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WO2025106977A1 - Dispositifs de macroencapsulation anti-fibrotique à élution de médicament (dream) pour l'administration de cellules thérapeutiques - Google Patents

Dispositifs de macroencapsulation anti-fibrotique à élution de médicament (dream) pour l'administration de cellules thérapeutiques Download PDF

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Publication number
WO2025106977A1
WO2025106977A1 PCT/US2024/056396 US2024056396W WO2025106977A1 WO 2025106977 A1 WO2025106977 A1 WO 2025106977A1 US 2024056396 W US2024056396 W US 2024056396W WO 2025106977 A1 WO2025106977 A1 WO 2025106977A1
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Prior art keywords
cells
delivery system
preparation
therapeutic delivery
implantable therapeutic
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Minglin Ma
Tung T. Pham
Daniel BOWERS
James Flanders
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Cornell University
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Cornell University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/64—Animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • the present invention relates to drug-eluting anti-fibrotic microencapsulation (DREAM) devices for delivery of therapeutic cells, the use of such devices for delivering a therapeutic agent to a subject in need thereof and thereby treating the subject for one or more diseases or conditions, as well as methods of making such devices.
  • DREAM drug-eluting anti-fibrotic microencapsulation
  • Implantation of engineered therapeutic cells to continuously deliver biomolecules is a promising strategy for treating chronic diseases such as type 1 diabetes, hemophilia, anemia, and Parkinson’s disease.
  • biomolecules e.g., insulin, antihemophilic factor, erythropoietin, dopamine
  • the clinical applications of cell therapy are limited due to the requirement of lifelong immunosuppression to protect the implanted cells from the host immune system.
  • engineered cells generally pose a risk of unwanted events such as teratoma. Therefore, it is critical to developing a strategy for immunoprotection and safe delivery of these cells. Over the past few decades, encapsulation of cells in semipermeable and retrievable systems has been proposed to tackle these issues.
  • the perm-selectivity allows for diffusion of nutrients/oxygen and therapeutic biomolecules while preventing the penetration of immune cells. Besides, cell confinement within the systems could completely prevent cell escape, thus, averting the risks of unwanted events.
  • the most intensively studied cell encapsulation system so far is hydrogel microcapsules, which can be implanted into the peritoneal cavity via a minimally invasive laparoscopic procedure. However, the inability to reliably retrieve all implanted capsules raises safety concerns in clinical applications.
  • the present invention is directed to overcoming these and other deficiencies in the art.
  • a first aspect of the present disclosure relates to an implantable therapeutic delivery system.
  • This system comprises a hydrogel matrix comprising at least one therapeutic agent and a membrane that partially or fully encapsulates the hydrogel matrix.
  • the membrane includes a nitinol mesh-reinforced hydrogel.
  • the membrane includes a nitinol mesh-reinforced nanofibrous material.
  • the membrane includes a nitinol -reinforced hydrogel and nanofibrous material.
  • a second aspect of the present disclosure relates to a method of delivering a therapeutic agent to a subject in need thereof. This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject.
  • a third aspect of the present disclosure relates to a method of treating diabetes in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having diabetes.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating diabetes while the therapeutic delivery system remains implanted.
  • a fourth aspect of the present disclosure relates to a method of treating a bleeding disorder in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having a bleeding disorder.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating the bleeding disorder while the therapeutic delivery system remains implanted.
  • a fifth aspect of the present disclosure relates to a method of treating a lysosomal storage disease in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having the lysosomal storage disease.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating the lysosomal storage disease while the therapeutic delivery system remains implanted.
  • a sixth aspect of the present disclosure relates to a method of treating a neurological disorder in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having the neurological disorder.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating the neurological disorder while the therapeutic delivery system remains implanted.
  • a seventh aspect of the present disclosure relates to a method of treating a cancer in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having cancer.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating the cancer while the therapeutic delivery system remains implanted.
  • An eighth aspect of the present disclosure relates to a method of treating a chronic eye disease in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having a chronic eye disease.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating the chronic eye disease while the therapeutic delivery system remains implanted.
  • a ninth aspect of the present disclosure relates to a method of treating a kidney failure in a subject.
  • This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having a kidney failure.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating kidney failure while the therapeutic delivery system remains implanted.
  • a tenth aspect of the present disclosure relates to a method of treating a chronic pain in a subject. This method involves implanting the implantable therapeutic delivery system according to the first aspect into the subject having a chronic pain condition.
  • the implanted therapeutic delivery system is capable of delivering to the subject one or more therapeutic agents effective for treating chronic pain while the therapeutic delivery system remains implanted.
  • An eleventh aspect of the present disclosure relates to a method of forming a cell encapsulation system suitable for implant.
  • This method involves providing a hydrogel precursor solution comprising at least one therapeutic agent in the hydrogel precursor solution; and introducing the hydrogel precursor solution internally of a membrane comprising a nitinol mesh- reinforced hydrogel and/or nanofibrous material, and allowing the hydrogel precursor to form a hydrogel matrix that is partially or fully encapsulated by the membrane.
  • DRug- Eluting Anti-fibrotic Macroencapsulation devices termed DREAM devices, which address the above-noted deficiencies of other cell encapsulation devices.
  • DREAM devices DRug- Eluting Anti-fibrotic Macroencapsulation devices
  • NIREA Nitinol-Reinforced Alginate
  • NIREN Nitinol-Reinforced Nanofibrous
  • NIREA and NIREN membranes prevent device kink and cause minimal stress on intraperitoneal organs, thereby improving the safety of the devices and potentially reducing host responses to the devices.
  • different device configurations were designed to improve the encapsulation capacity of the device while maintaining the optimal mass transportation distance, which is crucial for functions of islets/B cells.
  • the elasticity of NIREA and NIREN membranes allowed the establishment of a facile method to prepare devices having a tube-in-tube configuration where the islets/SC-P clusters are encapsulated within the thin wall of the device (see FIG. 1).
  • devices can be prepared using a flat bar stock configuration with a thickness less than 800 pm, which results in a diffusion distance of ⁇ 400 pm (see FIG. 2).
  • This device configuration can be scaled up by simply increasing width and length.
  • Also disclosed herein is a method for preparing crystalline particles of anti- fibrotic drugs, and their use to prevent foreign body response to a cell encapsulation device.
  • crystalline particles of several anti-fibrotic drugs including nintedanib, pirfenidone, and GW2580 — were prepared and loaded into the inner lumen of the devices. That is, the anti-fibrotic drug particles were loaded into the hydrogel matrix.
  • the crystalline forms and particle sizes were optimized to achieve long-term and continuous drug release, maintaining a steady drug level in the vicinity of free-floating, z.e., unanchored, devices in the intraperitoneal cavity to mitigate fibrotic reactions.
  • Loading drugs into the hydrogel matrix core of device instead of on the device surface, could avoid particle detachment and structural changes of the device surface after those crystalline drugs dissolve.
  • FIG. 1 shows schematic illustrations for proposed designs of tubular DREAM devices.
  • FIG. 2 shows proposed designs for flat bar DREAM devices and the encapsulation capacity of each version.
  • FIGs. 3A-3D show characterizations of nanofiber membranes made of different medical -grade elastomers.
  • FIG. 3A shows SEM images of a nanofiber membrane prepared using different concentrations of PEBAX (5%, 7.5%, 10%, and 15%).
  • FIGs. 3B-3C show fiber size of nanofiber membrane prepared using different concentrations of PEBAX (5%, 7.5%, 10%, and 15%).
  • FIG. 3D shows SEM images and stretchability of PEBAX, QTHAN, and QFLEX membranes.
  • FIGs. 4A-4H show characterizations of NIREN tubes.
  • FIG. 4A shows macroscopic images of tubular nitinol tubes prepared with different lengths.
