Non-invasive removable cell encapsulation device

Abstract

A treatment device includes a bag having opposing first and second ends, and a first composite layer and a second composite layer extending between the opposing first and second ends. The first composite layer includes a first cell-permeable layer extending between the opposing first and second ends, and a first cell-retaining layer extending between the opposing first and second ends. The bag includes a reservoir formed between the first and second composite layers that contacts the first cell-retaining layer, and at least one port in fluid communication with the reservoir. The treatment device also includes a removal element configured to operably engage the first end of the bag such that the first end can be moved toward the second end by flipping. In some embodiments, each of the first and second composite layers includes a plurality of pleats that gradually detach from tissue to remove the treatment device non-invasively.

Description

Technical Field

[0001] This disclosure relates to implantable biological devices, and more specifically to implantable encapsulation devices that can be removed non-invasively. Background Technology

[0002] Biotherapy is an increasingly viable approach for treating peripheral artery disease, aneurysms, heart disease, Alzheimer's and Parkinson's diseases, autism, blindness, diabetes, and other conditions. In general, biotherapy involves introducing cells, viruses, viral vectors, bacteria, proteins, antibodies, and other bioactive components into the patient's body through surgical or interventional procedures, placing the bioactive components within the patient's tissue bed. Typically, the bioactive components are first placed in a device, which is then inserted into the patient. Alternatively, the device can be inserted first, followed by the addition of the bioactive components.

[0003] These devices are typically implanted temporarily in the patient's body. However, even temporary devices can grow into the surrounding tissue, making removal difficult. For example, removal using conventional methods involving cutting through surrounding tissue can cause trauma. Furthermore, these procedures can lead to patient discomfort and the inability to reuse the same tissue in future procedures. Therefore, there is a need for implantable devices that encapsulate cells and / or other biological components, allowing for non-invasive removal from the patient. Summary of the Invention

[0004] The terms “disclosure,” “this disclosure,” “the present invention,” and “current disclosure” as used herein are used generically to refer to all subject matter in this patent application and the following claims. The inclusion of these terms should not be construed as limiting the subject matter described herein or limiting the meaning or scope of the following claims. This summary is a highly generalized overview of various aspects of this disclosure and introduces some concepts that are further described in detail in the following detailed description section. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to define the scope of the claimed subject matter. The subject matter should be understood with reference to suitable portions of the specification, any or all of the drawings, and each claim. Embodiments of this disclosure relate to a therapeutic device comprising a bag having opposing first and second ends. The bag includes a first composite layer and a second composite layer extending between opposing first and second ends. The first composite layer includes a first cell-permeable layer extending between opposing first and second ends and a first cell-retaining layer extending between opposing first and second ends. The bag also includes a reservoir positioned between the first and second composite layers, the reservoir contacting the first cell-retaining layer. The bag also includes at least one port in fluid communication with the reservoir. The bag also includes a removal element configured to operably engage a first end of the bag, such that the first end can be moved toward a second end of the bag by flipping it over.

[0005] In some embodiments, each of the first composite layer and the second composite layer includes a plurality of folds.

[0006] In some embodiments, the first cell-permeable layer has pores large enough to allow vascular tissue to grow through it.

[0007] In some embodiments, the pore size is greater than 5.0 micrometers, such as as measured by porosity methods.

[0008] In some embodiments, the first cell retention layer has pores large enough to prevent vascular tissue from growing inward.

[0009] In some embodiments, the pore size is less than 1 micrometer, as measured by porosity methods.

[0010] In some embodiments, at least one of the first cell-permeable layer and the first cell-retaining layer comprises an expandable fluoropolymer.

[0011] In some embodiments, the second composite layer includes a second cell-permeable layer extending between opposing first and second ends and a second cell-retaining layer extending between opposing first and second ends.

[0012] Various embodiments of this disclosure also relate to a method comprising engaging a removal element configured to operatively engage a first end of a therapeutic device implanted in a tissue recess, wherein the implanted therapeutic device and the tissue recess define a plane. The method further comprises applying tension to the removal element along a first direction parallel to the plane. The method further comprises moving the removal element along the first direction to move the first end of the implanted therapeutic device toward a second end of the implanted therapeutic device opposite to the first end, such that the implanted therapeutic device is dislodged from the tissue recess, wherein the movement step flips the implanted therapeutic device to remove the implanted therapeutic device from the tissue recess non-invasively.

[0013] In some embodiments, the treatment device includes a bag having opposing first and second ends. The bag includes a first composite layer and a second composite layer extending between the opposing first and second ends. The first composite layer includes a first cell-permeable layer extending between the opposing first and second ends. The first composite layer also includes a first cell retention layer extending between the opposing first and second ends. The bag also includes a reservoir formed between the first and second composite layers. The reservoir contacts the first cell retention layer. The bag also includes at least one port in fluid communication with each reservoir. The treatment device further includes a removal element configured to operably engage the first end of the bag, such that the first end can be moved toward the second end by flipping.

[0014] In some embodiments, each of the first composite layer and the second composite layer includes a plurality of folds.

[0015] In some embodiments, the method further includes moving the treatment device from a first relaxed state to a second extended state, wherein in the first relaxed state, tissue in a plurality of folds formed in at least one of a first composite layer and a second composite layer is engaged in a tissue cavity, and in the second extended state, at least some of the folds are stretched apart, thereby causing a portion of the tissue to detach from the at least some folds. The movement steps include a plurality of discrete, individual movements, whereby the tissue gradually detaches from the plurality of folds of the bag, such that the bag is removed from the tissue cavity non-invasively.

