WO1993021902A1 - Dispositif implantable therapeutique et biocompatible - Google Patents

Dispositif implantable therapeutique et biocompatible Download PDF

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Publication number
WO1993021902A1
WO1993021902A1 PCT/US1993/003850 US9303850W WO9321902A1 WO 1993021902 A1 WO1993021902 A1 WO 1993021902A1 US 9303850 W US9303850 W US 9303850W WO 9321902 A1 WO9321902 A1 WO 9321902A1
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WO
WIPO (PCT)
Prior art keywords
implantable device
cells
film
cavity
tube
Prior art date
Application number
PCT/US1993/003850
Other languages
English (en)
Inventor
Robert S. Ward
Veronica Jean Chater
Robert Kuhn
Original Assignee
Somatix Therapy Corporation
The Polymer Technology Group, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Somatix Therapy Corporation, The Polymer Technology Group, Inc. filed Critical Somatix Therapy Corporation
Publication of WO1993021902A1 publication Critical patent/WO1993021902A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/022—Artificial gland structures using bioreactors

Definitions

  • This invention relates to an implantable, biocompatible, therapeutic or prophylactic device for introducing live cells into the body of the subject in need of a therapeutic prophylactic treatment.
  • the cells contained in the device are placed in a
  • the present device has at least one portion of its outside surface made from a non-porous, semi-permeable, biocompatible film having specific tensile strength, ultimate elongation, and water absorption, the film being permeable to molecules of variable molecular weights, e.g., up to about 6,000 and higher, and in some cases, up to about 600,000 molecular weight and higher, and substantially impermeable to cells and particulate matter.
  • the device When the device is filled with live functional cells, the device is implanted in a specific part in a subject's body in a manner such that the cells are placed in direct interactive contact with the subject's body fluids, permitting the cells to reproduce and/or remain viable.
  • the cells exert their therapeutic effect on the subject in response to the continuous interactive communication with the subject's body fluids.
  • microencapsulation with friable gels have employed microporous semi-permeable membranes.
  • Such membranes have been fabricated from impermeable polymers with pores being introduced into the material through processing conditions and/or leachable additives.
  • microporous membranes utilized by the prior art are made from inherently impermeable polymers and do not support long-term cell viability. Other semi-permeable membranes demonstrate poor blood
  • a microporous membrane may have acceptable high permanent flux in a pressure-driven process such as ultrafiltration, but, at the same time, have very low permeability in a concentration-driven process such as the in vivo method of this invention.
  • a body fluid such as blood
  • AVCOTHANE-51 ® resulted from the combination of two commercially available polymers, a silicone and a polyurethane, both of which are widely used as fabric coatings.
  • AVCOTHANE-51 ® is utilized in biomedical devices such as an intra-aortic balloon. The sole improvements introduced for its biomedical
  • AVCOTHANE-610 ® Another biomedical polyurethane, AVCOTHANE-610 ® , also called
  • CARDIOMAT-610 ® and ANGIOFLEX ® are presently being used in blood pumps and trileaflet heart valves.
  • thermoplastic material PELETHANE ® was first applied to the manufacture of cannulae for blood vessels, and later of catheters. This material had originally been developed as an extrusion molding resin exhibiting superior hydrolytic stability over their polyester-based counterparts. Table 1 below lists some of the biomedical polyurethanes available in the U.S. market.
  • polyetherurethane block or segmented copolymers exhibit good biocompatibility along with high strength and elastomeric properties. This unique combination of properties is due in part to the two-phase morphology of the polyurethane
  • aggregated aromatic or aliphatic urethane or urea segments constitute a hard glassy or semicrystalline phase, while low glass transition temperature (Tg)
  • oligomeric segments comprise the liquid-like, rubbery soft phase or segment.
  • polyurethane depends on many factors, including hard and soft segment chemistry, segment polarity
  • the chemistry of the soft segment affects the degree of phase separation in the polymer, which in turn affects its bulk and surface properties and
  • thermoplastic segmented block copolymers where one block or segment is glassy or crystalline (hard segment) and another is rubbery or liquid-like (soft segment), the permeation of molecules occurs
  • the relatively impermeable hard segment provides physical integrity to the polymer by virtue of its strong intermolecular interactions with like segments on adjacent
  • U.S. Patent 3,804,786 to Sekmakas discloses water-dispersible cationic resins, particularly polyurethane resins prepared by reaction of a
  • resinous polyepoxide with a polyisocyanate to provide an hydroxy-functional polyurethane with tertiary amine functionality. These resins are useful for electrode position at the cathode.
  • U.S. Patent 3,826,768 to Suzuki and Osonol discloses a process for preparing polyurethane compositions by dispersion of polyurethane-containing isocyanates made from polyols and organic isocyanates in water under specified conditions.
  • thermoplastic polyurethanes prepared by a specified method.
  • the thus produced elastomers are useful for automotive products, applications such as cattle ear tags, coatings and coated fabrics.
  • U.S. Patent 4,190,566 to Noll et al. relates to non-ionic, water dispersible polyurethanes with substantially linear molecular structure and lateral polyalkylene oxide polyether chains containing ethylene oxide units of specified content.
  • sustained release delivery means comprising a biologically active agent, i.e., a drug, a linear hydrophilic block polyoxyalkylene-polyurethane copolymer, and optionally a buffer.
  • a biologically active agent i.e., a drug, a linear hydrophilic block polyoxyalkylene-polyurethane copolymer, and optionally a buffer.
  • hydrophilic soft segment is used. Only the hard segment is hydrophobic.
  • U.S. Patent 4,202,957 to Bunk, et al. discloses polyurethane polyether-based elastomers which are thermoplastic and recyclable, and have increased high temperature resistance that makes them suitable for injection molding.
  • a polyurethane comprising a reaction product of a polymerizate of tetrahydrofuran and an alkylene oxide, an organic polyisocyanate and a chain extender which is an aliphatic polyol or a polyamine.
  • U.S. Patent 4,367,327 to Holker et al. relates to a breathable polyurethane film for coating fabrics to make them waterproof.
  • the polyurethane film comprises in stoichiometric amounts a hard segment made of a low molecular weight diisocyanate with a difunctional compound, and a soft segment comprising polyethylene glycol. The mechanical properties of the film are improved by crosslinking with a
  • U.S. Patent 4,849,458 to Reed et al. discloses a hydrophilic, segmented polyether polyurethane-urea exhibiting increased tensile strength and elongation when wet with water. The polymers form clear films that are permeable to water vapor.
  • polyurethane elastomers Some of them, moreover, have found biomedical applications virtually without being modified. However, despite their widespread use, many biomaterials were originally developed for nonmedical uses. In fact, most polyurethane
  • AVCOTHANE-51 ® resulted from the combination of two commercially available polymers, a silicone and a polyurethane, both of which are widely used as fabric coatings.
  • AVCOTHANE-51 ® is utilized in biomedical devices such as an intra-aortic balloon. The sole improvements introduced for its biomedical
  • AVCOTHANE-610 ® also called CARDIOMAT-610 ®
  • ANGIOFLEX ® are presently being used in blood pumps and trileaflet heart valves.
  • thermoplastic material PELETHANE ® was first applied to the manufacture of cannulae for blood vessels, and later of catheters. This material had originally been developed as an extrusion molding resin exhibiting superior hydrolytic stability than their polyester-based counterparts.
  • polyurethaneureas are available commercially, some of which were discussed above, none forms membranes of permeability, strength, flexibility and
  • U.S. Patent No. 4,631,0532 Taheri discloses an apparatus for the oxygenation of blood that comprises a hollow membrane with a central tubular portion and radially outwardly extending diffusion elements.
  • the membrane is disposed within a sheath and both are supported by a flexible wire, one end of the membrane and the sheath being secured to the wire, and the other end of the membrane and the sheath being secured to a separate tube through which oxygen is supplied to the hollow membrane.
  • U.S. Patent No. 4,710,167 to Lazorthes relates to an implantable device for chronically injecting a substance such as a therapeutant.
  • the device is to be implanted in an accessible subcutaneous zone of the body of the patient.
  • the device has an injection chamber bounded by an integral rigid case having a recess of rounded, concave shape.
