at least 50 microns. In some embodiments, the width is at least about 50 microns (e.g., 50 microns to 100 microns), at least 100 microns (e.g., 100 to 150 microns), or at least 150 microns (e.g., 150 microns to 200 microns). Note that all ranges described herein are exemplary in nature and include any and all values therebetween.

[0051] The reservoir 108 is configured to hold the cells 136 within the treatment device 100, as shown, for example, in FIG. 3. In some embodiments, the treatment device 100 containing the cells 136 therein is configured to be placed on a patient's tissue bed to enable the cells 136 to provide a biological treatment to the patient.

[0052] In some embodiments, the cells 136 are introduced into the reservoir 108 of the treatment device 100 via one or more ports 107 as shown in FIG. 1. The ports 107 can be located in various regions along the body 102 of the treatment device 100 as long as the ports 107 extend through the first composite layer 104 to the reservoir 108 to enable introduction of the cells 136 into the reservoir 108. In some embodiments, the cells 136 are introduced in the form of a suspension or slurry in a medium. The cells 136 can be individual cells, cell aggregates, or cell clusters. In some embodiments, the medium can be a cell culture or cell growth medium and can optionally contain desired nutrients and / or other biomolecules. In some embodiments, insertion of the cells 136 via the port 107 can be accomplished by a syringe.

[0053] The cells 136 can be introduced into the reservoir 108 before or after inserting the treatment device 100 into a patient. For example, the treatment device 100 can be inserted into a patient to enable angiogenesis such that vascular tissue grows into the cell permeable layers 118, 122 of the device 100. Next, the cells 136 can be added while the treatment device 100 is in vivo. In another embodiment, the cells 136 can be added to the reservoir 108 of the treatment device 100 before inserting the treatment device 100 into a patient's tissue bed.

[0054] As described above, the lumen 112 is surrounded by the cell-permeable layer 120, which promotes angiogenesis of the therapeutic device 100 from the lumen 112. Further, the cell-permeable layer 116 promotes angiogenesis of the therapeutic device 100 from outside the therapeutic device 100. Thus, angiogenesis occurs from both within the lumen and outside the therapeutic device 100, as shown in FIG. 2. Angiogenesis from both the lumen 112 of the therapeutic device 100 and outside the therapeutic device 100 can, in some embodiments, increase the volume of the cells contained in the reservoir 108 because the cells are obtaining nutrients from both sides of the therapeutic device 100. In some embodiments, the thickness of the reservoir 108 can expand by an amount from about 0.01 microns to about 400 microns. In other embodiments, the thickness of the reservoir 108 can expand from about 0.01 microns to about 200 microns. In other embodiments, the thickness of the reservoir can increase from about 0.01 microns to about 300 microns. In other embodiments, the thickness of the reservoir can increase from about 0.01 microns to about 350 microns.

[0055] In some embodiments, the treatment device 100 is fabricated as described below. The following description is merely exemplary, and thus, the method of forming the treatment device 100 is not limited to this description. In some embodiments, the second composite layer 106 is formed by first wrapping at least one layer (e.g., 1 layer, 2 layers, 3 layers, 4 layers, etc.) of a porous ePTFE membrane around a mandrel (e.g., a 4 mm stainless steel mandrel) to form the cell-permeable layer 120 of the second composite layer 106. The porous membrane can be of the type described in U.S. Patent No. 5,814,405 to Branca et al. The opposing edges of the porous ePTFE membrane are fixed to each other using a local heat source, such as a soldering iron, so that the cell-permeable layer 120 takes the form of a tube. Next, at least one layer (e.g., 1 layer, 2 layers, 3 layers, 4 layers, etc.) of a cell-retaining porous membrane is wrapped onto the mandrel over the cell-permeable layer 120 to form the cell-impermeable layer 122 of the second composite layer 106. The cell-retaining porous membrane can be of the type described in U.S. Patent No. 5,476,589 to Bacino. Subsequently, a local heat source is used to fix the opposing edges of the cell-retaining porous membrane to each other so that the cell-impermeable layer 122 takes the form of a tube.