[0016] In some embodiments, the second composite layer includes a second cell-permeable layer extending between opposing first and second ends and a second cell-retaining layer extending between opposing first and second ends.

[0017] Embodiments of this disclosure also relate to a treatment device including opposing first and second ends, wherein the opposing first and second ends define a longitudinal axis therebetween. The treatment device further includes a first composite layer extending between the first and second ends. The first composite layer includes a first plurality of folds. The treatment device further includes a second composite layer extending between the first and second ends. The second composite layer includes a plurality of second folds. The treatment device further includes a storage portion formed between the first and second composite layers, the storage portion having a length, a width, and a depth. The treatment device further includes at least one port in fluid communication with the storage portion. The treatment device is movable between a first relaxed state and a second extended state, in which the first plurality of folds and the second plurality of folds extend in a direction substantially perpendicular to the longitudinal axis, and in the second extended state, the first plurality of folds and the second plurality of folds are configured to be stretched between the first and second ends, thereby being substantially parallel to the longitudinal axis.

[0018] In some embodiments, at least one of the first composite layer and the second composite layer includes a cell-permeable layer extending between opposing first and second ends and a cell-retaining layer extending between opposing first and second ends.

[0019] Various embodiments of this disclosure also relate to a method comprising engaging a first end of a therapeutic device implanted in a tissue recess, wherein the implanted therapeutic device and the tissue recess define a plane. The method further comprises applying tension to the first end along a first direction parallel to the plane to move the therapeutic device from a first relaxed state to a second extended state, wherein in the first relaxed state, a plurality of folds formed on the therapeutic device engage tissue in the tissue recess, and in the second extended state, at least some of the folds are stretched apart, thereby disengaging a portion of the tissue from the at least some folds. The movement steps include a plurality of discrete, individual movements, whereby the tissue gradually disengages from the plurality of folds of the pouch, such that the pouch is removed from the tissue recess non-invasively.

[0020] In some embodiments, the treatment device includes opposing first and second ends. The opposing first and second ends define a longitudinal axis between them. The treatment device also includes a first composite layer extending between the first and second ends. The first composite layer includes a first plurality of folds. The treatment device also includes a second composite layer extending between the first and second ends. The second composite layer includes a second plurality of folds. The treatment device also includes a reservoir formed between the first and second composite layers, the reservoir having a length, a width, and a depth. The treatment device also includes at least one port in fluid communication with the reservoir. The treatment device is movable between a first relaxed state and a second extended state, in the first relaxed state the first plurality of folds and the second plurality of folds extend in a direction substantially perpendicular to the longitudinal axis, and in the second extended state the first plurality of folds and the second plurality of folds are configured to be stretched between the first and second ends, thereby being substantially parallel to the longitudinal axis.

[0021] In some embodiments, at least one of the first composite layer and the second composite layer includes a cell-permeable layer extending between opposing first and second ends and a cell-retaining layer extending between opposing first and second ends.

[0022] In some embodiments, at least one of the first composite layer and the second composite layer is a cell-permeable layer.

[0023] In some embodiments, at least one of the first composite layer and the second composite layer is a cell retention layer. Attached Figure Description

[0024] The accompanying drawings are included to provide a further understanding of the present disclosure, and the drawings are incorporated in and form part of this specification, illustrate embodiments, and together with the description serve to explain the principles of the present disclosure.

[0025] Figure 1 This is a perspective view showing a treatment device according to an embodiment described herein;

[0026] Figure 2 This illustrates a tissue cavity according to an embodiment described herein. Figure 1 A cross-sectional view of the treatment device shown;

[0027] Figure 3 This illustrates an embodiment according to the description herein. Figure 1 The diagram shows a cross-sectional view of the treatment device, in which a removal tool applies a tangential force to the removal element of the treatment device;

[0028] Figure 4 This illustrates an embodiment according to the description herein. Figure 1 The treatment device shown and Figure 3 The cross-sectional view of the removal tool shown shows the flipping of the treatment device initiated by the removal tool;

[0029] Figure 5 It is shown Figure 1 The treatment device shown and Figure 3 The cross-sectional view of the removal tool shown shows the treatment device being flipped by the removal tool through an inner cavity portion extending through it;

[0030] Figure 6 This illustrates the effect after vascularization according to the embodiments described herein. Figure 1 An enlarged cross-sectional view of a portion of the treatment device shown;

[0031] Figure 7 This is a perspective view illustrating a treatment device including folds according to an embodiment described herein;

[0032] Figure 8 This illustrates a tissue cavity according to an embodiment described herein. Figure 7 A cross-sectional view of the treatment device shown;

[0033] Figure 9 This illustrates a tissue cavity according to an embodiment described herein. Figure 7 A cross-sectional view of the treatment device shown;

[0034] Figure 10 This illustrates removal from a tissue depression initiated by a removal tool according to an embodiment described herein. Figure 7 A cross-sectional view of the treatment device shown;

[0035] Figure 11 This illustrates the embodiments described herein. Figure 10 The removal tool shown partially removed the tissue from the cavity. Figure 7 A cross-sectional view of the treatment device shown;

[0036] Figure 12 This illustrates a partially removed state according to the embodiments described herein. Figure 7 The treatment device shown and Figure 10 The cutaway view of the removal tool shown shows approximately half of the folds unfolded;

[0037] Figure 13 This illustrates an embodiment according to the description herein. Figure 10 The removal tools shown and Figure 7 The cross-sectional view of the treatment device shown, with all the folds unfolded;

[0038] Figure 14 This illustrates an embodiment according to the description herein. Figure 7 An enlarged cross-sectional view of a portion of the treatment device shown. Detailed Implementation

[0039] Those skilled in the art will readily understand that various aspects of this disclosure can be implemented by any number of methods and devices configured to perform the intended functions. It should also be noted that the accompanying drawings referenced herein are not necessarily drawn to scale and may be enlarged to illustrate various aspects of this disclosure, and in this regard, the drawings should not be construed as limiting. Furthermore, the terms "therapeutic device" and "device" are used interchangeably herein. It should be understood that the term "therapeutic device" is also used interchangeably with the term "cell containment device" herein.