  • the case has a rim onto which is impermeably fixed an elastic membrane by its own rim.
  • the elastic membrane when at rest, is essentially planar.
  • a catheter is connected to the injection chamber.
  • U.S. Patent NO. 4,718,894 to Lazorthes discloses a manually actuated, implantable device to sequentially feed doses of a substance such as a therapeutant.
  • the device comprises a reservoir consisting of a flexible pouch, a filling site located at the rim of the pouch and a manual pump.
  • the pump has a rigid case with a recess and bearing and expulsion membrane so as to bound a volume chamber.
  • a safety means prevents any accidental injection in the event of a spurious pressure exerted on the flexible pouch.
  • U.S. Patent No. 4,877,029 to Valentini et. al. relates to a medical device employing semipermeable material such as a acrylic copolymers, polyurethane isocyanate and other biocompatable semipermeable polymers.
  • the device utilizes these materials in a tubular semipermeable conduit to receive ends of severed or damaged nerves.
  • the conduits define lumens through which axions can regenerate to restore motor and/or sensory function.
  • U.S. Patent No. 4,904,260 to Ray et al relates to the implantation of two prosthetic disc capsules side-by-side into a damaged disc of the human spine that permits the maintenance of height and motion thereof.
  • a device for in vivo extrapulmonary blood gas exchange provided with a bundle and a plurality of elongated gas permeable tubes bound at each end, the tubes being enclosed within an air tight proximal and distal chamber.
  • U.S. Patent No. 4,911,689 to Hatler discloses percutaneous oxygenator having a Y shaped tubular connector and a number of hollow, gas-permeable fibers provided with loops.
  • the fiber loops can be crimped and/or twisted into a helical arrangement to enhance gas exchange.
  • U.S. Patent No. 4,825,940 to Meyer et aj. relates to a biocompatible covering surrounding the fixation helix of an implantable cardiac electrode and its lead for intravenous insertion to a selected cardiac chamber.
  • U.S. Patent No. 4,950,256 to Luther et al. 4,892 discloses an intravascular catheter comprising a cannula for insertion into a vascular system of a patient coated with a hydrophilic polymer containing polymyxin in the polymer to prevent the growth of microorganisms.
  • a device for inserting in wounds and wound cavities consisting of a container with a
  • the walls of the container consisting at least partly of a membrane, preferably a semi-permeable membrane, allowing the active substance to escape into the wound area.
  • container is preferably a dialysis tube that is conveniently connected to a drainage tube.
  • U.S. Patent No. 4,892,538 to Aebischer et al. discloses a device for delivering a neurotransmitter from an implanted, neurotransmitter-secreting cell culture to a target region in a subject.
  • the cell culture is maintained within a biocompatible, semi-permeable membrane that permits the diffusion of the neurotransmitter therethrough while excluding
  • viruses, antibodies, and other detrimental agents present in the external environment from gaining access thereto are viruses, antibodies, and other detrimental agents present in the external environment from gaining access thereto.
  • U.S. Patent No. 4,209,014 to Sefton relates to an implantable device for dispensing a medicament in two modes: a basal delivery rate and an augmented rate.
  • the device includes a permeable elastic material adapted to be repeatedly compressed by a solenoid-operated piston.
  • the device delivers a basal rate when the piston is inoperative and an augmented rate when permeable elastic material is compressed.
  • U.S. Patent No. 4,353,888 to Sefton discloses the encapsulation of mammalian cells in a polymeric membrane to form beads ready for introduction into a host body.
  • the membrane allows the passage of cell substrates and secretions but prevents the passage of larger molecules such as antibodies. These are intended to be transplanted into a host for delivery of insulin while the cells are protected against the immune reaction of the antibodies of the host.
  • the encapsulation is done in a non-solvent such as PEG and a polymer such as acrylic/methacrylic acid ester copolymers.
  • the polymer may be polyurethane having characteristics different from the polymer utilized in the film or membrane of this invention.
  • U.S. Patent No. 4,772,267 to Brown discloses a catheter assembly shown in Figure 1 of the patent.
  • the catheter comprises a cannula, a flashback plug, a protector, and other parts.
  • U.S. Patent No. 4,911,717 to Gaskill, III discloses an intravascular artificial organ having a flexible, hollow, semi-permeable catheter containing living cells or tissue.
  • the catheter is made of a material permitting the passage of molecules of molecular weight up to 50,000 Daltons.
  • the device that can be inserted into the human body, particularly into a body cavity, for supplying a hormone to a patient.
  • Pancreatic islet cells may removably be positioned in the housing to provide a hormone supply to the patient.
  • a sensor is located within a subcutaneous segment and connected to a dispenser releasing medication into the housing and to the patient.
  • an improved implantable device that is biocompatible, can permeate electrolytes and nutrients from the blood and other body fluids to permit the growth of live viable cells and therefore permitting them to live and thrive while implanted inside a human body to interact with the body fluids and provide a therapeutic or prophylactic treatment needed by a patient.
  • the repeated injection of a therapeutic to a patient has many disadvantages including pain and infection.
  • the injections are usually
  • a more effective treatment is that where the level of a compound is maintained more or less constant in accordance with the body's needs.
  • Diabetes mellitus and other hormone-related diseases are characterized by either low levels or high levels of a component in blood.
  • a low level of insulin production results in hyperglycemia, polyuria and wasting.
  • the use of a sensor to detect changes in the blood levels of a component has been applied in association with an injection system when the levels vary from the norm. This is complex and still presents the problems of producing pain and infection as potential consequences.
  • live cells or tissue have been implanted in a patient.
  • the transplantation of tissue has met with limited success because of immune rejection due to a poor tissue match.
  • the membrane protects the cells but allows the free passage of hormones and nutrients.
  • the capsules may be injected or
  • This invention relates to an implantable, biocompatible device possessing at least one cavity within which live cells can be introduced and
  • the improvement comprising at least one portion of the outside of the device comprises a non-porous, semi-permeable, biocompatible film formed from a copolymer comprising about 5 to 45 wt% of at least one hard segment, and about 95 to 55 wt% of at least one soft segment comprising at least one hydrophilic, hydrophobic or amphipathic oligomer selected from the group consisting of aliphatic polyols, aliphatic and aromatic polyamines and mixtures thereof; the film having a tensile strength greater than about 350 psi and up to about 10,000 psi, and ultimate elongation greater than about 300% and up to about 1,500%, and a water absorption such that the sum of the volume fraction of absorbed water and the hydrophilic volume fraction of the soft segment exceeds about 100% and is up to about 2,000% of the dry polymer volume and exceed
  • invention relates to any of the aforementioned implantable, biocompatible therapeutic or
  • prophylactic devices wherein a hydrogel that
  • Figure 1 shows a device comprising an oval, rectangular or decameric ring made of a semi-rigid polymer, two large sections of the internal cavity being enclosed by the film which is solvent sealed to the ring.
  • Figure 2 shows a multiple packet of film tubes which may be heat-sealed at one or both ends, or at other points.
  • Figure 3 shows a film insert lacking a semi-rigid structure and including various tubes placed along side one another that are heat-sealed by themselves at both ends.
  • Figure 4(a) is a perspective view showing a mattress-style device made of two flat sheets of film heat-sealed around the periphery thereat and at different areas within the films to define various internal cavities with all cavities in flow
  • This device has an opening that may be filled with cells and a medium, and where the opening may be heat-sealed prior to implantation.
  • Figure 4(b) shows the top of the mattress-style device as it is filled with cells and medium.
  • Figure 5 shows a continuous film tube that is end-plugged with a semi-rigid disk of e.g., silicone or polyurethane.
  • the plug may be solvent-bonded to the film.
  • Figure 6 shows a similar continuous tube with plugs at both ends and further having a means for maintaining the tube in an extended position.
  • This may be a stiffener made of a semi-rigid or rigid polymer positioned within the tube.
  • Figure 7(a) shows a film tube that is end-sealed with an end portion that strengthens it. It also has a means for maintaining the tube in an extended position that may be made of a semi-rigid or rigid material.
  • Figure 7(b) is a similar device comprising multiple tubes, the device having one center
  • FIGs 8(a), (b) and (c) are three different views of a disk comprising four film chambers in the form of a wagon wheel. In this embodiment the chambers are not connected to one another.