  • FIG. 4B shows a representative bright-field image of nitinol mesh. Scale bar: 1000 pm.
  • FIGs. 4C-4D show representative SEMZEDS image showing the hierarchical structure of NIREN membrane. Scale bar: 50 pm (FIG. 4C) and 100 pm (FIG. 4D).
  • FIG. 4E shows an image showing a 10-cm NIREN tube was bent without kink.
  • FIGs. 4F-4H show the flexibility and elasticity of NIREN tube. The tube returned to its original shape after being twisted.
  • FIGs. 5A-5B show preparation and characterizations of flat bar NIREN tubes.
  • FIG. 5A shows a digital image showing the installation of nitinol tubes on the stainless-steel mandrel for collecting nanofibers.
  • FIG. 5B shows a NIREN tube maintained the open lumen while the neat nanofiber tube with the same thickness could not.
  • FIGs. 6A-6D show mechanical characteristics of flat bar NIREN tubes.
  • FIGs. 6A-6B show macroscopic images showing the device could be bent without kink.
  • FIGs. 6C-6D show shape-memory feature of the NIREN tube. The tube quickly returned to its original shape after being bent and twisted.
  • FIGs. 7A-7D show a method to load cells/islets in a tube-in-tube NIREN device.
  • FIG. 7A shows that to load cells/islets in the space between 2 NIREN tubes, cell suspension is first deposited on the inner tube (diameter: 5 mm).
  • FIG. 7B shows representative images showing the distribution of 150 pm polystyrene beads used to mimic pancreatic islets between two nitinol tubes.
  • FIG. 7C shows representative images showing the insertion of a 23-cm long NIREN tube into a 25-cm long NIREN tube. The diameter of both tubes was 5 mm.
  • FIG. 7D shows the final device possessed the similar elasticity and shape memory feature of the NIREN tube.
  • FIGs. 8A-8C show preparation of NIREA tubes.
  • FIG. 8A shows a schematic illustration demonstrating a method for preparation of NIREA tubes.
  • FIG. 8B shows bright-field images of the flat bar (left) and tubular (right) NIREA devices. Scale bar: 5 mm.
  • FIG. 8C shows stability of the alginate layer. The device could be bent without the detachment of alginate layer. Scale bar: 2 mm.
  • FIG. 9A-9I show mechanical characteristics of flat bar NIREA tubes.
  • FIGs. 9A- 9B show images showing a 25-cm NIREA tube.
  • FIGs. 9C-9G show the elasticity of NIREA tube allows the devices to be bent without kink.
  • FIGs. 9H-9I show the device could be twisted and rolled around a rod, which is beneficial for minimally invasive implantation of the device into intraperitoneal (IP) cavity by the laparoscopic procedure.
  • IP intraperitoneal
  • FIG. 10 shows a method for cell loading into a flat bar NIREA device.
  • the elasticity of the NIREA membrane allows for wider open of the device by applying pressure to the edges of the device.
  • Cell suspension can be loaded through the open end.
  • the device returns to its original shape after pressure is released.
  • the device can be sealed using alginate hydrogel.
  • FIGs. 11A-11B show preparation of crystalline anti -fibrotic drugs.
  • FIG. 11 A shows a schematic illustration demonstrating the method for preparation of crystalline drugs.
  • FIG. 11B shows bright-field images of crystalline nintedanib, GW2580, and pirfenidone prepared with different particle sizes.
  • FIGs 12A-12B show the effect of Nintedanib on the morphology and viability of human islets.
  • FIG. 12A shows bright-field images of human islets incubated with nintedanib at different concentrations (0, 0.1, 0.2, 0.5, 1, and 2 pM) for 24 h. Scale bar: 500 pm (upper) and 300 pm (lower).
  • FIG. 12B shows viability assessment of islets incubated with nintedanib at different concentrations (0, 0.1, 0.2, 0.5, and 2 pM) for 24 h using live/dead staining. Scale bar: 500 pm.
  • FIG. 13A-13C show post-implantation evaluation of Nylon 6 devices without drug and Nylon 6 devices containing 3.5 mg of either crystalline nintedanib or crystalline GW2580.
  • FIG. 13A shows Masson’s trichrome staining of devices retrieved 1 month after implantation. Scale bar: 100 pm.
  • FIG. 13B shows phase-contrast images of crystalline GW2580 in the core of the device retrieved 1 month after implantation. Scale bar: 2000 pm (upper) and 400 pm (lower).
  • FIG. 13C shows phase-contrast images of crystalline nintedanib in the core of the device retrieved 1 month after implantation. Scale bar: 2000 pm (upper) and 400 pm (lower). [0031] FIGs.
  • FIG. 14A-14D show evaluation of nanofibrous DREAM devices after 6-week implantation in Gottingen minipigs.
  • FIG. 14A shows laparoscopic images of devices with or without crystalline nintedanib at day 0 and day 42 after being implanted into the intraperitoneal cavity of Gottingen minipigs.
  • FIG. 14B shows a macroscopic image (left) and Masson’s trichrome staining (right) showing the fibrotic responses to the device without crystalline nintedanib. Scale bar: 500 pm.
  • FIG. 14C shows Masson’s trichrome staining of the device containing crystalline nintedanib. Scale bar: 200 pm.
  • FIG. 14D shows images showing the presence and morphology of crystalline nintedanib in the core of the device. Scale bar: 5 mm (upper) and 400 pm (lower).
  • FIGs. 15A-15G show evaluation of a nintedanib-eluting flat bar NIREA device after 2-month implantation in the intraperitoneal cavity of a farm pig.
  • FIG. 15A shows a bright- field image of the device before implantation.
  • FIG. 15B shows a laparoscopic image showing the location of the device after implantation.
  • FIGs. 15C-15D show macroscopic images showing the device after 2-month implantation.
  • FIG. 15E shows a bright-field image of the whole device retrieved after 2-month implantation. Scale bar: 5000 pm.
  • FIG. 15F shows a dark-field image of the alginate layer peeled off from the device. Scale bar: 2000 pm.
  • FIG. 15G shows phase-contrast images showing crystalline particles in the device.
  • FIG. 16 shows that one example of using 2 layers of the nanofibrous membrane is the integration of a nitinol mesh between two layers of nanofibrous material to mitigate delamination issues arising from suboptimal interaction between the nanofibrous layers and the nitinol mesh.
  • the fibers from the outer nanofibrous layer can infiltrate the pores of the nitinol mesh and bond with the inner nanofibrous layer, thereby preventing the detachment of the outer fibrous layer.
  • FIG. 17 shows that the thickness of the nitinol mesh could fall within the 10 to 100 pm range. This mesh could be crafted from nitinol wire with a diameter ranging from 10 to 100 pm, where the thickness of the mesh aligns with the wire's diameter used for its construction.
  • the present disclosure relates to implantable cell therapeutic delivery systems, methods of producing these systems, and methods of using the same.
  • This implantable therapeutic delivery system includes a hydrogel matrix comprising at least one therapeutic agent and a membrane that partially or fully encapsulates the hydrogel matrix.
  • the membrane includes a nitinol mesh-reinforced hydrogel and/or nanofibrous material.
  • the nitinol reinforced membrane is elastic, soft but durable to maintain the original shape and avoid kink as well as potential injuries to vital organs after implantation.
  • the membrane is also thin enough for efficient mass transport.
  • the membrane includes a nitinol mesh -reinforced hydrogel.
  • the membrane includes a nitinol mesh-reinforced nanofibrous material.
  • the membrane includes a nitinol -reinforced hydrogel and nanofibrous material.
