Geometrically deformable implantable containment devices for retention of biological moieties

Abstract

To provide good encapsulation devices, etc.SOLUTION: There are provided herein encapsulation devices that include an inner layer, an outer layer, a cell containment layer positioned between the inner and outer layer, and structural elements disposed within the cell containment layer to separate the inner and outer layers by a separation distance. The structural elements define reservoir spaces for the retention of a biological moiety (such as cells) therein. The structural elements maintain a separation distance both under external compressive forces and under internal expansive forces. In some embodiments, a reinforcing layer is positioned between the inner layer and the cell containment layer. In addition, the encapsulation device may include at least one configuration element. There are also disclosed methods of placing encapsulation devices in a body conduit intra-luminally, extra-luminally, and via an open surgical procedure.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Field The present invention relates to the field of implantable biological devices and biological therapies, and more particularly to geometrically deformable encapsulation devices for containing biological moieties, including methods for placing the encapsulation devices in and / or around a body conduit. [Background technology]

[0002] background Biological therapy is becoming an increasingly viable method for treating peripheral artery disease, aneurysms, heart disease, Alzheimer's and Parkinson's disease, autism, blindness, diabetes, and other medical conditions.

[0003] Generally, with respect to biological therapy, cells, viruses, viral vectors, bacteria, proteins, antibodies, genes, and other biologically active moieties can be introduced into a patient by surgical or interventional methods that place the biologically active moiety into the patient's tissue bed. Often, the biologically active moiety is first placed into a device that is then inserted into the patient. Alternatively, the device can be inserted into the patient first, with the biologically active moiety added later.

[0004] Implanting an external device into the body can provoke an immune response that makes it difficult, if not impossible, for blood vessels to form in the immediate vicinity of the contained biological moiety, thereby limiting access to oxygen and nutrients necessary to maintain the survival and health of the encapsulated cells. When the contained biological moiety is placed within or around a blood vessel, an immune response can occur, potentially causing the cells to be disrupted and / or killed during implantation into the vessel. Thus, there is a need in the art for containment devices that can be deployed within or around a lumen (e.g., blood vessel) to provide more direct access to a source of oxygen and nutrients for the contained biological moiety (e.g., cells), thereby enabling the biological moiety (e.g., cells) to survive and secrete therapeutically useful substances. Summary of the Invention

[0005] Abstract According to one embodiment ("Embodiment 1"), an implantable encapsulation device includes an inner layer, an outer layer, and a containment layer including an inner layer, an outer layer, and a structural element disposed between the inner layer and the outer layer to maintain a separation distance between the inner layer and the outer layer. The structural element defines a plurality of reservoir spaces for disposing at least one biological moiety therein. The structural element also maintains the separation distance under both an external compressive force and an internal expansion force. At least one of the inner layer and the outer layer is a composite layer including a cell-releasing layer and a cell-retaining layer. Furthermore, the encapsulation device has a substantially tubular configuration and is configurable from a first tubular configuration having a first diameter to a second tubular configuration having a second diameter.

[0006] According to another embodiment ("Embodiment 2"), in addition to embodiment 1, a filling tube is disposed in at least one of the reservoir spaces between the structural elements for disposing a biological moiety in the reservoir space.

[0007] According to another embodiment ("embodiment 3"), in addition to embodiment 1 or embodiment 2, the device includes a reinforcing layer disposed between the inner layer and the containment layer.

[0008] According to another embodiment ("embodiment 4"), in addition to embodiment 1 or embodiment 2, the device includes a reinforcing layer disposed between the outer layer and the containment layer.

[0009] According to another embodiment ("embodiment 5"), in addition to embodiment 1 or embodiment 2, a reinforcing layer is disposed outside the outer layer.

[0010] According to another embodiment ("embodiment 6"), in addition to any one of embodiments 3 to 5, the reinforcing layer includes a shape memory material.

[0011] According to another embodiment ("Embodiment 7"), in addition to any one of embodiments 1 to 6, the inner layer is a composite layer comprising a cell-releasing layer and a first cell-retaining layer, and the outer layer is a second cell-retaining layer.

[0012] According to another embodiment ("Embodiment 8"), in addition to any one of embodiments 1 to 7, the outer layer is a composite layer comprising a cell-releasing layer and a first cell-retaining layer, and the inner layer is a second cell-retaining layer.

[0013] According to another embodiment ("Embodiment 9"), in addition to any one of embodiments 1 to 8, the inner layer is a first composite layer including a first cell-releasing layer and a first cell-retaining layer, and the outer layer is a second composite layer including a second cell-releasing layer and a second cell-retaining layer.

[0014] According to another embodiment (“embodiment 10”), in addition to any one of embodiments 1-9, the structural element comprises a shape memory material.

[0015] According to another aspect ("Aspect 11"), in addition to any one of aspects 1 to 10, the at least one biological moiety is selected from a cell, a virus, a viral vector, a bacterium, a protein, an antibody, a gene, DNA, RNA, and combinations thereof.

[0016] According to another embodiment ("embodiment 12"), in addition to embodiment 11, the cell is selected from a prokaryotic cell, a eukaryotic cell, a mammalian cell, a non-mammalian cell, a stem cell, and combinations thereof.

[0017] According to another embodiment ("Embodiment 13"), in addition to any one of embodiments 1-12, at least one of the inner layer and the outer layer is a cell-release layer, and the at least one biological moiety is microencapsulated.

[0018] According to another embodiment ("Embodiment 14"), in addition to any one of embodiments 1-13, the structural element is adhered to at least one of the first layer and the second layer.

[0019] According to another aspect ("Aspect 15"), in addition to any one of aspects 1 to 14, the inner layer is a first composite layer including a first cell-opening layer, the outer layer is a second composite layer including a first cell-opening layer, the structural element is adhered to the first cell-opening layer and the second cell-opening layer of the first composite layer and the second composite layer, and the structural element does not penetrate into the first cell-opening layer or the second cell-opening layer.

[0020] According to another embodiment ("Embodiment 16"), in addition to any one of embodiments 1-15, at least two reservoir spaces are fluidly interconnected.

[0021] According to another embodiment ("Embodiment 17"), in addition to any one of embodiments 1-15, the at least two reservoir spaces are separate.

[0022] According to one embodiment ("Embodiment 18"), an encapsulation device includes a first composite layer including a first cell-releasing layer and a first cell-retaining layer, a second composite layer including a second cell-releasing layer and a second cell-retaining layer, a containment layer disposed between the first composite layer and the second composite layer, and at least one form element including a shape memory material. The containment layer includes a structural element disposed therein to maintain a separation distance between the first composite layer and the second composite layer. The structural element defines a plurality of reservoir spaces for disposing at least one biological moiety therein.

[0023] According to another aspect ("Aspect 19"), in addition to aspect 18, the at least one form element is disposed between the first cell-releasing layer and the first cell-retaining layer.

[0024] According to another aspect ("Aspect 20"), in addition to aspect 18 or aspect 19, the at least one form element is disposed between the second cell-releasing layer and the second cell-retaining layer.

[0025] According to another aspect ("Aspect 21"), in addition to any one of aspects 18 to 20, the at least one first morphological element is positioned between the first cell-releasing layer and the first cell-retaining layer, and the at least one second morphological element is positioned between the second cell-releasing layer and the second cell-retaining layer.

[0026] According to another aspect ("Aspect 22"), in addition to any one of aspects 18 to 20, the at least one form element is positioned outward on the first cell-opening layer, and the first cell-opening layer forms an outer surface of the encapsulation device.

[0027] According to another aspect ("Aspect 23"), in addition to any one of aspects 18 to 20, the at least one form element is positioned outside the second cell-opening layer, and the second cell-opening layer forms an outer surface of the encapsulation device.

[0028] According to another aspect ("Aspect 24"), in addition to any one of aspects 18-20, the at least one form element replaces the structural element and is disposed between the first composite layer and the second composite layer.

[0029] According to another aspect ("Aspect 25"), in addition to any one of aspects 18 to 24, the biological moiety is selected from a cell, a virus, a viral vector, a bacterium, a protein, an antibody, a gene, DNA, RNA, and combinations thereof.

[0030] According to another embodiment ("embodiment 26"), further to embodiment 25, the cell is selected from a prokaryotic cell, a eukaryotic cell, a mammalian cell, a non-mammalian cell, a stem cell, and combinations thereof.

[0031] According to another aspect ("Aspect 27"), in addition to any one of aspects 18 to 26, the structural element is adhered to the first cell-opening layer of the first composite layer and the second cell-opening layer of the second composite layer, and the structural element does not penetrate into the pores of the first cell-opening layer or the second cell-opening layer.

[0032] According to another embodiment ("embodiment 28"), in addition to any one of embodiments 18 to 27, the reservoir spaces within the cell containment layer are interconnected.

[0033] According to another embodiment ("embodiment 29"), in addition to any one of embodiments 18-28, the reservoir spaces within the cell containment layer are separate.

[0034] According to another aspect ("Aspect 30"), in addition to any one of aspects 18-29, the structural elements maintain the separation distance under both an external compressive force and an internal expansion force.