  • Figure 8(d) shows a wagon wheel with seven film chambers where six film chambers surround a central film chamber, and all the outer chambers are connected to the inner or central film chamber through connecting channels within the disk.
  • Figure 9 shows a strip made of a semi-flexible material containing three film chambers connected to one another by channels within the structure. Cells and medium can be injected into any one of the film chambers through the structure material which then closes up again.
  • Figure 10(a) shows a semi-flexible polymeric structure containing two film chambers that are not connected to one another. Cells and medium may be injected through the polymeric structure.
  • Figure 10(b) is similar to 10(a) but contains a flow channel connecting the two chambers.
  • Figure 10(c) is still a similar structure containing six different film chambers that can be filled with cells and medium. These structures may be made as a punched pad and as in the case of Figure 10(b) the chambers may also be connected to one another.
  • Figure 11(a) shows a device formed by a ring and a film chamber before being filled with cells and medium.
  • This device has a port for allowing the equalization of internal and external pressure, particularly during filling of the chamber, which is done via a syringe through the polymeric material of the ring.
  • the film is solvent bonded to the ring and the pressure equalization port is inserted laterally into the ring material.
  • Figure 11(b) shows the device after being filled with cells and medium. The openings made by a syringe in the ring material close by themselves.
  • Figure 11(c) is another embodiment of the ring-film device that contains a port for
  • This port has a non-bonded area which is heat-sealed after filling.
  • the membrane is solvent-bonded to the disk.
  • Figure 12(a) shows an intradermal device similar to the one of Figure 11 except that the chamber is skewed to one side of the disk and the thicker part of the disk contains a port for injection of cells and medium. This device is inserted under the skin and the fat pad positioned thereunder. The cells and the medium are injected with a syringe through the port of injection positioned under the skin after the device has been implanted.
  • Figure 12(b) is a
  • Figure 12(c) is a perspective side view of the device showing the connector channel between the chamber and the port of injection.
  • the latter can be made in color for best visibility and made of silicone and polyurethane semi-rigid material.
  • Figure 13(a) shows a device comprising a semi-flexible structure with holes that are, e.g., punched into the structure and a long film tube that is woven through the hose of the structure.
  • Figure 13(b) shows a similar structure where the tube(s) are heat-sealed to the structure.
  • Figure 14(a) is a different embodiment of the device of Figure 13 (a).
  • the device of Figure 14(a) is made of two oblong disks that have holes that can accommodate the diameter of the film tube.
  • the film tube is woven through the two oblong disks, and the disks are kept apart and the tube in an extended position by a means for holding them in that
  • Figure 14(b) is a perspective side view of the device of Figure 14 (a).
  • Figure 15(a) is a representative view of the blood flow system in an individual.
  • the ends of the figure represent the arterial anastomosis and the venous anastomosis. It is at one of these points that the device exemplified in Figure 15(b) is inserted after being filled with cells and medium. The internal cavity is opened and in flow
  • a film tube in accordance with the invention to reach the cells that are lodged in an open matrix, e.g., foam matrix, it having interconnected pores for strength and free cell-permeant communication.
  • an open matrix e.g., foam matrix
  • an impermeable tubular structure made of a flexible polymer that prevents the permeation of plasma under arterial pressure.
  • tissue interface On the outside of this impermeable barrier there is a microporous tissue interface providing a controlled degree of tissue ingrowth and fixation. This permits the device to stay in place and
  • Figure 16 shows another circulatory device in the form of a catheter made of a semi-rigid inner conduit that is connected to a port of entry for the cells and medium and a second port to permit pressure equalization.
  • the device in the form of a catheter comprises two concentric chambers, the inner one being the semi-rigid stiffener and fill port, and the outer one where the cells grow.
  • the fill port runs the length of the catheter and has an opening at the opposite end from the ports of entry and pressure equalization. At the same end where the opening is positioned there is a soft radio opaque tip for insertion thereof.
  • FIG 17 shows another circulatory device similar to the one shown in Figure 15(b) but
  • this device comprising various inner tubes for blood flow instead of one.
  • this device has two septa and tapered ends.
  • Figure 18 is another embodiment of the device shown in Figure 14(a) and 14(b). This embodiment of the device has two disks with openings through which a film tube is woven between the two disks and a means for inserting the device and maintaining the tubes in an extended position.
  • Figure 19(a) is a variation of the device of
  • the device also has an outer flexible covering with openings for passage of fluids that permit the interaction of, e.g., blood components with the cells lodged inside the film tubes.
  • the outer flexible cover is semipermeable and may or may not have openings, but permits the passage of fluids such as those used in wound drain materials.
  • Figure 19(b) is similar to the device of Figure 19(a) and shows the flexibility of the insert.
  • Figure 20(a) is a front view of another
  • FIG. 20(b) is a side view of a similar device.
  • Figure 21(a) shows an embodiment of the device that is similar to that of Figure 20 except for the fact that the ends of the tubes are heat-sealed at the two ends but there is no reinforcement provided those points. This figure shows the device before being inserted.
  • Figure 21(b) shows the device in place after being implanted.
  • the film tubes are filled with cells and engorged.
  • the outside of the device may be a mesh implant housing or a matrix to keep the device in place.
  • the polymers of the present invention may be synthesized to have a specific permeability to a given permeant and/or to have a. specific molecular weight cutoff, by implementing an empirical, yet systematic approach.
  • the empirical nature of the method is mandated by the nature of the phenomenon of permeability through dense membranes, the properties of specific permeants or non-permeants, including their solubility properties, molecular size and conformation.
  • the inventors provide herein a
  • polymeric membranes is determined for the most part by the diffusivity and solubility of the permeants in the membrane polymer. If the membrane polymer absorbs a significant amount of the solvent, then the permeation of the solutes will be determined by the diffusivity and solubility of the permeants in the solvent-swollen membrane polymer.
  • the solvent must be capable of dissolving the solute/permeant. It follows, thus, that the absorption of the solvent by the membrane may increase contribution of the solubility factor to the permeability coefficient by making the environment within the membrane polymer more like the pure solvent than it was in the dry state.
  • plasticizer for the membrane polymer.
  • Plasticization involves a degree of dissolution of the polymer by the plasticizer.
  • the glass transition temperature of the mixture will generally decrease. A decreased glass transition temperature suggests that the plasticizer may facilitate the relative movement of macromolecular chains by inserting themselves between adjacent chains to increase the intermolecular spacing there between.
  • plasticizer/solvents may reduce the degree of possible polymer-polymer interactions through specific interactions between the polymer and the plasticizer/solvent. A reduction in the soft segment crystallinity upon hydration, which occurs with certain membrane polymers of the present invention, is an example of the latter mechanism.
  • the absorption of a solvent by a membrane polymer may enhance the membranes permeability by increasing both the diffusivity and the solubility of a particular permeant.
  • specific permeability rate and/or molecular weight cutoff is to vary the composition and morphology of the membrane. This will effect an enhancement of the amount of solvent absorbed, and of the extent of solubility and diffusivity that results from greater solvent absorption.
  • the structure vs. property relationships provided in Table 1 may be used to adjust the permeability properties of the membrane through an iterative process of synthesis, membrane casting and permeability measurement, until the desired values for the intended use are attained.
  • the permeant is a water-soluble macromolecule and that the solvent is water or an aqueous fluid.
  • the solvent is water or an aqueous fluid.
  • similar approaches may be applied that are suited for other solvent/permeant systems by modifying the soft segment to facilitate the absorption of a non aqueous solvent, for example.
  • (+) and (-) refer to the nature of the effect and its intensity:
  • inventions may preferably have a molecular weight of about 160 to 10,000, and more preferably about 200 to 2,000. Its components also have preferred molecular weights as shown in Table 2 below. Table 2 : Preferred Molecular Weights for Hard
  • the content of hard segment of the copolymer is typically about 5 to 45 wt%, the remainder of the polymer consisting of soft segment, which may be a combination of hydrophilic, hydrophobic and
  • the copolymer comprises about 9 to 30 wt% of the hard segment, and more preferably 10 to 28 wt% thereof.
