Anchor Regions for Implantable Medical Devices

Abstract

Disclosed are devices for encapsulating biological entities (e.g., cells), which are implanted into a patient's tissue bed to provide biological therapy. The encapsulation device includes a non-active region (e.g., a welded region) disposed around the periphery of the device. The non-active region is non-porous and prevents cellular ingrowth and / or angiogenesis therein. An anchor region, including an ingrowth layer and a bonding layer, can be attached or otherwise secured to the non-active region. The open microstructure of the ingrowth layer allows for rapid cellular and / or vascular ingrowth and stability of the encapsulation device within the host tissue. In some embodiments, the non-active region can be formed in place of the cell-retaining region of the encapsulation device.

Description

[Technical Field]

[0001] Field The present disclosure relates generally to implantable medical devices, and more particularly to cell encapsulation devices that include an anchor region on an inactive region, the anchor region including an ingrowth layer that allows for rapid ingrowth of cells and / or blood vessels, thereby stabilizing the cell encapsulation device within host tissue. [Background technology]

[0002] background Biological therapy has become an increasingly viable method for treating various diseases, such as diabetes, heart disease, Alzheimer's disease, Parkinson's disease, and various other disorders. Generally, therapies, such as cells, viruses, viral vectors, or other biological entities, can be introduced into patients via surgical methods. The biological entities are first inserted into an encapsulation device, which is then implanted into the patient's target site. However, micro-movements can occur after implantation, potentially causing device positional instability and leading to chronic inflammatory responses. Furthermore, micro-movements can reduce collagenous growth and angiogenesis, which are necessary for the proper function of the encapsulation device.

[0003] Thus, there remains a need for encapsulation devices with optimized stability (eg, improved integration and fixation of the encapsulation device into host tissue) and function of the encapsulation device in the body. Summary of the Invention

[0004] Abstract In one embodiment ("Embodiment 1"), a cell encapsulation device includes a cell retention region, a non-active region, and an anchor region disposed over at least a portion of the non-active region, the anchor region including an open microstructure configured to promote tissue ingrowth.

[0005] In addition to Example 1, according to another example ("Example 2"), the open microstructure comprises a porous polymer having a plurality of anchor features defined by dimensions between about 0.1 microns and about 100 microns.

[0006] In addition to embodiment 1 or embodiment 2, according to another embodiment ("embodiment 3"), the inactive region is disposed along the periphery of the cell-retention region.

[0007] In addition to any one of the above embodiments, according to another embodiment ("Embodiment 4"), the device includes at least one inactive region disposed on the cell-retaining region.

[0008] According to another embodiment ("embodiment 5"), in addition to any one of the preceding embodiments, the anchor region comprises expanded polytetrafluoroethylene.

[0009] In addition to any one of the preceding embodiments, according to another embodiment ("Embodiment 6"), at least 15% of the area of ​​the non-active region is covered by the anchor region.

[0010] According to another embodiment ("embodiment 7"), in addition to any one of the preceding embodiments, the anchor region includes a tie layer and an ingrowth layer.

[0011] In addition to any one of the preceding embodiments, according to another embodiment ("Embodiment 8"), the bonding layer comprises a first plurality of fibrils, the ingrowth layer comprises a second plurality of fibrils, and the fibril density of the bonding layer is greater than the fibril density of the ingrowth layer.

[0012] In addition to any one of the preceding embodiments, according to another embodiment ("Embodiment 9"), the ingrowth layer is configured to allow tissue ingrowth within the pores of the ingrowth layer.

[0013] According to another embodiment ("embodiment 10"), in addition to any one of the above embodiments, the ratio of active area / inactive area is 50% to 150%.

[0014] In one embodiment ("Embodiment 11"), a cell encapsulation device includes an active region covering at least one reservoir containing cells and defined by a perimeter and surface area, a sealing region disposed around the active region, and an open microstructure layer disposed over at least a portion of the anchor region, the open microstructure defined by interconnected fibrils, the open microstructure defined by a thickness of between 5 microns and 600 microns.

[0015] In addition to Example 11, according to another example ("Example 12"), the open microstructure fibrils have dimensions between 0.1 microns and 100 microns.

[0016] According to another embodiment ("embodiment 13"), further to embodiment 11 or embodiment 12, the open microstructure has fibrils with dimensions less than 1 micron.

[0017] According to another embodiment ("embodiment 14") in addition to any one of embodiments 11 to 13, at least 15% of the sealing region is covered by the anchor region.

[0018] According to another embodiment ("embodiment 15") in addition to any one of embodiments 11 to 14, 40% to 95% of the sealing region is covered by the anchor region.

[0019] According to another embodiment ("embodiment 16") in addition to any one of embodiments 11 to 15, 60% to 99% of the sealing region is covered by the anchor region.

[0020] According to another embodiment ("embodiment 17") in addition to any one of embodiments 11 to 16, the open microstructure is welded to the non-active region.

[0021] According to another embodiment ("embodiment 18") in addition to any one of embodiments 11 to 17, the open microstructure is comprised of a first layer and a second layer, each of the first layer and the second layer comprising fibrils, and the first layer is defined by a fibril density that is higher than the fibril density of the second layer.

[0022] In one embodiment ("Embodiment 19"), an anchor region for use in an implantable medical device configured to promote tissue integration includes a bonding layer and an ingrowth layer attached to the bonding layer, the ingrowth layer comprising a porous polymer having a plurality of anchor features defined by dimensions between about 0.1 microns and about 100 microns, the porous polymer configured to integrate with tissue.

[0023] In addition to Example 19, according to another example ("Example 20"), the bonding layer is configured to weld to the implantable medical device.

[0024] In addition to embodiment 19 or embodiment 20, according to another embodiment ("embodiment 21"), the bonding layer has a first plurality of fibrils, the ingrowth layer has a second plurality of fibrils, and the fibril density of the bonding layer is greater than the fibril density of the ingrowth layer. [Brief explanation of the drawings]

[0025] 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.

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

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

[0028] [Figure 2A] FIG. 2A is a cross-sectional schematic diagram of a semipermeable membrane according to some embodiments.

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

[0030] [Figure 4] FIG. 4 is a cross-sectional schematic diagram of the cell encapsulation device of FIG. 3 according to some embodiments.

[0031] [Figure 5] FIG. 5 is a schematic top view of a cell encapsulation device having open anchor regions on the periphery of the device, according to some embodiments.

