Method and apparatus for sealing implantable membrane encapsulation devices

• US 6,123,700 A
• Filed: 01/30/1998
• Issued: 09/26/2000
• Est. Priority Date: 06/23/1993
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Rein, David H., Cain, Brian M., Mills, John F., Dionne, Keith E., Warner, Nicholas F., Doherty, Edward J., Hazlett, Tyrone F.
• Primary Examiner(s): Coggins, Wynn Wood
• Assistant Examiner(s): NGUYEN, ANH TUAN TUONG
• Application Number:
  US09/016,223
• Time in Patent Office: 970 Days
• Field of Search: 604/890.1, 604/891.1, 604/93, 604/175, 604/185, 604/501, 604/502, 600/579, 424/422, 424/424
• US Class Current: 604/890.1
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L

Abstract

A sealed, implantable, encapsulation device (20) for diffusing a biologically active product or function to an individual which includes a substantially non-porous fitting (32) including an inner surface (33) defining an access port (34). A permselective, porous, membrane (21), having an interior surface (22), cooperates with the fitting inner surface (33) to form a storage cavity (23) therebetween. The membrane interior surface (22) is in substantially cell-tight dry sealing engagement with fitting (32) to seal cavity (23). Living cells (24) are disposed in the cavity (23) which are capable of secreting the biologically active product to an individual. The membrane (21) is of a material capable of permitting the passage of substances between the individual and cells required to provide the biological product or function. A plug member (35) is positioned in the access port (34) and seated in cell-tight sealing engagement with the fitting inner surface (33). A method for sealing the implantable encapsulation device (20) is also provided.

Claims

1. A sealed, implantable, hollow membrane encapsulation device for providing a biologically active product or function to an individual, said encapsulation device comprising:

(a) a permselective, hollow, porous membrane shaped so as to form a cell-impervious encapsulating enclosure including;

(1) an exterior surface,

(2) an interior surface, said interior surface defining a storage cavity, and

(3) at least one opening, said at least one opening providing open communication between said storage cavity and the exterior of said enclosure;

(b) a non-permeable fitting disposed within or about said at least one opening so as to make substantially cell-tight dry sealing engagement between said fitting and said enclosure, said fitting

(1) comprising a thermoplastic tubular fitting member including an inwardly facing surface defining an open bore extending therethrough and

(2) dimensioned so as to permit introduction of living cells into said storage cavity;

(c) living cells disposed in said cavity capable of secreting a biologically active product or of providing a selected biological function to an individual, said membrane permitting passage therethrough of substances secreted by said cells; and

(d) a non-permeable, non-porous cell-tight plug at a distal end of said thermoplastic tubular fitting member, wherein said plug is formed by pinching and fusing the sides of said thermoplastic tubular fitting member together at a distal end of said member to form a cell-tight seal of said open bore.

2. The encapsulation device as defined in claim 1, wherein said tubular fitting member is composed of polyurethane.

3. The encapsulation device as defined in claim 1, wherein said plug further includes an adhesive disposed over said fused distal end of said thermoplastic tubular fitting member.

4. The encapsulation device as defined in claim 1, wherein said open bore is inwardly tapered, and said plug is alternately formed by inserting a separate plug member that is conical-shaped and formed for mating engagement with said inwardly-tapered open bore.

5. The encapsulation device as defined in claim 1, wherein said plug is alternately formed by inserting a separate plug member that has external screw threads mating with corresponding screw threads on the open bore of said thermoplastic tubular fitting member in a manner forming said cell-tight seal of said open bore.

6. The encapsulation device as defined in claim 5, wherein said plug further includes an adhesive disposed over said screw-threaded plug member, to form a cell-tight seal with said fitting.

7. The encapsulation device as defined in claim 1, wherein said plug is alternately formed by inserting a separate plug member formed of a polymeric elasticity memory material characterized by:

(a) a first transverse cross-sectional area smaller than the fitting open bore transverse cross-sectional area at a first temperature and

(b) a second transverse cross-sectional area larger than the fitting open bore transverse cross-sectional area at a second temperature, said second temperature being the body temperature of an individual,

whereby said plug member is force-fit in said open bore to provide said cell-tight seal.

8. A sealed, implantable, hollow membrane encapsulation device for providing a biologically active product or function to an individual, said encapsulation device comprising:

(a) a permselective hollow, porous, membrane shaped so as to form a cell-impervious encapsulating enclosure including;

(1) an exterior surface,

(2) an interior surface, said interior surface defining a storage cavity, and

(3) first and second openings, said first and second openings providing open communication between said storage cavity and the exterior of said enclosure;

(b) living cells disposed in said cavity capable of secreting a biologically active product or of providing a selected biological function to an individual, said membrane permitting passage therethrough of substances secreted by said cells; and

(c) first and second sealing means at said first and second openings of said membrane, said second sealing means comprising a substantially non-porous plug member of a larger transverse cross-sectional area than a transverse cross-sectional area defined by said membrane interior surface proximate said second opening, such that force-fit disposition of said plug member within said second opening prior to introduction of said living cells in said storage cavity results in a cell-tight dry seal with the membrane interior surface, closing said second opening; and

(d) an intermediate layer between said plug member and membrane interior surface proximate said second opening, said interior surface, plug member, and adhesive layer forming a cell-tight dry seal;

wherein said plug member includes an open bore extending through said plug member into said storage cavity, wherein said second sealing means further comprises a hollow tube disposed within said open bore and projecting distally therefrom, wherein a cell-tight dry seal is formed between said open bore and said hollow tube, and wherein said encapsulation device further comprises a third sealing means disposed in a distal region of said hollow tube and forming a cell-tight seal therewith.