  • a typical content of the soft segment is about 91 to 70 wt%, and more preferably about 90 to 72 wt%.
  • other proportions of hard and soft segments are also suitable for practicing this invention.
  • a polymer made from this composition will have the properties described in Table 4 below.
  • Thickness about 5 to 100 microns
  • Thickness about 1 to 100 microns
  • This invention also provides a non-porous, semi-permeable, biocompatible film that comprises the block copolymer of the invention.
  • the film is formed from the copolymer of this invention.
  • the film is coated onto a support.
  • the film is an integrated part of the substrate and is made of the same or similar polymer.
  • the non-porous film of the invention is provided in the form of a flexible sheet and a hollow membrane or fiber.
  • the flexible sheet may be prepared as a long rollable sheet of about 10 to 15 inches width and 1 to 6 feet length.
  • the thickness of the sheet which may be about 5 to 100 microns, and more preferably about 19 to 25 microns when it is to be used without support or reinforcement.
  • the flexible sheet is prepared from the block copolymer of the invention by methods known in the art, typically, by casting, and more preferably by casting on a web or release liner.
  • the composition may be coated as a film onto a substrate.
  • a reinforcing web e.g., a fabric
  • the film or membrane may be thinner, e.g., as thin as about 1 micron, whereas when used unsupported the thickness may only be as low as about 5 to 10 microns.
  • membranes When membranes are fabricated from the polymer of the invention by knife-over-roll casting onto a release paper, web or liner in the form of dry films, they may have an about 1 to 100 micron nominal thicknesses on a continuous coating line.
  • 20-foot-long continuous web coater may be utilized having, e.g., a maximum web width of 15 inches equipped with two forced-air ovens.
  • a maximum web width of 15 inches equipped with two forced-air ovens.
  • the coater may be modified for clean operation by fitting the air inlet ducts with High Efficiency Particulate Air (HEPA) filters.
  • HEPA High Efficiency Particulate Air
  • a nitrogen-purged coater box may be used to hold and dispense filtered polymer solutions or reactive prepolymer liquids.
  • other set-ups are also suitable.
  • a casting solvent e.g., dimethylformamide
  • a casting solvent e.g., dimethylformamide
  • membrane and substrate may be further dried to reduce residual solvent content to less than about 100 ppm, as determined by liquid chromatography.
  • the thickness of the fully-dried cast films may be measured by, e.g., using a spring micrometer sensitive to 0.0001 inch (2.5 ⁇ M) or visually by using a microscope.
  • the membrane of this invention may have any shape resulting from a process utilizing a liquid which is subsequently converted to a solid during or after fabrication, e.g., solutions, dispersions, 100% solids prepolymer liquids, polymer melts, etc.
  • Converted shapes may also be further modified using methods such as die cutting, heat sealing, solvent or adhesive bonding or any of a variety of other
  • the membrane when in the form of a hollow tube, the membrane is
  • the hollow membrane may easily be prepared in long rollable form, and be cut to a length of about 0.75 to 31 inches, and more preferably about 0.5 to 6 inches.
  • any device known or to be designed that comprises at least a portion thereof made of this semi-permeable, biocompatible film or membrane of this invention is encompassed within the confines of the present invention.
  • the film or membrane utilized in the manufacture of the present device has very specific characteristics that permit the permeation of molecules of desired molecular weights without permitting, at the same time, the passage of cells or particulate matter, or high molecular weight
  • the film or membrane of the invention does not permit the passage of molecules having molecular weights larger than a certain desired cut-off point.
  • the films may be produced that are custom tailored for specific applications.
  • the film utilized in the devices of this invention is non-porous and may be provided in the form of a flexible sheet, a hollow membrane or fiber.
  • the flexible sheet may be prepared as a long reliable sheet of about ten to fifteen inches in width, and about one to six feet in length.
  • the thickness of the sheet which may be about five to one hundred microns, and more preferably about nineteen to twenty-five microns when it is used without a support or reinforcement.
  • the non-porous film or membrane of this invention is semi-permeable, has a tensile strength greater than about 350 psi and up to about 10,000 psi, an ultimate elongation greater than about 300% up to about
  • hydrophilic volume fraction of the self segment comprising the polymer exceeds about 100% and up to about 2,000% of the dry polymer volume, and exceeds about 50% and is up to about 95% of the wet polymer volume, and is permeable to molecules of up to about 6,000 to 600,000 molecular weight and substantially impermeable to cells and particulate matter.
  • the films or membrane of this invention may be formed from a biocompatible, hydrophilic, segmented biocompatible polyurethane copolymer that comprises about 5 to 45 wt% of at least one hard segment, and about 95 to 55 wt% of at least one soft segment comprising at least one hydrophilic, hydrophobic, or amphipathic oligomer selected from the group
  • Particularly preferred aliphatic polyols for the soft segment are those selected from the group consisting of linear, branched and graft polyalkylene oxides, polyalylene and polyalkenyl oxides, random and block copolymers thereof, polycarbonate polyols, hydroxyl-terminated silicones, random and block copolymers thereof, with polyalkylene oxides, linear and
  • the soft segment of the polymers are selected from the group consisting of amine-terminated polyalkylene oxides and random, block and graft copolymers thereof, amine-terminated
  • polydialkyl siloxanes random and block copolymers thereof with polyalkylene oxides and mixtures thereof.
  • the end group may be selected from
  • monofunctional aliphatic polyols of the end cap may be selected from the group consisting of
  • monofunctional polyalkylene oxides, siloxane and mixtures thereof, and the monofunctional amines of the end group may be selected from the group
  • dialkyl amines consisting of dialkyl amines, amine functional siloxanes, amine terminated polyalkylene oxides, and mixtures thereof.
  • the soft segment is selected from the group consisting of reaction products of an organic diisocyanate with a polyamine and a polyol.
  • the organic diisocyanate of the hard segment may be selected from the group consisting of alkyl
  • diisocynates arylalkyldiisocyanates, alkyl-cycloalkyl diisocynates, alkylaryl diisocyanates, cycloalkyl diisocyanates, aryl diisocyanates, and cycloalkylaryl diisocyanates, which may be further substituted with oxygen and mixtures thereof.
  • the polyol of the hard segment may be selected from the group consisting of alkylene cycloalkylene and arylene diols, triols, tetraalcohols,
  • the polyamine of the hard segment may be any polyamine of the hard segment.
  • cycloalkyl and arylamines which may be further substituted with N, O or halogen, complexes thereof with alkali metal salts and mixtures thereof.
  • the soft segment comprises a
  • polyethylene oxide of molecular weight greater than about 3,000 daltons, and more preferably greater than about 8,000 daltons. In another preferred
  • the soft segment comprises a blend of polyols selected from the group consisting of a polyethylene oxide of molecular weight greater than about 3,000 daltons polyethylene oxide-polytetramethylene oxide and a polyethylene oxide homopolymer, a polyethylene oxide-polytetramethylene oxide copolymer and an ethylene oxide-polyethylene oxide copolymer, a polyethylene oxide polypropylene oxide copolymer and a polyethylene oxide homopolymer, a polyethylene oxide-polypropylene oxide copolymer and a polypropylene oxide homopolymer, a polyethylene oxide homopolymer and a polytetramethylene oxide homopolymer, a polyethylene oxide-containing polymer and a polycarbonate homopolymer, a polyethylene oxide-containing polymer and a polybutadiene
  • the soft segment comprises a blend of a polyethylene oxide-polytetramethylene oxide copolymer and a polyethylene oxide homopolymer.
  • Another preferred soft segment is a blend of a polyethylene oxide-polytetramethylene oxide copolymer and a polyethylene oxide-polypropylene oxide
  • Still another preferred soft segment is a blend of a polyethylene oxide-polytetramethylene oxide copolymer and an ethylene-oxide Polypropylene oxide polymer. Still another preferred soft segment is a blend of a polyethylene oxide-polypropylene oxide copolymer and a polyethylene oxide homopolymer. Another preferred soft segment still is a blend of a polyethylene oxide-polypropylene copolymer and a polypropylene oxide homopolymer. Also preferred is another soft segment comprising a blend of a
  • polytetramethylene oxide homopolymer providing the copolymer with a decreased tensile strength and an elongation in the width state when compared to its dry state.