[0056] Next, the mandrel is heat-treated (e.g., placed in a convection oven), and then removed from the oven and cooled to ambient temperature (e.g., about 20°C). This heat treatment causes the membranes forming the second composite layer (i.e., the membrane forming the cell-permeable layer 120 and the membrane forming the cell-impermeable layer 122) to adhere to each other. The close contact with the mandrel minimizes distortion of the microstructure of the membranes.

[0057] Following the formation of the second composite layer 106, a reservoir 108 is formed. In some embodiments, to form the reservoir 108, a spacer can be applied to the surface of the cell-impermeable layer 122 of the second composite layer 106. In such embodiments, the height of the spacer determines the depth of the reservoir 108. In some embodiments, the depth of the reservoir 108 is selected according to the type of cells to be contained therein.

[0058] Next, the first composite layer 104 is similarly formed by wrapping at least one layer (e.g., 1 layer, 2 layers, 3 layers) of a cell-retaining porous membrane around a larger mandrel (e.g., a 5 mm stainless steel mandrel) in a manner similar to the above process to form a cell-impermeable layer 118. Next, at least one layer (e.g., 1 layer, 2 layers, 3 layers, 4 layers, etc.) of the porous membrane is wrapped on the cell-impermeable layer 118 and on the same, larger mandrel to form the cell-permeable layer 116 of the first composite layer 104. The opposing edges of each of the cell-impermeable layer 118 and the cell-permeable layer 116 are fixed to each other, and the first composite layer 104 is heat-treated as described above.

[0059] Upon cooling, the first composite layer 104 is removed from the mandrel and placed on top of the second composite layer 106 still disposed on the mandrel, thereby forming the wall of the tubular body 102. At this point, the ports 107 can be positioned, if desired, such that they are in fluid communication with the reservoir 108. Next, a heat source is used to melt the ends of the first and second composite layers, bond and seal the ends of the first and second composite layers 104, 106 together. In some embodiments, the first composite layer 104 is also bonded to the spacer disposed on the second composite layer 106 by a heat source to form the tubular body of the treatment device. At this point, the treatment device 100 can be trimmed at each end.

[0060] In one embodiment, the treatment device 100 is pressure tested to verify a seal at the end of the treatment device 100 between the first composite layer and the second composite layer 104, 106 by applying pressure to port 107. Once the test is complete, the treatment device 100 is peeled from the mandrel. The resulting treatment device 100 has a lumen for tissue invasion and ingrowth, an inner and outer surface with open pores to permit rapid angiogenesis, and a cell reservoir with dense pores for retaining cells therein.

[0061] II. Articles Comprising a Plurality of Treatment Devices Having Angiogenically Developed Lumens Figures 5 - 8 show a treatment device 200 and an article 400 comprising a plurality of treatment devices 200. Referring to Figure 7, in some embodiments, the plurality of treatment devices 200 are interconnected to be substantially parallel to each other along the length of the article 300. Looking at Figure 5, in some embodiments, each treatment device 200 includes a first open end 230 and a second open end 232. In some embodiments, the treatment device 200 includes a connecting member 260 at the first end 230. A lumen 212 extends through the tubular body 205 (e.g., tubular member) of the treatment device 200 from the first end 230 to the second end 232 such that the tubular body 205 is open at both ends 230, 232.

[0062] In one embodiment shown in FIG. 5, the treatment device 200 includes a body 205, a first open end 230, and a second open end 232. A lumen 212 extends from the first open end 230 to the second open end 232. In some embodiments, the treatment device 200 includes a first composite layer 204 and a second composite layer 206, which are sealed along at least a portion of their perimeter 210. Referring now to FIG. 6, a reservoir 208 is formed between the first composite layer and the second composite layer 204, 206. The first composite layer and the second composite layer 204, 206, and the reservoir 208 therebetween define the wall of the treatment device 200. The cross-section of the treatment device 200 can be, for example, circular, oval, or elliptical. In some embodiments, the lumen 212 extends through the entire body 205 of the treatment device 200. In some embodiments, the inner diameter ID of the treatment device 200 is defined by the cross-sectional diameter of the lumen 212. In some embodiments, the outer surface of the first composite layer 204 defines the outer diameter OD of the treatment device 200 (see FIG. 5). As described above with respect to the treatment device 100, the lumen 212 of the treatment device 200 allows for the ingrowth of vascular tissue or capillary network 237 from within the lumen 212 into the cell permeable layer 220 of the second composite layer 206. Further, the cell permeable layer 216 of the first composite layer 204 promotes angiogenesis of the treatment device 200 from the outside of the treatment device 200. Since the capillary network 237 is formed in the cell impermeable layers 216, 220, the distance between the cells contained in the reservoir 208 and the nutrient source (i.e., the vascular tissue or capillary network) is minimized, allowing the cells in the reservoir 208 to grow at an increased rate.