  • the membrane fully encapsulates the hydrogel matrix such that the hydrogel matrix and its contents are immuno-isolated. That is, immune cells of the subject into which the implantable cell therapeutic delivery system is implanted cannot infiltrate the hydrogel matrix. This can be achieved by physically sealing any opening used during assembly of the implantable cell therapeutic delivery system, such as by thermally sealing the opening.
  • the variety of membrane constructions are not limited to any particular shape or configuration. Exemplary shapes or configurations are presented in the accompanying examples and include tubular and flat bar configurations.
  • the nitinol reinforced membrane is used to prepare a device with a tube-in-tube configuration.
  • the membrane comprises a nitinol mesh-reinforced hydrogel material.
  • the nitinol mesh-reinforced hydrogel material comprises one or more nitinol mesh layers.
  • the hydrogel material can comprise a natural polymeric material, a synthetic polymeric material, or a combination thereof.
  • Suitable natural polymeric materials that can be used include, without limitation, collagen, hyaluronate, fibrin, alginate, agarose, chitosan, bacterial cellulose, elastin, keratin, derivatives thereof, and combinations thereof.
  • the hydrogel material comprises a pure alginate, a modified alginate, or a mixture of pure and modified alginate.
  • the modified alginate is a zwitterionically modified alginate.
  • Suitable synthetic polymeric materials include, without limitation, polyethylene glycol (PEG), poly(acrylic acid), poly(ethylene oxide), poly(vinyl alcohol), polyphosphazene, poly(hydroxyethyl methacrylate), triazole-zwitterion hydrogels (TR- qCB, TR-CB, TR-SB), poly(sulfobetaine methacrylate), carboxybetaine methacrylate, poly[2- methacryloyloxyethyl phosphorylcholine, N-hydroxyethyl acrylamide, a copolymer thereof, a derivatives thereof, and a combination thereof.
  • PEG polyethylene glycol
  • poly(acrylic acid) poly(ethylene oxide)
  • poly(vinyl alcohol) polyphosphazene
  • poly(hydroxyethyl methacrylate) triazole-zwitterion hydrogels
  • TR- qCB, TR-CB, TR-SB triazole-zwitterion hydrogels
  • the nitinol mesh-reinforced hydrogel material has a thickness of about 10 to about 200 pm, about 10 to about 50 pm, about 50 to about 100 pm, about 100 to about 150 pm, or about 150 to about 200 pm, such as about 10 to about 20 pm, about 20 to about 30 pm, about 30 to about 40 pm, about 40 to about 50 pm, about 50 to about 60 pm, about 60 to about 70 pm, about 70 to about 80 pm, about 80 to about 90 pm, about 90 to about 100 pm, about 100 to about 110 pm, about 110 to about 120 pm, about 120 to about 130 pm, about 130 to about 140 pm, about 140 to about 150 pm, about 150 to about 160 pm, about 160 to about 170 pm, about 170 to about 180 pm, about 180 to about 190 pm, or about 190 to about 200 pm.
  • the nitinol mesh-reinforced hydrogel material is present at or adjacent to an internal surface thereof and the hydrogel material extends from the internal surface to an external surface thereof.
  • the membrane comprises a nitinol mesh-reinforced nanofibrous material.
  • the nitinol mesh-reinforced nanofibrous material can comprise one or more nitinol mesh layers.
  • the nitinol mesh-reinforced nanofibrous material comprises one or more nanofiber layers, such as first and second nanofibrous layers with the nitinol mesh sandwiched between the first and second nanofibrous layers, optionally wherein fibers of the first and second nanofibrous layers are bonded to another via pores in the nitinol mesh. This is illustrated in FIG. 16.
  • the one or more nanofiber layers can be formed of one or more medical -grade elastomers. Suitable medical -grade elastomers that can be used include, without limitation, polyether block amide, polycarbonate urethane, thermoplastic silicon-polycarbonate-urethane, polyether urethane, and combinations thereof.
  • the nitinol mesh-reinforced nanofibrous material has a thickness of about 10 to about 100 pm, about 10 to about 50 pm, or about 50 to about 100 pm, such as about 10 to about 20 pm, about 20 to about 30 pm, about 30 to about 40 pm, about 40 to about 50 pm, about 50 to about 60 pm, about 60 to about 70 pm, about 70 to about 80 pm, about 80 to about 90 pm, about 90 to about 100 pm.
  • the nitinol mesh is present at or adjacent to an internal surface thereof and the nanofiber layer is present at or adjacent to an external surface thereof.
  • the membrane is porous but impermeable to cellular migration.
  • the nitinol mesh has a thickness of about 10 to about 100 pm, about 10 to about 50 pm, or about 50 to about 100 pm, such as about 10 to about 20 pm, about 20 to about 30 pm, about 30 to about 40 pm, about 40 to about 50 pm, about 50 to about 60 pm, about 60 to about 70 pm, about 70 to about 80 pm, about 80 to about 90 pm, about 90 to about 100 pm.
  • the nitinol mesh is formed of nitinol wire having a diameter of about 10 to about 100 pm, about 10 to about 50 pm, or about 50 to about 100 pm, such as about 10 to about 20 pm, about 20 to about 30 pm, about 30 to about 40 pm, about 40 to about 50 pm, about 50 to about 60 pm, about 60 to about 70 pm, about 70 to about 80 pm, about 80 to about 90 pm, about 90 to about 100 pm.
  • the nitinol mesh has a pore size from about 50 to 5000 pm, including about 50 to about 150 pm, about 150 to about 250 pm, about 250 to about 500 pm, about 500 to about 750 pm, about 750 to about 1000 pm, about 1000 to about 1500 pm, about 1500 to about 2000 pm, about 2000 to about 2500 pm, about 2500 to about 3000 pm, about 3000 to about 3500 pm, about 3500 to about 4000 pm, about 4000 to about 4500 pm, or about 4500 to about 5000 pm.
  • FIG. 17 Several embodiments in these ranges are illustrated in FIG. 17.
  • the delivery system has a tube-like configuration having a diameter of about 100 pm to about 1 cm, including about 100 to about 500 pm, about 500 to about 1000 pm, about 1000 to about 2000 pm, about 3000 to about 4000 pm, about 4000 to about 5000 pm, about 5000 to about 6000 pm, about 6000 to about 7000 pm, about 7000 to about 8000 pm, about 8000 to about 9000 pm, or about 9000 to about 10000 pm.
  • the implantable therapeutic delivery system comprises a tube-in-tube configuration, wherein the inner and outer tubes independently comprise a membrane comprising a nitinol mesh-reinforced hydrogel or nanofibrous material, wherein a hydrogel matrix is positioned between the inner and outer tubes.
  • elastic, shape-memory NIREN or NIREA tubes are used for device construction.
  • the hydrogel matrix is a natural polymeric material, a synthetic polymeric material, or a combination thereof.
  • Suitable natural and synthetic polymeric materials include those of the present disclosure, as defined herein with respect to the hydrogel material used to form NIREA membranes.
  • the at least one therapeutic agent of the hydrogel matrix comprises a drug. In some embodiments, the at least one therapeutic agent is released from a preparation of cells positioned within the hydrogel matrix. In some embodiments, there is a first therapeutic agent in the hydrogel matrix, and a second therapeutic agent released from a preparation of cells positioned within the hydrogel material.
  • the membrane that partially or fully encapsulates the hydrogel matrix comprises a first nitinol mesh-reinforced nanofibrous material
  • the delivery system further comprises a second hydrogel matrix external of the first nitinol mesh-reinforced nanofibrous material, which is partially or fully encapsulated by a nitinol mesh-reinforced hydrogel or nanofibrous material.
  • the second hydrogel matrix includes a preparation of cells, which release a therapeutic agent.
  • the preparation of cells can include a preparation of single cells or a preparation of cell aggregates.
  • the preparation of cells includes a preparation of primary cells or a preparation of immortalized cells.