9. The encapsulation device as defined in claim 8, wherein said plug member comprises a polymeric elasticity memory material and is characterized by:

(a) a first transverse cross-sectional area at a first temperature that is smaller than a transverse cross-sectional area defined by said membrane interior surface proximate said second opening, and

(b) a second transverse cross-sectional area at a second temperature that is larger than said membrane interior surface cross-sectional area, said second temperature being the body temperature of an individual, whereby disposition of said plug member within said second opening results in a friction-fit cell-tight baffler closing said second opening at said body temperature.

10. A prefilling assembly for forming a sealed, implantable, hollow membrane encapsulation device comprising:

(a) a permselective hollow, porous, membrane shaped so as to form a cell-impervious encapsulating enclosure including;

(1) an exterior surface,

(2) an interior surface, said interior surface defining a storage cavity, and

(3) at least one opening, said at least one opening providing open communication between said storage cavity and the exterior of said enclosure;

(b) a non-permeable, non-porous fitting disposed within or about said at least one opening so as to make a substantially cell-tight dry seal between said fitting and said membrane, said fitting including;

(1) a frangible neck portion projecting outwardly from said at least one opening and defining a central bore extending through said neck portion into said storage cavity,

(2) a housing portion continuous with and extending outwardly from said neck portion; and

(3) a central passage in axial alignment with said central bore,

wherein said central bore and aligned central passage provide open communication through said fitting with the exterior of said encapsulating enclosure, and wherein at least said central passage is dimensioned so as to permit insertion of a filler tube for introduction of materials through the central passage and central bore into said storage cavity.

11. A prefilling assembly as defined in claim 10, wherein said fitting further includes a seal member dimensioned to fit within said central passage.

12. A prefilling assembly as defined in claim 11, wherein the distal portion of the central passage widens to provide a generally cup-shaped cavity and wherein said seal member is dimensioned to snugly fit within said cup-shaped cavity so as to be stably retained within said cup-shaped cavity.

13. A prefilling assembly as defined in claim 11, wherein said seal member has a bole therethrough that aligns with the central passage, which hole is dimensioned to snugly accommodate a filler tube, said hole having a diameter smaller than the external diameter of said filler tube.

14. A prefilling assembly as defined in claim 13, wherein said fitting further includes a cap member dimensioned to snugly fit within said cup-shaped cavity and to seat against said seal member, which cap member includes a port therethrough that aligns axially with the hole of said seal member.

15. A prefilling assembly as defined in claim 11, wherein said seal member is composed of silicone.

16. A prefilling assembly as defined in claim 10, wherein said frangible neck portion is constructed so as to permit the distal housing portion of said fitting to be broken off, thereby exposing a bonding surface that will accommodate a cell-tight seal closing the central bore of said neck portion.

17. A prefilling assembly as defined in claim 16, wherein the central bore, the central passage, the hole and the port are axially aligned so as to permit guiding passage of a filler tube comprising a hypodermic syringe needle through the length of the fitting, so that the needle extends into said storage cavity.

18. A prefilling assembly as defined in claim 17, wherein said seal member is a septum.

19. A method for forming a sealed, implantable, hollow membrane encapsulation device for providing a biologically active product or function to an individual, said method comprising the steps of:

(a) providing a permselective, porous, membrane shaped so as to form a cell-impervious encapsulating enclosure including an exterior surface, an interior surface and an opening, said interior surface defining a storage cavity and said opening providing open communication between said storage cavity and the exterior of said enclosure;

(b) contacting said opening with a non-permeable, non-porous fitting in such a manner as to form a cell-tight dry seal between said fitting and said enclosure, wherein said fitting closes said opening and wherein said fitting comprises a frangible neck portion in contact with said opening and a housing portion extending outwardly therefrom, said fitting having an access bore extending through said neck portion and a central passage extending through said housing portion, said access bore and said central passage being aligned so as to provide open communication between said storage cavity and the exterior of said enclosure, said fitting further comprising a seal member disposed within or about said central passage, said seal at least partly closing said central passage but being penetrable by a filler tube;

(c) inserting a filler tube through said seal member and at least partly through said central passage and, optionally, at least partly through said access bore;

(d) depositing in said cavity, through said filler tube, living cells capable of secreting a biologically active product or of providing a selected biological function to an individual, said membrane permitting passage therethrough of substances secreted by said cells and required to provide said biological product or function;

(e) withdrawing said filler tube;

(f) breaking off the housing portion of said fitting at the frangible neck portion, thereby exposing a bonding surface of said fitting; and

(g) contacting said bonding surface with sealing means so as to close the access bore of the neck portion and to form a cell-tight seal of said enclosure.