[0063] As shown in FIG. 6, in some embodiments, the first composite layer 204 is a composite layer substantially similar to the first composite layer 104 and includes a cell permeable layer 216 and a cell impermeable layer 218 disposed adjacent to the cell permeable layer 216. Similarly, in some embodiments, the second composite layer 206 is a composite layer substantially similar to the second composite layer 106 and includes a cell permeable layer 220 and a cell impermeable layer 222.

[0064] In some embodiments, the cell-permeable layers 216, 220 are substantially similar to the cell-permeable layers 116, 120 in that they are cell internal growth layers (e.g., cell-permeable layers) and have the characteristics described above with respect to at least the cell-permeable layers 116, 120. The cell-impermeable layers 218, 222 are substantially similar to the cell-impermeable layers 118, 122 in that they are cell internal growth layers (e.g., cell-impermeable layers) and have the characteristics described above with respect to at least the cell-impermeable layers 118, 122.

[0065] In some embodiments, the cell-permeable layers 216, 220 and the cell-impermeable layers 218, 222 can include any of the materials listed above with respect to the cell-permeable layers 116, 120 and the cell-impermeable layers 118, 122. The reservoir 208 can be formed in substantially the same manner and can have the characteristics described above with respect to at least the reservoir 108. Specifically, the reservoir 208 is formed between the cell-impermeable layers 218, 222 of the treatment device 200. The reservoir 208 is configured to hold the cells 236 within the treatment device 200 of the article 400 disposed in the patient's tissue bed to enable the cells to provide a biological treatment to the patient. In some embodiments, the cells 236 are introduced into the reservoir 208 of the treatment device 200 via the first access port and the second access ports 215, 225 shown in FIG. 7.

[0066] In some embodiments, the treatment device 202 is expandable in that it can be easily configured so that the treatment device 200 can be used to accommodate these cells while ensuring the survival and function of cells of various shapes and sizes (e.g., across the entire range of the diameter, length, cross-sectional shape, quantity, etc. of the treatment device 200 within the article 400). In some embodiments, the treatment device 200 can vary its diameter and length to achieve the desired amount of surface area necessary for optimal performance. The tubular configuration uses the smallest possible area within the host's anatomical structure but is designed to provide an appropriate surface area for the performance of the treatment device 200 within the article 400.

[0067] Further, the lumen 212 extending through the treatment device 200 reduces the distance between the cells in the reservoir 208 and their nutrient source, i.e., the vascular tissue. Similar to the lumen 112 of the treatment device 100, the lumen 212 is circumferentially surrounded by the cell-permeable layer 220, which promotes angiogenesis of the treatment device 200 from the lumen 212. Further, the cell-permeable layer 216 promotes angiogenesis of the treatment device 200 from the outside of the treatment device 200. Thus, angiogenesis occurs from both the inside of the lumen 212 and the outside of the treatment device 200, as shown in FIG. 6. This angiogenesis, or the formation of the capillary network 237, from both the lumen 212 of the treatment device 200 and the outside of the treatment device 200 allows the cells to obtain nutrients from both the inside and outside of the treatment device 200, and in some embodiments, can more than double the volume of the cells contained within the reservoir 208.

[0068] In the embodiments disclosed herein, the treatment device 200 can have an inner diameter in the range of about 100 microns to about 5 mm, about 150 microns to about 4.5 mm, about 200 microns to about 4 mm, or about 250 microns to about 3.5 mm. In some embodiments where multiple treatment devices 200 are used, the treatment devices 200 are separated from each other by a distance of about 0.1 micron to about 3 mm, about 5 microns to about 2.5 mm, about 10 microns to about 2 mm, about 25 microns to about 1.5 mm, or about 50 microns to about 1 mm.