  • the preparation of cells can include mammalian cells. Suitable mammalian cells that can be used include, without limitation, primate cells, rodent cells, canine cells, feline cells, equine cells, bovine cells, and porcine cells. In some embodiments, the preparation of cells includes human cells.
  • the preparation of cells can include stem cells or stem cell derived cells.
  • the stem cells can be pluripotent, multipotent, oligopotent, or unipotent stem cells.
  • Suitable stem cells include, without limitation, embryonic stem cells, epiblast cells, primitive ectoderm cells, primordial germ cells, and induced pluripotent stem cells.
  • the preparation of cells can include, one or more of smooth muscle cells, cardiac myocytes, platelets, epithelial cells, endothelial cells, urothelial cells, fibroblasts, embryonic fibroblasts, myoblasts, chondrocytes, chondroblasts, osteoblasts, osteoclasts, keratinocytes, hepatocytes, bile duct cells, islet cells, thyroid, parathyroid, adrenal, hypothalamic, pituitary, ovarian, testicular, salivary gland cells, adipocytes, embryonic stem cells, mesenchymal stem cells, neural cells, endothelial progenitor cells, hematopoietic cells, precursor cells, mesenchymal stromal cells, Baby Hamster Kidney (BHK) cells, Chinese Hamster Ovary cells, Human Amniotic Epithelial (HAE) cells, choroid plexus cells, chromaffin cells, adrenal chromaffin cells
  • the preparation of cells includes a preparation of islet cells that release insulin and glucagon.
  • the preparation of islet cells can be a preparation of human cells, porcine cells, or rodent islets.
  • the preparation of islets comprises a density between about IxlO 3 to 2xl0 6 islet equivalents (IEQs)/mL.
  • the preparation of islets can comprise a density ranging between about lxl0 3 up to about 5xl0 3 , lxl0 3 up to about IxlO 4 , IxlO 3 up to about 5xl0 4 , IxlO 3 up to about IxlO 5 , IxlO 3 up to about 5xl0 5 , IxlO 3 up to about IxlO 6 , 5xl0 3 up to about IxlO 4 , 5xl0 3 up to about 5xl0 4 , 5xl0 3 up to about IxlO 5 , 5xl0 3 up to about 5xl0 5 , 5xl0 3 up to about IxlO 6 , 5xl0 3 up to about 2xl0 6 , IxlO 4 up to about 5xl0 4 , IxlO 4 up to about IxlO 5 , IxlO 4 up to about 5xl0 5 , IxlO 4 up to about 5xl0 5
  • the therapeutic agent can include one or more cell factors or biologically active agents to enhance cell growth, differentiation, and/or survival of the cells positioned within the hydrogel matrix.
  • Suitable biologically active agents include, without limitation, a protein, peptide, antibody or antibody fragment thereof, antibody mimetic, a nucleic acid, a small molecule, a hormone, a growth factor, an angiogenic factor, a cytokine, an anti-inflammatory agent, an anti-fibrotic agent, and combinations thereof.
  • Exemplary growth factors include, without limitation, fibroblast growth factors (FGFs) such as FGF1, FGF4, FGF19, and FGF21; nerve growth factors (NGFs), epiderma growth factors (EGFs), transforming growth factors, hepatocyte growth factors (HGFs), platelet- derived growth factors (PDGFs), insulin-like growth factors (IGFs), IGF binding proteins, basic fibroblast growth factors, and vascular endothelial growth factors (VEGF).
  • FGFs fibroblast growth factors
  • FGFs nerve growth factors
  • EGFs epiderma growth factors
  • HGFs hepatocyte growth factors
  • PDGFs platelet- derived growth factors
  • IGFs insulin-like growth factors
  • IGF binding proteins IGF binding proteins
  • basic fibroblast growth factors vascular endothelial growth factors
  • Exemplary angiogenic factors include, without limitation, VEGF, bFGF, HGF, PDGF, ANG-1, and IGF-1.
  • Exemplary cytokines include, without limitation, interleukins, lymphokines, monokines, colony stimulating factors, chemokines, interferons and tumor necrosis factor (TNF).
  • Exemplary anti-inflammatory agents include, without limitation corticosteroids such as prednisone, cortisone, and methylprednisolone; and non-steroidal anti-inflammatory agents (NSAIDs) such as ibuprofen, naproxen, celecoxib, diclofenac, indomethacin, oxaprozin, and piroxicam.
  • antifibrotic agents include, without limitation, nintedanib, GW2580 (the cFMS Receptor Tyrosine Kinase Inhibitor 5-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]- phenyl]methyl]pyrimidine-2,4-diamine), and pirfenidone.
  • the anti- fibrotic agent can be in crystalline form. While several of these agents have previously been evaluated for preventing fibrotic responses against intraperitoneally inserted alginate microcapsules (see Farah et al., "Long-term Implant Fibrosis Prevention in Rodents and Nonhuman Primates Using Crystallized Drug Formulations," Nat.
  • degradable materials to release pirfenidone for the treatment of corneal abrasion (Tawfik et al., “Dual Drug-loaded Coaxial Nanofibers for the Treatment of Corneal Abrasion,” Internat ’I J Pharmaceutics, 581 : 119296 (2020), which is hereby incorporated by reference in its entirety), but the degradable materials precluded immuno-isolation, afforded limited drug-loading capacity, and achieved a fairly short ( ⁇ 10 h) drug release period that was incompatible with long-term delivery.
  • FIG. 1 illustrates an exemplary embodiment of the therapeutic delivery system 10 having a tube-in-tube construction.
  • the system 10 includes an inner NIREN membrane 12 containing crystalline drugs 14 dispersed in a hydrogel matrix 16 and an outer NIREA or NIREN membrane 18 for immunoisolation and shape maintenance.
  • the outer tube is made of the NIREN membrane if cell escape prevention is desired.
  • Pancreatic islets or beta-cell clusters 20 are suspended in alginate hydrogel 22, which is loaded in the space between the inner tube and the outer tube.
  • the devices can be scaled up in both radial and longitudinal directions to achieve different encapsulation capacities.
  • a device with diameter of 10 mm and length of 250 mm is estimated to be able to accommodate a clinical dose (-400,000 IEQ) of islets to cure diabetes in humans at cell encapsulation density of 35,000 IEQ.
  • FIG. 2 illustrates several exemplary embodiments of therapeutic delivery systems 40, 50, 60, and 70, which generally have a flat bar shape construction.
  • the system 40 includes a NIREA membrane that encapsulates a hydrogel matrix containing a crystalline anti-fibrotic drug and pancreatic islets or beta-cell clusters.
  • the system 50 includes a NIREA membrane that encapsulates a hydrogel matrix containing a crystalline anti-fibrotic drug. Externally of the NIREA membrane is a thicker alginate matrix containing pancreatic islets or beta-cell clusters.
  • the system 60 includes a NIREN membrane that encapsulates a hydrogel matrix containing a crystalline anti-fibrotic drug and pancreatic islets or beta-cell clusters.
  • the system 70 includes a membrane that includes a nitinol mesh reinforced with both a nanofibrous layer and a cross-linked alginate layer. In this system, the membrane encapsulates a hydrogel matrix containing a crystalline anti-fibrotic drug and pancreatic islets or beta-cell clusters.
  • Another aspect of the present disclosure relates to a method of forming a cell encapsulation system suitable for implant.
  • This method involves providing a hydrogel precursor solution comprising at least one therapeutic agent in the hydrogel precursor solution; and introducing the hydrogel precursor solution internally of a membrane comprising a nitinol mesh- reinforced hydrogel or nanofibrous material, and allowing the hydrogel precursor to form a hydrogel matrix that is partially or fully encapsulated by the membrane.
  • Initial membrane assembly can be carried out as described in the Examples.