[0040] This document describes a therapeutic device for encapsulating biological components, wherein the biological device is implanted into a patient, such as into a tissue bed, to provide biotherapy. The therapeutic device may include a cell encapsulation device, a drug delivery device, or a gene therapy device. This document also describes methods for forming the device and methods for introducing biological components into the device. In some embodiments, the therapeutic device is a bag formed of composite layers. Each composite layer has a porous polymer layer for retaining the biological component and a porous layer capable of forming blood vessels. The cell retention layer and the cell-permeable layer have different porosities and may comprise the same or different materials, or be formed from the same or different materials. In some embodiments, the porosity of the cell retention layer is less than the porosity of the cell-permeable layer. The composite layers are spaced apart from each other to define at least one storage space for retaining the biological component.

[0041] In some embodiments, biological portions suitable for encapsulation and implantation using the devices described herein include cells, viruses, viral vectors, gene therapies, bacteria, proteins, polysaccharides, antibodies, and other bioactive portions. For simplicity, biological portions are referred to as cells hereinafter; however, this specification does not limit biological portions to cells or any particular type of cell, and the following description also applies to non-cellular biological portions. In some embodiments, various types of prokaryotic cells, eukaryotic cells, mammalian cells, non-mammalian cells, and / or stem cells may be used with the cell encapsulation devices of this disclosure.

[0042] In some embodiments, cells are encapsulated (microencapsulated) within a biomaterial of natural or synthetic origin, including but not limited to hydrogel materials. In some embodiments, cells secrete therapeutically useful substances. In some embodiments, such substances include hormones, growth factors, trophic factors, neurotransmitters, lymphokines, antibodies, or other cellular products that provide therapeutic benefit to the device receptor. Examples of such therapeutic cellular products include, but are not limited to, insulin, growth factors, interleukins, parathyroid hormone, erythropoietin, transferrin, and factor VIII. In some embodiments, 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 "multiple cells" may be replaced by "biological part" or "multiple biological parts," respectively.

[0043] I. A treatment device that can be removed non-invasively by flipping.

[0044] This document describes a method for removing a flipped therapeutic device used to encapsulate cells. In some embodiments, the therapeutic device is implanted into the tissue of a patient to be treated. After treatment is completed, or when removal is required in other circumstances, the therapeutic device can be removed from the patient's tissue by tension to minimize or avoid damage to the tissue integrated into and / or surrounding the device. In at least one embodiment, a removal element of the device is engaged, for example, by a device removal tool. The device removal tool applies tension to the removal element, causing a first end of the therapeutic device to flip inward toward a second end of the therapeutic device through itself. As the first end of the therapeutic device is pulled toward the second end, the therapeutic device is removed (e.g., peeled) from the surrounding tissue without trauma and can then be withdrawn from the patient. As used herein, "without trauma" is intended to mean removal that minimizes or avoids trauma to the tissue.

[0045] exist Figure 1-6An embodiment of a therapeutic device for encapsulating cells is shown. This therapeutic device is scalable (scale-proportionable) in that it can be easily constructed in a range of sizes (e.g., circumference) to accommodate cells while ensuring their survival and function. According to one embodiment, the therapeutic device 100 includes a pouch 102 and a removal element 114 attached to the pouch. The pouch 102 extends from a first end 130 to a second end 132. In some embodiments, the pouch 102 may be tubular. However, depending on the anatomical location of the implant, the pouch may be any other shape, such as, for example, substantially planar. The pouch 102 includes a first composite layer 104 and a second composite layer 106. A storage portion 108 is formed between the first composite layer 104 and the second composite layer 106. The storage portion 108 is a containing space in which cells are accommodated and can be accessed through at least one port 107 in fluid communication with the storage portion 108. The perimeter 110 of the pouch 102 is sealed up to the location of the port 107. In one exemplary embodiment, the inner cavity 112 extends through the bag 102, as... Figure 2 The figures depict an inner cavity 112, the diameter of which is exaggerated to show the device removal tool reaching through it. However, the device removal tool may only need to slide through the inner cavity 112, so the inner cavity 112 does not need to remain "open". Furthermore, the diameter may be just large enough to insert the device removal tool. In some embodiments, as the tool is inserted through the inner cavity 112, the tool will create its own space through the inner cavity 112. The removal element 114 of the treatment device 100 is attached to a first end 130 of the pouch 102 for non-invasive removal of the treatment device 100 by flipping.

