Anchoring region of implantable medical device

Abstract

A device for encapsulating biological entities (e.g., cells) is disclosed, wherein the encapsulated device is implanted in a tissue bed of a patient to provide biological therapy. The packaged device includes an inactive region (e.g., a solder region) located around an outer periphery of the device. The inactive region is non-porous and prevents cell ingrowth and / or vascularization therein. An anchoring region comprising an ingrowth layer and a bonding layer may be attached or otherwise secured to the inactive region. The open microstructure of the ingrowth layer allows rapid ingrowth of cells and / or blood vessels to stabilize the encapsulated device within the host tissue. In some embodiments, an inactive region may be formed at a location (s) on a cell retention region of the encapsulated device.

Description

Technical Field

[0001] The present disclosure generally relates to implantable medical devices, and more particularly to a cell encapsulation device including an anchoring region on a non-active region, wherein the anchoring region includes an ingrowth layer that allows for rapid inward growth of cells and / or blood vessels to stabilize the cell encapsulation device within host tissue. Background Art

[0002] Biotherapies are increasingly becoming a viable method for treating various diseases such as diabetes, heart disease, Alzheimer's disease, Parkinson's disease, and various other diseases. Generally, a therapeutic agent such as cells, viruses, viral vectors, or other biological entities can be introduced into a patient by a surgical method. The biological entity can first be inserted into an encapsulation device and then implanted at a target location in the patient. However, after implantation, micromotion may occur, which may disrupt the positioning of the device and trigger a chronic inflammatory response. In addition, micromotion may reduce the collagenous ingrowth and vascularization required for the normal operation of the encapsulation device.

[0003] Therefore, there is still a need for an encapsulation device having optimized stability (such as improved host tissue integration and anchoring of the encapsulation device) and the function of the encapsulation device in vivo. Summary of the Invention

[0004] In one aspect ("Aspect 1"), a cell encapsulation device includes a cell retention region, a non-active region, and an anchoring region disposed on at least a portion of the non-active region, wherein the anchoring region includes an open microstructure configured to promote tissue ingrowth.

[0005] According to another aspect of Aspect 1 ("Aspect 2"), the open microstructure includes a porous polymer having a plurality of anchoring features defined by a size between about 0.1 micrometer and about 100 micrometers.

[0006] According to another aspect of Aspect 1 or Aspect 2 ("Aspect 3"), the non-active region is disposed along the perimeter of the cell retention region.

[0007] According to another aspect of any of the foregoing aspects ("Aspect 4"), it includes at least one non-active region located on the cell retention region.

[0008] According to another aspect of any of the foregoing aspects ("Aspect 5"), the anchoring region includes expanded polytetrafluoroethylene.

[0009] According to another aspect of any of the foregoing aspects (Aspect "6"), at least 15% of the area of the non-active region is covered by the anchoring region.

[0010] Another aspect according to any of the foregoing aspects (Aspect "7"), wherein the anchoring region includes a bonding layer and an ingrowth layer.

[0011] Another aspect according to any of the foregoing aspects ("Aspect 8"), wherein the bonding layer includes a first plurality of fibrils, the ingrowth layer includes a second plurality of fibrils, and the fibril density of the bonding layer is greater than the fibril density of the ingrowth layer.

[0012] Another aspect according to any of the foregoing aspects ("Aspect 9"), wherein the ingrowth layer is configured to allow tissue to grow inwardly into the pores of the ingrowth layer.

[0013] Another aspect according to any of the foregoing aspects ("Aspect 10"), wherein the ratio of the active region / inactive region is 50% to 150%.

[0014] In one aspect ("Aspect 11"), a cell encapsulation device includes: an active region that covers at least one reservoir containing cells and is defined by a perimeter and a surface area; a sealing region disposed around the perimeter of the active region; an open microstructure layer disposed on at least a portion of the anchoring region, wherein the open microstructure is defined by interconnected fibrils, and wherein the thickness of the open microstructure is between 5 micrometers and 600 micrometers.

[0015] Another aspect according to Aspect 11 ("Aspect 12"), wherein the fibrils of the open microstructure have a size between 0.1 micrometer and 100 micrometers.

[0016] Another aspect according to Aspect 11 or Aspect 12 ("Aspect 13"), wherein the fibrils of the open microstructure have a size less than 1 micrometer.

[0017] Another aspect according to any of Aspects 11 to 13 (Aspect "14"), wherein at least 15% of the sealing region is covered by the anchoring region.

[0018] Another aspect according to any of Aspects 11 to 14 (Aspect "15"), wherein 40% to 95% of the sealing region is covered by the anchoring region.

[0019] Another aspect according to any of Aspects 11 to 15 (Aspect "16"), wherein 60% to 99% of the sealing region is covered by the anchoring region.

[0020] Another aspect according to any of Aspects 11 to 16 (Aspect "17"), wherein the open microstructure is welded to the sealing region.

[0021] Another aspect (“Aspect 18”) according to any one of Aspects 11 to 17, wherein the open microstructure is composed of a first layer and a second layer, wherein both the first layer and the second layer include fibrils, and wherein the fibril density of the first layer is higher than the fibril density of the second layer.

[0022] In one aspect (“Aspect 19”), an anchoring region for use with an implantable medical device to promote tissue integration includes a bonding layer and an ingrowth layer attached to the bonding layer, wherein the ingrowth layer comprises a porous polymer having a plurality of anchoring features sized between about 0.1 micrometer and about 100 micrometers, and wherein the porous polymer is configured to integrate with tissue.

[0023] Another aspect (“Aspect 20”) according to Aspect 19, wherein the bonding layer is configured to be welded to the implantable medical device.

[0024] Another aspect (“Aspect 21”) according to Aspect 19 or Aspect 20, wherein the bonding layer has a first plurality of fibrils, the ingrowth layer has a second plurality of fibrils, and wherein the fibril density of the bonding layer is greater than the fibril density of the ingrowth layer. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to further understand the present disclosure. The drawings illustrate embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure.