[0035] According to one embodiment ("Embodiment 31"), a method of deploying an intraluminal device includes accessing a body conduit having an interior surface, following a catheter to a target location on the body conduit, and deploying an encapsulation device within the body conduit, the encapsulation device configured to fit within the body conduit. The encapsulation device includes at least one reservoir space containing a biological moiety therein, a first cell-releasing layer on a first side of the at least one reservoir space, the first cell-releasing layer facing the interior surface of the body conduit, and a first cell-retaining layer on a second side of the reservoir space.

[0036] According to another aspect ("Aspect 32"), in addition to aspect 31, the encapsulation device includes a second cell-releasing layer adjacent to the first cell-retaining layer, the second cell-releasing layer facing a central portion of the body conduit.

[0037] According to another aspect ("Aspect 33"), in addition to aspect 32, the encapsulation device includes a second cell-retaining layer disposed between the first cell-release layer and the at least one reservoir space.

[0038] According to another aspect ("Aspect 34"), in addition to any one of aspects 31 to 33, the at least one reservoir space is disposed within a containment layer that includes a structural element therein that defines the at least one reservoir space.

[0039] According to another embodiment ("Embodiment 35"), further to embodiment 34, the structural elements maintain the separation distance under both an external compressive force and an internal expansion force.

[0040] According to another embodiment ("embodiment 36"), in addition to any one of embodiments 31-35, the method includes inserting a guidewire and tracing a catheter over the guidewire to the target location.

[0041] According to another aspect ("Aspect 37"), in addition to any one of aspects 31-36, the encapsulation device is constrained within the catheter.

[0042] According to another aspect ("Aspect 38"), in addition to any one of aspects 31-37, the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

[0043] According to another embodiment ("Embodiment 39"), in addition to any one of embodiments 31-38, the biological moiety releases a therapeutic product into the body conduit.

[0044] According to another embodiment ("Embodiment 40"), in addition to any one of embodiments 31-39, the body vessel is a blood vessel.

[0045] According to another embodiment ("Embodiment 41"), in addition to any one of embodiments 31-39, the bodily conduit is a gastrointestinal conduit.

[0046] According to an embodiment ("Embodiment 42"), a method of deploying an intraluminal device includes accessing a body conduit at a target location point, tracing a catheter to the target location point, and deploying an encapsulation device at the target location point. The encapsulation device includes at least one reservoir space containing a biological moiety therein. The at least one reservoir space is disposed within a containment layer having at least one structural element therein. A separation distance is maintained during deployment of the encapsulation device.

[0047] According to another embodiment ("embodiment 43"), in addition to embodiment 42, the method includes inserting a guidewire and following a catheter over the guidewire to the target location.

[0048] According to another aspect ("Aspect 44"), in addition to aspect 43, the encapsulation device is constrained within the catheter.

[0049] According to another aspect ("Aspect 45"), in addition to any one of aspects 42-44, the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

[0050] According to another embodiment ("Embodiment 46"), in addition to any one of embodiments 42-45, the biological moiety releases a therapeutic product into the body conduit.

[0051] According to another embodiment ("Embodiment 47"), in addition to any one of embodiments 42-46, the body conduit is a blood vessel.

[0052] According to another embodiment ("Embodiment 48"), in addition to any one of embodiments 42-46, the bodily conduit is a gastrointestinal conduit.

[0053] According to another embodiment ("embodiment 49"), in addition to any one of embodiments 42-48, there is also included a cell-release layer disposed adjacent the interior surface of the body conduit.

[0054] According to another embodiment ("embodiment 50"), in addition to any one of embodiments 42-49, the encapsulated device includes a cell-retaining layer as an inner layer.

[0055] According to another aspect ("Aspect 51"), in addition to any one of aspects 42 to 50, a first cell-release layer is disposed on a first side of the containment layer, and a second cell-release layer is disposed on a second side of the containment layer.

[0056] According to one embodiment ("Embodiment 52"), a method of deploying an extraluminal device includes accessing a first bodily conduit at a first target entry point, inserting a guidewire into the first bodily conduit at the first target entry point, tracing a catheter over the guidewire to a target exit point on the first bodily conduit, exiting the first bodily conduit at the target exit point using an accessory tool, tracing the guidewire to a second target exit point on a second bodily conduit, entering the second bodily conduit using an accessory tool, and deploying an encapsulation device at the second target exit point on the second bodily conduit. The encapsulation device includes at least one reservoir space containing a biological moiety therein, the at least one reservoir space having a first cell-retaining layer thereon. The encapsulation device forms a third conduit connecting the first bodily conduit and the second bodily conduit. The cell-retaining layer then forms an inner lining of the third bodily conduit.

[0057] According to another aspect ("Aspect 53"), in addition to aspect 52, the encapsulation device is constrained within the catheter.

[0058] According to another aspect ("Aspect 54"), further to aspect 51 or aspect 53, the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

[0059] According to another embodiment ("embodiment 55"), in addition to any one of embodiments 52-54, the biological moiety releases a therapeutic product.

[0060] According to another embodiment ("embodiment 56"), in addition to any one of embodiments 52-55, the body vessel is a blood vessel.

[0061] According to another embodiment ("embodiment 57"), in addition to any one of embodiments 52-55, the bodily conduit is a gastrointestinal conduit.

[0062] According to another aspect ("Aspect 58"), in addition to any one of aspects 52-57, the encapsulation device includes a containment layer including at least one reservoir space and a structural element that maintains a separation distance under an external compressive force and an internal expansion force.

[0063] According to another aspect ("Aspect 59"), in addition to any one of aspects 52 to 58, the encapsulation device includes a second cell-retaining layer on a side of at least one reservoir space opposite the first cell-retaining layer.

[0064] According to one embodiment ("Embodiment 60"), a method of deploying an extraluminal device includes accessing a bodily conduit at a first target entry point, inserting a guidewire into the bodily conduit at the first target entry point, following a catheter over the guidewire to a target exit point prior to a desired bypass region of the bodily conduit, following a catheter over the guidewire to a target exit point prior to the desired bypass region of the bodily conduit, exiting the bodily conduit at the first target exit point using an accessory tool, following the guidewire to a second target entry point on the bodily conduit at a location after the desired bypass region of the bodily conduit, and deploying an encapsulation device at the second target entry point such that the encapsulation device connects the first target exit point and the second target entry point. The encapsulation device includes at least one reservoir space containing a biological moiety therein and a cell-free layer. A portion of the cell-free layer is adjacent to an interior surface of the bodily conduit.

[0065] According to another aspect ("Aspect 61"), in addition to aspect 60, the encapsulation device is constrained within the catheter.

[0066] According to another aspect ("Aspect 62"), further to aspect 60 or aspect 61, the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

[0067] According to another embodiment ("Embodiment 63"), in addition to any one of embodiments 60-62, the biological moiety releases a therapeutic product into the body conduit.

[0068] According to another embodiment ("embodiment 64"), in addition to any one of embodiments 60-63, the body vessel is a blood vessel.

[0069] According to another embodiment ("Embodiment 65"), in addition to any one of embodiments 60-63, the bodily conduit is a gastrointestinal conduit.

[0070] According to another embodiment ("embodiment 66"), in addition to any one of embodiments 60-65, the desired bypass region is an occlusion.

[0071] According to one embodiment ("Embodiment 67"), a method of deploying an encapsulation device includes surgically accessing a target location point at a first target entry point on a first bodily conduit, resecting a portion of the bodily conduit at the target location point, and replacing the resected portion of the bodily conduit at the target location point with an encapsulation device via an end-to-end anastomosis. The encapsulation device includes structural elements that form a reservoir space within a containment layer, and the reservoir space contains a biological moiety therein.

[0072] According to another embodiment ("Embodiment 68"), in addition to embodiment 67, the containment layer has a first side, a cell-retaining layer is disposed on the first side of the containment layer, and the cell-release layer is disposed on the cell-retaining layer and adjacent to the inner surface of the body conduit.

[0073] According to another embodiment ("embodiment 69"), further to embodiment 67 or embodiment 68, the biological moiety releases a therapeutic product into the body conduit.

[0074] According to another embodiment ("embodiment 70"), in addition to any one of embodiments 67-69, the body conduit is a blood vessel.

[0075] According to another embodiment ("Embodiment 71"), in addition to any one of embodiments 67-70, the bodily conduit is a gastrointestinal conduit.

[0076] According to one embodiment ("Embodiment 72"), a method of placing an encapsulation device includes surgically accessing a target location point on a bodily conduit, forming a slit in the bodily conduit at the target location point to access the bodily conduit, and inserting an encapsulation device into the bodily conduit at the target location point. The encapsulation device includes at least one reservoir space containing a biological moiety therein, the at least one reservoir space having a cell-release layer thereon positioned adjacent an interior surface of the bodily conduit.

[0077] According to another embodiment ("embodiment 73"), in addition to embodiment 72, the biological moiety releases a therapeutic product into the body conduit.

[0078] According to another embodiment ("embodiment 74"), in addition to embodiment 72 or embodiment 73, the body conduit is a blood vessel.

[0079] According to another embodiment ("embodiment 75"), in addition to embodiment 72 or embodiment 73, the bodily conduit is a gastrointestinal conduit.