[0046] like Figure 6 As depicted, in some embodiments, the first composite layer 104 is a composite layer comprising a cell-permeable layer 116 and a cell retention layer 118 disposed adjacent to the cell-permeable layer 116. Similarly, the second composite layer 106 is also a composite layer comprising a cell-permeable layer 120 and a cell retention layer 122. The cell retention polymer layer is impermeable for inward cell growth. The cell-permeable layer allows vascular tissue to grow into and through the pores of the cell-permeable layer up to the cell retention layer. In some embodiments, the cell-permeable layers 116 and 120 of the first composite layer 104 and the second composite layer 106 are formed of the same material. In other embodiments, the cell-permeable layers 116 and 120 are formed of different materials. Both cell-permeable layers 116 and 120 are cell-permeable layers with sufficient porosity to allow vascular tissue 137 to grow from the patient into and through the pores of the cell-permeable layers 116 and 120, such as... Figure 6As depicted, the inward growth of vascular tissue through the cell-permeable layer facilitates the transfer of nutrients from the patient to the cells encapsulated within the therapeutic device. However, the inward growth of vascular tissue does not extend through the cell-retaining layer.

[0047] In some embodiments, the cell-permeable layers 116, 120 have an average pore size of less than 5 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116, 120 is 5 to 30 micrometers, as measured by porosity methods. In other embodiments, the average pore size of the cell-permeable layers 116, 120 is 7 to 30 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116, 120 is 10 to 30 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116, 120 is 15 to 30 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116, 120 is 25 to 30 micrometers.

[0048] In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 5 micrometers to 25 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 5 micrometers to 20 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 5 micrometers to 15 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 5 micrometers to 10 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 5 micrometers to 7 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 7 micrometers to 15 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 10 micrometers to 27 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 12 micrometers to 15 micrometers. In other embodiments, the average pore size of the cell-permeable layers 116 and 120 is 17 micrometers to 25 micrometers.

[0049] As described herein, various cell types can grow into the cell-permeable layer of the porous material of the therapeutic device 100. The dominant cell type growing into the porous material depends primarily on the implantation site, the composition and permeability of the material, and any biological agents, such as, for example, cytokines and / or cell adhesion molecules, which may be included in or introduced through the porous material(s). In some embodiments, vascular endothelium is the dominant cell type growing into the porous material used in the cell encapsulation device. Figure 6 As depicted, the vascularization of the porous material is promoted by a well-established population of vascular endothelial cells in the form of a capillary network 137, as the material, originating from the patient's tissue, enters and penetrates the thickness of the material, very close to the inner surface of the device 100, but does not penetrate the cell retention layer.

[0050] The cell-retaining layer and the cell-permeable layer should each have sufficient compliance to allow the therapeutic device to fold onto itself during the flipping process. Therefore, in some embodiments, only vascularization of the cell-permeable layer is allowed to reach a predetermined degree, so as not to interfere with the compliance of the therapeutic device.

[0051] Cell retention layers 118 and 122 are impermeable to inward cell growth, and are therefore cell retention layers. Both cell retention layers 118 and 122 have pores small enough to prevent inward blood vessel growth.

[0052] In some embodiments, the average pore size of the cell retention layers 118 and 122 is less than 5 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.001 micrometers to 5 micrometers, as measured by porosity methods. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.001 micrometers to 0.5 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.001 micrometers to 0.1 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.001 micrometers to 0.05 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.001 micrometers to 0.01 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.005 micrometers to 0.001 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is from 0.001 micrometers to 0.002 micrometers.

[0053] In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.005 micrometers to 5 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.01 micrometers to 5 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.05 micrometers to 5 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.1 micrometers to 5 micrometers. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.5 micrometers to 5 micrometers.

[0054] In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.01 μm to 0.5 μm. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.005 μm to 0.2 μm. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.25 μm to 0.75 μm. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.1 μm to 0.2 μm. In other embodiments, the average pore size of the cell retention layers 118 and 122 is 0.015 μm to 0.045 μm.

[0055] The small pore size allows the cell retention layers 118 and 122 to function as cell retention layers, holding the cells within the storage section 108 inside the treatment device 100. However, this small pore size allows nutrients and other biomolecules to enter, while allowing cellular waste and treatment products to leave. These cell retention layers 118 and 122 are referred to as cell retention layers.

[0056] In some embodiments, the cell-permeable layers 116, 120 and / or the cell-retaining layers 118, 122 include, but are not limited to, alginate, cellulose acetate, polyalkylene glycols such as polyethylene glycol and polypropylene glycol, trivinyl polymers such as polyvinyl alcohol, chitosan, polyacrylates such as polyethylene-copolyacrylic acid, agarose, hydrolyzed polyacrylonitrile, polyacrylonitrile copolymers, polyethylene acrylates such as polyethylene-copolyacrylic acid, porous polytetrafluoroethylene (PTFE), porous modified polytetrafluoroethylene polymers, porous tetrafluoroethylene (TFE) copolymers, porous polyalkylene compounds such as porous polypropylene and porous polyethylene, porous polyvinylidene fluoride, porous polyester sulfone (PES), porous polyurethane, porous polyester, and copolymers and combinations thereof. In some embodiments, materials that can be used as one or both of the cell-permeable layers include biomaterial textiles.

[0057] In some embodiments, the cell-permeable layers 116, 120 and / or the cell-retaining layers 118, 122 may include porous polyvinylidene fluoride (PVDF) as taught in U.S. Patent No. 9,441,088 to Sbriglia et al., porous poly(p-xylene) (ePPX) as taught in U.S. Patent Publication No. 2016 / 0032069 to Sbriglia, porous ultra-high molecular weight polyethylene (eUHMWPE) as taught in U.S. Patent No. 9,926,416 to Sbriglia, porous ethylene tetrafluoroethylene (eETFE) as taught in U.S. Patent No. 9,932,429 to Sbriglia, vinylidene fluoride-co-tetrafluoroethylene or trifluoroethylene [VDF-co-(TFE or TrFE)] polymers as taught in U.S. Patent No. 9,441,088 to Sbriglia, copolymers and combinations thereof, and collections or fiber matrices of woven or nonwoven fibers or yarns, alone or in combination.