[0069] In some embodiments, such as the embodiment shown in FIG. 7, the treatment devices 200 are movable independently of each other and thus can flex the article 400 and / or conform to tissue and / or tissue movement. In some embodiments, the reservoirs 208 of the treatment devices 200 are fluidly connected, such as by connection members 260 (shown in FIGS. 7 and 8), and thus cells inserted into one treatment device 200 can flow into a separate treatment device 200. The article 400 includes, in this embodiment, at least one filling port 275 that is in fluid communication with the treatment device 200 at a first end of the treatment device 200. The filling port 275 allows for the insertion of cells into the reservoir 208 of the treatment device 200. The article 400 can also include at least one flush port 255 that is in fluid communication with the treatment device 200 at a second end of a different treatment device 200, as shown in FIG. 8. The filling port 275 and the flush port 255 can be located anywhere along the length of the treatment device 200 as long as they are in fluid communication with the reservoir 208. In some embodiments, the treatment device includes a single port (not shown) that can be used for both filling and flushing. Once filled, the treatment device 200 is sealed, as discussed below.

[0070] The filling port 275 and the flash port 255 can be repeatedly opened and closed using a seal 250. The seal 250 includes, but is not limited to, a cap, plug, clamp, compression ring, or valve. The seal 250 can be attached to the filling port 275 or the flash port 255 using friction, a clamp, or a screw including threads and grooves. Depending on the intended use of the article 400, the filling port 275 and / or the flash port 255 are sealed to create an airtight or other liquidtight seal. The article 400 is intended for a permanent or long-term (e.g., at least three weeks) implant procedure in a patient.

[0071] III. Treatment Device with a "C" - shaped Configuration Figures 11 - 12 show an embodiment of a treatment device 300 including a body 302. The treatment device 300 is substantially similar to the treatment device 100, except that, instead of having a tubular configuration, as can be seen in Figures 9 - 10, the treatment device 300 is substantially C - shaped. Specifically, the body 302 can be substantially toroidal or ring - shaped around a central space 331, and the opening 333 extends through a side surface of the body 302. The body 302 is defined by a first composite layer 304 and a second composite layer 306 and is sealed along at least a portion of their perimeter 310. A reservoir 308 is formed between the first composite layer and the second composite layer 304, 306. The first composite layer and the second composite layer 304, 306 and the reservoir 308 form the wall of the body 302. A port 307 is in fluid communication with the reservoir 308 and provides a path for accessing the reservoir 308 to fill, flush, or drain the reservoir 308. The port 307 can be located anywhere on the body 302 as long as it provides a path from outside the body 302 of the treatment device 300 to the reservoir 308. The opening 333 enables angiogenesis from outside the body 302 of the treatment device 300 and into the central space 331 (e.g., from both sides of the reservoir 308) and reduces the distance between the cells contained within the reservoir 308 of the treatment device 300 and the nutrients provided by the vascular tissue, as described in more detail below.

[0072] As described above with respect to the first composite layer and the second composite layers 104, 106 and 204, 206 respectively, both the first composite layer 304 and the second composite layer 306 are porous enough to allow the growth of vascular tissue from the patient into the pores of the cell-permeable layer.

[0073] As shown in FIG. 12, in some embodiments, a first composite layer 304 similar to the first composite layer 104 of the treatment device 100 includes a cell-permeable layer 316 and a cell-impermeable layer 318 disposed adjacent to the cell-permeable layer 316. A second composite layer 306 similar to the second composite layer 106 of the first treatment device 100 includes a cell-permeable layer 320 and a cell-impermeable layer 322 disposed adjacent to the cell-permeable layer.

[0074] The cell-permeable layers 316, 320 are substantially similar to the cell-permeable layers 116, 120 in that they are cell ingrowth layers and have at least the characteristics described above with respect to the cell-permeable layers 116, 120. The cell-impermeable layers 318, 322 are substantially similar to the cell-impermeable layers 118, 122 in that they are cell ingrowth layers and have at least the characteristics described above with respect to the cell-impermeable layers 118, 122.

[0075] In some embodiments, the cell-impermeable layers 318, 322 and the cell-permeable layers 316, 320 comprise the same material. For example, in some embodiments, the cell-impermeable layers and the cell-permeable layers 318, 322 and 316, 320 each comprise any of the materials listed above respectively for the cell-impermeable layers and the cell-permeable layers 118, 122 and 116, 120.