[0032] [Figure 6] FIG. 6 is a photographic schematic of a portion of an anchor region and active region (eg, mesh) including an ingrowth layer of a cell encapsulation device, according to some embodiments.

[0033] [Figure 7] FIG. 7 is a top view of the most open expanded polytetrafluoroethylene (ePTFE) layer of Example 1 taken under an optical microscope at 50x magnification, according to some embodiments.

[0034] [Figure 8] FIG. 8 is a scanning electron micrograph (SEM) of a cross section of a biocompatible membrane composite formed according to Example 1, according to some embodiments.

[0035] [Figure 9A] FIG. 9A shows representative histology images showing improved collagenized tissue ingrowth in Examples 1 and 3 according to some embodiments, and no improvement in collagenized tissue ingrowth in the active areas of Comparative Examples 4, 5, F, and 6. [Figure 9B] FIG. 9B is a representative histology image showing improved collagenized tissue ingrowth in Examples 1 and 3 according to some embodiments, and no improved collagenized tissue ingrowth in the active areas of Comparative Examples 4, 5, F, and 6. [Figure 9C] FIG. 9C is a representative histology image showing improved collagenized tissue ingrowth in Examples 1 and 3 according to some embodiments, and no improved collagenized tissue ingrowth in the active areas of Comparative Examples 4, 5, F, and 6. [Figure 9D] FIG. 9D is a representative histology image showing improved collagenized tissue ingrowth in Examples 1 and 3 according to some embodiments, and no improved collagenized tissue ingrowth in the active areas of Comparative Examples 4, 5, F, and 6. [Figure 9E] FIG. 9E is a representative histology image showing improved collagenized tissue ingrowth in Examples 1 and 3 according to some embodiments, and no improvement in collagenized tissue ingrowth in the active areas of Comparative Examples 4, 5, F, and 6.

[0036] [Figure 10A] FIG. 10A is a representative histology image of capsule thickness for Examples 1 and 3 and Comparative Examples 4, 5, and 6 according to some embodiments. [Figure 10B] FIG. 10B is a representative histology image of capsule thickness for Examples 1 and 3 and Comparative Examples 4, 5, and 6 according to some embodiments. [Figure 10C] FIG. 10C is a representative histology image of capsule thickness for Examples 1 and 3 and Comparative Examples 4, 5, and 6 according to some embodiments. [Figure 10D] FIG. 10D is a representative histology image of capsule thickness for Examples 1 and 3 and Comparative Examples 4, 5, and 6 according to some embodiments. [Figure 10E] FIG. 10E is a representative histology image of capsule thickness for Examples 1 and 3 and Comparative Examples 4, 5, and 6 according to some embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0037] Detailed Description Those skilled in the art will readily appreciate that the various aspects of the present disclosure can be implemented by any number of methods and apparatuses configured to perform their intended functions. It should also be noted that the accompanying figures referenced herein are not necessarily drawn to scale and may be exaggerated for purposes of illustrating various aspects of the present disclosure, and in that regard, the figures should not be construed as limiting. In particular, directional references such as "up," "down," "top," "left," "right," "front," and "back" are intended to refer to the orientation in which the components and directions are shown and described in the referenced figure(s). It should also be noted that all ranges described herein are exemplary in nature and include all values ​​therebetween. Furthermore, all references cited herein are incorporated by reference in their entirety. The terms "implantable medical device" or "implantable device" may be used interchangeably herein with the terms "cell encapsulation device" or "encapsulation device."

[0038] The present disclosure is directed to a device for encapsulating biological entities (e.g., cells), where the encapsulation device is implanted into a patient, e.g., a tissue bed, to provide biological therapy. The encapsulation device includes a non-active region located around the periphery of the device. The non-active region is non-porous and prevents cellular ingrowth and / or angiogenesis therein. An anchor region, including an ingrowth layer and a bonding layer, can be attached or otherwise secured to the non-active region. The open microstructure of the ingrowth layer allows for rapid cellular and / or vascular ingrowth and stabilizes the encapsulation device within the host tissue. In some embodiments, the non-active region can be formed in a location above the cell-retaining region of the encapsulation device. As used herein, the term "about" should be understood to mean + / - 10% of the specified unit of measurement.

[0039] Biological entities suitable for encapsulation and implantation using the devices described herein include cells, viruses, viral vectors, bacteria, proteins, antibodies, and other biologically active entities. For simplicity, the biological entities will be referred to herein as cells; however, this description is not intended to limit 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, eukaryotic, mammalian, non-mammalian, and / or stem cells can be used in the cell encapsulation devices of the present invention. In some embodiments, the cells are microencapsulated within biomaterials of natural or synthetic origin, including, but not limited to, hydrogel biomaterials. In some embodiments, the cells secrete therapeutically useful substances. Such substances include hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cell products that provide a therapeutic benefit to the device recipient. Examples of such therapeutic cell products include, but are not limited to, insulin, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, and factor VIII. Non-limiting examples of suitable growth factors include vascular endothelial growth factor, platelet-derived growth factor, platelet-activating factor, transforming growth factor, bone morphogenetic protein, activin, inhibin, fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, glial cell line-derived neurotrophic factor, growth differentiation factor 9, epidermal growth factor, and combinations thereof. It should be understood that throughout this disclosure, the terms "cell" or "cell population" can be replaced with "biological entity" or "biological entities," respectively. Furthermore, the terms "cell encapsulation device," "encapsulation device," and "device" may be used interchangeably herein.

[0040] FIG. 1 shows a top view of an embodiment of a cell encapsulation device 10. However, it should be understood that the embodiments described herein are applicable to a wide variety of implantable medical devices, and the cell encapsulation device as shown in FIG. 1 is intended for illustrative purposes only. It should be understood that any device intended to remain or remain within a patient's body is considered within the scope of the present disclosure. As shown in FIG. 1 , the cell encapsulation device 10 has a cell retention region 12 (e.g., a reservoir), a non-active region 20, and an anchor region 24 disposed on the non-active region 20. The non-active region 20 is covered by the anchor region 24, e.g., the non-active region 20 overlaps with, is coextensive with, is overlaid by, or is otherwise covered or partially covered by the anchor region 24. In some embodiments, the anchor region 24 may be disposed on only a portion of the non-active region 20. In further embodiments, the anchor region 24 may additionally and / or alternatively be disposed on other regions of the device 10, including the non-active region. As used herein, the term "inactive region" defines an area or region of a cell encapsulation device (or implantable medical device) that is not directly overlying a cell-containing region 12 of the cell encapsulation device 10 and / or that does not allow cell or vascular ingrowth and is incapable of providing mass transport to or from the cell-containing region 12. As used herein, the term "active region" is intended to refer to an area or region that is directly overlying a cell-containing region 12 and / or that allows mass transport to or from the cell-retaining region 12. As shown in FIG. 1, the cell encapsulation device 10 can have two anchor regions 24 disposed thereon. As further described herein with reference to FIGS. 3 and 4, in some embodiments, the cell encapsulation device 10 has two or more anchor regions 24 disposed thereon.