  • Other preferred soft segments are those comprising a blend of a polyethylene oxide-containing polymer and a polycarbonate homopolymer, and blend of a polyetheylene oxide-containing polymer and a polybutadiene homopolymer, a blend of a polyethylene oxide-containing polymer and a polyisobutylene homopolymer.
  • the film of the invention may be prepared by casting, and more preferably by casting on a web or release liner.
  • composition may be coated as a film onto a substrate.
  • a reinforcing web such as a fabric
  • the film or membrane may be thinner than when standing alone. Thicknesses of one micron and less are possible, whereas when used unsupported, the
  • Membranes or films may be made from the polymer of the invention by knife-over-roll casting onto a release paper web or liner in the form of dry films, they may have about one to one hundred micron nominal thickness on a continuous coating line. A twenty-foot long continuous web of film may be utilized having, for example, a maximum web width of fifteen inches. The details of the preparation of the film or membrane and the hollow fibers is
  • This invention arose from a desire by the inventors to improve on prior art technology for the in vivo treatment of patients suffering from a metabolic disease.
  • a typical application of the present device is for the implementation of gene therapy to compensate for any deficiencies that the genetic makeup of a patient may have.
  • a patient suffering from diabetes may be treated by implanting one of the present devices that is filled with cells capable of producing, i.e., insulin or another compound, when in direct contact with the patient's blood flow or other bodily fluids.
  • the device serves to implant regulatable cells that are capable of responding to changes in the levels of the compound to be regulated in blood.
  • a method for the in vivo treatment utilizing the present device is disclosed in co-pending, co-filed U.S. Application entitled "METHOD OF CULTURING VIABLE CELLS AND METHOD OF REGULATING BLOOD GLUCOSE LEVELS BY IMPLANTATION OF VIABLE CELLS IN NON-POROUS SEMI-PERMEABLE MEMBRANE", by Robert S. Ward, John Monahan and Robert Kuhn, (Attorney Docket No. SOMA 20111.USA) the portions thereof relating to the method of utilizing the present device and the related kits being incorporated herein by reference.
  • the device (48) shown in Figure 1 is made of two polymeric film (1) sections in accordance with this invention that are solvent-sealed (3) to an oval, rectangular or decameric ring (2) made of a semi-rigid polymeric material such as polyurethane, silicone, and the like. Other materials that are not necessarily permeable to nutrients and the medium may also be utilized as long as they are biocompatible.
  • Each portion of the film (1) is solvent-sealed (3) all around the ring (2) and on one side thereof.
  • This embodiment of the invention may comprise a ring (2) of different shapes and thicknesses.
  • the ring (2) may be circular, it may be in the shape of a polygon with varying numbers of sides such as three, four, five, six, seven, eight, nine, ten, eleven, twelve sides, and the like.
  • the ring (2) itself may be thin or it may have some thickness in the direction determined by a plane intersecting both film (1) planes. This type of device is
  • the embodiment shown in Figure 2 consists of a multiplicity of film tubes (12) or packets that are filled with cells and medium and then heat-sealed (5) to one another at one or both ends thereof.
  • the device shown has three film tubes (12) or packets filled with cells that will be sealed together.
  • the embodiment shown in Figure 3 consists of several film tubes (12) heat-sealed to one another (7) at their ends, and may be attached (46) to a support (13) or end portion.
  • the device shown in Figure 4 is similar to an inflatable mattress. It consists of two films (1) that are heat-sealed (9) to one another to define cavities (47) therewithin. These cavities are filled with cells by means of a syringe (20) and a needle (50) through an opening (8) for insertion of the needle (50). Once the cells have been introduced into the device, the opening (8) may be heat-sealed (9) to obtain a totally sealed device.
  • Figure 4(a) shows a perspective side view of the device (48) whereas Figure 4(b) shows a top view of the device (48).
  • the embodiment of the device (48) of this invention shown in Figure 5 consists of a continuous tube (12) having a plug (10) at one end thereof. The plug (10) is placed on the inside of the tube and it may be made of a semi-rigid material and affixed to the tube (12).
  • FIG. 6 A similar embodiment of the device (48) is shown in Figure 6.
  • the first addition is a second plug (10) or reinforcement positioned inside the tube (12) at the opposite end to the first plug (10) or reinforcement.
  • the second addition is a means (11) for maintaining a tube (12) in an extended position.
  • the means (11) may be affixed to the terminal plugs (10) and be made of a semi-rigid or rigid material.
  • FIG. 7 Another embodiment of the present device (48) is shown in Figure 7. This consists of a film tube (12) shown in Figure 7(a).
  • the film tube (12) is
  • the means (11) for maintaining the film tube (12) in an extended position (11) is provided with an opening (14) or port for the introduction of the cells and the medium into the device (48).
  • the ends of the film tube (12) are heat-sealed by
  • FIG. 7(b) consists of three to four film tubes (12) that are reinforced by two or three means (11) for maintaining the tubes (12) in an extended position.
  • the ends (46) of the film tubes (12) are heat-sealed to one another and reinforced with an end portion (13) to strengthen the tube (12) seal.
  • FIG 8. This device (48) is in the form of a disk (15) that is provided with openings (49) that may be molded or punched out once the disk (15) is formed.
  • Film chambers (16) are formed for lodging the cells and the medium by positioning two portions of the film (1) of the invention covering each opening (49) on both sides.
  • FIG. 8 (a) is the top view of a four chamber device (48).
  • Figure 8(b) is a perspective top side view of the same device (48) and
  • Figure 8(d) is the top view of a seven device (48) consisting of six cell chambers (16) positioned around the border of the disk (15) and a center cell chamber (16). All the peripheral chambers (16) are in flow
  • FIG. 9 shows another variation of the embodiment of the device (48) of Figure 8.
  • a semi-rigid structure (18) has three openings (49) defining three cell chambers (16) surrounded by the film (1) of this invention.
  • the three cell chambers (16) are in flow communication with one another by two means of flow communication (17).
  • the cells and the medium are injected into the semi-rigid structure (18) by means of a syringe (20) and a needle (50).
  • Figure 10(a) shows a semi-rigid structure (18) with openings (49) surrounded by the film (1) of this invention. These cavities are filled with cells and medium by
  • the device (48) shown in Figure 10(b) is similar to the one of Figure 10(a) except that it also contains a means for flow communication (17) between the two chambers (16) in the form of a connector between them.
  • a device (48) with six cell chambers (16) is illustrated in Figure 10(c) above.
  • the chambers (16) are not in flow communication with one another.
  • the device (48) shown in Figure 11 is called an "Insulette". It has a semi-rigid ring (2) with two openings (24) each of which is covered with film (1). Each piece of film (1) is solvent-sealed (3) to the borders of the ring (2).
  • FIG. 10(b) is similar to the one of Figure 10(a) except that it also contains a means for flow communication (17) between the two chambers (16) in the form of a connector between them.
  • a device (48) with six cell chambers (16) is illustrated in Figure 10(c) above.
  • the chambers (16) are not in flow communication with one another.
  • FIG 11(a) a syringe (20) with a needle (50) are shown in the process of inserting cells and medium through the ring (2).
  • a port (19) for allowing the equalization of internal and external pressure is also shown attached to the side of the ring (2). This port (19) permits air to come out of the cell chamber (16) when material is introduced therein.
  • Figure 11(b) shows the device (48) from a perspective top side view as in Figure 11(a) but where the chamber (16) is already filled with cells and medium.
  • the syringe (20) is removed as is the port (19) for equalizing internal and external pressure. Any openings (49) left by this removal will self seal or may otherwise be sealed with a soldering iron.
  • Figure 11(c) shows a top view of a similar device that also contains a non-bonded fill area or port (14) for injection of cells and medium, through which a syringe's (20) needle (50) injects the cells into the chamber (16). After the syringe is removed, the port (14) may be removed and the opening (49) leftover may be sealed by itself or be sealed with a soldering iron.
  • Figure 12 shows an intradermal disk
  • Figure 12(a) is a side view of the ring as it is envisioned when implanted under the epidermis (21).