  • the membranes are typically presented on a support structure, which may just be a support structure that is of a similar size and configuration of the final device shape, or alternatively can be a rotatable mandrel or shaft.
  • NIREN membranes can be prepared by first coating the nitinol mesh with a polymer solution to facilitate binding of electrospun polymer fibers to the nitinol mesh. This can be carried before or after placement of the nitinol mesh on the support structure. Thereafter, electrospinning of polymer fibers is carried out to achieve a polymer nanofiber membrane of desired dimension and pore properties formed on the nitinol mesh. With the use of a mandrel as a support structure, it is possible to obtain tubular-shaped NIREN membranes. Regardless of its final shape or configuration, the NIREN membrane can be removed from the support structure for subsequent use in device assembly.
  • NIREA membranes can be prepared by first soaking a support structure in a solution that will facilitate coating of the support structure with a cross-linking agent.
  • a cross-linking agent such as calcium and polyethylene glycol solution can be used to promote cross-linking of an alginate solution.
  • a nitinol mesh can be installed onto the support structure and then immersed in the alginate precursor solution to facilitate formation of the NIREA membrane. Thereafter, the NIREA membrane can be removed from the support structure for subsequent use in device assembly. This process is illustrated in FIG. 8A.
  • the support structure can take the form of an inner nitinol mesh that is installed over a mandrel or other support, which is then soaked in the solution containing the cross-linking agent.
  • a second (outer) nitinol mesh is installed onto the support structure prior to immersing in the alginate precursor solution.
  • NIREA membranes Similar procedures used in forming the NIREA membranes can also be used to form other nitinol mesh-reinforced hydrogel membranes containing hydrogel materials other than alginate.
  • Other cross-linking agent solutions can, of course, be used to support crosslinking of other hydrogel precursor solutions as is well known in the art.
  • both processes can be used to form nitinol mesh-reinforced hydrogel and nanofibrous material membranes.
  • the membrane at one end (or side) of the device can be sealed closed using, e.g., a thermal sealer or a material that otherwise completely seals that end (or side) of the device closed to maintain the capacity for immuno-separation.
  • Forming the hydrogel matrix can be achieved by causing cross-linking of the hydrogel precursors as disclosed herein. Briefly, the hydrogel precursor solution containing one or more therapeutic agent(s) dispersed therein can be introduced into the region internally of the membrane and then cross-linking of the hydrogel precursors can be carried out to form the hydrogel. As is well known in the art, the cross-linking agent will differ depending on the type of hydrogel precursors used and hydrogel matrix to be formed. Nevertheless, once the hydrogel matrix is formed internally of the membrane, the other end (or side) of the membrane can sealed closed using the same approach. This ensures that the interior of the device is closed to maintain the capacity for immuno-separation while also allowing molecules to pass through the membrane.
  • both ends can be sealed after forming the hydrogel matrix.
  • FIG. 7A shows a method for loading cells/islets in the space between two NIREN tubes.
  • the inner tube can first be coated with a cell suspension (containing cells and a solution of hydrogel precursors) and then cross-linking affords the cells/islets embedded in a hydrogel matrix form outside the inner tube.
  • a cell suspension containing cells and a solution of hydrogel precursors
  • cross-linking affords the cells/islets embedded in a hydrogel matrix form outside the inner tube.
  • the NIREN membrane is elastic in nature, the NIREN inner tube can be stretched, thereby reducing its diameter, which allows the NIREN inner tube to be inserted into a NIREN outer tube.
  • the inner tube After the stretching force is released, the inner tube returns to its original shape, pushing the cells to the area near the surface of the device, i.e., adjacent to the inner surface of the NIREN outer tube.
  • the thickness of cell encapsulation layer is dictated by the volume of alginate solution.
  • the NIREN outer tube can optionally be coated with an additional hydrogel layer, if desired, and the interior space of the NIREN inner tube can be loaded with a hydrogel matrix containing anti-fibrotic agent. Thereafter, the ends can be sealed as described herein.
  • the delivery system can then be implanted in a subject for delivery of therapeutic agent(s) to the subject while the device remains implanted.
  • the devices can be implanted using laproscopic surgical procedures or open surgical sites, and the devices can be placed subcutaneously, transcutaneously, preperitoneally, transperitoneally, or intraperitoneally.
  • implanting involves suturing the device or system to a body wall of the subject; anchoring the device to a body wall of the subject via a transabdominal portal; wrapping the delivery device or system in omentum of the subject; positioning the device in a cavity between the liver and the diaphragm; or anchoring the device to the diaphragm.
  • Unanchored implantation is also contemplated.
  • exemplary subjects include, without limitation, a human, a mouse, a rat, a dog, a cat, a pig, a sheep, a cow, a horse, and a nonhuman primate.
  • the systems can be used to deliver a therapeutic agent to a subject in need thereof.
  • the treatment by implantation can be carried out for a limited duration over a period of days, weeks, or months.
  • the method of treatment further involves retrieving the implantable cell containing device from the subject when no longer needed or when the device needs replacement, and optionally implanting a replacement implantable therapeutic deliver system after the initial device is retrieved.
  • the introduction of one or more contrast agents allows for monitoring of the device.
  • Methods of in vivo monitoring include but are not limited to confocal microscopy, 2- photon microscopy, high frequency ultrasound, optical coherence tomography (OCT), photoacoustic tomography (PAT), computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). These alone or combined can provide useful means to monitoring the implantable device. Monitoring of the device may be used to determine when to remove and replace a device, as necessary.
  • the subject has diabetes, is in need of diabetes treatment, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein, which comprises a preparation of cells that release insulin, glucagon, or a combination thereof for the treatment of diabetes in the subject.
  • exemplary cells that release the therapeutic agent include one or more of islet cells, islets derived from a preparation of stem cells such as pluripotent, multipotent, oligopotent, or unipotent stem cells, including embryonic stem cells, epiblast cells, primitive ectoderm cells, primordial germ cells, and induced pluripotent stem cells.
  • the subject has a bleeding disorder, is in need of treatment for the bleeding disorder, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein, which comprises a preparation of cells that release a therapeutic agent that treats the bleeding disorder.
  • the bleeding disorder can be any bleeding disorder, such as hemophilia A, hemophilia B, von Willebrand disease, Factor I deficiency, Factor II deficiency, Factor V deficiency, Factor VII deficiency, Factor X deficiency, Factor XI deficiency, Factor XII deficiency, and Factor XIII deficiency
  • the therapeutic agent is a blood clotting factor selected from the group of Factor I, Factor II, Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of recombinant myoblasts, mesenchymal stromal cells, endothelial cells, induced pluripotent stem cell derived endothelial cells, induced pluripotent stem cell derived mesenchymal stromal cells, and a combination thereof.
  • the subject has a lysosomal storage disorder, is in need of treatment for the lysosomal storage disorder, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein into the subject having the lysosomal storage disorder.
  • the therapeutic agent is an enzyme selected from the group of a-L-iduronidase, Iduronate-2- sulfatase, a-glucuronidase, Arylsulfatase A, alpha-Galactosidase A, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of hematopoietic stem cells, fibroblasts, myoblasts, Baby Hamster Kidney (BHK) cells, Chinese Hamster Ovary cells, Human Amniotic Epithelial (HAE) cells, mesenchymal stromal cells, induced pluripotent stem cell derived mesenchymal stromal cells, and combinations thereof.
  • hematopoietic stem cells hematopoietic stem cells
  • fibroblasts myoblasts
  • BHK Baby Hamster Kidney
  • HAE Human Amniotic Epithelial
  • mesenchymal stromal cells mesenchymal stromal cells
  • induced pluripotent stem cell derived mesenchymal stromal cells and combinations thereof.