[0058] In some embodiments, the cell-permeable layers 116, 120 and / or the cell retention layers 118, 122 are expandable fluoropolymer membranes. For example, the cell-permeable layers 116, 120 and / or the cell retention layers 118, 122 may comprise expandable polytetrafluoroethylene (ePTFE) or expandable modified polytetrafluoroethylene. In some embodiments, the cell-permeable layers 116, 120 and / or the cell retention layers 118, 122 are expandable polytetrafluoroethylene membranes (e.g., ePTFE membranes).

[0059] In some embodiments, one or both of the cell retention layers 118, 122 and the cell permeable layers 116, 120 of the treatment device 100 are made primarily or entirely of a porous material having selective sieving and / or porous properties. In some embodiments, the porous material is primarily based on size-controlled solutes, biochemicals, viruses, and cells, for example, through the material. Non-limiting examples of porous materials include, but are not limited to, one or more of the materials described above for the inner and outer layers, including biomaterial textiles.

[0060] In one embodiment, the treatment device 100 does not include a composite layer. Instead, the treatment device includes a first cell-permeable layer and a second cell-permeable layer. In such an embodiment, cells to be inserted into the treatment device 100 are microencapsulated (microencapsulated), which provides the cells with isolation from the host immune response but allows the cells to receive nutrients, etc. (e.g., the cells can obtain nutrients and other biomolecules from the environment outside the device 100 and excrete waste products and therapeutic substances). In some embodiments, the cells may be microencapsulated within biomaterials of natural or synthetic origin, including but not limited to hydrogels.

[0061] Turning Figure 6 As described above, the storage section 108 is formed between the first composite layer 104 and the second composite layer 106 of the bag 102. Specifically, the storage section 108 is formed between the cell retention layers 118 and 122 of the bag 102. As used herein, the term "storage section" is intended to define the total area within the treatment device 100 between the first and second cell retention layers and within the perimeter of the treatment device 100 in which cells are placed (or in which cells reside). The storage section 108 may take various forms, such as, for example, channels or geometries (e.g., generally rectangular, circular, square, semi-circular, semi-elliptical, etc.).

[0062] like Figure 6As depicted, the storage portion 108 is configured to retain cells 136 within the treatment device 100 to allow the cells to secrete substances that are therapeutically useful for providing biotherapy to a patient. In some embodiments, cells 136 are introduced into the storage portion 108 of the treatment device 100 via one or more ports 107 fluidly connected to it. The ports 107 may be located anywhere along the perimeter of the treatment device 100, provided they are in fluid communication with the storage portion 108 and can be accessed from outside the treatment device 100. In some embodiments, the ports 107 are located at the perimeter of the treatment device 100. In some embodiments, the ports 107 extend through the sealed perimeter between the first composite layer 104 and the second composite layer 106 of the sealed bag 102, such that cells are introduced into the storage portion 108 of the bag 102 through an opening in the bag material.

[0063] In some embodiments, cells 136 are introduced into the medium in the form of a suspension or slurry. Cells 136 may be single cells, cell aggregates, or cell clusters. In some embodiments, the medium may be a cell culture or cell growth medium, optionally comprising desired nutrients and / or other biomolecules. In some embodiments, cell insertion through port 107 can be achieved using a syringe.

[0064] Cells 136 can be introduced into the storage section 108 before or after the treatment device 100 is inserted into the patient. For example, the treatment device 100 can be inserted into the patient and allow vascularization, enabling vascular tissue to grow into the vascularized layer of the device 100. Cells 136 can then be added while the treatment device 100 is in the body. Alternatively, cells 136 can be added to the treatment device 100 before it is inserted into the patient's tissue bed.

[0065] As previously described, in some embodiments, the treatment device 100 includes a bag 102. In some embodiments, the bag may be tubular in shape. The bag 102 includes a hollow interior 112 extending from a first end 130 of the bag 102 through it to a second end 132 of the bag 102. Figure 6 As depicted, the outer surface 134 of the cell-permeable layer 116 of the first composite layer 104 forms the outer wall of the bag 102. Furthermore, the inner lumen 112 is defined by the lumen-facing surface 135 of the cell-permeable layer 120 of the second layer 106, as shown... Figure 2 What is depicted.

[0066] although Figure 1-6An inner cavity 112 with an exaggerated perimeter relative to the size of the bag 102 is depicted; however, the perimeter of the inner cavity 112 may be very small, or in some embodiments substantially nonexistent, such that the opposing sides 135 of the surfaces facing the inner cavity are in contact. In some embodiments, the inner cavity 112 has a perimeter, for example, from 1 mm to 10 mm. In other embodiments, the inner cavity has a perimeter from 3 mm to 10 mm. In other embodiments, the inner cavity has a perimeter from 5 mm to 10 mm. In other embodiments, the inner cavity has a perimeter from 7 mm to 10 mm. In other embodiments, the inner cavity has a perimeter from 9 mm to 10 mm.

[0067] In other embodiments, the cavity has a circumference ranging from 1 mm to 9 mm. In other embodiments, the cavity has a circumference ranging from 1 mm to 7 mm. In other embodiments, the cavity has a circumference ranging from 1 mm to 5 mm. In other embodiments, the cavity has a circumference ranging from 1 mm to 3 mm.