[0080] According to one embodiment ("Embodiment 76"), a method of deploying an extraluminal bypass or shunt device includes surgically accessing a first target location point on a first bodily conduit, connecting a first end of an encapsulation device to the first target location point on the first bodily conduit, and connecting a second end of the encapsulation device to a second target location point on a second bodily conduit. The encapsulation device includes a cell-retaining layer and at least one reservoir space containing at least one biological moiety therein. The encapsulation device forms a third conduit connecting the first bodily conduit and the second bodily conduit. The cell-retaining layer forms an interior surface of the third conduit.

[0081] According to another embodiment ("embodiment 77"), in addition to embodiment 76, the at least one biological moiety releases a therapeutic product.

[0082] According to another embodiment ("embodiment 78"), further to embodiment 76 or embodiment 77, the first body conduit and the second body conduit are each blood vessels.

[0083] According to another embodiment ("embodiment 79"), further to embodiment 76 or embodiment 77, the first body conduit and the second body conduit are each gastrointestinal conduits.

[0084] According to one embodiment ("Embodiment 80"), a method of placing an encapsulation device includes surgically accessing a target location in a bodily conduit and placing the encapsulation device around an exterior surface of the bodily conduit such that the encapsulation device substantially surrounds at least a portion of the bodily conduit. The encapsulation device includes at least one reservoir space containing a biological moiety therein. The at least one reservoir space has a cell-release layer disposed on a surface thereof, the cell-release layer adjacent to the exterior surface of the bodily conduit.

[0085] According to another embodiment ("embodiment 81"), further to embodiment 80, the at least one biological moiety releases a therapeutic product.

[0086] According to another embodiment ("embodiment 82"), in addition to embodiment 80 or embodiment 81, the first body conduit and the second body conduit are each blood vessels.

[0087] According to another embodiment ("embodiment 83"), in addition to embodiment 80 or embodiment 81, the first body conduit and the second body conduit are each gastrointestinal conduits. [Brief explanation of the drawings]

[0088] BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings 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.

[0089] [Figure 1A] FIG. 1A is a schematic illustration of a cross section of a tubular encapsulation device having an inner composite layer and an outer composite layer according to embodiments described herein.

[0090] [Figure 1B] FIG. 1B is a schematic illustration of a cross section of the tubular encapsulation device of 1A including a reinforcing layer therein, according to an embodiment described herein.

[0091] [Figure 2] FIG. 2 is a schematic illustration of a cross section of a tubular encapsulation device having a composite inner layer and an outer layer comprising only a cell-retaining layer, according to embodiments described herein.

[0092] [Figure 3] FIG. 3 is a schematic illustration of a cross section of a tubular encapsulation device having a composite outer layer and an inner layer comprising only a cell-retaining layer, according to embodiments described herein.

[0093] [Figure 4] FIG. 4 is a schematic illustration of a cross section of a porous material used to construct an encapsulation device according to embodiments described herein.

[0094] [Figure 5A] FIG. 5A is a schematic illustration of a cross section of an encapsulation device including form elements that allow for geometric shape changes, according to embodiments described herein. [Figure 5B] FIG. 5B is a schematic illustration of a cross section of an encapsulation device including form elements that allow for geometric shape changes according to embodiments described herein. [Figure 5C] FIG. 5C is a schematic illustration of a cross section of an encapsulation device including form elements that allow for geometrical changes according to embodiments described herein.

[0095] [Figure 6] FIG. 6 is a schematic illustration of a cross section of a portion of an encapsulation device configurable from a first geometric shape to a second geometric shape according to embodiments described herein.

[0096] [Figure 7A] FIG. 7A is a planar frame formed from a shape memory material according to embodiments described herein. [Figure 7B] FIG. 7B is a planar frame formed from a shape memory material according to embodiments described herein.

[0097] [Figure 7C] FIG. 7C is a diagram illustrating the non-planar configuration of FIGS. 7A and 7B, respectively, according to embodiments described herein. [Figure 7D] FIG. 77D illustrates the non-planar shapes of FIGS. 7A and 7B, respectively, according to embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0098] Detailed Description Those skilled in the art will readily appreciate that the various aspects of the present disclosure may be implemented by any number of methods and apparatuses configured to perform the intended functions. It should also be noted that the accompanying drawings referred to herein are not necessarily drawn to scale and may be exaggerated to illustrate various aspects of the present disclosure, and in that regard, the drawings should not be construed as limiting. It should be understood that the terms "encapsulation device" and "housing device" may be used interchangeably herein.

[0099] Described herein are devices for housing biological moieties, which are implanted intravascularly or extravascularly in or around a patient's vessels (e.g., blood vessels) to provide biological therapy. Biological moieties suitable for encapsulation and implantation using the devices described herein include cells, viruses, viral vectors, bacteria, proteins, antibodies, genes, DNA, RNA, and other biologically active moieties. In some embodiments herein, the biological moieties are cells, however, nothing in this description should be construed as limiting the biological moieties to cells or any particular type of cell, and the following description also applies to non-cellular biological moieties.

[0100] Various types of prokaryotic and eukaryotic cells, mammalian cells, non-mammalian cells, and stem cells can be used with devices for encapsulating biological moieties, also referred to herein as cell containment devices. In some embodiments, the cells secrete therapeutically useful substances. Such therapeutically useful substances include hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cellular products that provide a therapeutic effect to the device recipient. Examples of such therapeutic cellular products include, but are not limited to, hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cellular products that provide a therapeutic effect to the device recipient. Examples of such therapeutic cellular products include, but are not limited to, insulin, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, collagen, elastin, tropoelastin, exosomes, vesicles, gene fragments, and Factor VIII. Non-limiting examples of suitable growth factors include vascular endothelial growth factor, platelet-derived growth factor, platelet-activating factor, transforming growth factor, bone morphogenetic protein, activin, inhibin, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, glial cell line-derived neurotrophic factor, growth differentiation factor-9, epidermal growth factor, and combinations thereof.

[0101] 1A is a schematic diagram of a cross section of a tubular encapsulation device 100 including an inner layer 110, an outer layer 120, and at least one containment layer 130 disposed between the inner layer 110 and the outer layer 120. The containment layer 130 includes structural elements 140 that maintain a separation distance 135 during geometric changes of the device 100. The structural elements 140 maintain the separation distance 135 from a first diameter to a second diameter (e.g., during collapse and subsequent expansion of the device 100). Furthermore, the separation distance 135 is maintained both under external compressive forces and internal distension forces. The structural elements 140 define a plurality of reservoir spaces 150 within the containment layer 130 for disposing biological moieties. The separation distance 135 can be up to 100 microns. In some embodiments, separation distance 135 can be at least about 100 microns, at least about 150 microns, at least about 200 microns, at least about 250 microns, or at least about 500 microns (or more). In some embodiments, separation distance 135 can range from about 150 microns to about 500 microns, from about 200 microns to about 500 microns, from about 100 microns to about 250 microns, or from about 150 microns to about 250 microns. In one embodiment, maintaining separation distance 135 allows inner layer 110 to be in a substantially parallel relationship with outer layer 120.

[0102] In some embodiments, the reinforcing layer 160 can be disposed between the inner layer 110 and the containment layer 130, as generally shown in FIG. 1B . In other embodiments, the reinforcing layer 160 can be disposed between the outer layer 120 and the containment layer 130. In further embodiments, the reinforcing layer 160 can be disposed externally (e.g., on the outside of the outer layer 120 or the inner layer 110). In some embodiments, the structural element 140 can itself be reinforcing and formed from a shape memory material, such as the form elements 525, 526 shown in FIGS. 5A-5C , which are described in more detail below. It should be understood that the release layer 110 and / or the outer layer 120 can comprise a single layer or can be formed from a composite layer as described herein. Non-limiting examples of materials suitable for the reinforcing layer 160 include metal elements (e.g., metal stents), shape memory materials, porous materials, or non-porous materials, as described herein. In some embodiments, the cross section of encapsulation device 100 can have a generally cylindrical, oval, or elliptical shape.

[0103] In some embodiments, at least one of the inner layer 110 and the outer layer 120 comprises a composite layer. Figures 1A and 1B show an embodiment in which the inner layer 110 and the outer layer 120 are composite layers. The inner layer 110 comprises a cell-releasing layer 112 and a cell-retaining layer 114 disposed adjacent to the cell-releasing layer 112. The outer layer 120 can also be a composite layer including a cell-releasing layer 122 disposed adjacent to the cell-retaining layer 124. The cell-retaining layers 114, 124 are disposed on either side of the containment layer 130 such that the containment layer 130 (and the reservoir space 150 therein) is sandwiched between the cell-retaining layers 114, 124. The cell-releasing layers 112, 122 of the inner layer 110 and the outer layer 120 can comprise or be formed from the same or different materials. Similarly, the cell-retaining layers 122, 124 of the inner and outer layers 110, 120 can comprise or be formed from the same or different materials. Furthermore, the cell-releasing layers 112, 122 can have a porosity less than that of the cell-retaining layers. It should be understood that embodiments in which the porosity of the cell-releasing layers 112, 122 is equal to or greater than that of the cell-retaining layers are considered within the scope of the present disclosure. In the embodiment shown in FIGS. 1A and 1B, ingrowth of host tissue, such as host vascular tissue, can occur in both the cell-releasing layers 112, 122. The cell-releasing layers 112, 122 are sufficiently porous to allow tissue, such as vascular tissue, to grow from the patient into the pores of the cell-releasing layers 112, 122 and up to, but not through, the cell-retaining layers 114, 124.