[0076] The reservoir 308 is formed between the first composite layer 304 and the second composite layer 306 of the body 302 of the treatment device 300 in the same manner as the reservoir 108. The reservoir 308 is configured to hold cells 336 within the treatment device 300, and the treatment device 300 is placed on a patient's tissue bed as shown in FIG. 12, enabling the cells 336 to provide biological therapy to the patient. In some embodiments, the cells 336 are introduced into the reservoir 308 of the treatment device 300 via one or more ports 307. In some embodiments, the port 307 extends through the first composite layer 304 of the body 302 of the treatment device 300 so that the cells 336 can be introduced into the reservoir 308.

[0077] As described above, the treatment device 300 is substantially toroidal in some embodiments. The body 302 includes a central space 331 and an opening 333, enabling angiogenesis to occur along the first composite layer 304 on the outer surface of the treatment device 300 and along the second composite layer 306 within the central space 331. Thus, the toroidal design of the treatment device 300 reduces the distance between the cells 336 in the reservoir 308 and their nutrient source, i.e., the vascular tissue or capillary network 337. Further, angiogenesis from both the second composite layer 306 within the central space 331 of the treatment device 300 and the first composite layer 304 on the outer surface of the treatment device 300 allows the cells 336 to obtain nutrients from both sides (i.e., inside and outside) of the treatment device 300, enabling the volume of the cells 336 contained in the reservoir 308 to be increased by more than twofold in some embodiments.

[0078] In some embodiments, the treatment device 300 is stackable, as shown in FIG. 11. As shown, each of the treatment devices 300 includes a first portion 380 of the outer surface 378 and an opposing second portion 382 of the outer surface 378. In these embodiments, at least two treatment devices 300 are arranged in a parallel configuration such that the first portion 380 of the outer surface 378 of the first treatment device 300 is adjacent to the second opposing portion 382 of the outer surface 378 of the second treatment device 300 with the first and second ends 330, 332 of the treatment devices 300 being substantially aligned. In some embodiments, the first portion 380 of the outer surface includes an opening 333, while the second portion 382 does not include an opening. In other embodiments, each of the first portion 380 includes an opening 333 and the second portion includes an opening 337. In other embodiments, the openings 333, 337 are substantially aligned with each other such that angiogenesis extends from outside the treatment device 300 through the central space 331 of the treatment device 300 to form a connection of the angiogenesis-treated treatment devices 300. In another embodiment, one treatment device 300 can include an opening 333, while the second treatment device 300 can have two openings 333, 337.

[0079] IV. Biodegradable Materials In some embodiments, one or both of the composite layers of the treatment devices 100, 200, 300 are or include a bioabsorbable material. The bioabsorbable material can be formed as a solid (molded article, extruded product or crystal), a self - aggregating web, a raised webbing or a screen. In some embodiments, one or more layers of the bioabsorbable material are attached to a non - bioabsorbable material having macroscopic porosity to enable cell permeation (e.g., a cell - permeable layer) to form a composite material. In other embodiments, a non - bioabsorbable material having microscopic porosity to reduce or prevent cell permeability is releasably attached to a porous self - aggregating web to enable non - traumatic removal of the treatment devices 100, 200, 300 from the patient within a few days after the implant procedure. Resorption by the patient can promote favorable type 1 collagen deposition, angiogenesis and reduction of infection. In some embodiments, a screen is incorporated into the treatment devices 100, 200, 300 to prevent "pillowing" of the device when the captured cells begin to proliferate. In other examples, the bioabsorbable material can be incorporated as a powder into a cell encapsulation device. Non - limiting examples of suitable bioabsorbable materials include, but are not limited to, polyglycolide:trimethylene carbonate (PGA:TMC), polylactic acid, polyglycolic acid, poly(glycolide), poly(lactide - co - caprolactone), poly(caprolactone), poly(carbonate), poly(dioxanone), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate - co - valerate) and their copolymers and blends.