  • the disk (15) or ring (2) is
  • FIG. 1 is a top view of the device (49) and Figure 12(c) is a top side view of the device (49) after the chamber (16) is filled with cells and medium. In this view a means for flow communication (17) between the port (14) for
  • FIG. 13 Another embodiment of the present device (48) is shown in Figure 13.
  • This device (48) consists of a frame made of a semi-flexible structure (23) provided with openings (24) of a size such that they can accommodate the width or diameter of the film tube (12) when it is woven through the openings (24) as shown in Figure 13(a). The two ends (46) of the tube are sealed after the tube (12) is filled with cells and medium.
  • This figure shows a top view of the device (48) having a film tube (12) woven through the opening (24) of the semi-flexible
  • Figure 13(b) is a top view of a similar device (48), except for the fact that the tubes (12) are heat-sealed (25) to the semi-flexible structure (23).
  • This embodiment of the device (48) is made of a multiplicity of film tubes (12) and not of one tube (12) that is interwoven through the openings (24) of the semi-flexible structure (23).
  • a similar device (48) is shown in Figure 14.
  • two disks (15) are positioned at a certain distance from one another and held at that distance by means (11) for maintaining the film tube (12) in an extended position. This may be in the form of a rod or any other means for attaining the same purpose.
  • one film tube (12) is woven through the openings (24) of the two disks (15).
  • Figure 14(b) shows a top perspective view of the same device (48).
  • Figure 15(a) shows a schematic representation of the blood flow (26) system in the body, having an arterial anastomosis (27) point and a venus
  • FIG 15(b) shows a cross-sectional view of the device (48) of this invention where a tubular film (12) of the invention defines an internal cavity (31) for the blood to flow through.
  • a tubular film (12) of the invention defines an internal cavity (31) for the blood to flow through.
  • Around the film tube (12) is an open matrix (28) for lodging and growth of the cells positioned inside and impermeable flexible outer tube (29).
  • Outside of the tube (29) is a microporous tissue interface (30) that controls the degree of tissue ingrowth and fixation of the device (48).
  • This device (48) is inserted in the blood vessels (26) at the arterial anastomosis (27) or venus anastomosis (52) points shown in Figure 15(a).
  • a semi-rigid device (48) in the form of a catheter or cannula is shown in Figure 16.
  • This device (48) is comprised of several sections. One section is surrounded by a film tube (12) in
  • the injection (14) for the cells and the medium is connected to a semi-rigid inner tube (35) positioned lengthwise inside the film tube (12).
  • the semi-rigid inner tube (35) defines therewithin an internal cavity (16) or fill chamber.
  • the cells grow in a cell chamber (33) surrounding the semi-rigid inner tube
  • Figure 17 shows a device (48) consisting of an semi-rigid outside smaller tube (35) with tapered sections (39) at both sides ending in tubular end portions (27) for insertion into the blood vessel.
  • a cutout (38) of the semi-rigid tube (35) shows a multiplicity of film tubes (12)
  • FIG 17(b) is a cross-sectional view of the device (48) and shows the multiplicity of film tubes (12) as well as the matrix (28) for lodging and growth of the cells.
  • the impermeable flexible outer tube (29) On the outside surface of the impermeable flexible outer tube (29) is positioned a microporous tissue interface (30) to facilitate the anchoring of the device (48) to the body tissue.
  • Figure 18 shows a variation of the device of Figure 14.
  • two semi-rigid disks (15) are made of a semi-rigid material (23) and provided with openings (24) that can accommodate the diameter of a film tube (12).
  • a multiplicity of film tubes (12) are filled with cells and medium and extended between the two disks (15) and pass through the openings (24) and heat-sealed to one another (7) or to the disk (15).
  • the device (48) is provided with a means (41) for insertion of the device and maintenance of the tubes in the extended position that is affixed to the two disks (15). This permits the insertion of its device and its lodging in the proper place.
  • Figure 19 shows a tampon-like device (48) made of a flexible outer structure (43) that may be made of an impermeable or a semi-permeable
  • the flexible outer tube (43) is provided with a multiplicity of openings (36) and a multiplicity of film tubes (12) lodged inside the flexible materials (43).
  • the tubes are heat-sealed at both ends (3) to one another as well as to the flexible outer tube (5).
  • the device has a means for removal (42) attached to one end thereof.
  • Figure 19(a) shows the device (48) in its rigid position.
  • Figure 19(b) shows the flexibility of the device (48).
  • Still another embodiment of the device (48) of this invention is shown in Figure 20.
  • This device (48) is referred to as a cassette and comprises of multiplicity of film tubes (12) parallel to one another that are heat-sealed to a structural polymer (25) for strength.
  • FIG. 20(a) shows a front view of the device (48) whereas Figure 20(b) shows a side view of the device (48).
  • Figure 21 shows a cassette consisting of a plurality of film tubes (12) heat-sealed at both ends to one another (7) at one end of the heat-sealed tubes (45) it is inserted a means for inserting and removing the device (44).
  • Figure 21(a) shows the entire device with the removable means of insertion (44) whereas Figure 21(b) shows the device filled with cells and implanted into a matrix (28) where the film tubes (12) are engorged.
  • the devices further comprise a hydrogel that comprises greater than about 35% water within the cavity of the device.
  • the hydrogel serves to immobilize the cells within the device, thus insuring an even cell distribution within the device.
  • Suitable water-swellable gels are alginates (e.g. sodium alginate, ammonia alginates, potassium alginates, propylene glycol alginates, algins), guar gum, gum tragacanth, locust bean gum, methocel, xanthan gum, polyethylene oxide, polypropylene oxide, dextrans, acrylates, methacrylates, polyvinyl
  • Those gums or resins capable of "crosslinking” may be used crosslinked or linear.
  • sodium alginate may be used "as is” or converted to its insoluble calcium form.
  • the preferred hydrogel is an alginate wherein the water content is greater than about 90%.
  • the most preferred hydrogel is calcium alginate.
  • hydrogel that comprises greater than about 35% water, be used to suspend the cells.
  • the hydrogel serves to
  • the most preferred embodiment of the instant invention comprises the implantation of a dense membrane in the form of hollow fibers where the hollow fiber is filled with calcium alginate with a water content greater than about 90%.
  • the geometry of the dense membrane can be in any form including sheets, larger diameter tubes, etc.

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  • Transplantation (AREA)
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Abstract

L'invention se rapporte à un dispositif implantable et biocompatible, comprenant au moins une cavité dans laquelle des cellules vivantes peuvent être introduites et maintenues de sorte que, lorsque le dispositif est implanté chez un sujet, les cellules sont placées en interaction continue avec les fluides corporels du sujet afin de produire un effet thérapeutique ou prophylactique nécessitant un contact interactif direct avec les fluides corporels. Au moins une partie externe du dispositif comprend une pellicule non poreuse, semi-perméable et biocompatible composée d'un copolymère comprenant de 5 à 45 % en poids environ d'au moins un segment dur, et de 95 à 55 % en poids environ d'au moins un segment mou, pratiquement imperméable à des cellules et à des matières particulaires. De nombreux modes de réalisation du dispositif de cette invention sont décrits.