[0104] In some embodiments, only one of the inner and outer layers of an encapsulation device is a composite layer. In at least one embodiment, as shown in FIG. 2 , first layer 110 of encapsulation device 200 may be a composite layer including cell-releasing layer 112 and cell-retaining layer 114, while outer layer 210 includes only cell-retaining layer 250. Containment layer 130 may be disposed between first layer 110 and cell-retaining layer 250, more specifically, between cell-retaining layer 114 and cell-retaining layer 250. Containment layer 130 includes structural elements 140 that define multiple reservoir spaces 150 for disposing one or more biological moieties. In another embodiment, as shown in FIG. 3 , outer layer 120 of encapsulation device 300 may be a composite layer including cell-releasing layer 122 and cell-retaining layer 124, while inner layer 110 includes only cell-retaining layer 220. The containment layer 130, containing the reservoir space 150 therein, can be disposed between the cell-retaining layer 220 and the outer layer 120. More specifically, the containment layer 130 can be disposed between the cell-retaining layer 114 and the cell-retaining layer 220. It should be understood that the cell-releasing layers 112, 122 allow for the ingrowth of host tissue cells. As with the above-described embodiment, the cell-retaining layers 114, 250 (FIG. 2) and the cell-retaining layers 220, 124 (FIG. 3) are disposed on either side of the containment layer 130, containing the structural element 140 and the reservoir space 150 (and biological moiety). The structural element 140 also defines a separation distance 135 that is maintained under both external compressive and internal expansion forces. It should be understood that the embodiments shown in FIGS. 1A, 1B, 2, and 3 are exemplary in nature, and that various orientations of the cell-releasing layer, cell-retaining layer, and reinforcement element 160 exist and are considered within the scope of this disclosure.

[0105] In some embodiments, the cell-retaining layer is impermeable to cellular ingrowth. For example, in some embodiments, both cell-retaining layers have an average pore size small enough to prevent host tissue ingrowth, such as vascular tissue ingrowth. As one non-limiting example, the average pore size of the cell-retaining layer can be less than about 5 microns, less than about 1 micron, or less than about 0.5 microns, as measured by porometry. The small pore size enables the cell-retaining layer to maintain biological moieties disposed within the reservoir space of the containment layer within the encapsulation device.

[0106] At least one of the encapsulation devices 100, 200, 300 described herein is configurable from a first tubular configuration having a first diameter to a second tubular configuration having a second diameter, such as when the device is physically collapsed and placed within a catheter for insertion into a patient. In at least one embodiment, the encapsulation device is deployed using a minimally invasive procedure. The delivery system most commonly includes a restraining member that maintains the device in the second tubular configuration (i.e., collapsed or collapsed state) for delivery through a body conduit (e.g., a blood vessel) to a desired site. Once the device is positioned at the desired site, the restraining member is released, allowing the encapsulation device to expand or otherwise return to its first tubular configuration (i.e., expanded state). The structural elements described herein maintain a separation distance during collapse, delivery, and subsequent expansion to their original shape and size (e.g., pre-collapsed shape).

[0107] Various cell types can be grown within the cell-open layer of an encapsulation device as described herein. The predominant cell type grown into a particular porous material (e.g., cell-open layer) depends primarily on the implantation site, the material's composition, permeability, and biological factors incorporated into or introduced through the porous material. In some embodiments, vascular tissue is the predominant cell type grown into the cell-open layer of an encapsulation device. In other embodiments, liver tissue is the predominant cell type grown into a porous material for use in an encapsulation device. In a further embodiment, bone tissue is the predominant cell type grown into a porous material for use in an encapsulation device. In other non-limiting embodiments, gastrointestinal tissue, urinary tract tissue, respiratory tissue, nervous tissue, lymphatic tissue, and connective tissue are the predominant cell types grown into a porous layer (e.g., cell-open layer) within an encapsulation device. Vascularization of the cell-open layer with well-established vascular cell populations in the form of capillary networks is promoted, resulting in vascularization of the material from the patient's tissue into and across the thickness of the cell-open layer adjacent to the interior surface of the device, but not beyond the cell-retaining layer.

[0108] In further embodiments, neither the first nor the second layer is a composite layer, but rather comprises only a cell-retaining layer. In embodiments in which the encapsulation device comprises only a cell-retaining layer and not a cell-release layer, the encapsulation device may optionally be used with a housing that can reside or be placed within a patient's body and is made from a material that allows for the engraftment of surrounding tissue. In some embodiments, the housing may be implanted within the patient for a period of time sufficient to allow for the engraftment of surrounding tissue before the device is inserted into the housing. In other embodiments, the device and housing may be inserted into the patient together.

[0109] In yet another embodiment, neither the first nor the second layer is a composite layer. Instead, the first and / or second layer is a cell-opening layer that allows some entry of host cells into the encapsulation device, or allows entry and vascularization of host cells into the encapsulation device. Furthermore, the biological moiety within the containment layer is free to move in and out of the encapsulation device. In some embodiments, the biological moiety inserted into the encapsulation device can be microencapsulated within a biomaterial of natural or synthetic origin, including, but not limited to, a hydrogel biomaterial. Encapsulation isolates the biological moiety (e.g., cells) from the host immune response.

[0110] Materials useful as the first and second porous layers within the composite layer include, but are not limited to, alginate, cellulose acetate, polyalkylene glycols such as polyethylene glycol and polypropylene glycol, polyvinyl 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 polytetrafluoroethylene (PTFE), modified polytetrafluoroethylene polymers, tetrafluoroethylene (TFE) copolymers, porous polyalkylenes such as porous polypropylene and porous polyethylene, porous polyvinylidene fluoride, porous polyestersulfone (PES), porous polyurethane, porous polyester, and copolymers and combinations thereof. In some embodiments, materials useful as the outer porous layer include biomaterial textiles.

[0111] In some embodiments, one or both of the inner and outer layers of the encapsulation device are made primarily or entirely from a porous material having selective sieving and / or porosity properties. The porous material can be made from any biocompatible material with suitable permeability properties. The porous material controls the passage of solutes, biochemicals, viruses, cells, etc., through the material primarily based on size. Non-limiting examples of suitable porous materials include one or more of the materials described above for the inner and outer layers, including, but not limited to, biomaterial textiles.

[0112] In embodiments in which the porous material is porous only through a portion of its thickness, the molecular weight cutoff or sieving properties of the porous membrane begin at the surface. As a result, certain solutes and / or bioactive moieties, such as cells, cannot penetrate the porous spaces of the material and pass from one side to the other. Figure 4 shows a cross-sectional view of a porous material 400 useful in the encapsulation devices described herein. The selective permeability of the porous material 400 precludes cells 405 from migrating or growing into the spaces of the porous material 400 while allowing bidirectional flow of solutes 410 across the thickness of the porous material 400. Vascular endothelial cells can bind and form capillaries thereon. Additional cell types, such as liver tissue cells, nervous tissue cells, lymphatic tissue cells, gastrointestinal tissue cells, connective tissue cells, urinary tract tissue cells, respiratory tissue cells, and bone tissue cells, can bind and form organized or unorganized tissue thereon. Such capillary formation or vascularization or organized or disorganized tissue formation in porous material 400 can enhance the flow of fluids and solutes between the patient's tissue and the contents of the encapsulation device.

[0113] In some embodiments, the inner and outer layers are flexible, but the structural elements maintain the encapsulation device as a generally tubular structure in its expanded configuration. The structural elements maintain the separation distance under an applied force across the diameter of the device. The applied force can be an external compressive force that would tend to collapse the reservoir space between the first and second layers in the absence of the structural elements. For example, a clinician can apply a compressive force to collapse a tubular device before or during insertion. When the external compressive force reduces the distance between the inner and outer layers of the encapsulation device, cells (i.e., biological moieties) within the encapsulation device can be exposed to undesirable mechanical stimuli, such as compressive stimuli, which can minimize cellular functionality or result in cell death.

[0114] Alternatively, the applied force can be an internal expansion force that would tend to expand the containment layer between the inner and outer layers into a round, balloon-like membrane in the absence of the structural element. For example, pressure can be required to inject a biological moiety (e.g., multiple cells) into the reservoir space. In one example, the pressure can be caused by overexpansion during insertion, e.g., due to operator error. In another example, the pressure can be caused by cell proliferation (e.g., pillowing) due to cell growth and proliferation. It should be understood that the structural element maintains the separation distance both under external compression and internal expansion forces.

[0115] The structural elements divide the containment layer into at least two reservoir spaces. The boundaries of the reservoir spaces are defined by the structural elements, the outer layer, and the inner layer (or reinforcing layer, if present). The number of reservoir spaces is not particularly limited, and the cell containment layer can include up to 100,000 or more reservoir spaces. In some embodiments, the at least two reservoir spaces are interconnected by the structural elements and by channels formed between the structural elements. In other embodiments, the at least two reservoir spaces are separate (i.e., not fluidically connected). In other embodiments, some of the reservoir spaces may be interconnected, and other portions of the reservoir spaces may be separate (not connected).