[0080] In some embodiments, incorporating a bioabsorbable component into treatment devices 100, 200, 300 helps facilitate the implant procedure. For example, the bioabsorbable material can be temperature sensitive in some embodiments. In particular, the bioabsorbable material is much harder at lower temperatures and softer at higher temperatures (e.g., the body temperature of the patient after the implant procedure) so that the bioabsorbable material becomes more compliant and adaptable after the implant procedure. As a result, due to the longitudinal strength of the bioabsorbable material formed, the clinician can place the treatment devices 100, 200, 300 in the patient with less effort and less trauma to the host, and at the time of the implant procedure, the bioabsorbable material becomes more compliant and adaptable.

[0081] V. Selective Permeability of the Porous Layer In some embodiments, the porous material is porous only through a portion of its thickness such that the molecular weight cut-off or sieving characteristics of the porous membrane begin at the surface. As a result, certain solutes and / or cells enter the porous spaces of the material and do not pass from one side to the other. For example, the selective permeability of the porous material allows for the bidirectional flux of solutes across the thickness of the porous material while precluding the migration or growth of cells within the spaces of the porous material. Next, vascular endothelial cells can bind and form capillaries thereon. Such capillary formation or angiogenesis of the porous material can enhance the flow of fluids and solutes between the patient's tissue and the contents of the treatment devices 100, 200, 300.

[0082] In some embodiments, the permeability of the porous material can be continuously varied across the thickness of the porous material of the treatment devices 100, 200, 300 described herein. For example, the selective permeability of the porous material can vary continuously across the thickness of the material. In some embodiments, the permeability of the porous material varies from one cross-sectional region of the material to another cross-sectional region to form a layered structure.

[0083] In some embodiments, the permeability of the porous material varies throughout its thickness by an additional layer of the porous material. For example, in some of the therapeutic devices described herein, the selective permeability of the porous material varies across the thickness of the porous material with one or more additional layers of the porous material. The additional layer of the porous material can have the same composition and permeability as the first layer of the porous material, or one or more of the additional layers can have a different composition and / or permeability.

[0084] In another embodiment, the selective permeability of the porous material is altered by impregnating the void spaces of the porous material with a hydrogel material. The hydrogel material can be impregnated into all or substantially all of the void spaces (e.g., pores of the porous membrane) of the porous material or only a portion of the void spaces. For example, by impregnating the porous material with a hydrogel material in a continuous band within the porous material adjacent to and / or along the inner surface of the porous material, the selective permeability of the porous material is varied from the outer cross-sectional region of the porous material to the inner cross-sectional region of the porous material.

[0085] The composition of the hydrogel material impregnated in the porous materials of the first composite layer and the second composite layer depends largely on the particular porous material used in the construction of the device, the degree of permeability required for a given application, and the biocompatibility of the hydrogel material. Non-limiting examples of useful hydrogel materials for use in therapeutic devices 100, 200, 300 include, but are not limited to, hydrolyzed polyacrylonitrile, alginate, agarose, carrageenan, collagen, gelatin, polyvinyl alcohol, poly(2-hydroxyethyl methacrylate), poly(N-vinyl-2-pyrrolidone), polyethylene glycol, polyethyleneimine, fibrin-thrombin gel or gellan gum and their copolymers, either alone or in combination. In certain embodiments, the total thickness of the porous material (e.g., PTFE) / hydrogel composite can range from 30 μm to 1000 μm.

[0086] In yet other embodiments, the permeability of the porous material can be varied across the thickness of the porous material using additional layers of the porous material and further layers of the hydrogel material. One advantage of these embodiments is that this configuration provides a strong cellular and humoral immune isolation barrier.

[0087] In some embodiments, the bioabsorbable material can have the ability to regenerate reactive oxygen species (ROS) at different levels within the patient's body. ROS have been shown to facilitate various cellular responses within the patient's body, including, but not limited to, inhibition or promotion of cell proliferation, differentiation, migration, apoptosis, and angiogenesis.

[0088] In some embodiments, as described herein, the materials used to construct the treatment devices 100, 200, 300 are essentially radiopaque. Materials that are not essentially 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 skill in the art. The radiopacity of the materials used to construct the treatment devices 100, 200, 300 described herein is used primarily to facilitate the surgical placement of the treatment devices 100, 200, 300 or to locate the treatment devices 100, 200, 300 within the patient after the implant procedure.