  • the subject has a neurological disorder, is in need of treatment for the neurological disorder, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein, which comprises a preparation of cells that release a therapeutic agent that treats the neurological disorder.
  • the neurological disorder is Parkinson’s disease, Alzheimer’s disease, epilepsy, Huntington’s disease, Amyotrophic lateral sclerosis, chronic pain, a sensory disorder such as visual loss, hearing loss, peripheral nerve injury, and spinal cord injury
  • the therapeutic agent is selected from the group of cerebrospinal fluid, extracellular fluid, levodopa, nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), BLP-1, brain- derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), enkephalin, adrenaline, catecholamine, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of choroid plexus cells, chromaffin cells, pheochomocytoma cell line PC 12, human retinal pigment epithelial cells, NGF-secreting Baby Hamster Kidney (BHK) cells, myoblasts, human bone marrow-derived stem cells transfected with GLP-1, BDNF-producing fibroblasts, NGF-producing cells, CNTF -producing cells, adrenal chromaffin cells, BDNF-secreting Schwann cells, myogenic cells, embryonic stem cell-derived neural progenitor cells, and combinations thereof.
  • BHK Baby Hamster Kidney
  • the subject has a cancerous condition, is in need of treatment for the cancerous condition, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic deliver system as described herein into the subject having the cancerous condition.
  • the therapeutic agent is one or more of IL-2, endostatin, cytochrome P450 enzyme, a tumor antigen, a cytokine, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of IL-2-secreting myoblasts, endostatin-secreting cells, Chinese Hamster Ovary cells, cytochrome P450 enzyme overexpressed feline kidney epithelial cells, irradiated tumor cells, and combinations thereof.
  • the subject has a chronic eye disease, is in need of treatment for the chronic eye disease, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein into the subject having the chronic eye disease.
  • the chronic eye disease may be any one of age- related macular degeneration, diabetic retinopathy, retinitis pigmentosa, glaucoma, macular telangiectasia, and combinations thereof.
  • the therapeutic agent is one or more trophic factors that protect compromised retinal neurons and restore neural circuits, such as any one or more of ciliary neurotrophic factor, antagonists against vascular endothelial growth factor and platelet-derived growth factor, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of human retinal pigment epithelium cells, recombinant human retinal pigment epithelium cells, and combinations thereof.
  • the subject has kidney disease (kidney failure), is in need of treatment for the kidney disease (kidney failure), and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein into the subject having the kidney disease (kidney failure).
  • the therapeutic agent is dopamine, atrial natriuretic peptide, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of renal proximal tubule cells, mesenchymal stem cells, and combinations thereof.
  • the subject has chronic pain, is in need of treatment for the chronic pain, and the method of delivering a therapeutic agent to the subject involves implanting an implantable therapeutic delivery system as described herein into the subject having the chronic pain.
  • the chronic pain can be any chronic pain condition including, without limitation, those caused by degenerative back and knee, neuropathic back and knee, or cancer.
  • the therapeutic agent is catecholamine, opioid peptides, enkephalins, and combinations thereof.
  • Exemplary cells that release the therapeutic agent include one or more of chromaffin cells, neural precursor cells, mesenchymal stem cells, astrocytes, and genetically engineered cells, and combinations thereof.
  • Nintedanib and GW2580 were purchased from LC Laboratories (Woburn, MA). Pirfenidone was purchased from Neta Scientific, Inc (Hainesport, NJ). Braided nitinol tubes were supplied by Secant Medical, LLC (Telford, PA). Polyamide 6 (Nylon 6), barium chloride, calcium chloride, formic acid, and tetrahydrofuran were purchased from Sigma Aldrich (St. Louis, MO). Polyamide 12 (Rilsamid Aesno Med) and polyether block amide (PEBAX 2533 SA 01 MED) were provided by Arkema (Colombes, France).
  • Polycarbonate urethane (QTHAN- ARC-95A), thermoplastic silicon-polycarbonate-urethane (QSIL-ARCS-90A), and polyether urethane (QFLEX-ARE-93 A) are generous sample gifts from Biomerics (Salt Lake City, UT).
  • Thermoplastic silicon-polycarbonate-urethane (TSPU; Carbosil 20 90A) was purchased from DSM Biomedical Inc (Berkely, CA).
  • Ultrapure sodium alginate (PRONOVA SLG100) was supplied by Novamatrix (Sandvika, Norway).
  • l,l,l,3,3,3-hexafluoro-2-propanol was purchased from Oakwood Chemical (Estill, SC).
  • a stock solution of nintedanib was prepared by dissolving nintedanib in cellgrade DMSO at 5.82 mg/mL. The solution was filtered through a sterile 0.22 pm syringe filter and diluted with CMRL 1066 (supplemented with 10% FBS) to a series of solutions (0.1 pM, 0.2 pM, 0.5 pM, 1 pM, 2 pM). Approximately 300 IEQ of human islets was incubated in 3 mL of each solution for 48 hours. Islet viability was assessed by dual fluorescence staining using a LIVE/DEAD viability/toxicity kit. The fluorescence images were captured using an EVOS fl microscope.
  • Nanofibrous membranes were prepared using custom-built electrospinning system consisting of a syringe pump (Harvard Apparatus, MA), a constantly moving needle holder, and a rotating collector connected to a high voltage supply (Gamma High Voltage, Ormond Beach, FL).
  • Polyamide 6 Nylon 6
  • polyamide 12 Rilsamid Aesno Med
  • polyether block amide PEBAX 2533 SA 01 MED
  • polycarbonate urethane QTHAN-ARC- 95 A
  • thermoplastic silicon-polycarbonate-urethane TSPU; Carbosil 20 90A or QSIL-ARCS- 90A
  • polyether urethane QFLEX-ARE-93 A
  • Polyamide 6, PEBAX, QFLEX was dissolved in a hexafluoroisopropanol (HFIP)/formic acid (FA) blend (8/2; v/v).
  • HFIP hexafluoroisopropanol
  • FA formal acid
  • Carbosil was dissolved in a tetrahydrofuran (THF)/dimethylformamide (DMF) blend (3/2; v/v).
  • Polyamide 12 and QTHAN were dissolved in HFIP.
  • Polymer concentrations, pumping rates, spinneret, voltage, working distance listed in Table 1 were optimized beforehand to achieve targeted fiber size and good reproducibility (Table 1).
  • Conductive stainless-steel rods and flat bars were used to collect fibers to prepare tubular tubes and flat tubes, respectively.
  • GW2580 (100 mg) was dissolved in 150 mL of ethyl acetate and heated to 75°C. Then, 0 to 150 mL of hexanes was added to the drug solution to prepare crystalline particles of different sizes. The mixture was briefly mixed for 5 seconds and incubated at 25°C for 24 hours. After that, the supernatant was decanted, and the particles were washed twice with hexanes followed by drying under vacuum for 12 hours. The particles were submerged in ethanol for 1 hour and dried in a biosafety hood.
  • Pirfenidone (1 gram) was dissolved in 5 to 10 mL of ethyl acetate and heated to 40-75°C depending on the targeted size of crystalline particles. Then, 0-10 mL hexanes were added to the drug solution; the mixture was briefly mixed for 5 seconds and incubated at 25°C for 4 hours. After that, the supernatant was decanted and the particles were washed twice with hexanes, followed by drying under vacuum for 12 hours.
  • nitinol tubes were first soaked in 0.5% polymer solution to facilitate better binding of polymeric fibers to nitinol wires. The tube was then installed on a stainless steel mandrel, which has the same size and morphology as the nitinol tube. The mandrel was used to collect electrospun fibers. The electrospinning time was optimized beforehand to get ⁇ 25-pm thick nanofiber membrane on the nitinol tube. After that, the tube was removed from the mandrel and dried in a vacuum oven at RT for 24 hours to remove residual solvents.