[0041] The non-active region 20 may be defined as the area where two composite layers are welded or otherwise adhered and / or bonded to form a seal around the periphery of the device 10. As shown in FIG. 1, the non-active region 20 is defined by the area around the periphery of the cell encapsulation device 10, although the non-active region 20 can have a variety of configurations. In the embodiment shown in FIG. 1, the non-active region 20 defines the periphery of the cell encapsulation device 10 and has an overall length L1. As shown in FIG. 1, the overall 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. Furthermore, a length L3 is defined by the difference between the overall length L1 of the cell encapsulation device 10 and the length L2, which is the maximum length of the cell retention region 12. While the above dimensions are referred to as lengths, in some embodiments (not shown), the cell retention region 12 has a different configuration and the maximum dimension may be defined as a width and / or thickness.

[0042] As shown in the cross-sectional view of FIG. 2, cell encapsulation device 10 can include first and second composite layers 14 and 16, which are sealed around their peripheries to form cell retention region 12. Cell retention region 12 is configured to receive cells or other therapeutic biological entities. First and second composite layers 14 and 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 first and second composite layers 14, 16 are impermeable to cellular ingrowth. For example, both inner porous layers 13, 17 have an average pore size small enough to prevent vascular ingrowth (e.g., less than about 1 micron, as measured by porometry). In contrast, outer porous layers 11, 15 have sufficient porosity to allow tissue ingrowth into the pores of the outer porous layer (e.g., greater than about 1 micron, as measured by porometry). Tissue ingrowth through the outer porous layers 11, 15 facilitates the transfer of nutrients and biomolecules from the body to cells encapsulated in the cell retention region 12 of the device 10. In some embodiments, the cell retention region 12 may be formed from one or more single layers (e.g., layers that are not composite layers) (not shown). In further embodiments, the cell retention region 12 may be formed from a cell-impermeable layer only (not shown) or a cell-impermeable layer and two (or more) cell-permeable layers (not shown). The region defined by the outer porous layers 11, 15 and capable of transporting materials into and out of the cell retention region 12 may be referred to herein as the active region. Implantable devices comprising more layers than the first composite layer 14 and / or the second composite layer 16 are considered within the scope of the present invention.

[0043] The first composite layer 14 and the second composite layer 16 can be bonded around the periphery of the first composite layer 14, 16 to form an inactive region 20. The inactive region 20 forms the periphery of the cell encapsulation device 10. The first composite layer 14 and the second composite layer 16 can be bonded via any of a variety of welding techniques, fusion mechanisms, or adhesive mechanisms. In some embodiments, the first composite layer 14, 16 are bonded via thermoplastic welding, ultrasonic welding, fusion, adhesives, mechanical engagement between layers, and various other applicable methods of bonding polymer layers known to those skilled in the art.

[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 from a semipermeable material with selective sieving and / or porosity properties. Semipermeable materials control the passage of solutes, biochemicals, viruses, and cells through the material primarily based on size, for example. In embodiments where the semipermeable material is porous through only a portion of its thickness, the molecular weight cutoff or sieving properties of the semipermeable membrane begin at the surface. As a result, certain solutes and / or cells do not pass through the porous spaces of the material by ingressing from one side to the other. FIG. 2A shows a cross-sectional view of a porous material 70 useful in the cell encapsulation device 10 described herein, where the selective permeability of the porous material 70 prevents cells 72 from migrating or growing into the spaces of the porous material 70 while allowing the bidirectional flow of solutes 74 throughout the entire thickness of the porous material 70. The region defined by the semipermeable membrane that allows material transport into and out of the cell retention region 12 may also be referred to herein as the active region.

[0045] The process of bonding the first and second composite layers 14, 16 can render the exterior surface of the inactive region 20 non-porous. In some embodiments, the first and second composite layers 14, 16 can be fused together, such as by heat and pressure, without the use of an adhesive. Heat and pressure fusion can eliminate surface porosity and densify the surface microstructure where the fusion occurs. Thus, a non-porous surface is formed on the exterior of the inactive region 20 after the first and second composite layers 14, 16 are fused together (without an adhesive). In some embodiments, thermoplastic welding is used, whereby the pores in the first and second composite layers 14, 16 are filled, partially filled, covered, embedded, or otherwise absorbed with molten polymer material. In additional embodiments in which the first and second composite layers 14, 16 are self-adhesive, bonding the first and second composite layers 14, 16 together by methods such as heat welding or ultrasonic welding can collapse the pores to form a smooth, non-porous surface. The bonding of the first and second composite layers 14, 16 creates an area where migration of nutrients or therapeutic agents into and / or out of the inactive area 20 is inhibited. Furthermore, cell or tissue integration into the inactive area 20 cannot occur. Thus, the inactive area 20 can be an inactive area of ​​the cell encapsulation device 10.

[0046] Cell encapsulation device 10 can include additional inactive regions separate from seal region 20. One non-limiting example of an inactive region can be a structural frame or reinforcing member disposed around encapsulation device 10 to provide rigidity and ease of handling to device 10. In some embodiments, additional elements, such as a filling tube used to deliver therapeutic biological entities to device 10, can be inactive regions of device 10 because they do not allow cell or tissue ingrowth. Various other inactive regions can be defined on device 10, such as, but not limited to, a structural frame, suture tabs, or holes.