Examples

[0089] Example A treatment device with an inner diameter of 4 mm and a length of 50 mm is described in this specification. The second composite layer is initially formed by winding three layers of an open porous ePTFE membrane around a 4 mm stainless steel mandrel to form the cell-permeable layer of the second composite layer. The open porous membrane can be of the type described in U.S. Patent No. 5,814,405 to Branca et al. For example, a local heat source such as a Weller soldering iron is used to adhere the opposing edges of the open porous membrane to each other so that the cell-permeable layer takes the form of a tube. In one embodiment, the membrane has an open pore structure with an intermodal distance of about 10 - 30 microns. Next, two layers of the cell-retaining porous membrane are wound onto the steel mandrel over the cell-permeable layer to form the inner porous layer of the second composite layer. The cell-retaining porous membrane can be of the type described in U.S. Patent No. 5,476,589 to Bacino. Subsequently, a local heat source is used to adhere the opposing edges of the cell-retaining porous membrane to each other so that the inner porous layer takes the form of a tube. In this embodiment, the cell-retaining membrane has a pore size in the range of 0.05 - 0.4 micrometers.

[0090] Next, the mandrel is placed in a convection air oven set at 365 °C for about 15 minutes and then removed from the oven and cooled to ambient temperature (e.g., 20 °C). This heat treatment causes the membranes forming the second composite layer to adhere to each other. Due to the close contact with the mandrel, distortion of the microstructure is minimized. Next, a spacer is applied to the surface of the second composite layer to form a reservoir. The spacer is, in some embodiments, an adhesive dot of fluorinated ethylene propylene (FEP) placed on the surface of the cell-retaining layer. The height of the spacer determines the depth of the reservoir, which varies depending on the type of cells to be accommodated. The height of the spacer is about 500 microns. A continuous band of FEP is also placed at each end of the inner porous layer to later adhere the first and second composite layers. In some embodiments, the bands of FEP are placed about 50 mm apart.

[0091] Next, the first composite layer is similarly formed by winding two layers of the cell-retaining porous membrane around a 5 mm stainless steel mandrel to form the inner porous layer as described above. Next, three layers of the open porous membrane are wound onto the same 5 mm mandrel on top of the inner porous layer to form the cell-permeable layer of the first composite layer. The opposing edges of each of the inner porous layer and the cell-permeable layer are adhered to each other, and the first composite layer is heat-treated as described above.

[0092] After cooling to room temperature, the first composite layer is removed from the 5 mm mandrel and pulled over the second composite layer still disposed on the 4 mm mandrel to form the wall of the tubular body. At this point, ports are placed to be in fluid communication with the reservoir space. Next, a local heat source is used to melt the FEP band at the end of the second composite layer. The melted FEP flows into the pores of the first and second composite layers, adhering and sealing the ends of the first and second composite layers to each other. The first composite layer is also adhered by a local heat source to the FEP spacer disposed on the second composite layer to form the tubular body of the treatment device. At this point, the treatment device can be trimmed at both ends.