[0068] In other embodiments, the cavity has a circumference of 2 mm to 7 mm. In other embodiments, the cavity has a circumference of 5 mm to 8 mm. In other embodiments, the cavity has a circumference of 2 mm to 5 mm. In other embodiments, the cavity has a circumference of 7 mm to 9 mm.

[0069] To remove the treatment device 100 non-invasively, the device 100 includes a removal element 114 attached to a first end 130 of a pouch 102. The removal element 114 allows removal of the treatment device 100 via tangential force rather than shear force, as will be described in more detail below. The removal element 114 can be any structure integrated into or attached to the pouch 102 that transmits tension to the first end 130 of the pouch 102. In some embodiments, such as Figure 1-4 As depicted, the removal element 114 is a pull tab. In other embodiments, the removal element 114 includes filaments, cords, straps, tubes, sutures, sheets, or other longitudinal elements. The removal element 114 is biocompatible and may be metallic or polymeric. In some embodiments, the removal element 114 includes ePTFE or another robust, inert, biocompatible material(s). In some embodiments, the removal element 114 is attached to the second composite layer 106 of the treatment device 100. In some embodiments, the removal element 114 is attached to the bag by tying, bonding, or using one or more fasteners(s). In other embodiments, the removal element 114 is formed as an integral part of the bag 102. An integral removal element 114 eliminates the possibility of failure at the connection point between the bag 102 and the removal element 114 in other "attachment" modes. In some embodiments, such as Figure 3-5As depicted, the removal element 114 extends from the first end 112 of the bag 102 and enters the inner cavity 112 to be accessed (contacted) by the device removal tool 140. Specifically, the device removal tool 140 is inserted from the second end 132 of the bag 102 into the inner cavity 112 to grasp the removal element 114. Thus, force can be applied to the removal element 114 through the inner cavity 112 to remove the device 100 by flipping it over, as will be described in further detail below.

[0070] exist Figures 2-5 In the described method of use, the treatment device 100 is implanted into a recess in the patient's tissue 138. The treatment device 100 can be implanted into the patient before or after the introduction of cells 136 into the storage portion 108. Once the treatment device is no longer needed, it is removed from the patient's tissue by tangential force to minimize or avoid trauma to the surrounding tissues. Specifically, the removal element 114 is engaged by a device removal tool 140 through the lumen 112, such as... Figure 3 As depicted. Tension is applied to the removal element 114 by the removal tool 140, causing the first end 130 of the bag 102 to be pulled toward the second end 132 of the bag 102 into the inner cavity 112, as shown. Figure 4 As depicted. As the device removal tool 140 is further pulled through the lumen 112, such that the first end 130 follows the device removal tool 140 through the lumen 112 toward the outside of the bag 102, the bag 102 is removed non-invasively (e.g., dissected) from the patient's surrounding tissues and ultimately flipped through the lumen 112, as... Figure 5 As depicted. Once the treatment device 100 is removed from the recess of the tissue 138, it can be withdrawn from the patient's body by the device removal tool 140.

[0071] Although the embodiments of this disclosure describe a treatment device that flips through a lumen, other embodiments in which the treatment device can be flipped in various other ways are contemplated and are considered within the scope of this disclosure. The treatment device may take any other shape or form, provided that at least one surface of the treatment device is free, i.e., not attached to tissue. For example, in some embodiments of this disclosure, the treatment device is substantially planar or patch-like, without an end-lumen extending therethrough. In this embodiment, a single surface of the treatment device is attached to tissue via vascularization, while opposing surfaces prevent tissue attachment and are therefore free or unattached to tissue. In this embodiment, a removal element is attached to the free surface such that the attached side can be peeled off from the tissue when tension is applied to the removal element.

[0072] II. Treatment device that can be removed through folds

[0073] In another embodiment, this document describes a method for removing a treatment device by incorporating multiple folds in the treatment device. In some embodiments, the treatment device is implanted into, for example, a patient's tissue. Once implanted, the treatment device is removed from the tissue by applying tension to the removal element to minimize trauma to the patient's surrounding tissue, as described in detail above. For example, a second end of the treatment device may be engaged by a device removal tool, and tension is applied to the second end to pull it away from the first end of the treatment device. As the second end is pulled in the direction of tension, the first microfold closest to the second end unfolds. As the device removal tool pulls the second end further away from the first end, each individual microfold unfolds one after another until the treatment device is removed non-invasively from the patient's surrounding tissue (e.g., peeled off).

[0074] Figures 7-14 An exemplary embodiment of a treatment device 300 extending from a first end 330 to a second end 332 is depicted. The treatment device 300 includes a first composite layer 304 and a second composite layer 306, which are sealed along a portion of their perimeter 310. A reservoir 308 is formed between the first composite layer 304 and the second composite layer 306. The reservoir 308 is a containing space in which cells are accommodated and is accessible through at least one port 307 in fluid communication with the reservoir 308. The perimeter 310 of the treatment device 300 is sealed up to the location of the port 307. The port 307 extends through the sealed perimeter 310 and is in fluid communication with the reservoir 308. In some embodiments, an inner cavity 312 extends through the treatment device 300, such as... Figure 8 What is depicted.