  • a nitinol tube was installed on a stainless-steel mandrel, which has the same size and morphology as the nitinol tube.
  • the tube and the mandrel were then immersed in a calcium solution (0.5 g/mL) containing polyethylene glycol (PEG) 6000 (0.13 g/mL).
  • the tube was dried out in an oven at 80°C for 15 minutes.
  • the dried tube fixed on the mandrel was then inserted into a second nitinol tube.
  • the system was then immersed in a 3% alginate solution for 10 seconds to facilitate the formation of alginate hydrogel.
  • the outer tube was detached from the inner tube and washed 3 times with normal saline.
  • Nylon 6 device was chosen as a model to evaluate the anti-fibrotic effect of crystalline drugs (Liu et al., "A Safe, Fibrosis-Mitigating, and Scalable Encapsulation Device Supports Long-Term Function of Insulin-Producing Cells," Small, 18(8):e2104899 (2021), which is hereby incorporated by reference in its entirety).
  • the device was designed using a concentric configuration where a fibrous tube was inserted into another fibrous tube.
  • the length, diameter, pore size, and thickness of the outer tube were 2.5 cm, 3.2 mm, 1.05 pm, and 70 pm whereas those of the inner tube were 2 cm, 2 mm, 1.70 pm, and 100 pm.
  • This device was known to cause severe fibrotic reactions after being implanted into the intraperitoneal cavity of C57BL/6 mice (Liu et al., "A Safe, Fibrosis-Mitigating, and Scalable Encapsulation Device Supports Long-Term Function of Insulin-Producing Cells," Small, 18(8):e2104899 (2021), which is hereby incorporated by reference in its entirety).
  • drug loading nintedanib or GW2580
  • crystalline particles were dispersed in 0.75% SLG100 at 50 mg/mL; 70 pL of drug suspension was injected into the inner tube with one end sealed using a thermal sealer.
  • the tube was then immersed in a saline solution containing 95 mM Ca 2+ and 5 mM Ba 2+ for cross-linking.
  • the excess liquid on the tube was observed using sterile tissue papers, and the open end of the tube was sealed using a thermal sealer.
  • the tube containing the drug was inserted into the other tube, followed by thermally sealing the ends of the outer tube.
  • 70 pL of 0.75% SLG100 was injected into the inner tube.
  • the devices were stored in 50 mL of normal saline until implantation.
  • the devices were retrieved 1 -month post-implantation and washed 3 times with saline.
  • the outer tubes were fixed in 4% PF A at room temperature for 12 hours.
  • the tubes were then dehydrated using a series of graded ethanol solutions, embedded in paraffin, sectioned, and stained by Cornell Histology Core Facility.
  • the inner tube was peeled off to expose the alginate core containing crystalline drugs. The morphology and mass reduction of the particles was observed under an inverted microscope (EVOS fl).
  • DREAM devices made of NIREN Carbosil membrane were used to evaluate the effect of crystalline nintedanib in female Gottingen minipigs.
  • a nitinol tube (diameter: 5 mm, length: 10 cm) was installed on a stainless-steel rod (diameter: 5 mm). The rod was then used to collect electrospun fibers.
  • Carbosil was used at 8% (w/v) in a THF:DMF (8:2) blend. The nanofibers were spun at 0.5 mL/h under the voltage of 13 kV. A 23G blunt needle was used as the spinneret. The spinning time was 4 hours.
  • the tubes were then removed from the mandrel and placed in a vacuum oven for 24 hours to remove residual solvents.
  • the tube was sterilized by soaking in 70% ethanol for 1 hour and UV radiation for 1 hour.
  • One end of the tube was thermally sealed using a commercial thermal sealer (Impulse Sealer Supply, CA).
  • Crystalline nintedanib was dispersed in 0.75% SLG100 solution at 100 mg/mL; approximately 2 mL of the suspension was loaded into the device. After that, the device was immersed in a normal saline solution containing 95 mM Ca 2+ and 5 mM Ba 2+ for crosslinking. The excess liquid was absorbed using sterile tissue papers prior to sealing the open end.
  • An 8-cm flat bar DREAM device made of NIREA membrane was loaded with 0.6 mL crystalline nintedanib suspension in 0.75% SLG100 (27 mg/mL). The device was placed onto the omentum of a female farm pig through a 5-mm instrument port inserted percutaneously into the abdomen. Then, the port sites were closed using a 3-0 polydioxanone suture. After 2 months, the device was retrieved through an incision generated through the abdomen wall.
  • NIREN membrane should be elastic, soft but durable to maintain the original shape and avoid kink as well as potential injuries to vital organs after implantation into the abdomen. Meanwhile, the membrane should be thin enough for efficient mass transport.
  • different medical -grade elastomers including polyether block amide (PEBAX 2533 SA 01 MED), polycarbonate urethane (QTHAN-ARC-95A), thermoplastic silicon-polycarbonate-urethane (Carbosil 20 90A or QSIL-ARCS-90A), polyether urethane (QFLEX- ARE-93 A) were first screened for preparing nanofibrous membranes.
  • PEBAX 2533 SA 01 MED polycarbonate urethane
  • QTHAN-ARC-95A polycarbonate urethane
  • Carbosil 20 90A or QSIL-ARCS-90A thermoplastic silicon-polycarbonate-urethane
  • QFLEX- ARE-93 A polyether urethane
  • FIGs. 3 A, 3D SEM examination revealed the nonwoven structure with interconnected pores of these membranes.
  • Devices made of PEBAX, QTHAN, and QLEX could be stretched more than 3 times of their original lengths and were able to return to their original shapes after the force was released (FIG. 3D).
  • the fiber size and porosity of these membranes could be tuned by adjusting the polymer concentrations. For example, increased fiber sizes and porosity were achieved when the concentrations of PEBAX increased from 5% to 15%.
  • the fiber sizes were 146.03 ⁇ 55.95 nm, 286.87 ⁇ 79.61 nm, 376.11 ⁇ 111.16 nm, and 787.05 ⁇ 164.84 nm when PEBAX was used at 5%, 7.5%, 10%, and 15%, respectively (FIGs. 3B-3C).
  • Shape-memory, braided nitinol tubes were used to reinforce the nanofibrous membrane. The shape, diameter, and length of the tube could be easily tuned to adapt to different animal models and encapsulation volume.
  • Tubular nitinol tubes with a diameter of 5 mm were used for preparation of tubular NIREN versions (FIGs. 1, 4A-4H) and flat bar nitinol tubes (1 cm x 800 pm cross-section) were used for flat bar NIREN versions (FIGs. 2, 5 A-5B, 6A-6D).
  • the thickness and pore size of the nitinol mesh were -25 pm and 100-150 pm, which negligibly affect the mass transport (FIGs. 4A-4B).
  • NIREN membrane in which a thin layer of nanofibrous membrane was firmly coated on braided nitinol tube (FIGs. 4C-4D).
  • NIREN membrane could maintain the shape even when the thickness of the membrane was lower than 50 pm (FIG. 5B).
  • the neat nanofiber membranes with the same thickness were not able to keep the lumen open.
  • the NIREN tube could be bent without kink and quickly returned to the original shape after being twisted (FIGs. 4E-4H, 6A-6D).
  • SHIELD encapsulation device in which cells are encapsulated within the device cylindrical wall (Liu et al., "A Safe, Fibrosis-Mitigating, and Scalable Encapsulation Device Supports Long-Term Function of Insulin-Producing Cells," Small, 18(8):e2104899 (2021), which is hereby incorporated by reference in its entirety).
  • SHIELD device consisted of two rigid Nylon 6 tubes: an inner tube with a diameter of 2 mm and an outer tube with a diameter of 3.2 mm. A thin layer of cell-laden alginate hydrogel (-500 pm) was deposited on the inner tube and inserted into the outer tube.