[0047] The material forming the frame is not particularly limited as long as it provides the necessary rigidity, is compatible with the implant environment, and has the necessary rigidity. Non-limiting examples of useful materials include polymeric materials such as polyetheretherketone (PEEK), polyethylene terephthalate (PET), polypropylene, polyethylene, polymethyl methacrylate, polyethyl methacrylate, polyacrylate, polyalphahydroxy acid, polycaprolactone, polydioxanone, polyester, polyglycolic acid, polyglycol, polylactide, polyorthoester, polyphosphate, polyoxaester, polyphosphoester, polyphosphonate, polysaccharide, polytyrosine carbonate, silicone, polyurethane, polyurethane containing ionic or mesogenic components produced by the prepolymer method, block copolymer of polyethylene terephthalate (PET) and polyethylene oxide (PEO), block copolymer containing polystyrene and poly(1,4-butadiene), and ABA triblock copolymer made from poly(2-methyl-2-oxazoline) and polytetrahydrofuran, and copolymers or polymer blends thereof. Metallic frames can also be constructed using materials such as spring temper 316SST, spring temper cobalt chromium alloys (such as Co-28Cr-6Mo or Co-35Ni-20Cr-10Mo), spring temper titanium-based alloys (such as Ti-6AI-4V), or spring temper nickel titanium alloys (such as Nitinol, copper aluminum nickel, copper zinc aluminum, aluminum, iron manganese silicon alloys). The frame material can be inherently biocompatible, or it can be a material that is not inherently biocompatible but has been made biocompatible, such as with a biocompatible coating. Non-limiting examples of inherently biocompatible frame materials include PEEK, Nitinol, or Ti-6AI-4V.

[0048] 2, anchor region 24 may be disposed over at least a portion of inactive region 20 to provide a porous, outward-facing surface that allows for tissue integration and ingrowth. In other words, inactive region 20 is not prone to tissue integration or ingrowth, while anchor region 24 is prone to and allows for tissue integration into anchor region 24, as described further herein.

[0049] Anchor region 24 can be disposed on at least a portion of a surface of inactive region 20. In some embodiments, anchor region 24 can be disposed on inactive region 20, for example, by fusing, welding, gluing, or otherwise attaching to inactive region 20. In some embodiments, the surface of inactive region 20 includes an upper surface 21 and a lower surface 23. Anchor region 24 can be attached to at least a portion of one or both of upper surface 21 and lower surface 23 of inactive region 20.

[0050] In some embodiments, the surface area of ​​anchor region 24 is about 90% of the surface area of ​​non-active region 20. In these embodiments, the surface area of ​​non-active region 20 may comprise the total surface area of ​​non-active region 20 on both the top surface 21 and the bottom surface 23 of non-active region 20. Thus, in embodiments in which anchor region 24 is disposed on both the top surface 21 and the bottom surface 23 of non-active region 20, the surface area of ​​anchor region 24 may be defined as the total surface area of ​​anchor region 24 disposed on both the top surface 21 and the bottom surface 23.

[0051] In some embodiments, the surface area of ​​anchor region 24 can vary. For example, anchor region 24 can have a surface area that is at least 15% of the surface area of ​​non-active region 20. In further embodiments, anchor region 24 can have a surface area that is at least 15% of the total surface area of ​​non-active region 20. In other non-limiting examples, anchor region 24 can have a surface area that is between about 5% and about 100% of the surface area of ​​non-active region 20, between about 5% and about 99% of the surface area of ​​non-active region 20, between about 5% and about 90% of the surface area of ​​non-active region 20, between about 15% and about 85% of the surface area of ​​non-active region 20, between about 20% and about 75% of the surface area of ​​non-active region 20, between about 30% and about 60% of the surface area of ​​non-active region 20, or between about 40% and about 50% of the surface area of ​​non-active region 20. In further embodiments, anchor region 24 can have a surface area of ​​about 15% to about 100%, about 15% to about 99%, about 25% to about 99%, about 35% to about 99%, about 45% to about 99%, about 55% to about 99%, about 65% to about 99%, or about 75% to about 99% of the surface area of ​​inactive region 20.

[0052] The anchor region 24 may be defined as a portion having an open microstructure that is disposed on the non-active region 20 and is directly exposed to native tissue (i.e., host tissue) during implantation. As shown in FIG. 2 , the anchor region 24 may be formed from an ingrowth layer 28 and a bonding layer 26. The ingrowth layer 28 of the anchor region 24 has an open microstructure that can promote cellular and tissue ingrowth on and within the anchor 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, allowing cells to enter and exit the layer or region and allowing cellular ingrowth and / or tissue ingrowth / integration. It should be understood that the bonding layer 26 does not have sufficient porosity to allow cellular or vascular ingrowth. Herein, a layer that limits or prevents tissue ingrowth and / or integration of weld material may be referred to as a “sealing” layer.

[0053] The open microstructure of the ingrowth layer 28 can include a plurality of anchoring features that allow cell and / or tissue ingrowth onto and into the outer porous layer 11, 15 of the cell encapsulation device 10 and to wrap around and anchor in the ingrowth layer 28 in the anchoring region 24. The anchoring features can be fibrils and / or fibers. Furthermore, the anchoring features can be defined by a dimension, such as a diameter, having a value between about 0.1 microns and about 100 microns. In some embodiments, the size of the anchoring features can range from about 0.1 microns to about 80 microns, about 0.1 microns to about 75 microns, about 0.1 microns to about 70 microns, about 0.1 microns to about 65 microns, about 0.1 microns to about 50 microns, about 0.1 microns to about 25 microns, about 0.1 microns to about 10 microns, about 0.1 microns to about 2 microns, or about 0.1 microns to about 0.5 microns. In some embodiments, the dimension of the anchoring features can be defined as the average dimension or diameter of the anchoring features in the open microstructure. In these examples, the dimensions of the anchor features can be measured through scanning electron microscope (SEM) images taken of the anchor features.

[0054] In some embodiments, the rate at which tissue ingrowth penetrates and encapsulates the anchoring features of ingrowth layer 28, thus encapsulating anchoring region 24 and anchoring encapsulation device 10 within the surrounding tissue ingrowth, is faster than tissue integration in other regions of cell encapsulation device 10. The faster integration of tissue ingrowth into ingrowth layer 28 stabilizes cell encapsulation device 10 within the tissue bed and reduces the effects of micro-movement or migration of encapsulation device 10. As tissue integrates into anchoring region 24, device 10 is stabilized within the host tissue (i.e., micro-movement / micro-motion of device 10 is reduced), thereby promoting the development of vascularity around encapsulation device 10 and into outer porous membranes 11, 15. As a result, nutrients can be delivered to cell-retention region 12 more quickly.