[0026] Figure 1 is a schematic top view of a cell encapsulation device according to some embodiments;

[0027] Figure 2 is according to some embodiments Figure 1 of a cross-sectional schematic view of a cell encapsulation device;

[0028] Figure 2A shows a cross-sectional schematic view of a semipermeable membrane according to some embodiments;

[0029] Figure 3 is a schematic top view of a cell encapsulation device according to some embodiments;

[0030] Figure 4 is according to some embodiments Figure 3 of a cross-sectional schematic view of a cell encapsulation device;

[0031] Figure 5 is a schematic top view of a cell encapsulation device having an open anchoring region at the periphery of the device according to some embodiments;

[0032] Figure 6 Schematic diagram of a photo of an anchoring region of a cell encapsulation device according to some embodiments, including an ingrowth layer and a partial active region (e.g., a grid);

[0033] Figure 7 Top view of the most open expanded polytetrafluoroethylene (ePTFE) layer in Example 1 taken with an optical microscope at 50x magnification according to some embodiments;

[0034] Figure 8 Scanning electron micrograph (SEM) of a cross-section of a biocompatible membrane composite formed in Example 1 according to some embodiments;

[0035] Figures 9A - 9E Representative histological images according to some embodiments demonstrating improved ingrowth of collagen tissue in Examples 1 and 3, while there was no improvement in the ingrowth of collagen tissue in the active regions of Comparative Examples 4, 5, F, and 6; and

[0036] Figures 10A - 10E Representative histological images of the capsule thickness of Examples 1 and 3 and Comparative Examples 4, 5, and 6 according to some embodiments. Detailed Description

[0037] Those skilled in the art will readily appreciate that various aspects of the present disclosure can be implemented by any number of methods and devices configured to perform the intended functions. It should also be noted that the drawings referred to herein are not necessarily drawn to scale and may be enlarged to illustrate various aspects of the present disclosure. In this regard, these drawings should not be considered restrictive. Directional references such as "upper", "lower", "top", "left", "right", "front", and "rear" are intended to refer to the directions shown and described in the figures with reference to the components and directions. It should be noted that all ranges described herein are exemplary in nature and include any and all values therebetween. Additionally, all references cited herein are incorporated by reference in their entirety. The terms "implantable medical device" or "implantable device" may be used interchangeably with the terms "cell encapsulation device" or "encapsulation device" herein.

[0038] The present disclosure relates to a device for encapsulating biological entities (such as cells), wherein the encapsulation device is implanted into a patient (such as into a tissue bed) to provide biotherapy. The encapsulation device includes an inactive region located on the outer periphery of the device. The inactive region is non-porous and prevents inward growth of cells and / or angiogenesis therein. An anchoring region including an ingrowth layer and a binding layer can be attached or otherwise fixed to the inactive region. The open microstructure of the ingrowth layer allows for rapid inward growth of cells and / or blood vessels to stabilize the encapsulation device within the host tissue. In some embodiments, the inactive region can be formed at one or more locations on the cell retention region of the encapsulation device. It should be understood that the term "about" as used herein means + / - 10% of the specified measurement unit.

[0039] Biological entities suitable for encapsulation and implantation using the devices described herein include cells, viruses, viral vectors, bacteria, proteins, antibodies, and other bioactive entities. In short, the biological entities described herein refer to cells, but nothing in this specification limits the biological entities to cells or any particular type of cell, and the following description also applies to non-cellular biological entities. Various types of prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, and / or stem cells can be used with the cell encapsulation device of the present invention. In some embodiments, the cells are microencapsulated in a biological material of natural or synthetic origin, including but not limited to hydrogel biomaterials. In some embodiments, the cells secrete a therapeutically active substance. Such substances include: hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cell products that provide a therapeutic benefit to the recipient of the device. Examples of such therapeutic cell products include but are not limited to insulin, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, and factor VIII. Non-limiting examples of suitable growth factors include: vascular endothelial growth factor, platelet-derived growth factor, platelet-activating factor, transforming growth factor, bone morphogenetic protein, activin, inhibin, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, glial cell line-derived neurotrophic factor, growth differentiation factor-9, epidermal growth factor, and combinations thereof. It should be understood that throughout the content of the present disclosure, the term "cell" or "cells" can be replaced by "biological entity" or "biological entities" respectively. In addition, the terms "cell encapsulation device", "encapsulation device", and "device" can be used interchangeably herein.

[0040] Figure 1 A top view of an embodiment of the cell encapsulation device 10 is shown. However, it should be understood that the embodiments described herein can be applied to a variety of implantable medical devices, and as Figure 1The cell encapsulation device shown is merely exemplary in nature. It should be understood that any device intended to reside within a patient is considered to be within the scope of the present disclosure. As Figure 1 shown, the cell encapsulation device 10 has a cell retention region 12 (e.g., a reservoir), an inactive region 20, and an anchoring region 24 disposed on the inactive region 20. The inactive region 20 is covered by the anchoring region 24, including, for example, the inactive region 20 overlapping, coextending with, being overlaid by, or otherwise entirely or partially covered by the anchoring region 24. In some embodiments, the anchoring region 24 may be disposed only on a portion of the inactive region 20. In other embodiments, the anchoring region 24 may also and / or alternatively be located on other regions of the device 10 that include the inactive region. As used herein, the term "inactive region" is defined as the region in the cell encapsulation device (or implantable medical device) that is not directly above the cell accommodation region 12 of the cell encapsulation device 10 and / or where no cell or blood vessel ingrowth occurs, and where no mass transfer into or out of the cell accommodation region 12 can occur. As used herein, the term "active region" refers to the region directly above the cell accommodation region 12 and / or the region capable of mass transfer inside and outside the cell accommodation region 12. As Figure 1 shown, the cell encapsulation device 10 may have two anchoring regions 24 disposed thereon. As will be further described herein with reference to Figure 3 and 4 In some embodiments, the cell encapsulation device 10 has two or more anchoring regions 24 disposed thereon.

[0041] The inactive region 20 may be defined as the region where two composite layers are welded or otherwise adhered and / or joined together to form a seal around the perimeter of the device 10. As Figure 1 shown, the inactive region 20 is defined as the region around the outer perimeter of the cell encapsulation device 10, but the inactive region 20 may also have a variety of configurations. In the Figure 1 embodiment shown, the inactive region 20 defines the outer perimeter of the cell encapsulation device 10 and has a total length of L1. As Figure 1 shown, the total length L1 defines the maximum dimension of the cell encapsulation device 10. The cell encapsulation device 10 is also defined by a length L2, which is the maximum dimension of the cell retention region 12. Additionally, the length L3 is defined by the difference between the total length L1 of the cell encapsulation device 10 and the length L2 (the maximum length of the cell retention region 12). Although the above dimensions refer to length, in some embodiments (not shown), the cell retention region 12 may have a different configuration and the maximum dimension may be defined as width and / or thickness.