PCT/US1993/003850 1992-04-24 1993-04-23 Dispositif implantable therapeutique et biocompatible WO1993021902A1 (fr)

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004521A1 (fr) * 1993-08-10 1995-02-16 W.L. Gore & Associates, Inc. Dispositif d'encapsulage de cellules
EP0652735A1 (fr) * 1992-07-30 1995-05-17 The University Of Toledo Pancreas bioartificiel
WO1995018584A1 (fr) * 1994-01-11 1995-07-13 Baxter International Inc. Procede d'implantation de tissu dans un hote
WO1996039100A1 (fr) * 1995-06-05 1996-12-12 Baxter International Inc. Systeme de chargement de tissu pour des dispositifs biologiques implantables
US5641750A (en) * 1995-11-29 1997-06-24 Amgen Inc. Methods for treating photoreceptors using glial cell line-derived neurotrophic factor (GDNF) protein product
EP0791354A1 (fr) * 1996-02-23 1997-08-27 Dow Corning France S.A. Procédé de fabrication de dispositifs à libération contrÔlée
US5681740A (en) * 1995-06-05 1997-10-28 Cytotherapeutics, Inc. Apparatus and method for storage and transporation of bioartificial organs
WO1998002113A1 (fr) * 1996-05-29 1998-01-22 Baxter International Inc. Ensemble pour implants
US5773286A (en) * 1987-11-17 1998-06-30 Cytotherapeutics, Inc. Inner supported biocompatible cell capsules
US5776747A (en) * 1994-07-20 1998-07-07 Cytotherapeutics, Inc. Method for controlling the distribution of cells within a bioartificial organ using polycthylene oxide-poly (dimethylsiloxane) copolymer
US5782789A (en) * 1994-10-19 1998-07-21 Atrium Medical Corporation Macrochannel phosthetic/delivery patch
US5786216A (en) * 1987-11-17 1998-07-28 Cytotherapeutics, Inc. Inner-supported, biocompatible cell capsules
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5837234A (en) * 1995-06-07 1998-11-17 Cytotherapeutics, Inc. Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane
US5843431A (en) * 1994-07-20 1998-12-01 Cytotherapeutics, Inc. Controlling proliferation of cells before and after encapsulation in a bioartificial organ by gene transformation
EP0901796A2 (fr) * 1997-09-03 1999-03-17 Circe Biomedical, Inc. Dispositif d'encapsulation
US5902745A (en) * 1995-09-22 1999-05-11 Gore Hybrid Technologies, Inc. Cell encapsulation device
WO1999040899A1 (fr) * 1998-02-16 1999-08-19 Biomat B.V. Dispositif implantable et son utilisation
WO2002056956A1 (fr) * 2001-01-18 2002-07-25 Vladimir Kalina Appareil permettant d'induire une reponse immunitaire dans une therapie contre le cancer
US6495364B2 (en) * 1995-05-23 2002-12-17 Neurotech, S.A. Mx-1 conditionally immortalized cells
WO2005089671A1 (fr) * 2004-03-19 2005-09-29 Microislet, Inc. Dispositif de distribution intravasculaire implantable
WO2006040141A2 (fr) * 2004-10-12 2006-04-20 Capsulution Nanoscience Ag Dispositif segmente pour liberation decalee de molecules dans le sens tangentiel par films minces et utilisations correspondantes
WO2008027420A2 (fr) 2006-08-29 2008-03-06 The University Of Akron Dispositifs implantables pour la production d'insuline
WO2010057039A2 (fr) 2008-11-14 2010-05-20 Cythera, Inc. Encapsulation de cellules pancréatiques dérivées de cellules souches pluripotentes humaines
US9526880B2 (en) 2013-03-07 2016-12-27 Viacyte, Inc. 3-dimensional large capacity cell encapsulation device assembly
US20180126134A1 (en) * 2016-11-08 2018-05-10 W. L. Gore & Associates, Inc. Implantable Encapsulation Devices
US11623023B2 (en) 2016-11-10 2023-04-11 Viacyte, Inc. PDX1 pancreatic endoderm cells in cell delivery devices and methods thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4298002A (en) * 1979-09-10 1981-11-03 National Patent Development Corporation Porous hydrophilic materials, chambers therefrom, and devices comprising such chambers and biologically active tissue and methods of preparation
WO1991000119A1 (fr) * 1989-06-30 1991-01-10 Baxter International Inc. Dispositif implantable
US5026365A (en) * 1987-04-29 1991-06-25 The University Of Massachusetts Method and apparatus for therapeutically treating immunological disorders and disease states
US5035891A (en) * 1987-10-05 1991-07-30 Syntex (U.S.A.) Inc. Controlled release subcutaneous implant
WO1991019783A1 (fr) * 1990-06-15 1991-12-26 E.I. Du Pont De Nemours And Company Surfaces en polymere elastomere servant de support a des cellules de mammiferes et procedes de preparation associes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4298002A (en) * 1979-09-10 1981-11-03 National Patent Development Corporation Porous hydrophilic materials, chambers therefrom, and devices comprising such chambers and biologically active tissue and methods of preparation
US5026365A (en) * 1987-04-29 1991-06-25 The University Of Massachusetts Method and apparatus for therapeutically treating immunological disorders and disease states
US5035891A (en) * 1987-10-05 1991-07-30 Syntex (U.S.A.) Inc. Controlled release subcutaneous implant
WO1991000119A1 (fr) * 1989-06-30 1991-01-10 Baxter International Inc. Dispositif implantable
WO1991019783A1 (fr) * 1990-06-15 1991-12-26 E.I. Du Pont De Nemours And Company Surfaces en polymere elastomere servant de support a des cellules de mammiferes et procedes de preparation associes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZONDERVAN G. J., ET AL.: "DESIGN OF A POLYURETHANE MEMBRANE FOR THE ENCAPSULATION OF ISLETS OF LANGERHANS.", BIOMATERIALS., ELSEVIER SCIENCE PUBLISHERS BV., BARKING., GB, vol. 13., no. 03., 1 January 1992 (1992-01-01), GB, pages 136 - 144., XP000258851, ISSN: 0142-9612, DOI: 10.1016/0142-9612(92)90061-R *

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773286A (en) * 1987-11-17 1998-06-30 Cytotherapeutics, Inc. Inner supported biocompatible cell capsules
US5786216A (en) * 1987-11-17 1998-07-28 Cytotherapeutics, Inc. Inner-supported, biocompatible cell capsules
US5871767A (en) * 1991-04-25 1999-02-16 Brown University Research Foundation Methods for treatment or prevention of neurodegenerative conditions using immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US6960351B2 (en) 1991-04-25 2005-11-01 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US6322804B1 (en) 1991-04-25 2001-11-27 Neurotech S.A. Implantable biocompatible immunoisolatory vehicle for the delivery of selected therapeutic products
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5834001A (en) * 1991-04-25 1998-11-10 Brown University Research Foundation Methods for making immunoisolatory implantable vehicles with a biocompatiable jacket and a biocompatible matrix core
US5869077A (en) * 1991-04-25 1999-02-09 Brown University Research Foundation Methods for treating diabetes by delivering insulin from biocompatible cell-containing devices
US5874099A (en) * 1991-04-25 1999-02-23 Brown University Research Foundation Methods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5800828A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
EP0652735A1 (fr) * 1992-07-30 1995-05-17 The University Of Toledo Pancreas bioartificiel
EP0652735A4 (fr) * 1992-07-30 1995-08-09 Univ Toledo Pancreas bioartificiel.