[0055] As explained above, anchor region 24 can include a tie layer 26 configured to bond directly to non-active region 20 and an ingrowth layer 28 configured to bond to tie layer 26 and be exposed to and subsequently ingrowth from native tissue for the purposes of anchoring cell encapsulation device 10. In some embodiments, the fiber or fibril density of tie layer 26 can be greater than the fiber or fibril density of ingrowth layer 28 of anchor region 24, as determined by pore size (e.g., the pore size of tie layer 26 is less than 1 micron). In this manner, during the process of thermoplastically welding anchor region 24 to non-active region 20, molten polymer (e.g., welding material) can enter tie layer 26 but is inhibited from flowing or migrating into ingrowth layer 28, thereby maintaining the ability of ingrowth layer 28 to propagate cell and / or tissue ingrowth into anchor region 24.

[0056] In some embodiments, the tie layer 26 can be a component of the non-active region 20, rather than a component of the anchor region 24. For example, the non-active region 20 can include the tie layer 26 prior to attaching the anchor region 24 to the non-active region 20. In other embodiments, the ingrowth layer 28 can be an extension of the tie layer 26, providing an open layer onto which native tissue (i.e., host tissue) can grow to anchor the cell encapsulation device 10. In some embodiments, the tie layer 26 can be modified to allow cell and / or tissue integration and to bond with the non-active region 20. As such, the upper portion of the tie layer 26 can have a more open structure (e.g., lower fibril density) than the lower portion of the tie layer 26. In some embodiments, the tie layer 26 can be a sealing membrane (e.g., expanded polytetrafluoroethylene membrane (ePTFE)) or other microporous membrane.

[0057] In some embodiments, anchor region 24 (and / or ingrowth layer 28) can include any number of polymer layers. For example, anchor region 24 can include two layers (e.g., a bilayer), three layers (e.g., a trilayer), four layers, five layers, or more layers. When multilayer anchor region 24 is used, one side of the multilayer polymer film is configured to bond directly to non-active region 20, and the other side of the multilayer polymer film is configured to be exposed to native tissue for purposes of anchoring encapsulation device 10, followed by cell and / or tissue ingrowth. Bonding layer 26 can be a sealing layer or an open layer. When bonding layer 26 is an open layer, there can be another layer between bonding layer 26 and ingrowth layer 28 that prevents penetration of adhesive and / or welding material from bonding layer 26 into ingrowth layer 28. Furthermore, bonding layer 26 can be a composite layer with an open layer that allows the thermoplastic polymer to penetrate and a sealing layer that prevents the thermoplastic polymer from occluding ingrowth layer 28. The multilayer polymeric film can have a number of configurations, including, but not limited to, an open-closed-open configuration, a closed-open configuration, or a closed-open-open configuration.

[0058] In some embodiments, the anchor region 24 is comprised of a single expanded polytetrafluoroethylene (ePTFE) layer, a bilayer comprising ePTFE layers, one layer having a first pore size and the second layer having a second pore size, the first pore size being different from the second pore size. For example, the first pore size can be less than about 1 micron and the second pore size greater than about 2 microns. A trilayer comprising an ePTFE layer can have a larger pore size in the outer layer and a smaller pore size in the inner layer. In a trilayer composite comprising ePTFE, the ePTFE composite can have a sequence of dense, medium, and open pore sizes. Non-limiting layers that can be included in anchor region 24 include nonwoven layers (e.g., spunbond nonwoven polyethylene terephthalate (PET), bioabsorbable nonwovens, polyetheretherketone (PEEK), nonwovens laminated to ePTFE closed pore membranes, electrospun membranes, polytetrafluoroethylene (PTFE) electrospun membranes, and porous membranes formed by dissolving salts incorporated into the membrane (i.e., salt leaching). Methods for producing porous membranes include solvent-induced phase separation, vapor-induced phase separation, track etching, and sintering.

[0059] As best shown in FIG. 2, growth region 28 has a thickness. In some embodiments, the thickness can be from about 5 microns to about 600 microns. In some embodiments, the thickness can be from about 10 microns to about 600 microns, from about 15 microns to about 600 microns, from about 20 microns to about 600 microns, from about 20 microns to about 400 microns, from about 20 microns to about 100 microns, or from about 20 microns to about 50 microns. In-growth region 28 can have the same thickness on both sides of inactive region 20. However, in other embodiments, growth region 28 can be designed so that one side of cell encapsulation device 10 is thicker than the other side of device 10.

[0060] Although anchoring region 24 is described herein as being disposed on non-active region 20, in other embodiments, anchoring region 24 can be disposed on any non-active region of cell encapsulation device 10, as further described with reference to FIGS. 3 and 4 . For example, in embodiments in which a first membrane layer forms first composite layer 14 and a second membrane layer forms second composite layer 16, cell retention region 12 can be designed such that multiple portions of the first and second membrane layers are sealed together at multiple portions of cell retention region 12, resulting in multiple compartments or reservoirs in cell retention region 12. Non-active region 20 can be formed where portions of first composite layer 14 and second composite layer 16 are sealed to one another. The sealed region between first and second membrane layers or between first and second composite layers 14 and 16 can define non-active region 20 at which anchoring region 24 can be adhered. Other various non-active regions 20 include frames or reinforcing members disposed around the periphery of device 10 or around the active region.

[0061] When cell encapsulation device 10 is implanted into a subject, tissue can grow into engagement with the microstructure of ingrowth layer 28 in anchoring region 24 and propagate into the open microstructure. Such tissue ingrowth can anchor the surrounding tissue to cell encapsulation device 10 and / or fix the position of cell encapsulation device 10 within the target location. In particular, native tissue can engage cell encapsulation device 10 around the entire periphery of device 10, preventing micro-movement or migration of cell encapsulation device 10 within the tissue bed. As previously described herein, rapid tissue integration at anchoring region 24 can accelerate stabilization of cell encapsulation device 10 within the patient, resulting in more rapid formation of vasculature around encapsulation device 10. Nutrients can then be transferred to cell-retention region 12. As a result, targeted therapy of encapsulation device 10 can be more efficiently established, optimizing the function of cell encapsulation device 10.

