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EP-4329667-B1 - IMPLANTABLE DEVICE AND THERAPEUTIC SYSTEM WITH PASSIVE OXYGENATION

EP4329667B1EP 4329667 B1EP4329667 B1EP 4329667B1EP-4329667-B1

Inventors

  • VEDRINE, LIONEL
  • LASKAR, Christina
  • DHAL, PRADEEP
  • NELSON, CRAIG HARVEY
  • HUMPHRIES, MARK ROBSON
  • LEE, CARYS ELERI
  • HARDING, Nicholas Oliver

Dates

Publication Date
20260506
Application Date
20220425

Claims (14)

  1. An implantable device (100, 700) for providing a therapeutic agent (101), the implantable device comprising: a container (102, 702,) configured to contain a plurality of cells (103) capable of producing the therapeutic agent within an interior region (104, 704) of the container, the container defining: first pores (110, 710) defined by an interior wall portion (107, 707) of the container, the first pores having a first average size that (i) allows passage of the therapeutic agent and oxygen (111) through the first pores and (ii) prevents passage of immune cells (113) through the first pores, and second pores (114, 714) defined by an exterior wall portion (108, 708) of the container, the second pores having a second average size that is larger than the first average size, and the second pores being sized to promote vascularization (115) and oxygen transfer along the exterior wall portion, wherein the container has a generally tubular shape, wherein the interior region of the container has a width that is limited to accommodating a single cell (103) of the plurality of cells along a central axis (109, 709) of the container, such that at least a portion of a surface area of each cell of the plurality of cells (103) has direct exposure to the first pores of the interior wall portion, such that the plurality of cells is arrangeable within the container to receive a sufficient amount of oxygen for survival of the plurality of cells from passive diffusion of the oxygen through the first and second pores without an additional energy source for providing supplemental oxygen to the plurality of cells, and wherein the container comprises a tube, and wherein the tube has a spiral configuration (20) or a helical configuration (30).
  2. The implantable device (100, 700) of claim 1, wherein the implantable device has an external surface area to volume ratio of about 200 to about 5,000.
  3. The implantable device (100, 700) of any of claims 1 and 2, wherein the second average size of the second pores is configured to allow passage of the therapeutic agent (101) through the exterior wall portion (108, 708) to vasculature adjacent the implantable device.
  4. The implantable device (100, 700) of any of the preceding claims, wherein the first pores (110, 710) have first widths in a range of about 10 nm to about 400 nm, and wherein the second pores (114, 714) have second widths in a range of about 2 µm to about 60 µm.
  5. The implantable device (100, 700) of any of the preceding claims, wherein the container (102, 702) has a wall thickness in a range of 1 µm to 100 µm; and wherein the interior region (104, 704) has a width in a range of about 100 µm to about 2 mm.
  6. The implantable device (100, 700) of any of the preceding claims, wherein the interior region (104, 704) has a volume capacity of about 0.1 mL to about 1.5 mL or a volume capacity of about 0.1 mL to about 1.1 mL.
  7. The implantable device (100, 700) of any of the preceding claims, wherein the exterior wall portion (108, 708) is coated with a growth factor (117) that promotes vascularization (115), and: wherein the growth factor is covalently linked to the exterior wall portion, and/or wherein the growth factor is electrostatically bound to the exterior wall portion, and/or wherein the growth factor is site-specifically bound to the exterior wall portion, and/or wherein the growth factor is selected from the group consisting of: vascular endothelial growth factor (VEGF), placenta derived growth factor (PDGF), transforming growth factor beta (TGFβ), and fibroblast growth factor (FGF), and/or wherein the growth factor is vascular endothelial growth factor (VEGF), placenta derived growth factor (PDGF), transforming growth factor beta (TGFβ), fibroblast growth factor (FGF), or a combination thereof, and/or wherein the growth factor is vascular growth factor (VEGF).
  8. The implantable device (100, 700) of any of the preceding claims, further comprising the plurality of cells (103) contained within the interior region (104, 704) of the container (102, 702).
  9. The implantable device (100, 700) of claim 8, wherein the plurality of cells (103) are beta cells, and wherein the therapeutic agent (101) comprises insulin.
  10. The implantable device (100, 700) of any of the preceding claims, further comprising one or more additional containers (40, 50) associated with the container (102, 702), wherein each of the one or more additional containers contains an additional plurality of cells (103).
  11. The implantable device (700) of any of the preceding claims, wherein the container comprises a tubular wall (702) that comprises the interior (107, 707) and exterior wall portions (108, 708), wherein the tubular wall further defines third pores (773) arranged radially between the first and second pores, wherein the third pores have a third average size that is greater than the first average size and less than the second average size, wherein the tubular wall defines pores (770) formed by the first, third, and second pores such that the pores (770) gradually increase in size along a radially outward direction (772) from an interior surface (719) of the tubular wall to an exterior surface (716) of the tubular wall, and wherein the container comprises one or more of polycaprolactone, PTFE, ePTFE, nylon, polyether-ketone, polyether sulfone, polyester, polyvinylidene difluoride, and polysiloxane.
  12. The implantable device of any of claims 1-10, wherein the interior wall portion comprises a tubular member (107) and the exterior wall portion comprises a coating (108, 173) that surrounds the tubular member, wherein the tubular member has a first material formulation and the coating has a second material formulation that is different from the first material formulation, wherein the first material formulation comprises one or more of expanded polytetrafluoroethylene (ePTFE), mixed cellulose ester, polyethersulfone (PES), modified PES, alginate, polyethylene glycol (PEG), polyvinylpyrrolidone, poly(methylene-co-guanidine), polyvinyl alcohol, copolymer of vinyl pyrrolidone, hydroxypropyl methacylamide, hydroxypropyl methacrylate, hydroxyethyl methacrylate, poly(oxazolines), hyaluronic acid, polyoxazoline, polyhydroxypropylmethacrlamide, zwiterionic polymers, and polymers containing carboxybetaine, sulfobetaine, and phosphoryl choline groups, and wherein the second material formulation comprises one or more of polyvinylidene difluoride (PVDF), polycaprolactone (PCL), nylon (e.g., nylon-6), polytetrafluoroethylene (PTFE), ePTFE, polyether-ketone, polyether sulfone, polyester, polysiloxane, polyether ketone, poly(vinylidine fluoride-co-hexafluropropylene), cellulose acetate, and polypropylene.
  13. A therapeutic system (60, 70) comprising: the implantable device (100, 600, 700) of any one of claims 1-12, the implantable device configured to be implanted subcutaneously along a skin region (63, 73); and an accessory device (66, 77, 660) configured to cooperate with the implantable device for promoting delivery of oxygen to the plurality of cells.
  14. The therapeutic system (60, 70) of claim 13, wherein the accessory device (66, 77, 660) comprises: (i) a transdermal patch (77) that is configured to be secured to an exterior skin surface of the skin region (73), the transdermal patch comprising a plurality of needles (79) that carry a substance capable (74) of reacting to generate oxygen (75) for the plurality of cells (103) within the interior region (104, 704) of the container, or (ii) a cuff (66) that is configured to be secured to and apply pressure to the exterior skin surface of the skin region (63) to direct a flow of blood (64) towards the implantable device (100, 600, 700), or (iii) a sintered mesh (650) that surrounds the implantable device and that carries a substance capable (630) of reacting to generate oxygen.