[0116] In some embodiments, one or both of the inner and outer layers and / or the containment layer are or include a bioabsorbable material. The bioabsorbable material may be formed as a solid body (molded, extruded, or crystalline), a self-cohered web, raised webbing, or a screen. In some embodiments, one or more layers of bioabsorbable material are attached to a non-bioabsorbable material with macroscopic porosity that allows cell penetration (e.g., a cell-releasing layer) to form a composite. In other embodiments, a non-bioabsorbable material with microscopic porosity to reduce or prevent cell penetration is releasably attached to the porous self-cohered web, allowing the encapsulation device to be atraumatically removed from the patient's body several days after implantation. Resorption by the body may promote favorable type 1 collagen deposition, tissue integration, vascularization, and reduced infection. Certain materials, such as perfluorocarbon emulsions, fluorohydrogels, silicone oils, silicone hydrogels, soybean oil, silicone rubber, and polyvinyl chloride, as well as combinations thereof, are known to have high oxygen solubility. Such highly oxygen permeable materials enhance the transport of oxygen from the host tissue into the encapsulation device and can be utilized as structural elements or applied, for example, as a coating or filler on the structural elements.

[0117] 5A-5C are schematic cross-sectional views of an encapsulation device 500 including a first composite layer 510, a second composite layer 520, a containment layer 530 disposed between the first composite layer 510 and the second composite layer 520, and at least one structural element 540 disposed within the containment layer 530 to separate the first composite layer 510, 520 by a separation distance 535. The containment layer 530 includes the structural element 540 such that the separation distance 535 is maintained during geometric changes of the encapsulation device. The structural element 540 also defines the separation distance 535, which is maintained under both an external compressive force and an internal expansion force. The separation distance 535 between the first composite layer and the second composite layer is at most 100 microns. In some examples, the separation distance between the first composite layer and the second composite layer is at least 100 microns, e.g., at least 150 microns or at least 200 microns. In some examples, the separation distance can be about 250 microns, at least 250 microns, or greater than 500 microns. In some embodiments, the separation distance 535 can be in the range of about 150 microns to about 500 microns, about 200 microns to about 500 microns, about 250 microns to about 500 microns, about 100 microns to about 250 microns, or about 150 microns to about 250 microns. The structural elements 540 define a plurality of reservoir spaces 550 for disposing biological moieties (not shown) within the containment layer 530. The cell-releasing layers 512, 524 can comprise or be formed from the same or different materials. Similarly, the cell-retaining layers 512, 522 can comprise or be formed from the same or different materials. The cell-releasing layers 512 and 522 can have a porosity that is less than the porosity of the cell-retaining layers 514 and 524.

[0118] 5A , in some embodiments, the first composite layer 510 includes at least one first morphological element 525 disposed between the first cell-releasing layer 512 and the first cell-retaining layer 514. The second composite layer 520 also includes at least one second morphological element 526 disposed between the first cell-releasing layer 522 and the second cell-retaining layer 524. The first morphological element and the second morphological elements 525, 526 can be formed from the same material or different materials. Non-limiting examples of materials utilized for the first and / or second form elements 525, 526 include shape-changing materials, including, but not limited to, shape memory alloys such as nitinol, and shape memory polymers such as polyetheretherketone, polymethylmethacrylate, polyethylmethacrylate, polyacrylate, polyalphahydroxyacid, polycaprolactone, polydioxanone, polyester, polyglycolic acid, polyglycol, polylactide, polyorthoester, polyphosphate, polyoxaester, polyphosphate ester, polyphosphonate, polysaccharide, polytyrosine carbonate, polyurethane, and copolymers or polymer blends thereof. In at least one embodiment, one or more form elements is a nitinol stent. The form element induces a geometric change in the device, for example, from a first geometric shape (e.g., a generally planar configuration) to a second geometric shape (e.g., a generally cylindrical configuration). The encapsulation device can also be configured from a planar to a non-planar configuration, such as a folded or "jelly roll" configuration, a hyperbolic (e.g., hot dog bun) or a folded cylindrical configuration. Form elements 525, 526 also facilitate the implantation procedure, including facilitating changes in the profile of the encapsulation device during the implantation procedure. One or more of form elements 525, 526 can be reinforcing layer 160 as described above with reference to Figures 1-3.

[0119] The cell-releasing layers 512, 522 can include or be formed from the same or different materials. Similarly, the cell-retaining layers 514, 524 can include or be formed from the same or different materials. The cell-releasing layers 512, 522 can have a porosity that is less than the porosity of the cell-retaining layers 514, 524.

[0120] In another embodiment, as shown in FIG. 5B, at least one morphological element 525 is disposed on the exterior of encapsulation device 500. In particular, at least one first morphological element 525 is disposed on the outermost layer, adjacent cell-releasing layer 512. Furthermore, at least one second morphological element is disposed outwardly on cell-releasing layer 522. In particular, at least one second morphological element 526 is disposed adjacent cell-releasing layer 522, forming the outer layer of encapsulation device 500. FIG. 5C illustrates an embodiment in which at least one morphological element 525 is disposed between cell-retaining layers 514, 524, replacing a structural element. It should be understood that FIGS. 5A-5C are exemplary in nature, and various orientations of the cell-releasing layer, cell-retaining layer, and morphological elements 525, 526 are possible and are considered within the scope of the present disclosure.

[0121] In some embodiments, the first composite layer 510 and the second composite layer 520 are flexible. A structural element 540 separates the first composite layer 510 and the second composite layer 520 such that a separation distance 535 exists between the composite layers 510 and 520. The structural element 540 maintains the separation distance 535 under an applied force. As discussed above, the applied force can be an external compressive force that would tend to collapse the containment layer 530 between the first composite layer 510 and the second composite layer 520 in the absence of the structural element 540. Alternatively, the applied force can be an internal expansion force that would tend to expand the encapsulation layer between the first composite layer 510 and the second composite layer into a round, balloon-like membrane in the absence of the structural element. The structural element 540 maintains the separation distance 535 under both the external compressive force and the internal expansion force.

[0122] Similar to that described above, the structural element 540 divides the containment layer 530 into at least two reservoir spaces 550. The boundaries of the reservoir spaces 550 are defined by the structural element 540, the first composite layer 510, and the second composite layer 520. In Figures 5A and 5B, the reservoir spaces 550 are defined by the structural element 540, the first cell-retaining layer 514, and the second cell-retaining layer 524. The number of reservoir spaces 550 is not particularly limited, and the containment layer 530 can include up to 100,000 or more reservoir spaces. In some embodiments, the at least two reservoir spaces 550 are interconnected by the structural supports 540 and by channels formed between the structural supports 540. In other embodiments, the reservoir spaces 550 may be separate (i.e., not fluidically connected). In other embodiments, some of the reservoir spaces 550 may be interconnected and other portions of the reservoir spaces 550 may be separate (unconnected).

[0123] 6, encapsulation device 600 is shown including first porous layer 610, second porous layer 620, and at least one form element 625. At least one reservoir space 650 is formed by the boundaries of first porous layer 610, second porous layer 610, and form element 625. In some embodiments, form element 625 includes or is formed from a shape memory material, as described above, such that encapsulation device 600 is configured to geometrically change from a planar configuration to a non-planar configuration. In some embodiments, the geometric change can be from a non-planar configuration to a planar configuration.

[0124] In some embodiments, form element 625 is in the form of a frame formed from a shape memory material. Non-limiting examples of frames suitable for use in the encapsulation devices described herein include those shown in FIGS. 7A and 7B. It should be understood that FIGS. 7A and 7B are exemplary in nature and in no way limit the disclosure to these particular designs. Form element 625 can have a planar configuration as shown in FIGS. 7A and 7B. After implantation, form element 625 in FIGS. 7A and 7B assumes a non-planar configuration as shown in FIGS. 7C and 7D, respectively. In use, cell-releasing and cell-retaining layers (not shown) are permanently disposed on either side of form element 625. After implantation in a patient, the encapsulation device undergoes a geometric change from a first geometric configuration (e.g., a planar configuration) to a second geometric configuration (e.g., a circular configuration). In some embodiments, the encapsulation can undergo a geometric change from a planar configuration to, for example, a circular configuration, a jelly-roll configuration, a hyperbolic configuration, a pleated configuration, or a folded configuration.

[0125] The encapsulation devices described herein are useful for holding a biological moiety in place within a patient's intravascular or extravascular implant so that the biological moiety can provide biological therapy to the patient. While the examples provided herein focus on vascular implants and blood vessels, it is within the scope of this disclosure to deliver implantable devices intraluminally, extraluminally, or surgically to any conduit in any tissue bed in the body. U.S. Pat. No. 9,642,693 to Cully et al., U.S. Pat. No. 8,197,529 to Cully et al., U.S. Pat. No. 10,111,741 to Michalak, U.S. Pat. No. 10,779,980 to Sharma et al., U.S. Pat. No. 9,717,584 to Cully et al., U.S. Pat. No. 6,673,102 to Vonesh et al., U.S. Pat. No. 7,914,568 to Cully et al., U.S. Pat. No. 6,673,102 to Vonesh et al., and U.S. Pat. No. 6,352,561 to Leopold et al. exemplify the placement of devices in various tissue beds via both intraluminal and extraluminal placement of encapsulated devices. Minimally invasive procedures utilizing the vasculature and gastrointestinal tract have been previously disclosed, for example, in U.S. Pat. No. 7,914,568 to Cully et al., U.S. Pat. No. 6,673,102 to Vonesh et al., and U.S. Pat. No. 6,352,561 to Leopold et al.