[0062] The cell encapsulation device 10 can include multiple inactive regions 20 and / or anchor regions 24. For example, FIG. 3 illustrates an additional embodiment of a cell encapsulation device 10 including multiple inactive regions formed on the cell-retaining region 12 of the encapsulation device 10. FIG. 3 is a top schematic view of a cell encapsulation device 10 having four inactive regions (i.e., 20a, 20b, 20c, and 20d). The cell encapsulation device 10 includes a first inactive region 20a, which can be the same as the inactive region 20 described above with respect to FIG. 2. As shown in FIG. 3, the cell encapsulation device 10 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 each be a circular inactive region disposed on the cell-retaining region 12. It should be understood that the circular inactive regions shown in Figure 3 are exemplary, and that any geometric shape, such as a triangle, square, or oval, may form inactive region 20. In some embodiments, inactive regions 20b-d are point-bonded inactive regions. Furthermore, inactive regions 20a-d are inactive regions formed on cell-retaining region 12 of encapsulation device 10.

[0063] FIG. 4 is a cross-sectional view of cell encapsulation device 10 of FIG. 3 taken along line 4-4. As shown, inactive region 20a, which extends around the periphery of cell encapsulation device 10, includes anchor regions 24 disposed thereon. Additionally, inactive region 20c also includes anchor regions 24 disposed on either side of inactive region 20a. In the illustrated embodiment, both inactive region 20a and inactive region 20c include anchor regions 24 on either side of inactive region 20a, 20c, allowing for tissue integration within anchor regions 20a and 20c. While inactive regions 20b and 20d are not shown with anchor regions 24 disposed thereon, in some embodiments, anchor regions 24 may be disposed on one or both of inactive regions 20b and 20d. Note that anchor regions 24 disposed on inactive region 20c each include a bonding layer 26 and an ingrowth layer 28. Additionally, cell encapsulation device 10 can include any number of inactive regions 20, such as one, two, three, four, five, or more inactive regions 20. One, some, or all of these inactive regions 20 can be configured to have anchor regions 24 welded, glued, or otherwise attached thereto. Increasing the amount of ingrowth region 24 on an inactive region 20 increases the area of ​​cell encapsulation device 10 available for rapid tissue growth.

[0064] Figure 5 shows a top view of the cell encapsulation device 10 of Figure 1 having a modified anchor region 24 with a tissue ingrowth layer disposed thereon. The active region 12 is shown for illustrative purposes only. Figure 6 is an enlarged view of a portion of the anchor region 24 of Figure 5. The active region 12 is also shown in Figure 5. Referring to Figure 6, the ingrowth layer 28 includes anchor features that may include a plurality of fibrils 66 that terminate or originate at nodes 68. The voids between the nodes 68 and the fibrils 66 are defined as pores 70.

[0065] While the above embodiments refer to the anchor region 24 being disposed on the non-active region 20, the anchor region 24 can be disposed on any non-porous or otherwise non-active region that is desired to be covered with an ingrowth layer 28. The above embodiments of the anchor region 24 in combination with the device 10 can be particularly useful when the non-active region occupies a significant portion of the device 10. For example, it can be more difficult to quickly secure the device 10 within a subject when the area of ​​the non-active region is approximately equal to or larger than the area of ​​the active region, e.g., the area of ​​the cell-retaining region 12. This is because this anchoring in the non-active region becomes more pronounced when the area of ​​the active region is smaller than the area of ​​the non-active region, e.g., when the active region / non-active region ratio is 90%, and becomes even more desirable when the active region / non-active region ratio is 80%. Therefore, it may be desirable to increase the surface area on the tissue-facing surface of the device 10 that can interface and promote tissue ingrowth. In some embodiments, the ratio of active area to inactive area is about 50% to about 150%, about 50% to about 125%, about 50% to about 100%, or about 50% to about 75%.

[0066] Furthermore, although the implantable device is referred to primarily herein as cell encapsulation device 10, anchor region 24 is applicable to any type of implantable medical device. Anchor region 24 can be disposed on a non-active (e.g., non-porous) surface of any device that may be designed to be inserted into a patient. In this manner, the benefits of anchor region 24 can be used in conjunction with various types of devices requiring increased stability within a patient.

[0067] Test Method In vivo New Zealand White rabbit study to evaluate host tissues Sterile, empty encapsulated devices (i.e., without cells) were sealed in a filling tube before sterilization and implanted subcutaneously in the dorsum of New Zealand White rabbits using a blunt dissection delivery technique. After approximately 7 and 30 days, the animals were euthanized and the devices were retrieved for histological imaging.

[0068] Tissue samples were processed to reflect the skin and subcutaneous tissue, exposing the implanted encapsulated device. Device identification was performed using digital radiography (Faxitron UltraFocus System) as needed before en bloc removal of the encapsulated device and surrounding tissue. The orientation of the device was marked with staples. All excised devices and surrounding tissue were immersed in 10% neutral buffered formalin. Each device sample was assigned a unique accession number.

[0069] Three cross sections were taken from each sample. The three sections 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.

[0070] Images of the slides were taken using a Nikon DS-Fi series camera and Nikon NIS Elements microscope imaging software. At least three magnified images of each slide were captured. Measurements were taken using Nikon NIS Elements microscope imaging software, calibrated using a certified microscope micrometer.

[0071] SEM sample preparation and thickness measurement SEM samples were prepared by first fixing the membrane composite or membrane composite layer to a handling adhesive and facing the adhesive with the side opposite the surface intended for imaging. The film was then cut to provide an approximately 3 mm x 3 mm area for imaging. The samples were then sputter-coated using an Emitech K550X sputter coater and a platinum target. Images were then taken using a Thermo Scientific FEI Quanta 400 scanning electron microscope at a magnification and resolution sufficient to visualize a sufficient number of features for robust analysis, ensuring that the smallest dimension of each analyzed feature was at least 5 pixels in length. Layer thickness was measured using cross-sectional SEM images.

[0072] Surface roughness Surface roughness was measured using a Keyence VK-X1000 laser scanning confocal microscope and associated multi-file analyzer software. The sample was fixed to the microscope stage using tape around the peripheral area of ​​the device being measured. Images were then taken at 20x magnification using the VK-X1000. Surface roughness analysis was performed on a surface with a roughness of approximately 2.3 mm. 2 A surface area of ​​1000 nm was used, which allowed for sufficient resolution and representative analysis of the surface.