WO1995004521A1 (fr) * 1993-08-10 1995-02-16 W.L. Gore & Associates, Inc. Dispositif d'encapsulage de cellules
EP0938893A1 (fr) * 1993-08-10 1999-09-01 W.L. Gore & Associates, Inc. Dispositif d'encapsulage de cellules
US5980889A (en) * 1993-08-10 1999-11-09 Gore Hybrid Technologies, Inc. Cell encapsulating device containing a cell displacing core for maintaining cell viability
US6426214B1 (en) 1993-08-10 2002-07-30 Gore Enterprise Holdings, Inc. Cell encapsulating device containing a cell displacing core for maintaining cell viability
WO1995018584A1 (fr) * 1994-01-11 1995-07-13 Baxter International Inc. Procede d'implantation de tissu dans un hote
US6392118B1 (en) 1994-07-20 2002-05-21 Neurotech S.A. Mx-1 conditionally immortalized cells
US5935849A (en) * 1994-07-20 1999-08-10 Cytotherapeutics, Inc. Methods and compositions of growth control for cells encapsulated within bioartificial organs
US5833979A (en) * 1994-07-20 1998-11-10 Cytotherapeutics, Inc. Methods and compositions of growth control for cells encapsulated within bioartificial organs
US5795790A (en) * 1994-07-20 1998-08-18 Cytotherapeutics, Inc. Method for controlling proliferation and differentiation of cells encapsulated within bioartificial organs
US5840576A (en) * 1994-07-20 1998-11-24 Cytotherapeutics, Inc. Methods and compositions of growth control for cells encapsulated within bioartificial organs
US5843431A (en) * 1994-07-20 1998-12-01 Cytotherapeutics, Inc. Controlling proliferation of cells before and after encapsulation in a bioartificial organ by gene transformation
US5853717A (en) * 1994-07-20 1998-12-29 Cytotherapeutics, Inc. Methods and compositions of growth control for cells encapsulated within bioartificial organs
US5858747A (en) * 1994-07-20 1999-01-12 Cytotherapeutics, Inc. Control of cell growth in a bioartificial organ with extracellular matrix coated microcarriers
US5776747A (en) * 1994-07-20 1998-07-07 Cytotherapeutics, Inc. Method for controlling the distribution of cells within a bioartificial organ using polycthylene oxide-poly (dimethylsiloxane) copolymer
US5782789A (en) * 1994-10-19 1998-07-21 Atrium Medical Corporation Macrochannel phosthetic/delivery patch
US6495364B2 (en) * 1995-05-23 2002-12-17 Neurotech, S.A. Mx-1 conditionally immortalized cells
US5681740A (en) * 1995-06-05 1997-10-28 Cytotherapeutics, Inc. Apparatus and method for storage and transporation of bioartificial organs
WO1996039100A1 (fr) * 1995-06-05 1996-12-12 Baxter International Inc. Systeme de chargement de tissu pour des dispositifs biologiques implantables
US5837234A (en) * 1995-06-07 1998-11-17 Cytotherapeutics, Inc. Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane
US5902745A (en) * 1995-09-22 1999-05-11 Gore Hybrid Technologies, Inc. Cell encapsulation device
US5641750A (en) * 1995-11-29 1997-06-24 Amgen Inc. Methods for treating photoreceptors using glial cell line-derived neurotrophic factor (GDNF) protein product
EP0791354A1 (fr) * 1996-02-23 1997-08-27 Dow Corning France S.A. Procédé de fabrication de dispositifs à libération contrÔlée
FR2745180A1 (fr) * 1996-02-23 1997-08-29 Dow Corning Sa Procede de fabrication de dispositifs a liberation controlee
US5788977A (en) * 1996-02-23 1998-08-04 Dow Corning France S.A. Method of making controlled release devices
US5964261A (en) * 1996-05-29 1999-10-12 Baxter International Inc. Implantation assembly
WO1998002113A1 (fr) * 1996-05-29 1998-01-22 Baxter International Inc. Ensemble pour implants
EP0901796A3 (fr) * 1997-09-03 2000-09-13 Circe Biomedical, Inc. Dispositif d'encapsulation
EP0901796A2 (fr) * 1997-09-03 1999-03-17 Circe Biomedical, Inc. Dispositif d'encapsulation
EP0938894A1 (fr) * 1998-02-16 1999-09-01 Biomat B.V. Dispositif radio-opaque implantable et son utilisation
WO1999040899A1 (fr) * 1998-02-16 1999-08-19 Biomat B.V. Dispositif implantable et son utilisation
CZ298160B6 (cs) * 2001-01-18 2007-07-11 Prístroj pro vyvolání imunitní odezvy pri lécbe rakoviny
US7160716B2 (en) 2001-01-18 2007-01-09 Vladimir Kalina Device for inducing an immune response in cancer therapy
WO2002056956A1 (fr) * 2001-01-18 2002-07-25 Vladimir Kalina Appareil permettant d'induire une reponse immunitaire dans une therapie contre le cancer
WO2005089671A1 (fr) * 2004-03-19 2005-09-29 Microislet, Inc. Dispositif de distribution intravasculaire implantable
WO2006040141A2 (fr) * 2004-10-12 2006-04-20 Capsulution Nanoscience Ag Dispositif segmente pour liberation decalee de molecules dans le sens tangentiel par films minces et utilisations correspondantes
WO2006040141A3 (fr) * 2004-10-12 2006-10-05 Capsulution Nanoscience Ag Dispositif segmente pour liberation decalee de molecules dans le sens tangentiel par films minces et utilisations correspondantes
US8361489B2 (en) 2006-08-29 2013-01-29 The University Of Akron Implantable devices for producing insulin
EP2056759A4 (fr) * 2006-08-29 2011-11-30 Univ Akron Dispositifs implantables pour la production d'insuline
EP2056759A2 (fr) * 2006-08-29 2009-05-13 The University Of Akron Dispositifs implantables pour la production d'insuline
WO2008027420A2 (fr) 2006-08-29 2008-03-06 The University Of Akron Dispositifs implantables pour la production d'insuline
EP3363444A1 (fr) * 2008-11-14 2018-08-22 Viacyte, Inc. Encapsulation de cellules pancréatiques dérivées de cellules souches pluripotentes humaines
CN105349517B (zh) * 2008-11-14 2021-05-04 维赛特公司 源于人多能干细胞的胰腺细胞的包封
EP2356227A4 (fr) * 2008-11-14 2013-08-21 Viacyte Inc Encapsulation de cellules pancréatiques dérivées de cellules souches pluripotentes humaines
JP2014159477A (ja) * 2008-11-14 2014-09-04 Viacyte Inc ヒト多能性幹細胞由来膵臓細胞のカプセル化
CN105349517A (zh) * 2008-11-14 2016-02-24 维赛特公司 源于人多能干细胞的胰腺细胞的包封
US9913930B2 (en) 2008-11-14 2018-03-13 Viacyte, Inc. Encapsulation of pancreatic cells derived from human pluripotent stem cells
EP2356227A2 (fr) * 2008-11-14 2011-08-17 Viacyte, Inc. Encapsulation de cellules pancréatiques dérivées de cellules souches pluripotentes humaines
US11660377B2 (en) 2008-11-14 2023-05-30 Viacyte, Inc. Cryopreserved in vitro cell culture of human pancreatic progenitor cells
WO2010057039A2 (fr) 2008-11-14 2010-05-20 Cythera, Inc. Encapsulation de cellules pancréatiques dérivées de cellules souches pluripotentes humaines
US10272179B2 (en) 2008-11-14 2019-04-30 Viacyte, Inc. Encapsulation of pancreatic cells derived from human pluripotent stem cells
EP4176888A1 (fr) * 2008-11-14 2023-05-10 ViaCyte, Inc. Encapsulation de cellules pancréatiques dérivées de cellules souches pluripotentes humaines
US9526880B2 (en) 2013-03-07 2016-12-27 Viacyte, Inc. 3-dimensional large capacity cell encapsulation device assembly
US11077289B2 (en) 2013-03-07 2021-08-03 Viacyte, Inc. 3-dimensional large capacity cell encapsulation device assembly
US20180126134A1 (en) * 2016-11-08 2018-05-10 W. L. Gore & Associates, Inc. Implantable Encapsulation Devices
EP3578133A1 (fr) * 2016-11-08 2019-12-11 W.L. Gore & Associates, Inc. Dispositifs d'encapsulation implantables
EP3581149A1 (fr) * 2016-11-08 2019-12-18 W.L. Gore & Associates, Inc. Dispositifs d'encapsulation implantables
AU2017359159B2 (en) * 2016-11-08 2019-11-21 W.L. Gore & Associates, Inc. Implantable encapsulation devices
US11052230B2 (en) 2016-11-08 2021-07-06 W. L. Gore & Associates, Inc. Implantable encapsulation devices
CN110167485A (zh) * 2016-11-08 2019-08-23 W.L.戈尔及同仁股份有限公司 可植入的封装设备
CN110167485B (zh) * 2016-11-08 2022-07-08 W.L.戈尔及同仁股份有限公司 可植入的封装设备
KR102464471B1 (ko) 2016-11-08 2022-11-07 더블유.엘. 고어 앤드 어소시에이트스, 인코포레이티드 이식 가능한 캡슐화 디바이스
KR20190085522A (ko) * 2016-11-08 2019-07-18 더블유.엘. 고어 앤드 어소시에이트스, 인코포레이티드 이식 가능한 캡슐화 디바이스
WO2018089397A3 (fr) * 2016-11-08 2018-07-05 W.L. Gore & Associates, Inc. Dispositifs d'encapsulation implantables
US11938294B2 (en) 2016-11-08 2024-03-26 W. L. Gore & Associates, Inc. Implantable encapsulation devices
US11623023B2 (en) 2016-11-10 2023-04-11 Viacyte, Inc. PDX1 pancreatic endoderm cells in cell delivery devices and methods thereof

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