[0126] In at least one embodiment, the encapsulation device is deployed using a minimally invasive method. One non-limiting method utilizes a catheter, and the method of deploying the encapsulation device includes accessing the body conduit, following the catheter to a target location in the body conduit, and deploying the encapsulation device within the body conduit. The encapsulation device includes at least one reservoir space containing a biological moiety. The encapsulation device also includes a first cell-releasing layer on a first side of the at least one reservoir space. The cell-releasing layer faces the inner surface of the body conduit. A cell-retaining layer is disposed on a second side of the reservoir space. In some embodiments, the at least one reservoir space is disposed within the containment layer. The reservoir space has at least one structural element and a separation distance, and the separation distance is maintained both under an external compressive force and an internal expansion force. It should be understood that the encapsulation device is configured to conform to the target location within the body conduit. In some embodiments, the encapsulation device includes a reinforcement layer adjacent to the containment layer between the outer layer and the inner layer, or disposed outside the outer layer.

[0127] In another embodiment, a method for deploying an encapsulation device includes accessing a bodily conduit, tracing a catheter to a target location, and deploying the encapsulation device at the target location. The encapsulation device includes at least one reservoir space containing a biological moiety and having at least one structural element disposed therein. A separation distance is maintained during deployment. The encapsulation device has a first cell-releasing layer on a first side of the at least one reservoir space facing an inner surface of the bodily conduit. A second cell-releasing layer can be disposed on a second side of the at least one reservoir space. In some embodiments, a cell-retaining layer is disposed on the second side of the at least one reservoir space. The cell-retaining layer can be disposed on at least one of the first cell-releasing layer and the second cell-releasing layer. In some embodiments, the separation distance is maintained both under an external compressive force and an internal expansion force. It should be understood that the encapsulation device is configured to conform to the target location within the bodily conduit. In some embodiments, the encapsulation device can include a reinforcing layer disposed adjacent to the containment layer between the outer layer and the inner layer. In other embodiments, the reinforcing layer can be disposed outside the outermost layer of the encapsulation device. Further, the encapsulation device can include a containment layer in which the at least one reservoir space and the at least one structural element are disposed.

[0128] In one embodiment of deploying an extraluminal device, the method includes accessing a first bodily conduit, inserting a guidewire into the first bodily conduit, exiting the first bodily conduit at a target exit point using an accessory tool, following the guidewire to a target entry point on a second bodily conduit, entering the second bodily conduit using the accessory tool, and deploying an encapsulation device at the target entry point on the second bodily conduit. The encapsulation device includes at least one reservoir space containing a biological moiety therein, the reservoir space having a cell-retaining layer thereon. In such an embodiment, the encapsulation device forms a third conduit connecting the first bodily conduit and the second bodily conduit. The cell-retaining layer forms an inner layer of the third bodily conduit. The encapsulation device also includes at least one reservoir space and can include a containment layer including structural elements that maintain a separation distance under external compressive forces and internal expansion forces. In some embodiments, the encapsulation device includes a second cell-retaining layer on a side of the at least one reservoir space opposite the first cell-retaining layer.

[0129] In another embodiment, an encapsulation device can be utilized to bypass a desired bypass region (e.g., an occlusion) in a bodily conduit. In at least one embodiment, a method includes accessing a first bodily conduit at a first target entry point, inserting a guidewire into the bodily conduit at the first target entry point, tracing a catheter over the guidewire to a target exit point on the first bodily conduit prior to the desired bypass region, exiting the bodily conduit at the first target exit point using an attached tool, tracing the guidewire to a second target entry point on the bodily conduit subsequent to the desired bypass region, and entering the bodily conduit at the second target entry point using an attached tool, and deploying the encapsulation device at the second target entry point such that the encapsulation device connects the first and second target exit points. The encapsulation device includes at least one reservoir space containing a biological moiety therein and a cell-opening layer that, once deployed, becomes the outer surface of the deployed device and contacts the inner surface of the bodily conduit to allow vascularization into the cell-opening layer. In some embodiments, the cell-retaining layer is disposed on at least one side of at least one reservoir space.

[0130] Deployment of the extraluminal implant can be performed using open or minimally invasive surgery, such as, but not limited to, the transjugular intrahepatic portosystemic shunt (TIPS) described in U.S. Patent No. 6,673,102 to Vonesh et al. The cell-opening layer allows for ingrowth of vascular cells, for example, from blood vessels. The encapsulation devices described herein can also be used in open surgery. In one non-limiting embodiment, a method of deploying an encapsulation device includes accessing a first body conduit at a first target entry point, inserting a guidewire into the first body conduit, tracing a catheter over the guidewire from the first body conduit to a target exit point, exiting the first body conduit using an accessory tool, tracing the guidewire to a second target entry point on a second body conduit, accessing the second body conduit using the accessory tool, and deploying the encapsulation device at the second target entry point such that the encapsulation device connects the first body conduit and the second body conduit. The encapsulation device can include at least one reservoir space containing a biological moiety therein, wherein the reservoir space has a cell-retaining layer adjacent thereto. The at least one reservoir space is formed between structural elements. Both the at least one reservoir space and the structural element are disposed within the containment layer. The cell-retaining layer of the encapsulation device forms the inner layer of a third body conduit. In another embodiment, the cell-retaining layer is disposed on a first side of the containment layer, and the cell-release layer is disposed on the cell-retaining layer and adjacent to the inner surface of the body conduit.

[0131] In another embodiment utilizing open surgery, a target location on a body conduit is surgically accessed, a slit is formed on the body conduit to access the interior of the body conduit, and an encapsulation device is placed within the body conduit, the encapsulation device including at least one reservoir space therein for containing the biological moiety, the at least one reservoir space having a cell-free layer disposed on the interior surface of the body conduit.

[0132] In yet another embodiment of the open surgical procedure, the method includes surgically accessing a first target location point in a first bodily conduit, connecting a first end of an encapsulation device to the first target location point on the first bodily conduit, and connecting a second end of the encapsulation device to a second target location point on a second bodily conduit, wherein the cell-retaining layer forms an interior surface of a third conduit. The encapsulation device includes a cell-retaining layer and at least one reservoir space containing at least one biological moiety therein. The encapsulation device forms the third bodily conduit connecting the first bodily conduit and the second bodily conduit.

[0133] In a further embodiment, a method of placing an encapsulation device includes surgically accessing a bodily conduit at a target location such that the encapsulation device substantially surrounds at least a portion of the bodily conduit. The encapsulation device includes at least one reservoir space containing a biological moiety therein. In addition to the at least one reservoir space, a cell-releasing layer is disposed adjacent to the exterior of the bodily conduit on a surface of the at least one reservoir space.

[0134] Another method of placing an intraluminal device includes deploying an encapsulation device of any one of the embodiments described herein at a target location within a body conduit with the outer layer facing the wall of the body conduit, wherein the outer layer is a cell-free layer. The method can also include accessing the body conduit at the target location point and following a catheter over a guidewire to the target location point. In at least one embodiment, the device is constrained within the catheter. The encapsulation device can be deployed cystoscopically, laparoscopically, or bronchoscopically. It should be understood that the encapsulation device is configured to fit within the body conduit.

[0135] Another method of placing an intraluminal device includes deploying an encapsulation device of any one of the embodiments described herein at a target location within a body conduit with the outer layer facing the wall of the body conduit, wherein the outer layer is a cell-opening layer. The method can also include accessing the body conduit at the target location and following a catheter over a guidewire to the target location. In at least one embodiment, the device is constrained within the catheter. The encapsulation device can be deployed cystoscopically, laparoscopically, or bronchoscopically. It is understood that the encapsulation device is configured to fit within the body conduit.

[0136] A method of placing an extraluminal device includes accessing a first body conduit at a first target location point, creating a target exit point in the first body conduit at a second target location point, following a catheter over a guidewire to the target exit point on the first body conduit, exiting the first body conduit at the target exit point, following the guidewire to a second target entry point on a second body conduit, and deploying an encapsulation device of any one of the embodiments described herein at the second target entry point on the second body conduit such that the encapsulation device interconnects the first and second body conduits.

[0137] Another method of placing an extraluminal device includes accessing a body conduit at a first target entry point at a first target location point on the body conduit, following a guidewire over a catheter to a first target exit point at a second target location point on the body conduit, exiting the body conduit at the first target exit point, following the catheter over the guidewire to a second target entry point at a third target location point on the body conduit, entering the body conduit at the second target entry point, and deploying an encapsulation device according to any one of the embodiments described herein. This method can also include creating the second target entry point at the third target location point on the body conduit.