[0073] The images were then processed in the Multifile Analyzer software, and a tilted surface correction was performed to account for tilt. After image preprocessing, Rz values ​​were acquired in 21 line scans spaced approximately 30 microns apart, for a total of 42 line scans in both the x and y directions. The Rz values ​​from these 42 scans were averaged for the values ​​referenced here. The Multifile Analyzer software automatically performs the Rz calculation without requiring a cutoff wavelength. [Example]

[0074] example Example 1 In the first example, a cell encapsulation device was formed with an inactive region that contained an anchor region. A three-layer membrane of expanded polytetrafluoroethylene (ePTFE) was constructed according to the teachings of Example 4 of Bruhn et al., WO 2020 / 243668. The three-layer ePTFE membrane consisted of a first closed layer with a plurality of pores having a dense microstructure, a second open layer with a plurality of pores having an open microstructure, and a third open layer with a plurality of pores having the most open microstructure. Figure 7 shows a top view of the most open third ePTFE layer, photographed at 50x magnification with an optical microscope. The properties of the ePTFE trilayer are listed in Table 1 below. [Table 1]

[0075] The tri-layer ePTFE membrane was lightly bonded to a sheet of approximately 75 microns thick polycarbonate polyurethane film. Bonding was performed at 165°C for 30 seconds using a small spring-loaded hand press. This bonding process lightly secured the polycarbonate polyurethane film to the first sealing layer of the tri-layer ePTFE membrane, forming an ePTFE / polycarbonate polyurethane composite for handling. The ePTFE / polycarbonate polyurethane composite was then laser cut to the welded shape around the cell encapsulation device, as shown in WO 2020 / 243668 by Bruhn et al., element 1340 shown in Figure 13 therein.

[0076] Next, a cell encapsulation device was formed using the method described for Device B in accordance with the teachings of Bruhn et al. in WO 2020 / 243668. The cell encapsulation device described here differs from Device B described in Bruhn et al. in that (1) a vascularization layer is not used, and (2) a laser-cut ePTFE / polycarbonate polyurethane composite weld layer is used in place of the outermost top and bottom weld film layers shown as 1340 in Figure 13 of Bruhn et al. WO 2020 / 243668. This substitution of ePTFE / polycarbonate polyurethane composite thus provides open anchor regions 24 deposited in the top and bottom inactive regions of the encapsulation device.

[0077] A cross-section of the resulting non-active area of ​​the cell encapsulation device is shown in the scanning electron micrograph (SEM) shown in Figure 8. More specifically, a polycarbonate polyurethane layer B1 is shown infiltrating the first sealed layer P1 of ePTFE at the bottom of the device, bonding the ePTFE composite to the surface of the non-active area (e.g., the welded area). A second open ePTFE layer P2 is shown disposed on top of layer P1, and a third open ePTFE layer P3 is shown disposed on top of layer P2. As shown, the second and third open layers P2, P3 maintain an open microstructure, allowing for tissue ingrowth and device fixation.

[0078] Optical surface images were taken using a Keyence VK-X1000 laser scanning confocal microscope. Fibril diameter measurements were performed using the associated multi-file analyzer software. Fibril diameters in the non-active regions of the completed devices were measured and ranged from 0.285 microns to 2.980 microns.

[0079] The device of Example 1 (i.e., including an anchor layer around the device) was implanted into New Zealand White rabbits and evaluated in vivo compared to a control device, described herein as Comparative Example 6 (FIG. 9E). Histological examination was performed using H&E staining (i.e., histological staining with both hematoxylin and eosin) and trichrome staining. Seven days after implantation, the device of Example 1 demonstrated improved ingrowth into the exposed microstructure in the non-active area compared to the control device (shown in FIG. 9E). Furthermore, seven days after implantation, the device of Example 1 demonstrated more extensive and mature collagenous ingrowth into the active area of ​​the device compared to the control device (FIG. 9A). Furthermore, capsule thickness in the non-active area was measured by histological examination. At 30 days, the capsule thickness of the device of Example 1 (see FIG. 10A) was lower than that of the control device (FIG. 10E), indicating improved integrity and reduced micromotion and inflammation.

[0080] Example 2 In a second example, a cell encapsulation device was formed having an inactive region with an anchor region. A bilayer membrane of expanded PTFE was constructed according to the teachings of Example 2 of Bruhn et al., WO 2020 / 243663. The bilayer membrane consisted of a first, closed layer with multiple pores of small pore size and a second, open layer with multiple pores of larger pore size. The properties of the bilayer ePTFE described in Bruhn et al., WO 2020 / 243668, are listed in Table 2. [Table 2]

[0081] The bilayer membrane was lightly bonded to a sheet of approximately 75 microns thick polycarbonate polyurethane film. Bonding was performed at 165°C for 30 seconds using a small spring-loaded hand press. This bonding process lightly secured the polycarbonate polyurethane film to the first sealing layer of the bilayer ePTFE membrane, forming an ePTFE / polycarbonate polyurethane composite for handling. The ePTFE / polycarbonate polyurethane composite was then laser cut into the welded shape around the cell encapsulation device, as shown in WO 2020 / 243668 by Bruhn et al., element 1340 shown in Figure 13 therein.

[0082] Next, a cell encapsulation device was formed using the method described for Device B in accordance with the teachings set forth in WO 2020 / 243668 to Bruhn et al. The cell encapsulation device of Example 2 differs from Device B of WO 2020 / 243668 in that (1) a vascularization layer was not used, and (2) laser-cut ePTFE / polycarbonate polyurethane composite weld layers were used in place of the outermost top and bottom weld film layers shown as 1340 in Figure 13 of WO 2020 / 243668 to Bruhn et al. This substitution of ePTFE / polycarbonate polyurethane composite thus resulted in open anchor regions deposited on the top and bottom inactive regions of the cell encapsulation device.

[0083] Example 3 In a third example, a cell encapsulation device was formed having an inactive region with an anchor region. The cell encapsulation device was formed using the method described for Device B in accordance with the teachings of WO 2020 / 243668 by Bruhn et al. The cell encapsulation device of Example 3 differs from the cell encapsulation device described in WO 2020 / 243668 Device B in that (1) a low-density polyethylene (LDPE) film approximately 50 microns thick was used instead of the polycarbonate polyurethane welded film layer described as 1340 in Figure 13 of WO 2020 / 243668, (2) a vascularization layer was not used, and (3) an ethylene tetrafluoroethylene (ETFE) mesh with nominally 152 micron monofilaments spaced nominally 250 microns apart was used. The devices in this example were processed at a temperature of 160°C.