[0075] The first composite layer 304 and the second composite layer 306 can be formed in the same manner as the first composite layer 104 and the second composite layer 106 described herein, and have the same characteristics. In some embodiments, the first composite layer 304 is a composite layer including a cell-permeable layer 316 and a cell-retention layer 318. In some embodiments, the second composite layer 306 includes a cell-permeable layer 320 and a cell-retention layer 322. The cell-permeable layers 316, 320 and the cell-retention layers 318, 322 can be formed in the same manner as the cell-permeable layers 116, 120 and the cell-retention layers 118, 122, and have the same characteristics. Specifically, as Figure 14 The depicted cell-permeable layers 316 and 320 are cell-permeable layers that promote vascularization (i.e., formation of a capillary network 337) through which cell-retaining layers 319 and 322, which are impermeable to cell growth and vascularization. The cell-retaining layers may be very thin, allowing cells to still receive nutrients from the vascularized layers, but vascularization stops at the interface between the two layers.

[0076] like Figures 8-12As depicted, in an exemplary embodiment, each of the first composite layer 304 and the second composite layer 306 includes a plurality of folds 350. A "fold" as defined herein forms a ground-like pattern with alternating peaks and valleys. Because the first composite layer 304 and the second composite layer 306 include these folds 350, the treatment device 300 can be positioned as follows: Figure 9 The movement depicted is between a relaxed state and an extended state. In the relaxed state, multiple folds extend in a direction substantially perpendicular to the longitudinal axis of the treatment device 300. In the extended state, multiple folds are stretched between the first end 330 and the second end 332, thereby becoming substantially parallel to the longitudinal axis of the treatment device 300. Figure 11 The image depicts a partially extended state. Specifically, as the second end 332 of the bag 302 is pulled from the tissue bed, the tension applied to the treatment device 300 causes the folds 350 to unfold, thereby detaching the treatment device 300 from the tissue bed in which it is implanted. This movement from a relaxed state to an extended state allows the treatment device 300 to be removed from the patient's tissue bed with minimal trauma to the tissue in which it is implanted. Furthermore, multiple folds 350 can increase the effectiveness of the device because the folds increase the effective surface area. In some embodiments, the folds 305 may be formed according to the teachings of U.S. Patent No. 9,849,629 to Zaggl et al.

[0077] In some embodiments where the first composite layer 304 and the second composite layer 306 are composite layers, only the outer layer includes a plurality of pleats 350 covering the wrinkle-free inner layer. In some embodiments, both the inner and outer layers include a plurality of pleats 350.

[0078] The storage section 308 is formed between the first composite layer 304 and the second composite layer 306 of the treatment device 300. The storage section 108 may adopt various structures, such as planar shapes or geometric shapes (e.g., general forms such as rectangles, circles, squares, semicircles, semi-ovals, etc.).

[0079] like Figure 12 As depicted, the storage portion 308 is configured to retain cells 336 within the treatment device 300 placed in a patient's tissue bed, allowing the cells 336 to deliver biotherapy to the patient. In some embodiments, the cells 336 are introduced into the storage portion 308 of the treatment device 300 through one or more ports 307. Similar to ports 107, ports 307 may be located anywhere along the length of the treatment device 300, as long as they are in fluid communication with the storage portion 308. In some embodiments, ports 307 extend through a sealed perimeter between a first composite layer 304 and a second composite layer 306 of a sealed bag 302, allowing the cells 336 to be introduced into the storage portion 308.

[0080] In at least one embodiment of the treatment device 300, the treatment device 300 is implanted into a cavity in the patient's tissue 338, such as Figure 9 As depicted. The treatment device 300 may be implanted into a patient before or after introducing cells 336 into the storage portion 308 of the treatment device 300. When deemed necessary or required for removal, the treatment device 300 is removed from the patient's tissue by applying tension to minimize or reduce trauma to the tissue surrounding the device 300. In some embodiments, the second end 332 of the treatment device 300 is engaged by a device removal tool 340, such as Figure 10 The device removal tool 340, as depicted, can be, for example, a snare, a hemostat, etc., which allows removal of the treatment device 100 from the end closest to the user. The device removal tool 340 applies tension (T) to the second end 332, causing the second end 332 of the treatment device 300 to be pulled away from the first end 330, causing the first micro-fold closest to the second end 332 to unfold, such as... Figure 10 As depicted, when the device removal tool 340 further pulls the second end 332 away from the first end 330, the folds 350 unfold until the treatment device 300 is non-invasively detached from the patient's surrounding tissues, as... Figures 11-13 What is depicted.

[0081] III. Treatment devices that can be removed through folding and flipping.

[0082] In another embodiment, this document describes a method for removing a treatment device with multiple folds by flipping. In some embodiments, the treatment device is implanted into, for example, a patient's tissue. After treatment is complete, or in other cases when removal is required, the treatment device can be removed from the patient's tissue by tangential force to minimize or avoid damage to the tissue integrated into the treatment device. The removal element of the device is engaged, for example, by a device removal tool. The device removal tool applies tension to the removal element, causing a first end of the treatment device to flip inward toward a second end of the treatment device through itself. As the first end is pulled in the direction of tension, the first microfold closest to the first end unfolds. As the device removal tool pulls the first end toward the second end, individual microfolds unfold until the treatment device is removed non-invasively from the patient's surrounding tissue (e.g., peeled off).

[0083] Such a treatment device is substantially similar to treatment device 100 and includes a bag and a removal element attached thereto. The bag extends from a first end to a second end. The bag includes a first composite layer and a second composite layer. A storage portion is formed between the first and second composite layers. The storage portion is a containing space in which cells are accommodated and can be accessed through one or more ports in fluid communication with the storage portion. The perimeter of the bag is sealed to the location of one or more ports. In an exemplary embodiment, a hollow cavity extends through the bag. The removal element of the treatment device is attached to the first end of the bag for non-invasive removal of the treatment device by flipping.