[0138] Another method of placing an extraluminal device includes accessing a body conduit at a first target entry point at a first location on the first body conduit, following a guidewire over a catheter to a first target exit point at a second location on the first body conduit, exiting the first body conduit at the first target exit point, following the catheter over the guidewire to a second target entry point at a third location on a second body conduit, entering the second body conduit at the second target entry point, and deploying an encapsulation device of any one of the embodiments described herein.

[0139] A method for surgically placing an encapsulation device includes surgically accessing a target location point on a first bodily conduit at a first target entry point, resecting a portion of the bodily conduit at the target location point, and replacing the resected portion of the bodily conduit at the target location point with an encapsulation device described herein by an end-to-end anastomosis, wherein the encapsulation device contains a biological moiety therein.

[0140] Another method of placing an encapsulation device includes surgically accessing a target location point on a body conduit, forming a slit in the body conduit at the target location point to access the body conduit, and inserting an encapsulation device described herein into the body conduit at the target location point.

[0141] A further method for placing an encapsulation device includes surgically accessing a first target location point on a first body conduit, connecting a first end of an encapsulation device of any one of the embodiments described herein to the first target location point on the first body conduit, and connecting a second end of the encapsulation device to a second target location point on a second body conduit.

[0142] It should be understood that the encapsulation devices described with respect to the methods of disposing an encapsulation device may include any of the embodiments described herein and may also include any or all of the elements forming the encapsulation devices described herein. [Example]

[0143] example: A mandrel was obtained, including a proximal portion, a distal portion, and a shaft length. A first release film containing Kapton was wrapped around the proximal portion of the mandrel. A first ePTFE membrane containing a cell-releasing layer was then wrapped over the first release film. A second ePTFE membrane containing a reinforcing layer was then wrapped over the first ePTFE membrane, continuing to the distal portion of the mandrel. A third ePTFE membrane containing a cell-retaining membrane was then wrapped over the second ePTFE membrane.

[0144] A cylindrical laser-cut stent frame containing superelastic Nitinol was obtained, with a length shorter than the mandrel length. The stent frame was slid onto a third ePTFE membrane so that the stent frame was oriented over the proximal portion of the mandrel. A second release film containing Kapton was then wrapped around the cylindrical stent frame.

[0145] The mandrel containing the film, membrane, and stent frame was heated to 350°C for 15 minutes to bond the ePTFE membrane to one another. After heating, the mandrel was removed from the oven, the second release film was removed from the mandrel, and a film containing fluorinated ethylene propylene (FEP) was wrapped onto the distal end of the stent frame.

[0146] A fourth ePTFE membrane containing the structural elements was wrapped around the stent frame portion of the mandrel, and the distal portion of the wrapped membrane containing the second ePTFE membrane was inverted and slid axially to the proximal portion of the mandrel, thereby covering the stent frame with the inverted second ePTFE membrane.

[0147] An FEP-filled tube was inserted between the wrapped and inverted second ePTFE membranes at the proximal end of the mandrel. The FEP-filled tube was attached to the ePTFE membrane using a soldering iron at 320°C. The entire assembly was removed from the mandrel.

[0148] The resulting encapsulated device has a structure similar to that shown in Figure 1A, except that a nitinol stent frame insert is placed between the layer containing the structural elements and the second porous layer, and a filling tube is placed between the structural elements within the reservoir space.

[0149] The invention of this application has been described above generally and with reference to specific embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments without departing from the scope of the present disclosure. Therefore, it is intended that the embodiments cover the modifications and variations of the present invention provided they come within the scope of the appended claims and their equivalents.

Claims

1. Inner layer, an outer layer, and a containment layer disposed between the inner layer and the outer layer, the containment layer including a structural element disposed therein for maintaining a separation distance between the inner layer and the outer layer, wherein the structural element defines a plurality of reservoir spaces for disposing at least one biological moiety therein; 1. An implantable encapsulation device comprising: the structural elements maintain the separation distance under both external compressive forces and internal expansion forces; At least one of the inner layer and the outer layer is a composite layer including a cell-releasing layer and a cell-retaining layer; and An implantable encapsulation device, wherein the encapsulation device has a substantially tubular configuration and is configurable from a first tubular configuration having a first diameter to a second tubular configuration having a second diameter.

2. 10. The encapsulation device of claim 1, further comprising a fill tube disposed between said structural elements and within at least one of said reservoir spaces for disposing said biological moiety within said reservoir spaces.

3. The device of claim 1 or claim 2, further comprising a reinforcing layer disposed between the inner layer and the encapsulation layer.

4. The device of claim 1 or claim 2, further comprising a reinforcing layer disposed between the outer layer and the encapsulation layer.

5. The device of claim 1 or claim 2 , further comprising a reinforcing layer disposed outside the outer layer.

6. The device of any one of claims 3 to 5, wherein the reinforcing layer comprises a shape memory material.

7. the inner layer is a composite layer comprising a cell-releasing layer and a first cell-retaining layer; and The encapsulation device of any one of claims 1 to 6, wherein the outer layer is a second cell-retaining layer.

8. the outer layer is a composite layer comprising a cell-releasing layer and a first cell-retaining layer; and The encapsulation device of any one of claims 1 to 7, wherein the inner layer is a second cell-retaining layer.

9. the inner layer is a first composite layer comprising a first cell-releasing layer and a first cell-retaining layer; and The encapsulation device of any one of claims 1 to 8, wherein the outer layer is a second composite layer comprising a second cell-releasing layer and a second cell-retaining layer.

10. The encapsulation layer of any one of claims 1 to 9, wherein the structural elements comprise a shape memory material.

11. The encapsulation device of any one of claims 1 to 10, wherein the at least one biological moiety is selected from a cell, a virus, a viral vector, a bacterium, a protein, an antibody, a gene, DNA, RNA, and combinations thereof.

12. 12. The encapsulation device of claim 11, wherein the cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof.

13. At least one of the inner layer and the outer layer is a cell-opening layer; and The device of any one of claims 1 to 12, wherein the at least one biological moiety is microencapsulated.

14. The device of any one of claims 1 to 13, wherein the structural element is adhered to at least one of the first layer and the second layer.

15. the inner layer is a first composite layer including a first cell-release layer, and the outer layer is a second composite layer including a second cell-release layer; the structural element is adhered to the first and second cell-releasing layers of the first and second composite layers; and The encapsulation device of any one of claims 1 to 14, wherein the structural elements do not penetrate into the pores of the first cell-releasing layer or the second cell-releasing layer.

16. The device of any one of claims 1 to 15, wherein at least two reservoir spaces are fluidly interconnected.

17. The device of any one of claims 1 to 15, wherein the at least two reservoir spaces are separate.

18. a first composite layer comprising a first cell-releasing layer and a first cell-retaining layer; a second composite layer comprising a second cell-releasing layer and a second cell-retaining layer; a containment layer disposed between the first composite layer and the second composite layer, wherein the containment layer includes a structural element disposed therein for maintaining a separation distance between the first composite layer and the second composite layer, the structural element defining a plurality of reservoir spaces for disposing at least one biological moiety therein; and at least one form element comprising a shape memory material; 1. An encapsulation device comprising: An encapsulation device, wherein the encapsulation device is configurable between a first geometric configuration and a second geometric configuration.

19. 20. The encapsulation device of claim 18, wherein the at least one form element is disposed between a first cell-releasing layer and the first cell-retaining layer.

20. 20. The device of claim 18 or claim 19, wherein the at least one form element is disposed between the second cell-releasing layer and the second cell-retaining layer.

21. 21. The encapsulation device of any one of claims 18 to 20, wherein the at least one first morphological element is disposed between the first cell-releasing layer and the first cell-retaining layer, and the at least one second morphological element is disposed between the second cell-releasing layer and the second cell-retaining layer.

22. 21. The encapsulation device of any one of claims 18 to 20, wherein the at least one morphological element is disposed externally on the first cell-release layer, the first cell-release layer forming an exterior surface of the encapsulation device.

23. 21. The encapsulation device of any one of claims 18 to 20, wherein the at least one morphological element is disposed externally on the second cell-release layer, the second cell-release layer forming an exterior surface of the encapsulation device.

24. The device of any one of Claims 18-20, wherein the at least one form element replaces the structural element and is disposed between the first composite layer and the second composite layer.

25. The encapsulation device of any one of claims 18 to 24, wherein the biological moiety is selected from a cell, a virus, a viral vector, a bacterium, a protein, an antibody, a gene, DNA, RNA, and combinations thereof.

26. 26. The encapsulation device of claim 25, wherein the cells are selected from prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, stem cells, and combinations thereof.

27. the structural element is adhered to the first cell-releasing layer of the first composite layer and the second cell-releasing layer of the second composite layer; The encapsulation device of any one of claims 18 to 26, wherein the structural elements do not penetrate into pores of the first cell-releasing layer or the second cell-releasing layer.

28. The encapsulation device of any one of claims 18 to 27, wherein the plurality of reservoir spaces within the cell containment layer are interconnected.

29. The encapsulation device of any one of claims 18 to 28, wherein the multiple reservoir spaces within the cell containment layer are separate.

30. 30. The device of any one of claims 18-29, wherein the structural elements maintain the separation distance under both an external compressive force and an internal expansion force.