  • FIG. 1 It was anticipated that a device with a diameter of 10 mm and a length of 25 cm prepared by the same method could accommodate a clinical dose of human islets (FIG. 1).
  • the final device maintained the perfect cylindrical shape and possessed similar elasticity and shape-memory features of the NIREN single tube, which could be beneficial for preventing device kink and injuries to organs after implantation (FIGs. 7C-7D).
  • Alginate hydrogel has been widely used for cell encapsulation. However, its intrinsic mechanical weakness raises concerns for clinical applications as the breakage of hydrogel after long-term implantation could affect the immunoprotection and preclude the complete retrieval. To overcome this challenge, a simple and facile method was developed to reinforce the alginate hydrogel membrane with a nitinol mesh (FIG. 8A). A similar tube-in-tube structure from Example 2 was used for NIREA membranes. First, the inner nitinol mesh tube was pre-coated with calcium by simply submerging it in a calcium/PEG solution. The trellis nature of the nitinol membrane facilitated homogenous absorption of Ca 2+ into its pores.
  • the scalability of the flat bar NIREA device was demonstrated by preparing a 25-cm long device, which could accommodate -80,000 IEQ islets at an encapsulation density of 35,000 lEQ/mL (FIGs. 9A-9B).
  • a 2-cm wide, 50-cm long device with an encapsulation capacity of -300,000 IEQ islets can be prepared easily using the same method.
  • Cells can be loaded in the alginate coating layer by dispersing cells in alginate solution before gelation (FIG. 1) or loaded in the lumen of the device by simply injecting cell suspension in 0.75% SLG solution, followed by crosslinking in an isotoniclO mM Ca 2+ solution (FIG. 10).
  • FBR Foreign body response
  • Corticoids and anti-proliferative drugs have been shown to reduce fibroblast proliferation and collagen depositions on stents, peacemakers (Singarayar et al., "A Comparative Study of the Action of Dexamethasone Sodium Phosphate and Dexamethasone Acetate in Steroid-Eluting Pacemaker Leads," Pacing Clin. Electrophysiol., 28(4):311-315 (2005), which is hereby incorporated by reference in its entirety), biosensors (Friedl, "Corticosteroid Modulation of Tissue Responses to Implanted Sensors," Diabetes Technol Ther, 6(6):898-901 (2004), which is hereby incorporated by reference in its entirety).
  • GW2580 the effect and safety profiles of GW2580 is not validated in humans. Instead, in these examples the effects of nintedanib and pirfenidone were investigated because these are the only two drugs with validated anti-fibrotic effects for reducing fibrosis and scars in humans.
  • the drugs were prepared in crystalline form for long-term release and loaded into the core of the device to locally modulate the host reactions to the device while minimizing the systemic exposure to prevent unwanted side effects.
  • nintedanib, GW2580, or pirfenidone was first dissolved in ethyl acetate. The crystallization was initiated by adding hexanes to the drug solution. Drug concentration, temperature, solvent/anti -solvent ratio, and time were adjusted to achieve different sizes and morphology of crystalline particles (FIG. 1 IB).
  • crystalline nintedanib was used with the size distribution in a range of 200-300 pm prepared by adding 1 volume of hexanes to 4 volumes of nintedanib solution (0.5 mg/mL) at 70°C. The mixture was then kept at room temperature for 12 hours.
  • One criterion in this example is that the drug should not negatively affect the encapsulated cells.
  • human islets were incubated with different drug concentrations for 48 hours (FIGs. 12A-12B).
  • the islet viability was evaluated by dual fluorescence staining using a LIVE/DEAD viability/toxicity kit. No significant changes in islet morphology and the number of dead cells were observed in all conditions (up to 2 pM), indicating the compatibility of nintedanib with the islet encapsulation devices.
  • a tube-in-tube Nylon 6 device was chosen as a model to evaluate the anti-fibrotic effect of crystalline drug given that it previously caused severe fibrotic response after implantation in IP of C57BL/6 mice.
  • 3.5 mg of either crystalline nintedanib or crystalline GW2580 was loaded in the inner tube, which enables continuous dissolution of the drug thanks to the high porosity of both tubes.
  • the devices without drugs elicited strong fibrotic response, evidenced by thick layers of host cells and dense collagen matrix deposited on the device surface.
  • FIG. 15A-15B An 8-cm flat bar DREAM device made of NIREA membrane containing 16.2 mg of crystalline nintedanib was implanted into the IP cavity of a 2-month-old farm pig by a minimally invasive laparoscopic procedure (FIGs. 15A-15B). The device was explanted by a non-survival procedure after 2 months to evaluate the fibrotic response. Interestingly, the device was found free-floating in the IP space and no tissue adhesion was observed (FIG. 15C). More than 70% of the device surface was not microscopically covered by a fibrotic layer (FIGs. 15D-15F). Of note, the fibrotic response mainly occurred at the two sealed ends and the edges of the device. Most of the crystalline drug was found intact with less than 10% mass reduction (FIG. 15G).

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Abstract

L'invention concerne un système d'administration thérapeutique implantable, des procédés de fabrication de celui-ci, et des procédés d'utilisation de celui-ci. Ce système comprend une matrice d'hydrogel comprenant au moins un agent thérapeutique et une membrane qui encapsule partiellement ou complètement la matrice d'hydrogel. La membrane comprend un hydrogel renforcé par un maillage de nitinol ou un matériau nanofibreux.
PCT/US2024/056396 2023-11-17 2024-11-18 Dispositifs de macroencapsulation anti-fibrotique à élution de médicament (dream) pour l'administration de cellules thérapeutiques Pending WO2025106977A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160030360A1 (en) * 2014-08-01 2016-02-04 Massachusetts Institute Of Technology Modified alginates for anti-fibrotic materials and applications
US20190247306A1 (en) * 2009-03-13 2019-08-15 W. L. Gore & Associates, Inc. Articles and methods of treating vascular conditions
US20230017150A1 (en) * 2021-07-16 2023-01-19 The Asan Foundation Hydrogel stent and embolization device for cerebral aneurysm
US20230338035A1 (en) * 2013-08-16 2023-10-26 Microvention, Inc. Filamentary devices for treatment of vascular defects

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190247306A1 (en) * 2009-03-13 2019-08-15 W. L. Gore & Associates, Inc. Articles and methods of treating vascular conditions
US20230338035A1 (en) * 2013-08-16 2023-10-26 Microvention, Inc. Filamentary devices for treatment of vascular defects
US20160030360A1 (en) * 2014-08-01 2016-02-04 Massachusetts Institute Of Technology Modified alginates for anti-fibrotic materials and applications
US20230017150A1 (en) * 2021-07-16 2023-01-19 The Asan Foundation Hydrogel stent and embolization device for cerebral aneurysm

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BHAGAVATULA SHARATH, THOMPSON DEVON, DOMINAS CHRISTINE, HAIDER IRFANULLAH, JONAS OLIVER: "Self-Expanding Anchors for Stabilizing Percutaneously Implanted Microdevices in Biological Tissues", MICROMACHINES (BASEL), MDPI AG, SWITZERLAND, vol. 12, no. 4, Switzerland, pages 404, XP093317426, ISSN: 2072-666X, DOI: 10.3390/mi12040404 *
SIVAPERUMAN KALAIRAJ MANIVANNAN, BANERJEE HRITWICK, LIM CHWEE MING, CHEN PO-YEN, REN HONGLIANG: "Hydrogel-matrix encapsulated Nitinol actuation with self-cooling mechanism", RSC ADVANCES, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 9, no. 59, 25 October 2019 (2019-10-25), GB , pages 34244 - 34255, XP093116626, ISSN: 2046-2069, DOI: 10.1039/C9RA05360C *

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