[0084] Similar to treatment device 300, multiple folds are incorporated into the treatment device. In such an embodiment, each of the first and second composite layers includes multiple folds. Because the first and second composite layers include these folds, the treatment device can move within the patient's body between a relaxed state and an extended state. In the relaxed state, the multiple folds extend in a direction substantially perpendicular to the longitudinal axis of the treatment device, and in the extended state, the multiple folds are stretched between the first and second ends, thereby becoming substantially parallel to the longitudinal axis of the treatment device.

[0085] The first and second composite layers can be formed in the same manner as the first composite layer 104 and the second composite layer 106 described herein, and have the same properties. In some embodiments, the first composite layer is a composite layer comprising a cell-permeable layer and a cell-retaining layer. In some embodiments, the second composite layer comprises a cell-permeable layer and a cell-retaining layer. The cell-permeable layer and the cell-retaining layer can be formed in the same manner as the cell-permeable layers 116, 120 and the cell-retaining layers 118, 122, and have the same properties.

[0086] The storage section is formed between the first and second composite layers of the treatment device and is configured to hold the cells within a containment space. The storage section can be formed in the same manner as the storage section 108 described herein and has the same characteristics.

[0087] In at least one embodiment of the treatment device, the device is implanted into a cavity within the patient's tissue. The treatment device may be implanted before or after cell introduction. When deemed necessary or required for removal, the treatment device is removed from the patient's tissue by applying a tangential force to minimize or reduce trauma to the patient's surrounding tissues. Specifically, the removal element is engaged through the lumen by a device removal tool. Tension is applied to the removal element by the device removal tool, causing a first end of the bag to be pulled into the lumen toward a second end. Simultaneously, the first micro-fold closest to the first end unfolds. As the device removal tool is further pulled through the lumen, causing the first end to follow the tool through the lumen toward the outside of the bag, each individual micro-fold unfolds from the first end to the second end until the bag is non-traumatically detached from the patient's surrounding tissues and ultimately flipped through the lumen. Thus, due to the increased surface area of ​​the multiple folds 350, the treatment device of this embodiment allows for greater device efficacy while also employing a flipping removal technique to minimize trauma to surrounding tissues.

[0088] VI. Bioabsorbable materials

[0089] In some embodiments, one or both composite layers of the described therapeutic device are or include bioresorbable materials. Bioresorbable materials can be formed as solids (molded, extruded, or crystalline), self-adhesive meshes, raised meshes, or sieves. In some embodiments, one or more layers of bioresorbable material are attached to a non-bioresorbable material having a macroscopic porosity to allow cell permeation (e.g., a cell-permeable layer) to form a composite material. In other embodiments, a non-bioresorbable material having a microscopic porosity that reduces or prevents cell permeation can be releasely attached to a porous self-adhesive mesh to allow for non-invasive removal of the therapeutic device 100, 300 from the patient within a few days after implantation. Reabsorption into the patient can promote favorable type I collagen deposition, angiogenesis, and reduce infection. Furthermore, in some embodiments, the cell-permeable layer can be made of a bioresorbable material that can be tailored for reabsorption when an external therapeutic device is needed, thus facilitating removal because inward growth of tissue into the therapeutic device is less significant.

[0090] Non-limiting examples of suitable bioabsorbable materials include, but are not limited to: polyglycolic acid:trimethylene carbonate (PGA:TMC), polylactic acid, polyglycolic acid, poly(glycolic acid), poly(glycolic acid), poly(lactide-co-caprolactone), poly(caprolactone), poly(carbonate), poly(dioxanone), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate-co-valerate), and copolymers and blends thereof.

Claims

1. A treatment device, comprising: The bag includes: The first and second ends are opposite; A first composite layer and a second composite layer extending between the opposing first and second ends, wherein the first composite layer comprises: A first cell-permeable layer extends between the opposing first and second ends; and A first cell retention layer extends between the opposing first and second ends; and The second composite layer includes: A second cell-permeable layer extends between the opposing first and second ends; and A second cell retention layer extends between the opposing first and second ends; and An inner cavity extending from the first end through the treatment device to the second end, and the treatment device is a cell encapsulation device; A storage section is positioned between the first composite layer and the second composite layer, and the storage section contacts the first cell retention layer; At least one port, the at least one port being in fluid communication with the storage unit; and A removal element, which is attached to or integrated with the first end of the bag, extends from the first end into the inner cavity to be accessible by a device removal tool, such that during use, the device removal tool, inserted into the inner cavity from the second end of the bag, grasps the removal element to apply force through the inner cavity to the removal element so that the device is removed by flipping.

2. The apparatus as claimed in claim 1, characterized in that, The first cell-permeable layer has pores large enough to allow vascular tissue to grow through it.

3. The apparatus as described in claim 2, characterized in that, The pore size is greater than 5.0 micrometers, as measured by the porosity method.

4. The apparatus as claimed in claim 1, characterized in that, The first cell retention layer has pores large enough to prevent vascular tissue from growing inward.

5. The apparatus as described in claim 4, characterized in that, The pore size is less than 1 micrometer, as measured by the porosity method.

6. The apparatus as claimed in claim 1, characterized in that, At least one of the first cell permeable layer and the first cell retaining layer comprises an expandable fluoropolymer.

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