31. 1. A method of deploying an endoluminal device, comprising: accessing a body conduit having an interior surface; Tracing the catheter to a target location on the body vessel; and deploying an encapsulation device within the body conduit, wherein the encapsulation device is configured to fit within the body conduit; Including, The method, wherein the encapsulation device comprises at least one reservoir space containing a biological moiety therein, a first cell-releasing layer on a first side of the at least one reservoir space, wherein the first cell-releasing layer faces the inner surface of the body conduit, and a first cell-retaining layer on a second side of the reservoir space.

32. 32. The method of claim 31, wherein the encapsulation device comprises a second cell-releasing layer adjacent to the first cell-retaining layer and facing a central portion of the body conduit.

33. 33. The method of claim 32, wherein the encapsulation device comprises a second cell-retaining layer disposed between the first cell-releasing layer and the at least one reservoir space.

34. The method of any one of claims 31 to 34, wherein the at least one reservoir space is disposed within a containment layer that includes a structural element therein that defines the at least one reservoir space.

35. 35. The method of claim 34, wherein the structural elements maintain the separation distance under both an external compressive force and an internal expansion force.

36. 36. The method of any one of claims 31 to 35, comprising inserting a guidewire and following a catheter over the guidewire to the target location point.

37. The method of any one of claims 31 to 36, wherein the encapsulation device is constrained within the catheter.

38. 38. The method of any one of claims 31-37, wherein the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

39. The method of any one of claims 31 to 38, wherein the biological moiety releases a therapeutic product into the body conduit.

40. The method of any one of claims 31 to 39, wherein the body conduit is a blood vessel.

41. The method of any one of claims 31 to 40, wherein the body conduit is the gastrointestinal conduit.

42. 1. A method of deploying an endoluminal device, comprising: accessing a body conduit at a target location; Tracing the catheter to the target location point; and deploying an encapsulation device at the target location; Including, the encapsulation device includes at least one reservoir space containing a biological moiety therein, the at least one reservoir space being disposed within a containment layer having at least one structural element disposed therein; and A method in which separation distance is maintained during deployment.

43. 43. The method of claim 42, comprising inserting a guidewire and following a catheter over the guidewire to the target location point.

44. 44. The method of claim 43, wherein the encapsulation device is constrained within the catheter.

45. 45. The method of any one of claims 42-44, wherein the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

46. The method of any one of claims 42 to 45, wherein the biological moiety releases a therapeutic product into the body conduit.

47. The method of any one of claims 42 to 46, wherein the body conduit is a blood vessel.

48. The method of any one of claims 42 to 46, wherein the body conduit is the gastrointestinal conduit.

49. The method of any one of claims 42 to 48, comprising a cell-releasing layer disposed adjacent the interior surface of the body conduit.

50. The method of any one of claims 42 to 49, comprising a cell-retaining layer as an inner layer of the encapsulation device.

51. 51. The method of any one of claims 42 to 50, wherein a first cell-releasing layer is disposed on a first side of the containment layer and a second cell-releasing layer is disposed on a second side of the containment layer.

52. 1. A method of deploying an extraluminal device, comprising: accessing a first body conduit at a first target entry point; inserting a guidewire into the first body conduit at the first target entry point; following a catheter over the guidewire to a target exit point on the first body vessel; exiting said first body conduit at a target exit point using an accessory tool; following the guidewire to a second target entry point on a second body vessel; entering the second body conduit using an accessory tool; and deploying an encapsulation device at the second target entry point on the second body conduit, wherein the encapsulation device includes at least one reservoir space containing a biological moiety therein, the at least one reservoir space having a first cell-retaining layer thereon; Including, the encapsulation device forms a third conduit connecting the first body conduit and the second body conduit; and The cell-retentive layer forms the inner lining of the third body conduit.

53. 53. The method of claim 52, wherein the encapsulation device is constrained within the catheter.

54. 54. The method of claim 52 or claim 53, wherein the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

55. The method of any one of claims 52 to 54, wherein the biological moiety releases a therapeutic product.

56. 56. The method of any one of claims 52 to 55, wherein the body conduit is a blood vessel.

57. 56. The method of any one of claims 52 to 55, wherein the body conduit is the gastrointestinal conduit.

58. 58. The method of any one of claims 52 to 57, wherein the encapsulation device comprises a containment layer comprising structural elements that maintain a separation distance between the at least one reservoir space and the at least one reservoir space under an external compressive force and an internal expansion force.

59. 59. The method of any one of claims 52 to 58, wherein the encapsulation device comprises a second cell-retaining layer on an opposite side of the at least one reservoir space from the first cell-retaining layer.

60. 1. A method of deploying an extraluminal device, comprising: accessing a body conduit at a first target entry point; inserting a guidewire into the body conduit at the first target entry point; following a catheter over the guidewire to a target exit point prior to a desired bypass region of the body conduit; exiting the body conduit at the first target exit point using an accessory tool; following the guidewire to a second target entry point on the body conduit at a location after a desired bypass region of the body conduit; Entering the body conduit at the second target entry point using the accessory tool; and deploying an encapsulation device at the second target entry point such that the encapsulation device connects the first target exit point and the second target entry point, wherein the encapsulation device comprises at least one reservoir space containing a biological moiety therein and a cell-release layer; Including, A method wherein a portion of the cell-open layer is adjacent to an interior surface of the body conduit.

61. 61. The method of claim 60, wherein the encapsulation device is constrained within the catheter.

62. 62. The method of claim 60 or claim 61, wherein the encapsulation device is endoscopically deployed, cystoscopically deployed, laparoscopically deployed, or bronchoscopically deployed.

63. 63. The method of any one of claims 60 to 62, wherein the biological moiety releases a therapeutic product into the body conduit.

64. 64. The method of any one of claims 60 to 63, wherein the body conduit is a blood vessel.

65. 64. The method of any one of claims 60 to 63, wherein the body conduit is the gastrointestinal conduit.

66. 66. The method of any one of claims 60 to 65, wherein the desired bypass region is an occlusion.

67. 1. A method of deploying an encapsulation device, comprising: surgically accessing a target location point on a first body conduit at a first target entry point; ablating a portion of the body conduit at the target location point; and replacing the resected portion of the body conduit at the target location with an encapsulation device by an end-to-end anastomosis; Including, the encapsulation device includes a structural element that forms a reservoir space within a containment layer; and The method wherein the reservoir space contains a biological moiety therein.

68. the containment layer has a first side; 68. The method of claim 67, wherein a cell-retaining layer is disposed on the first side of the containment layer and a cell-releasing layer is disposed on the cell-retaining layer and adjacent the interior surface of the body conduit.

69. 69. The method of claim 67 or claim 68, wherein the biological moiety releases a therapeutic product into the body conduit.

70. 70. The method of any one of claims 67 to 69, wherein the body conduit is a blood vessel.

71. 70. The method of any one of claims 67 to 69, wherein the bodily conduit is the gastrointestinal conduit.

72. 1. A method of deploying an encapsulation device, comprising: surgically accessing a target location on a body vessel; forming a slit in the body conduit at the target location to access the body conduit; and inserting an encapsulation device into the body conduit at the target location; Including, the encapsulation device includes at least one reservoir space containing a biological moiety therein; and The at least one reservoir space has a cell-free layer thereon and is positioned adjacent to an interior surface of the body conduit.

73. 73. The method of claim 72, wherein the biological moiety releases a therapeutic product into the body conduit.

74. 74. The method of claim 72 or claim 73, wherein the body conduit is a blood vessel.

75. 74. The method of claim 72 or claim 73, wherein the body conduit is the gastrointestinal conduit.

76. 1. A method of placing an extraluminal bypass or shunt device, comprising: surgically accessing a first target location on a first body conduit; connecting a first end of an encapsulation device to a first target location point of the first body conduit; and connecting a second end of the encapsulation device to a second target location point on a second body conduit; Including, the encapsulation device includes a cell-retaining layer and at least one reservoir space containing at least one biological moiety therein; the encapsulation device forms a third conduit connecting the first body conduit and the second body conduit; and The cell-retentive layer forms an inner surface of the third conduit.

77. 77. The method of claim 76, wherein the at least one biological moiety releases a therapeutic product.

78. 78. The method of claim 76 or claim 77, wherein the first body conduit and the second body conduit are each blood vessels.

79. 78. The method of claim 76 or claim 77, wherein the first and second bodily conduits are each gastrointestinal conduits.

80. 1. A method of deploying an encapsulation device, comprising: surgically accessing a target location in a body conduit; and disposing the encapsulation device around an exterior surface of the body conduit such that the encapsulation device substantially surrounds at least a portion of the body conduit; Including, The method, wherein the encapsulation device includes at least one reservoir space containing a biological moiety therein, the at least one reservoir space having a cell-release layer disposed on a surface thereof, the cell-release layer being adjacent to an outer surface of the body conduit.

81. 81. The method of claim 80, wherein the at least one biological moiety releases a therapeutic product.

82. 82. The method of claim 80 or claim 81, wherein the first body conduit and the second body conduit are each blood vessels.

83. 82. The method of claim 80 or claim 81, wherein the first and second bodily conduits are each gastrointestinal conduits.

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