[0042] As Figure 2As shown in the cross-sectional view, the cell encapsulation device 10 may include a first composite layer 14 and a second composite layer 16, which are sealed at their perimeters to form a cell retention region 12. The cell retention region 12 is configured to receive cells or other therapeutic biological entities. The first composite layer 14 and the second composite layer 16 each include an outer porous layer 11, 15 disposed adjacent to an inner porous layer 13, 17. The inner porous layers 13, 17 of the first and second composite layers 14, 16 prevent inward cell growth. For example, the average pore size of the inner porous layers 13, 17 is small enough to prevent inward blood vessel growth (e.g., less than about 1 micron as measured by porosity). In contrast, the outer porous layers 11, 15 have sufficient porosity to allow tissue ingrowth into the pores of the outer porous layers (e.g., greater than about 1 micron as measured by porosity). Inward tissue growth through the outer porous layers 11, 15 facilitates the transfer of nutrients and biomolecules from the body to the cells encapsulated in the cell retention region 12 of the device 10. In some embodiments, the cell retention region 12 may be formed by one or more single layers (e.g., layers that are not composite layers) (not shown). In other embodiments, the cell retention region 12 may be formed only by a cell-impermeable layer (not shown) or a cell-impermeable layer and two (or more) cell-permeable layers (not shown). The region capable of material transport inside and outside the cell retention region 12 defined by the outer porous layers 11, 15 may be referred to herein as the active region. Implantable devices that include more than just the first composite layer 14 and / or the second composite layer 16 are considered to be within the scope of the present invention.

[0043] The first composite layer 14 and the second composite layer 16 may be joined together around the perimeters of the first and second composite layers 14, 16 to form an inactive region 20. The inactive region 20 forms the outer perimeter of the cell encapsulation device 10. The first composite layer 14 and the second composite layer 16 may be joined together by a variety of welding techniques, fusion mechanisms, or adhesive mechanisms. In some embodiments, the first and second composite layers 14, 16 are joined by thermoplastic welding, ultrasonic welding, fusion, adhesives, mechanical joining between layers, and various other suitable methods known to those skilled in the art for bonding polymers.

[0044] In some embodiments, one or both of the first composite layer 14 and the second composite layer 16 of the cell encapsulation device 10 are made primarily or entirely of a semipermeable material having selective sieving and / or porous properties. The semipermeable material controls the passage of, for example, solutes, biochemical substances, viruses, and cells through the material primarily based on size. In embodiments where the semipermeable material is porous only in a portion of its thickness, the molecular weight cut-off value or sieving characteristics of the semipermeable membrane begin at the surface. Thus, certain solutes and / or cells do not enter from one side and pass through the porous space of the material to the other side. Figure 2AA cross-sectional view of the porous material 70 available in the cell encapsulation device 10 described herein is shown, wherein the selective permeability of the porous material 70 prevents cells 72 from migrating or growing into the space of the porous material 70 while allowing solutes 74 to flow bidirectionally across the thickness of the porous material 70. The region capable of material transport inside and outside the cell retention region 12 defined by the semipermeable membrane may also be referred to herein as the active region.

[0045] The joining process of the first and second composite layers 14, 16 can result in a non-porous outer surface of the non-active region 20. In some embodiments, the first and second composite layers 14, 16 can be fused together, for example, by heating and pressurization, without using an adhesive. Fusing by heating and pressurization can result in a loss of surface porosity and can cause any microstructures at the surface where the fusion occurs to densify. Thus, after fusing (without an adhesive) the first and second composite layers 14, 16, a non-porous surface is formed outside the non-active region 20. In some embodiments, thermoplastic welding can be used, which causes the pores of the first and second composite layers 14, 16 to be filled, partially filled, covered, embedded, or otherwise drawn in by the molten polymeric material. In another embodiment (where the first and second composite layers 14, 16 are self-adhesive), joining the first and second composite layers 14, 16 by a method such as thermal welding or ultrasonic welding can cause the pores to collapse and become smooth and non-porous. The joining of the first and second composite layers 14, 16 creates a region that prohibits the transfer of nutrients or therapeutic agents into and / or out of the non-active region 20. Additionally, no cells or tissues can integrate into the non-active region 20. Thus, the non-active region 20 can be the non-active region of the cell encapsulation device 10.

[0046] The cell encapsulation device can include additional non-active regions separate from the sealing region 20. A non-limiting example of a non-active region can be a structural frame or a reinforcing member located at the periphery of the device 10 to provide rigidity and operability to the encapsulation device 10. In some embodiments, additional elements (such as perfusion tubes) for delivering therapeutic biological entities to the device 10 can be non-active regions of the device 10 because they do not allow cells or tissues to grow inwardly. Various other non-active regions can be defined on the device 10, such as, but not limited to, a structural frame, a suture pad, or a pore.

[0047] There is no particular limitation on the material forming the frame, as long as it provides the necessary stiffness, is compatible with the implantation environment, and has the necessary stiffness. Non-limiting examples of useful materials include, but are not limited to: polymer materials such as polyetheretherketone (PEEK), polyethylene terephthalate (PET), polypropylene, polyethylene, polymethyl methacrylate, polyethyl methacrylate, polyacrylate, poly-α-hydroxy acid, polycaprolactone, polydioxanone, polyester, polyglycolic acid, polyethylene glycol, polylactide, polyorthoester, polyphosphate, polyoxaester, polyphosphonate, polyphosphinate, polysaccharide, polytyrosine carbonate, silicone, polyurethane, polyurethane with ionic or mesogenic components prepared by the prepolymer method, block copolymers of polyethylene terephthalate (PET) and polyethylene oxide (PEO), block copolymers comprising polystyrene and poly(1,4-butadiene), and ABA triblock copolymers made of poly(2-methyl-2-oxazoline) and polytetrahydrofuran, and their copolymers or polymer blends. Metal frames can also be integrated using materials such as spring-tempered 316SST; spring-tempered cobalt-chromium alloys such as Co-28Cr-6Mo or Co-35Ni-20Cr-10Mo; spring-tempered titanium-based alloys such as Ti-6Al-4V or spring-tempered nickel-titanium alloys such as nitinol or copper-aluminum-nickel, copper-zinc-aluminum, aluminum and iron-manganese-silicon alloys. The frame material can be a material that is inherently biocompatible or a material that lacks inherent biocompatibility but is given biocompatibility, such as having a biocompatible coating. Non-limiting examples of inherently biocompatible frame materials include PEEK, nitinol, or Ti-6Al-4V.

[0048] As Figure 2 shown, the anchoring region 24 can be disposed on at least a portion of the inactive region 20 to provide an outward-facing porous surface that enables tissue integration and ingrowth. In other words, as will be further described herein, the inactive region 20 does not have a tendency for tissue integration or ingrowth, but the anchoring region 24 has a tendency for tissue integration such that tissue can integrate into the anchoring region 24.