[0084] Next, a nonwoven spunbond polyester weighing 1.00 oz / yd², with a trilobal fiber diameter of 21 microns and a thickness of 229 microns, was heat-pressed at 130°C to incorporate into the outer, non-active regions of the top and bottom outermost low-density polyethylene (LDPE) welded film layers of the macroencapsulated device. The device of Example 3 showed improved growth into the exposed microstructures (shown in Figure 9B) in the non-active regions compared to the control device (shown in Figure 9E). The capsule thickness of the device of Example 3 (see Figure 10B) was thinner than the control device (Figure 10E), resulting in improved integration and reduced micromotion and inflammation.

[0085] Example 4 Comparative Example A cell encapsulation device was formed according to the teachings set forth in WO2020 / 243668 to Bruhn et al. using the methods described for Device B. The cell encapsulation device of Example 4 differs from Device B of WO2020 / 243668 to Bruhn et al. in that a vascularized layer was not used and the outer welding surface was perforated as described herein.

[0086] After the device was formed, a 0.75 mm biopsy punch was used to create a macroscopic hole in the weld area. Nine holes were drilled around the periphery of the device, approximately 4.5 mm apart, through the non-active area.

[0087] The device of Example 4 was implanted in New Zealand White rabbits for in vivo evaluation, compared to the control device of Example 6, which had no hole. Histological examination, performed with H&E (hematoxylin and eosin) and trichrome staining at 7 days after implantation, showed no improvement in the device of Example 4 compared to the control device (see Figure 9E). As shown in Figure 9C, no improvement in collagenous tissue ingrowth was observed in the active area of ​​the device. At 28 days, the device of Example 4 demonstrated a delayed healing response in the punch area compared to the rest of the device, as evidenced by the lack of collagenous ingrowth at the puncture site. Rather than accelerating device attachment, the larger hole required longer for collagenous tissue integration, providing no significant advantage. The capsule thickness of the device of Example 4 is shown in Figure 10C.

[0088] Example 5 Comparative Example A cell encapsulation device was formed using the method described for Device B in accordance with the teachings set forth in WO 2020 / 243668 to Bruhn et al. The cell encapsulation device of Example 5 differs from Device B of WO 2020 / 243668 to Bruhn et al. in that a vascularized layer was not used and the outer weld surface was roughened as described herein. After sealing, fine non-porous features were pressed into the weld area using 350-grit sandpaper at 150°C. The height of the non-porous features was approximately 35 microns, as measured by confocal laser scanning microscopy on a Keyence VK-X1000 laser scanning confocal microscope.

[0089] The device of Example 5 was implanted into New Zealand White rabbits and evaluated in vivo compared to the control device of Example 6 (FIG. 9E), which did not have surface roughness added. Histological examination by H&E (hematoxylin and eosin staining) and trichrome staining at 7 and 28 days after implantation showed no improvement in the device of Example 5 (FIG. 9D) compared to the control (FIG. 9E). As shown in FIG. 9D, no improvement in collagenous tissue ingrowth was observed in the active area of ​​the device. The capsule thickness of the device of Example 4 and the control device is shown in FIGS. 10D and 10E, respectively.

[0090] Example 6 Comparative Example A cell encapsulation device was formed having an inactive region with a smooth, non-porous microstructure (FIG. 9E). The device of Example 6 was constructed using the method described for Device B in accordance with the teachings of Bruhn et al., WO 2020 / 243668. The thickness of the capsule is shown in FIG. 10E. The device of Example 6 differs from Device B of Bruhn et al., WO 2020 / 243668, in that a vascularized layer was not used.

[0091] 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. cell retention area, an inactive region, and an anchor region disposed over at least a portion of the non-active region; wherein the anchoring region comprises an open microstructure configured to promote tissue ingrowth.

2. The cell encapsulation device of claim 1 , wherein the open microstructure comprises a porous polymer having a plurality of anchoring features defined by dimensions between about 0.1 microns and about 100 microns.

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

4. The cell encapsulation device of any one of claims 1 to 3, comprising at least one inactive area disposed on the cell-retaining area.

5. The cell encapsulation device of any one of claims 1 to 4, wherein the anchor region comprises expanded polytetrafluoroethylene.

6. The cell encapsulation device of any one of claims 1 to 5, wherein at least 15% of the area of ​​the non-active region is covered by the anchor region.

7. The cell encapsulation device of any one of claims 1 to 6, wherein the anchoring region comprises an attachment layer and an ingrowth layer.

8. 8. The cell encapsulation device of claim 7, wherein the bonding layer comprises a first plurality of fibrils and the ingrowth layer comprises a second plurality of fibrils, the first fibril density of the bonding layer being greater than the second fibril density of the ingrowth layer.

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

10. The cell encapsulation device of any one of claims 1 to 9, wherein the ratio of active area to non-active area is between 50% and 150%.

11. an active region defined by a perimeter and a surface area, the active region covering at least one reservoir containing cells; a non-active region disposed around the active region; and an open microstructure layer disposed over at least a portion of the anchor region; wherein the open microstructure is defined by interconnected fibrils; and A cell encapsulation device, wherein the open microstructure is defined by a thickness of between 5 microns and 600 microns.

12. 12. The cell encapsulation device of claim 11, wherein the open microstructure fibrils have a size between 0.1 microns and 100 microns.

13. 13. The cell encapsulation device of claim 11 or 12, wherein the open microstructure fibrils have dimensions of less than 1 micron.

14. The cell encapsulation device of any one of claims 11 to 13, wherein at least 15% of the non-active region is covered by the anchor region.

15. The cell encapsulation device of any one of claims 11 to 14, wherein 40% to 95% of the non-active region is covered by the anchor region.

16. The cell encapsulation device of any one of claims 11 to 15, wherein 60% to 99% of the non-active region is covered by the anchor region.

17. The cell encapsulation device of any one of claims 11 to 16, wherein the open microstructure is welded to the non-active area.

18. 18. The cell encapsulation device of any one of claims 11-17, wherein the open microstructure is comprised of a first layer and a second layer, each of the first layer and the second layer comprising fibrils, and the first layer is defined by a first fibril density that is greater than a second fibril density of the second layer.

19. 1. An anchor region for use in an implantable medical device configured to promote tissue integration, said anchor region comprising: a bonding layer, and an ingrowth layer attached to the bonding layer; the ingrowth layer comprises a porous polymer having a plurality of anchor features defined by dimensions between about 0.1 microns and about 100 microns; and The porous polymer is configured to integrate with tissue, an anchoring region.

20. The anchor region of claim 19 , wherein the bonding layer is configured to weld with the implantable medical device.

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

Images