20. The method of claim 19, wherein said sealing means comprises a plug member disposed at least partly within said access bore.

21. The method of claim 19, wherein the access bore of the frangible neck portion is of a smaller dimension than the filler tube, such that penetration of the filler tube into said neck portion of the fitting is prevented.

22. The method of claim 19, wherein said filler tube comprises a syringe needle.

23. The method of claim 19, wherein said sealing means includes a curable adhesive material disposed about said bonding surface so as to close said access bore and form a cell-tight seal.

24. The method of claim 19, wherein said contacting step (g) is accomplished by melting at least a portion of said fitting to fill said access bore.

25. The method of claim 24 further comprising the step of forming a protective cap external to said melted fitting by depositing a layer of curable adhesive material thereon and causing it to solidify in situ.

26. The method of claim 19, wherein said sealing means comprises a screw-threaded bolt and said access bore includes corresponding screw threads for accepting said bolt.

27. The method of claim 19, wherein said fitting is molded in situ directly to the opening of said membrane.

28. The method of claim 19, wherein said contacting step (g) comprises fitting a cup-shaped end cap over said exposed bonding surface.

29. The method of claim 19, wherein said plug member is formed of a polymeric elasticity memory material and is characterized by:

(a) a first transverse cross-sectional area, at a first temperature, that is smaller than a transverse cross-sectional area of the access bore, and

(b) a second transverse cross-sectional area, at a second temperature, that is larger than the transverse cross-sectional area of the access bore, said second temperature being the body temperature of an individual.

30. The method of claim 29, wherein said first temperature is room temperature.

31. A method for manufacturing a dry sealed, implantable, hollow membrane encapsulation device containing living cells, said method comprising the steps of:

(a) providing a capsule formed from a permselective, hollow, porous, membrane, said capsule enclosing a storage cavity and having at least one opening to said storage cavity;

(b) disposing a non-porous, non-permeable fitting within or about said opening in such a manner as to form a cell-tight dry seal between said fitting and said opening, said fitting including an access bore therethrough providing open communication with said storage cavity;

(c) depositing living cells through said access bore into said storage cavity;

(d) inserting a plug member into said access bore, said plug member being formed of a polymeric elasticity memory material and characterized by a first transverse cross-sectional area, at a first temperature, that is smaller than a transverse cross-sectional area defined by said access bore, and characterized by a second transverse cross-sectional area, at a second temperature, that is larger than said transverse cross-sectional area defined by said access bore, said second temperature being the body temperature of an individual, whereby said plug member at said second temperature forms a cell-tight seal of said access bore.

32. The method of claim 31, wherein said fitting includes a hollow tube portion extending outwardly from the portion of said fitting disposed within or about said opening.

33. A method of depositing in a storage cavity of an implantable, hollow membrane encapsulation device living cells capable of providing a biologically active product or function to an individual,

(1) said encapsulation device including a permselective, porous, membrane shaped so as to form an encapsulating enclosure characterized by a storage cavity and an opening,

(2) said device further comprising a non-porous, non-permeable fitting disposed within or about said opening in such a manner as to form a cell-tight dry seal between said fitting and said membrane,

(3) said fitting having an access port extending through said fitting and providing open communication between said storage cavity and the exterior of said device, and

(4) said fitting including a frangible neck portion defining said access port and projecting outwardly from said device, and a hub assembly coupled to said frangible neck portion suitable for accepting and guiding a filler tube adjacent said access port, which hub assembly can be separated from said fitting by breaking off the hub assembly at the frangible region of said frangible neck portion,

(5) said method comprising the steps of:

(A) passing a filler tube, dimensioned to extend through said access port, into said access port to a position proximate said storage cavity;

(B) depositing said living cells from said filler tube into said cavity;

(C) withdrawing said filler tube;

(D) forming a cell-tight seal at said fitting access port by providing a plug member formed to cooperate with the access port of said fitting to form a cell-tight seal therewith.

34. The method of claim 33, wherein said fitting hub assembly is constructed to permit passage of a filler tube part way through said access port but not into said storage cavity.

35. The method of claim 34, which further comprises the step, after step (C), of breaking off said hub assembly at said frangible neck portion to expose a bonding surface, wherein the cell-tight sealing step (D) is performed on said bonding surface.

36. An implantable encapsulation device comprising:

(a) a tubular permselective hollow membrane having;

(1) an exterior surface,

(2) an interior surface, the interior surface of said tubular permselective hollow membrane generally defining a storage cavity, with living cells disposed in said cavity capable of secreting a biologically active product or of providing a selected biological function

(3) a closed end, and

(4) an open end;

(b) a fitting disposed in or about said open end so as to form a cell-tight, dry seal between said fitting and the open end of said tubular permselective hollow membrane, said tubular permselective hollow membrane and said fitting together making said storage cavity a cell-tight enclosure; and

wherein at least a portion of said fitting is of a resilient, self sealable material capable of permitting a syringe needle to penetrate therethrough to form an access port extending through said fitting, said material further being sufficiently resilient to cell-tight seal said access port upon withdrawal of said needle therefrom.