[0049] The anchoring region 24 can be disposed on at least a portion of the surface of the inactive region 20. In some embodiments, the anchoring region 24 can be disposed on the inactive region 20, such as fused, welded, adhered, or otherwise attached to the inactive region 20. In some embodiments, the surface of the inactive region 20 can include an upper surface 21 and a lower surface 23. The anchoring region 24 can be attached to at least a portion of one or both of the upper surface 21 and the lower surface 23 of the inactive region 20.

[0050] In some embodiments, the surface area of the anchoring region 24 is about 90% of the surface area of the non-active region 20. In these embodiments, the surface area of the non-active region 20 may include the total surface area of the non-active region 20 on the upper surface 21 and the lower surface 23 of the non-active region 20. Thus, in embodiments where the anchoring region 24 is disposed on the upper surface 21 and the lower surface 23 of the non-active region 20, the surface area of the anchoring region 24 may be defined as the total surface area of the anchoring region 24 disposed on the upper surface 21 and the lower surface 23.

[0051] In some embodiments, the surface area value of the anchoring region 24 can vary. For example, the surface area of the anchoring region 24 can be at least 15% of the surface area of the non-active region 20. In some other embodiments, the surface area of the anchoring region 24 can be at least 15% of the total surface area of the non-active region 20. In other non-limiting examples, the surface area of the anchoring region 24 can be from about 5% to about 100% of the surface area of the non-active region 20, the surface area of the anchoring region 24 can be from about 5% to about 99% of the surface area of the non-active region 20, the surface area of the anchoring region 24 can be from 5% to about 90% of the surface area of the non-active region 20, the surface area of the anchoring region 24 can be from 15% to about 85% of the surface area of the non-active region 20, the surface area of the anchoring region 24 can be from 20% to about 75% of the surface area of the non-active region 20, the surface area of the anchoring region 24 can be from 30% to about 60% of the surface area of the non-active region 20, or the surface area of the anchoring region 24 can be from 40% to about 50% of the surface area of the non-active region 20. In some other embodiments, the surface area of the anchoring region 24 can be from about 15% to about 100%, from about 15% to about 99%, from about 25% to about 99%, from about 35% to about 99%, from about 45% to about 99%, from about 55% to about 99%, from about 65% to about 99%, from about 75% to about 99% of the surface area of the non-active region 20.

[0052] The anchoring region 24 can be defined as a portion on the non-active region 20 where an open microstructure is provided and which is directly exposed to natural tissue (i.e., host tissue) upon implantation. As Figure 2 shown, the anchoring region 24 can be formed by an ingrowth layer 28 and a bonding layer 26. The ingrowth layer 28 of the anchoring region 24 has an open microstructure, which can promote the ingrowth of cells and tissue onto and within the anchoring region 24. In some embodiments, the open microstructure is a node and fibril microstructure. As used herein, the term "open" means that the described region or layer is cell-permeable, and cells can enter and / or leave the layer or region to allow cell ingrowth and / or tissue ingrowth / integration. It should be understood that the bonding layer 26 does not have sufficient porosity to allow cell or blood vessel ingrowth. Herein, a layer that restricts or prevents tissue ingrowth and / or the integration of the welding material can be referred to as a "tight" layer.

[0053] The open microstructure of the ingrowth layer 28 may include a plurality of anchoring features that allow cells and / or tissue to grow inwardly onto and into the outer porous layers 11, 15 of the cell encapsulation device 10 to surround and anchor within the ingrowth layer 28 of the anchoring region 24. The anchoring features may be fibrils and / or fibers. Additionally, the anchoring features may be defined by a dimension such as diameter, having a value between about 0.1 micrometer and about 100 micrometers. In some embodiments, the size range of the anchoring features may be about 0.1 micrometer to about 80 micrometers, about 0.1 micrometer to about 75 micrometers, about 0.1 micrometer to about 70 micrometers, about 0.1 micrometer to about 65 micrometers, about 0.1 micrometer to about 50 micrometers, about 0.1 micrometer to about 25 micrometers, about 0.1 micrometer to about 10 micrometers, about 0.1 micrometer to about 2 micrometers, or about 0.1 micrometer to about 0.5 micrometers. In some embodiments, the size of the anchoring features may be defined as the average size or diameter of the anchoring features of the open microstructure. In these examples, the size of the anchoring features may be measured by taking a scanning electron microscope (SEM) image of the anchoring features.

[0054] In some embodiments, tissue ingrowth penetrates and encapsulates the anchoring features within the ingrowth layer 28, thereby encapsulating the anchoring region 24 to anchor the encapsulation device 10 within the surrounding tissue ingrowth at a faster rate than tissue integration in other regions of the cell encapsulation device 10. The faster integration of tissue ingrowth into the ingrowth layer 28 stabilizes the cell encapsulation device 10 in the tissue bed and reduces the effect of any micromotion or displacement of the encapsulation device 10. Once the tissue is integrated into the anchoring region 24, the device 10 can be stabilized within the host tissue (i.e., reduced micromotion / fretting of the device 10), which in turn facilitates the development of vasculature around and within the outer porous membranes 11, 15 of the encapsulation device 10. Thus, nutrients can be delivered to the cell retention region 12 more quickly.

[0055] As described above, the anchoring region 24 may include a binding layer 26 configured to directly couple to the non-active region 20 and an ingrowth layer 28 configured to couple to the binding layer 26 and be exposed to native tissue and subsequently grow inwardly to anchor the cell encapsulation device 10. In some embodiments, the density of the fibers or fibrils of the binding layer may be greater than the density of the fibers or fibrils of the ingrowth layer 28 of the anchoring region 24, which density is determined by the pore size (e.g., the pore size of the binding layer 26 is less than 1 micrometer). In this way, during the process of thermally welding the anchoring region 24 to the non-active region 20, the molten polymer (e.g., the welding material) can enter the binding layer 26 but is inhibited from flowing into or entering the ingrowth layer 28, thereby maintaining the ability of the ingrowth layer 28 to allow cells and / or tissue to grow inwardly into the anchoring region 24.

[0056] In some embodiments, the bonding layer 26 can be part of the non-active region 20 rather than part of the anchoring region 24. For example, the non-active region 20 can include the bonding layer 26 before the anchoring region 24 is attached to the non-active region 20. In other embodiments, the ingrowth layer 28 can be a continuation of the bonding layer 26, thereby providing an open layer into which native tissue (i.e., host tissue) can grow and anchor the encapsulation device 10. In some embodiments, the bonding layer 26 can be modified such that it is capable of cell and / or tissue integration and bonding to the non-active region 20. In this way, the top of the bonding layer 26 can have a more open structure (e.g., a smaller fibril density) than the bottom of the bonding layer 26. In some embodiments, the bonding layer 26 can be a dense membrane [such as an expanded polytetrafluoroethylene membrane (ePTFE)] or other microporous membrane.