Description

Technical Field This disclosure relates to implantable devices that provide a therapeutic agent to treat a disease, such as implants that provide beta cell replacement therapy. Background In patients with type 1 or type 2 diabetes, either or both of mass and function of beta cells may be diminished, which can lead to insufficient insulin secretion and hyperglycemia. Cellular implants have been considered for treating such conditions. For example, a cellular implant may include a housing containing beta cells that are capable of producing insulin. Once the cellular implant is implanted into a patient's body, some or all of the cells within the housing may lack an adequate supply of oxygen. Therefore, cells within a cellular implant can be particularly vulnerable to death due to insufficient oxygen. Cell survival during this period is especially challenged in cases where a cellular implant is relatively large or has a relatively high cell density that locates some cells relatively far away from the surrounding housing and vascularization. US 2019/328289 A1 describes an encapsulation device system for therapeutic applications such as regulating blood glucose. The system may comprise an encapsulation device with a first oxygen sensor integrated inside the device and a second oxygen sensor disposed on an outer surface of the device, wherein the sensors allow for real-time measurements (such as oxygen levels) related to cells (e.g., islet cells, stem cell derived beta cells, etc.) housed in the encapsulation device. The system may also feature an exogenous oxygen delivery system operatively connected to the encapsulation device via a channel, wherein the exogenous oxygen delivery system is adapted to deliver oxygen to the encapsulation device. US 2018/126134 A1 describes implantable encapsulation devices for housing a biological moiety or a therapeutic device that contains a biological moiety. Particularly, aspects of the description are directed to an implantable apparatus that includes a distal end, a proximal end, a manifold including at least one access port positioned either at the distal end or the proximal end, and a plurality of containment tubes affixed to the manifold and in fluid communication with the at least one access port. Additionally, the encapsulation device may contain a flush port and a tube that are fluidly connected to the manifold. The containment tubes may contain therein a biological moiety (e.g., cells) or a therapeutic device (e.g. a cell encapsulation member). WO 2020/243665 A1 describes a biocompatible membrane composite including a cell impermeable layer and a mitigation layer. The cell impermeable layer is impervious to vascular ingrowth and prevents cellular contact from the host. Additionally, the mitigation layer includes solid features. The mitigation layer has therein bonded solid features. The cell impermeable layer and the mitigation layer can be intimately bonded or otherwise connected to each other to form a composite layer having a tight/open structure. A reinforcing component may optionally be positioned external to or within the biocompatible membrane composite to provide support to and prevent distortion. The biocompatible membrane composite may be used in or to form a device for encapsulating biological entities, including pancreatic lineage type cells such as pancreatic progenitors. WO 2020/068852 A1 describes an implantable medical device and methods for making and using the same. The device comprises a central hub structure in communication with at least one housing or pod capable of containing cells and therapeutic materials. Also described are membrane structures and methods of forming the same, the membranes comprising a gradient of varying porosity for use with the described devices, as well as other uses. US 2020/179121 A1 describes an implantable medical device comprising a liquid rope coil scaffold. The implant may consist essentially of the scaffold, where the scaffold is the implant and pores in the scaffold may incorporates one or more agents (i.e. drugs, growth factors), or the scaffold may comprise only part of the medical device, for example an implant that is partly or fully covered with a layer of the scaffold. The porosity of the scaffold may be tailored to suit the application, for example a porosity that is tailored to hold and release drug or biological molecules in vivo, a porosity to provide a surface roughness that is conducive to promotion of in-vivo bio-integration (for example vascularisation) or prevention of fibrosis, or a porosity that provides structural strength. The scaffold may be essentially tubular, or may be provided as a planar structure, or may be any shape and can be used to coat, fully or partially any shape or size of medical implant. Summary An implantable device and a therapeutic system according to the present invention are defined by claims 1 and 13, respectively. Further advantageous developments of the present invention