[0093] The treatment device is pressure tested to confirm that the seal is viable by applying pressure to the ports. When the test is complete, the treatment device is peeled from the mandrel. The resulting treatment device has a 4 mm lumen for tissue invasion and ingrowth, inner and outer surfaces with open pores to allow for rapid angiogenesis, and a cell reservoir with dense pores for retaining cells therein. The following are aspects of the present invention. (Aspect 1) A substantially tubular member including a lumen extending therethrough, A therapeutic device comprising: The wall of the substantially tubular member is A first composite layer, A second composite layer, and A reservoir between the first composite layer and the second composite layer, The reservoir is configured to receive and contain a biological moiety. A therapeutic device. (Aspect 2) The therapeutic device according to aspect 1, wherein the first composite layer includes a first cell-permeable layer and a first cell-impermeable layer, and the second composite layer includes a second cell-permeable layer and a second cell-impermeable layer. (Aspect 3) The substantially tubular member has a first end and a second end, Each of the first end and the second end is open to the lumen, such that angiogenesis occurs from the first cell-permeable layer of the first composite layer and the second cell-permeable layer of the second composite layer. The therapeutic device according to aspect 1 or 2. (Aspect 4) The therapeutic device according to any one of aspects 1 to 3, wherein the reservoir has a thickness of 50 microns to 200 microns. (Aspect 5) The therapeutic device according to any one of aspects 1 to 4, wherein the biological moiety is a plurality of cells. (Aspect 6) The therapeutic device according to aspect 5, wherein the plurality of cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof. (Aspect 7) The therapeutic device according to any one of aspects 1 to 6, further comprising a port in fluid communication with the reservoir. (Aspect 8) A plurality of substantially tubular members connected by a connecting member, A therapeutic device comprising: Each tubular member includes a lumen extending therethrough, Each of the plurality of substantially tubular members has a first end and a second end, Each of the first end and the second end is open to the lumen, and Each of the plurality of substantially tubular members A first composite layer, A second composite layer, and A reservoir between the first composite layer and the second composite layer, Each having a wall, The reservoir is configured to receive and contain a biological moiety. A therapeutic device. (Aspect 9) The treatment device according to aspect 8, wherein the plurality of substantially tubular members are interconnected by a connecting member at a first end or a second end of the plurality of substantially tubular members. (Aspect 10) The treatment device according to aspect 8 or 9, wherein the plurality of substantially tubular members are movable independently of each other. (Aspect 11) The treatment device according to any one of aspects 8 to 10, wherein the plurality of substantially tubular members are fluidly interconnected by a connecting member along the respective lengths of the plurality of substantially tubular members. (Aspect 12) The treatment device according to any one of aspects 8 to 11, wherein the reservoir has a thickness of 50 microns to 200 microns. (Aspect 13) A toroidal member having a first opening and a hollow interior therein, A treatment device comprising: The toroidal member, A first permeable composite layer, A second permeable composite layer, and A reservoir between the first composite layer and the second composite layer, Having a wall including, The reservoir is configured to receive and contain a biological portion. (Aspect 14) The treatment device according to aspect 13, wherein the toroidal treatment device has a second opening on the side opposite to and substantially aligned with the first opening. (Aspect 15) The treatment device according to aspect 13 or 14, further comprising a second toroidal member having a third opening disposed adjacent to the second opening therein. (Aspect 16) The treatment device according to aspect 15, wherein the first toroidal member and the second toroidal member are fluidly interconnected by the second opening and the third opening. (Aspect 17) The treatment device according to any one of aspects 13 to 16, wherein the biological portion is a plurality of cells. (Aspect 18) The treatment device according to aspect 17, wherein the plurality of cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof. (Aspect 19) The treatment device according to any one of aspects 13 to 18, wherein the first composite layer and the second composite layer each include a cell-permeable layer and a cell-impermeable layer. (Aspect 20) The treatment device according to any one of aspects 13 to 19, comprising a port in fluid communication with the reservoir.

Claims

A therapeutic device comprising a first body having a first opening extending through a side surface of the first body that is substantially C-shaped around a first central space, wherein the first body comprises a first permeable composite layer, a second permeable composite layer, and a reservoir disposed between the first permeable composite layer and the second permeable composite layer, wherein the reservoir is configured to receive and contain a biological moiety therein, and the first opening enables angiogenesis from outside the first body and from inside the first central space. A therapeutic device. Claim 2 The therapeutic device according to claim 1, wherein the first body has a second opening on a side opposite to and substantially aligned with the first opening. Claim 3 The therapeutic device according to claim 2, further comprising a second body having a third opening disposed adjacent to the second opening and having a substantially C-shape. Claim 4 The therapeutic device according to claim 3, wherein the first body and the second body are fluidly interconnected by the second opening and the third opening. Claim 5 The therapeutic device according to any one of claims 1 to 4, wherein the biological moiety is a plurality of cells. Claim 6 The therapeutic device according to claim 5, wherein the plurality of cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof. Claim 7 The therapeutic device according to any one of claims 1 to 6, wherein the first composite layer and the second composite layer each comprise a cell-permeable layer and a cell-impermeable layer. Claim 8 The therapeutic device according to any one of claims 1 to 7, comprising a port in fluid communication with the reservoir. Claim 9 The therapeutic device according to claim 1, wherein the first body has a second opening opposite to the first opening. Claim 10 A therapeutic device comprising a second body having a substantially C-shape and having a third opening and a second central space therein, wherein the third opening is aligned with a second opening of the first body such that the second opening and the third opening are aligned and fluidly connected, and the first body and the second body are adjacent to each other in a parallel configuration.

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