[0057] In some embodiments, the anchoring region 24 (and / or the ingrowth layer 28) can include any number of polymer layers. For example, the anchoring region 24 can include two layers (e.g., a bilayer membrane), three layers (e.g., a trilayer membrane), four layers, five layers or even more layers. When using a multi-layer anchoring region 24, one side of the multi-layer polymer membrane is configured to be in direct contact with and coupled to the non-active region 20, while the other side of the multi-layer polymer membrane is configured to be exposed to native tissue and subsequent cell and / or tissue ingrowth to anchor the encapsulation device 10. The bonding layer 26 can be a dense layer or an open layer. When the bonding layer 26 is an open layer, another layer can be present between the bonding layer 26 and the ingrowth layer 28 that prevents adhesives and / or welding materials from penetrating from the bonding layer 26 into the ingrowth layer 28. Additionally, the bonding layer 26 can be a composite layer that has an open layer to allow a thermoplastic polymer to melt in and a dense layer to prevent the thermoplastic polymer from blocking the ingrowth layer 28. The multi-layer polymer membrane can adopt various structures, such as but not limited to: open-dense-open structure, dense-open structure or dense-open-open structure.

[0058] In some embodiments, the anchoring region 24 can consist of a single expanded polytetrafluoroethylene layer (ePTFE layer), a bilayer containing an ePTFE layer, where one layer has a first pore size and the second layer has a second pore size, and the first pore size is different from the second pore size. For example, the first pore size can be less than about 1 micron and the second pore size can be greater than about 2 microns. A three-layer containing an ePTFE layer can include a large pore size on the outer layer and a smaller pore size on the inner layer. In a three-layer composite containing ePTFE, the ePTFE composite can be in a tight / medium / open pore size sequence. Non-limiting layers that can be included in the anchoring region 24 include non-woven layers [such as spunbond non-woven polyethylene terephthalate (PET), bioabsorbable non-wovens, polyetheretherketone (PEEK), non-wovens laminated with an ePTFE dense pore membrane, electrospun membranes, polytetrafluoroethylene (PTFE) electrospun membranes, and porous membranes formed by dissolving salts incorporated within the membrane (i.e., salt leaching)]. Methods for preparing porous membranes include solvent-induced phase separation, vapor-induced phase separation, track etching, and sintering.

[0059] As Figure 2 Best shown, the ingrowth region 28 has a certain thickness. In some embodiments, the thickness can be from about 5 microns to about 600 microns. In some embodiments, the thickness can range from about 10 microns to about 600 microns, about 15 microns to about 600 microns, about 20 microns to about 600 microns, about 20 microns to about 400 microns, about 20 microns to about 100 microns, or about 20 microns to about 50 microns. The thickness of the ingrowth region 28 can be the same on each side of the non-active region 20. However, in other embodiments, the ingrowth region 28 can be designed such that the thickness on one side of the cell encapsulation device 10 is greater than the thickness on the other side of the device 10.

[0060] Although the anchoring region 24 is described herein as being disposed on the non-active region 20, in other embodiments, the anchoring region 24 can be disposed on any (one or more) non-active regions of the cell encapsulation device 10, as will be further referenced Figure 3 and 4 as described. For example, in embodiments where a first membrane layer forms the first composite layer 14 and a second membrane layer forms the second composite layer 16, the cell retention region 12 can be designed such that portions of the first membrane layer and the second membrane layer can be sealed together in portions of the cell retention region 12 such that there are multiple compartments or reservoirs within the cell retention region 12. The non-active region 20 can also be formed in the portions where the first composite layer 14 and the second composite layer 16 are sealed together with each other. Then, the sealed region between the first membrane layer and the second membrane layer or the first composite layer 14 and the second composite layer 16 can define the non-active region 20 to which the anchoring region 24 can be associated. Various other non-active regions 20 include frames or reinforcing members located around the perimeter or around the active region of the device 10.

[0061] Once the cell encapsulation device 10 is implanted into a subject, tissue will grow and engage with the microstructures of the ingrowth layer 28 of the anchoring region 24 and proliferate into the open microstructures. This tissue ingrowth allows the tissue located around the cell encapsulation device 10 to fix to the cell encapsulation device 10 and / or anchor the position of the cell encapsulation device 10 within the target location. Specifically, natural tissue can engage with the cell encapsulation device 10 around the entire device 10 to inhibit any micromotion or displacement of the cell encapsulation device 10 within the tissue bed. As previously described herein, rapid tissue integration in the anchoring region 24 enables the cell encapsulation device 10 to be stabilized faster in the patient, and in turn enables the formation of a vasculature faster around the encapsulation device 10. Nutrients can then be transported to the cell retention region 12. Accordingly, a targeted therapy of the encapsulation device 10 can be more effectively established to optimize the function of the cell encapsulation device 10.

[0062] The cell encapsulation device 10 can include more than one inactive region 20 and / or anchoring region 24. For example, Figure 3 Another embodiment of the cell encapsulation device 10 is shown, which includes a plurality of inactive regions formed on the cell retention region 12 of the encapsulation device 10. Figure 3 is a top view of the cell encapsulation device 10 having four inactive regions (i.e., 20a, 20b, 20c, 20d). The cell encapsulation device 10 includes a first inactive region 20a, which can be the same as the inactive region 20 (refer to Figure 2 ) as described above. As Figure 3 shown, the cell encapsulation device further includes a second inactive region 20b, a third inactive region 20c, and a fourth inactive region 20d. The second, third, and fourth inactive regions 20b-d can be circular inactive regions disposed above the cell retention region 12, respectively. It should be understood that the circular inactive regions shown as Figure 3 are exemplary in nature, and any geometric shape (e.g., triangle, square, ellipse, etc.) can form the inactive region 20. In some embodiments, the inactive regions 20b-d are point-bonding inactive regions. In addition, the inactive regions 20a-20d are inactive regions formed on the cell retention region 12 of the encapsulation device 10.

[0063] Figure 4 is taken along line 4-4 of Figure 3Cross-sectional view of a cell encapsulation device. As shown, the inactive region 20a extends to the periphery of the cell encapsulation device 10 and includes an anchoring region 24 disposed thereon. Further, the inactive region 20c also includes anchoring regions 24 disposed on both sides of the inactive region 20a. In the illustrated embodiment, both the inactive region 20a and the inactive region 20c include anchoring regions 24 on both sides of the inactive regions 20a, 20c to allow tissue integration in the anchoring regions 20a and 20c. Although not shown, the anchoring regions 24 may be disposed on one or both of the inactive regions 20b, 20d. It should be noted that each anchoring region 24 located on the inactive region 20c includes a binding layer 26 and an ingrowth layer 28. Additionally, the cell encapsulation device 10 may include any number of inactive regions 20, such as one, two, three, four, or five or more inactive regions 20. One, some, or all of these inactive regions 20 may be configured to have anchoring regions 24 welded, adhered, or otherwise attached thereto. An increase in the amount of the ingrowth region 24 on the inactive region 20 increases the area of the cell encapsulation device 10 available for rapid tissue ingrowth.

[0064] Figure 5 shows Figure 1 Top view of the cell encapsulation device 10 having a modified anchoring region 24 with a tissue ingrowth layer disposed thereon. The active region 12 shown is for illustrative purposes only. Figure 6 shows Figure 5 Enlarged view of a portion of the anchoring region 24. Figure 5 The active region 12 is also shown. Referring to Figure 6 , the ingrowth layer 28 includes anchoring features that may include multiple fibrils 66 terminating or originating from nodes 68. The void between the nodes 68 and the fibrils 66 is defined as a pore 70.

[0065] Although the above-described embodiments mention that the anchoring region 24 is provided on the inactive region 20, the anchoring region 24 can be provided on any non-porous region or other inactive region that needs to be covered by the ingrowth layer 28. In cases where the inactive region occupies a large portion of the device 10, the above-described embodiments of the anchoring region 24 combined with the device 10 may be particularly applicable. For example, if the area of the inactive region is approximately equal to or greater than the area of the active region (e.g., the area of the cell retention region 12), the difficulty of achieving rapid anchoring of the device 10 in the subject's body will increase. This situation becomes more obvious when the area of the active region is smaller than the area of the inactive region. For example, when the active region / inactive region is 90%, this anchoring in the inactive region becomes more desirable, and even more so when the ratio of the active region / inactive region is 80%. Therefore, it may be necessary to increase the surface area that can engage and promote ingrowth of tissue on the tissue-facing surface of the device 10. In some embodiments, the ratio of the active region / inactive region is from about 50% to about 150%, from about 50% to about 125%, from about 50% to about 100%, or from about 50% to about 75%.

[0066] Further, although the implantable device is mainly referred to herein as the cell encapsulation device 10, the anchoring region 24 can be applied to any type of implantable medical device. The anchoring region 24 can be provided on any inactive (e.g., non-porous) surface of any device designed to be inserted into a patient. In this way, the advantages of the anchoring region 24 can be combined with various types of devices that require increased stability in the patient's body.

[0067] Testing method

[0068] In Vivo Studies in New Zealand White Rabbits to Evaluate Host Tissue

[0069] Sterile empty encapsulation devices (i.e., without cells) were sealed in perfusion tubes before sterilization and then implanted subcutaneously in the backs of New Zealand white rabbits using blunt dissection delivery techniques. After approximately 7 days and 30 days, the animals were euthanized and the devices were removed for histological imaging.

[0070] The tissue samples were processed by stripping the skin and subcutaneous tissue to expose the implanted encapsulation device. Digital radiography (Faxitron UltraFocus system) was used to identify the device if necessary before the entire encapsulation device and surrounding tissue were removed. The device orientation was marked with a staple. All explanted devices and surrounding tissue were immersed in 10% neutral buffered formalin. Each device sample was assigned a unique number.

[0071] Three cross-sectional slices were taken from each sample. The three slices of each device were embedded together in paraffin, cut into 5-10 micron thick sections, placed on slides and stained with hematoxylin and eosin (H&E) and Masson's trichrome.

[0072] Images of the slides were taken using a Nikon DS-Fi series camera and Nikon NIS Elements microscopy imaging software. At least three magnified images were taken for each slide. Measurements were made using Nikon NIS Elements microscopy imaging software, which was calibrated with a certified microscope micrometer.

[0073] SEM Sample Preparation and Thickness Measurement

[0074] When preparing SEM samples, the membrane composite or membrane composite layer was first fixed to an adhesive for handling, with the side opposite the side to be imaged facing the adhesive. Then the film was cut into an area of approximately 3 mm x 3 mm for imaging. The samples were then sputter-coated with a platinum target using an Emitech K550X sputter coater. Subsequently, images were taken using a Thermo Fisher Scientific FEI Quanta 400 scanning electron microscope, with a magnification and resolution that allowed for a sufficient number of features to be seen for reliable analysis, while ensuring that the minimum size of each analyzed feature was at least five pixel lengths. The layer thickness was measured through the cross-section of the SEM image.

[0075] Surface Roughness

[0076] Surface roughness was measured using a Keyence VK-X1000 laser scanning confocal microscope and the accompanying Multi File Analyzer Software. The sample was fixed to the microscope stage with tape, with the tape adhered to the peripheral area of the device under test. Subsequently, images were taken using the VK-X1000 at a magnification of 20x. The surface area used for analyzing surface roughness was approximately 2.3 mm 2 . This range ensured sufficient resolution and surface representative analysis.

[0077] Then, the images were processed in the Multi File Analyzer Software by performing a tilt plane correction to eliminate any tilt. After image preprocessing, 21 line scans were performed in the x and y directions respectively (42 line scans in total), with each line spaced approximately 30 microns apart, and the Rz value was obtained. The average value of the Rz values from these 42 scans was taken as the value cited in this article. The Multi File Analyzer Software automatically calculated the Rz value, and no cut-off wavelength was specified.

[0078] Example

[0079] Example 1

[0080] In the first embodiment, a cell encapsulation device having an inactive region and an anchoring region thereon was formed. First, an expanded polytetrafluoroethylene (ePTFE) three-layer film was constructed according to the teachings presented in Example 4 of Bruhn et al. in WO 2020 / 243668. The three-layer ePTFE film consists of a first dense layer (having a plurality of pores with a dense microstructure), a second open layer (having a plurality of pores with an open microstructure), and a third open layer (having a plurality of pores with the most open microstructure). Figure 7 A top view of the third most open ePTFE layer is shown, and the image was taken using an optical microscope at a magnification of 50x. The characteristics of the ePTFE three-layer are shown in Table 1 below:

[0081] Table 1

[0082] ePTFE characteristics as described in Example 1 of WO2020 / 243668

[0083] Description First tight layer Second open layer Third most open layer Maximum pore size (μm) 0.5754 Not measurable None Pore size (μm) 0.987 Not measurable 7.531 Thickness (μm) 5.45 22.6 93.12

[0084] The three-layer ePTFE film was gently bonded to a polycarbonate polyurethane film approximately 75 microns thick. The bonding process was carried out at 165 °C for 30 seconds using a small spring manual press. This bonding process gently adhered the polycarbonate polyurethane film to the first dense layer of the three-layer ePTFE film to form an ePTFT / polycarbonate polyurethane composite for processing. Then, the ePTFE / polycarbonate polyurethane composite was laser cut into the outer peripheral welding shape of the cell encapsulation device, such as the component 1340 shown in Figure 13 of Bruhn et al. in WO 2020 / 243668.

[0085] Subsequently, according to the teachings presented in Bruhn et al. in WO 2020 / 243668, a cell encapsulation device was formed using the method described in Device B. The cell encapsulation device described herein differs from Device B described in Bruhn et al. in WO 2020 / 243668 in that: (1) a vascularization layer was not used and (2) the outermost upper and lower welding film layers described as 1340 in Figure 13 of Bruhn et al. in WO 2020 / 243668 were replaced with a laser-cut ePTFE / polycarbonate polyurethane composite welding layer. Thus, the replacement of the ePTFE / polycarbonate polyurethane composite presents open anchoring regions 24 on the upper and lower inactive regions of the encapsulation device.

[0086] Figure 8The scanning electron microscopy (SEM) image shown depicts a cross-section of the non-active region of the resulting cell encapsulation device. More specifically, the polycarbonate polyurethane layer B1 is located at the bottom of the device and penetrates into the first tight layer of ePTFE P1 to bond the ePTFE composite to the surface of the non-active region (e.g., the welding region). The second open ePTFE P2 layer is located above the P1 layer, and the third open ePTFE P3 layer is located above the P2 layer. As shown, the second and third open layers P2, P3 retain their open microstructure, allowing tissue ingrowth and anchoring of the device.

[0087] Optical surface images were taken using a Keyence VK-X1000 laser scanning confocal microscope. The fibril diameter measurements were performed using the accompanying multi-file analysis software. The fibril diameters of the non-active region of the final device were measured and ranged from 0.285 micrometers to 2.980 micrometers.

[0088] The device of Example 1 (i.e., including the anchoring layer around the device perimeter) was implanted into New Zealand white rabbits for in vivo evaluation and compared with a control device [such as Comparative Example 6 described herein ( Figure 9E )]. Histological examinations were performed using H&E staining (i.e., histological staining with hematoxylin and eosin) and trichrome staining. At 7 days post-implantation, improved ingrowth was shown in the exposed microstructure of the non-active region of the Example 1 device compared to the control device (as Figure 9E shown). Additionally, at 7 days post-implantation, the Example 1 device showed a more extensive and mature collagenized ingrowth into the active region of the device compared to the control device ( Figure 9A ). Furthermore, the thickness of the capsule in the non-active region was measured histologically. At 30 days, the capsule thickness of the Example 1 device (see Figure 10A ) was lower than that of the control device ( Figure 10E ), indicating improved integration, reduced micromotion, and reduced inflammation.

[0089] Example 2

[0090] In a second embodiment, a cell encapsulation device having a non-active region and an anchoring region was formed. A bilayer membrane of expanded PTFE was constructed according to the teachings presented in Example 2 of Bruhn et al. in WO 2020 / 243663. The bilayer membrane consists of a first tight layer (having pores with a plurality of small pore diameters) and a second open layer (having pores with a plurality of larger pore diameters). The characteristics of the bilayer ePTFE described by Bruhn et al. in WO 2020 / 243663 are shown in Table 2.

[0091] Table 2 Characteristics of ePTFE in the Examples of WO2020 / 243668

[0092] Description First tight layer Second open layer Maximum pore size (μm) 0.3784 None Pore size (μm) 0.413 4.891 Thickness (μm) 5.85 36.00

[0093] The double-layer film was gently adhered to a polycarbonate polyurethane film approximately 75 microns thick. The adhesion process was carried out at 165 °C for 30 seconds using a small spring manual press. This adhesion process gently adhered the polycarbonate polyurethane film to the first tight layer of the double-layer ePTFE film, thereby forming an ePTFT / polycarbonate polyurethane composite for processing. Then, the ePTFE / polycarbonate polyurethane composite was laser cut into the outer peripheral welding shape of the cell encapsulation device, such as the component 1340 shown in Figure 13 of WO 2020 / 243668 by Bruhn et al.

[0094] Subsequently, according to the teachings presented by Bruhn et al. in WO 2020 / 243668, the cell encapsulation device was formed using the method described in Device B. The cell encapsulation device described in Example 2 differed from Device B described by Bruhn et al. in WO 2020 / 243668 in that: (1) a vascularization layer was not used and (2) the outermost upper and lower welding film layers described as 1340 in Figure 13 of WO 2020 / 243668 by Bruhn et al. were replaced with a laser-cut ePTFE / polycarbonate polyurethane composite welding layer. Thus, the replacement of the ePTFE / polycarbonate polyurethane composite presented open anchoring regions on the upper and lower non-active regions of the cell encapsulation device.

[0095] Example 3

[0096] In the third example, a cell encapsulation device with non-active regions and anchoring regions was formed. According to the teachings presented by Bruhn et al. in WO 2020 / 243668, the cell encapsulation device was formed using the method described in Device B. The cell encapsulation device described in Example 3 differed from the cell encapsulation device described in Device B of WO 2020 / 243668 in that: (1) a low-density polyethylene (LDPE) film approximately 50 microns thick was used instead of the polycarbonate polyurethane welding film layer (1340) described in Figure 13 of WO 2020 / 243668 by Bruhn et al.; (2) a vascularization layer was not used; and (3) an ethylene-tetrafluoroethylene (ETFE) mesh with a nominal 152-micron monofilament and a nominal spacing of 250 microns was used. These devices of this example were all processed at a temperature of 160 °C.

[0097] Then, at 130 °C, a non-woven spunbond polyester with a weight of 1.00 oz / yd 2 , a trilobal fiber diameter of nominally 21 microns, and a thickness of 229 microns was adhered by hot pressing to the outer non-active regions of the upper and lower low-density polyethylene (LDPE) welding film layers of the macro encapsulation device. Compared to the control device (such as Figure 9EAs shown), the device of Example 3 showed improved ingrowth into the exposed microstructure of the active region (such as Figure 9B shown). The capsule thickness of the device of Example 3 (see Figure 10B ) was lower than that of the control device ( Figure 10E ), indicating improved integration, reduced micromotion, and reduced inflammation.

[0098] Example 4

[0099] Comparative Example

[0100] According to the teachings presented by Bruhn et al. in WO 2020 / 243668, a cell encapsulation device was formed using the method described for Device B. The cell encapsulation device in Example 4 differed from Device B described by Bruhn et al. in WO 2020 / 243668 in that no vascularization layer was used and the external welding surface was perforated as described herein.

[0101] After device formation, macroscopic holes were punched in the welding area using a 0.75 mm biopsy punch. Nine holes were punched in the non-active area around the device, each hole spaced approximately 4.5 mm apart.

[0102] The device of Example 4 was implanted into New Zealand white rabbits for in vivo evaluation and compared with a control device of Example 6 that was not perforated. In histological examinations, the devices were stained with H&E (hematoxylin and eosin) and trichrome at 7 days post-implantation. The device of Example 4 did not show any improvement compared to the control device (see Figure 9E ). As Figure 9C shown, no improvement in collagen tissue ingrowth was observed in the active region of the device. At 28 days, the device of Example 4 showed a delayed healing response in the perforated area compared to the rest of the device, as evidenced by the lack of collagenous ingrowth at the perforation sites. Instead of accelerating attachment of the device, the large holes required an extended period for collagen tissue integration and did not confer any significant benefit. Figure 10C The capsule thickness of the device of Example 4 is shown in

[0103] Example 5

[0104] Comparative Example

[0105] According to the teachings presented by Bruhn et al. in WO 2020 / 243668, the method described using Device B was used to form a cell encapsulation device. The cell encapsulation device in Example 5 differs from Device B described by Bruhn et al. in WO 2020 / 243668 in that a vascularization layer was not used and the external welding surface was roughened as described herein. After sealing, microscale, pore-free features were pressed onto the welding area using 350-mesh sandpaper at 150 °C. Using confocal laser microscopy on a Keyence VK-X1000 laser scanning confocal microscope, the height of the pore-free features was approximately 35 microns.

[0106] The device of Example 5 was implanted into New Zealand white rabbits for in vivo evaluation and compared with a control device of Example 6 ([[]] Figure 9E ) without added surface roughness. In histological examinations, the devices of Example 5 ( Figure 9D ) and the control group ( Figure 9E ) were stained with H&E (hematoxylin and eosin) and trichrome at 7 days and 28 days post-implantation. The device of Example 5 did not show any improvement relative to the control group. As Figure 9D shown, no improvement in collagen tissue ingrowth was observed in the active area of the device. Figure 10D and Figure 10E show the capsule thickness of the device of Example 4 and the control device, respectively.

[0107] Example 6

[0108] Comparative Example

[0109] A cell encapsulation device was formed with an inactive area having a smooth, pore-free microstructure ( Figure 9E ). According to the teachings presented by Bruhn et al. in WO 2020 / 243668, the method described using Device B was used to construct the device of Example 6. The capsule thickness is as Figure 10E shown. The device of Example 6 differs from Device B in WO 2020 / 243668 by not using a vascularization layer.

[0110] The invention of the present application has been generally described above and in connection with specific embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments described herein without departing from the spirit and scope of the invention. Accordingly, the embodiments are intended to cover such modifications and variations of the invention as long as they come within the scope of the appended claims and their equivalents.

Claims

1. A cell encapsulation device, comprising: A cell retention region; An inactive region; and An anchoring region disposed on at least a portion of the inactive region, wherein the anchoring region includes an open microstructure configured to facilitate ingrowth of tissue.

2. The cell encapsulation device according to claim 1, wherein the open microstructure includes a porous polymer having a plurality of anchoring features defined by a size between about 0.1 micrometer and about 100 micrometers.

3. The cell encapsulation device according to claim 1 or claim 2, wherein the inactive region is disposed along the outer periphery of the cell retention region.

4. The cell encapsulation device according to any one of the preceding claims, comprising at least one inactive region located on the cell retention region.

5. The cell encapsulation device according to any one of the preceding claims, wherein the anchoring region comprises expanded polytetrafluoroethylene.

6. The cell encapsulation device according to any one of the preceding claims, wherein at least 15% of the area of the inactive region is covered by the anchoring region.

7. The cell encapsulation device according to any one of the preceding claims, wherein the anchoring region includes a binding layer and an ingrowth layer.

8. The cell encapsulation device according to claim 7, wherein the binding layer includes a first plurality of fibrils, the ingrowth layer includes a second plurality of fibrils, and wherein the density of the first fibrils of the binding layer is greater than the density of the second fibrils of the ingrowth layer.

9. The cell encapsulation device according to claim 7, wherein the ingrowth layer is configured to allow tissue to grow inwardly within the pores of the ingrowth layer.

10. The cell encapsulation device according to any one of the preceding claims, wherein the ratio of the active region / inactive region is 50% to 150%.

11. A cell encapsulation device, comprising: An active region that covers at least one reservoir containing cells and is defined by an outer periphery and a surface area; An inactive region disposed around the outer periphery of the active region; and An open microstructure layer disposed on at least a portion of the anchoring region, wherein the open microstructure is defined by interconnected fibrils; and wherein the thickness of the open microstructure is between 5 micrometers and 600 micrometers.

12. The cell encapsulation device according to claim 11, wherein the fibrils of the open microstructure have a size of 0.1 micrometers to 100 micrometers.

13. The cell encapsulation device according to claim 11 or claim 12, wherein the fibrils of the open microstructure have a size of less than 1 micrometer.

14. The cell encapsulation device according to any one of claims 11 to 13, wherein at least 15% of the inactive region is covered by the anchoring region.

15. The cell encapsulation device according to any one of claims 11 to 14, wherein 40% to 95% of the inactive region is covered by the anchoring region.

16. The cell encapsulation device according to any one of claims 11 to 15, wherein 60% to 99% of the inactive region is covered by the anchoring region.

17. The cell encapsulation device according to any one of claims 11 to 16, wherein the open microstructure is welded to the inactive region.

18. The cell encapsulation device according to any one of claims 11 to 17, wherein the open microstructure is composed of a first layer and a second layer, wherein both the first layer and the second layer include fibrils, and wherein the first fibril density of the first layer is higher than the second fibril density of the second layer.

19. An anchoring region for use with an implantable medical device, configured to facilitate tissue integration, the anchoring region comprising: Bonding layer; and an ingrowth layer attached to the bonding layer, wherein the ingrowth layer comprises a porous polymer having a plurality of anchoring features defined by a size of from about 0.1 micron to about 100 microns; and wherein the porous polymer is configured to integrate with tissue.

20. The anchoring region according to claim 19, wherein the bonding layer is configured to be welded to the implantable medical device.

21. The anchoring region according to claim 19 or claim 20, wherein the bonding layer has a first plurality of fibrils, the ingrowth layer has a second plurality of fibrils, and wherein the first fibril density of the bonding layer is greater than the second fibril density of the ingrowth layer.

Images