In vivo delivery of neurotransmitters by implanted, encapsulated cells

• US RE35,653 E
• Filed: 06/30/1993
• Issued: 11/04/1997
• Est. Priority Date: 11/17/1987
• Status: Expired due to Term

• Current Assignee: Neurotech S.A. (LivaNova Plc)
• Original Assignee: Brown University
• Inventors: Aebischer, Patrick, Winn, Shelley R., Galletti, Pierre M.
• Primary Examiner(s): Alexander, Vanitha
• Application Number:
  US08/085,504
• Time in Patent Office: 1,588 Days
• Field of Search: 604/890.1, 604/891.1, 604/27, 604/28, 604/36, 604/43, 604/93, 604/116, 623/11, 623/12, 424/422-424, 128/897-899
• US Class Current: 604/891.1
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61K 35/22 Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
• CPC Class Codes: A61K 35/30 Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
• 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
• CPC Class Codes: A61K 9/0085 Brain, e.g. brain implants; Spinal cord
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61M 2210/0687 Skull, cranium
• CPC Class Codes: A61M 2210/0693 Brain, cerebrum
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50
• CPC Class Codes: C12N 11/04 entrapped within the carrier, e.g. gel or hollow fibres
• CPC Class Codes: C12N 2533/30 Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 5/0012 Cell encapsulation
• CPC Class Codes: C12N 5/0614 Adrenal gland
• CPC Class Codes: C12N 5/0619 Neurons

Abstract

Methods and devices are disclosed for the delivery of a neurotransmitter from an implanted, neurotransmitter-secreting cell culture to a target region in a subject. The cell culture is maintained within a biocompatible, semipermeable membrane which permits the diffusion of the neurotransmitter therethrough while excluding viruses, antibodies, and other detrimental agents present in the external environment from gaining access. Implantable cell culture devices are disclosed, some of which may be retrieved from the subject, replaced or recharged with new, neurotransmitter-secreting cell cultures, and reimplanted.

Claims

1. A method of delivering a neurotransmitter to a subject afflicted with a neurotransmitter deficiency comprising the steps of:

encapsulating at least one neurotransmitter-secreting cell within a semipermeable membrane, said membrane allowing the diffusion of the neurotransmitter therethrough while excluding viruses, antibodies and other detrimental agents present in the external environment; and

implanting said encapsulated cell into a target region within a subject'"'"'s brain, such that the encapsulated cell secretes the neurotransmitter and thereby provide constitutive delivery of the neurotransmitter to the target region to treat the deficiency.

2. The method of claim 1 wherein said encapsulating step further comprises disposing said neurotransmitter-secreting cell within said semipermeable membrane, said membrane allowing the diffusion of solutes having a molecular weight of up to about 50,000 daltons therethrough.

3. The method of claim 1 wherein said encapsulating step further comprises disposing said neurotransmitter-secreting cell within, said semipermeable membrane, said membrane being composed of a material selected from the group consisting of acrylic copolymers, polyvinylidene fluoride, polyurethane isocyanates, polyalginate, cellulose acetate, polysulfone, polyvinyl alcohols, polyacrylonitrile, and derivatives and mixtures thereof.

4. The method of claim 1 wherein said implanting step is reversible, said semipermeable membrane being attached to a retrievable, nonresorpable, and biocompatible guide wire which enables removal of said device from said subject.

5. The method of claim 4 wherein said encapsulating step further comprises disposing said neurotransmitter-secreting cell within said membrane in a retrievable fashion, said membrane having a tubular shape with a first end and a second end, said ends each having a cap element removably attached thereto to enable extraction of said cells therein.

6. The method of claim 1 wherein said encapsulating step further comprises disposing within said membrane a neurotransmitter-secreting cell, said neurotransmitter being dopamine, and said neurotransmitter-secreting cell being selected from the group consisting of adrenal medulla tissue, ventral mesencephalic embryonic tissue, and neuroblastoid tissue.

7. The method of claim 1 wherein said encapsulating step further comprises disposing within said membrane a cell which secretes one of the group consisting of a precursor, analog, agonist, derivative, and fragment of a neurotransmitter which has neurotransmitter activity.

8. The method of claim 7 wherein said neurotransmitter is dopamine, and said precursor is L-dopa.

9. The method of claim 7 wherein said neurotransmitter is dopamine, and said analog is bromocriptine.

10. The method of claim 1 wherein said encapsulating step further comprises disposing within said membrane a neurotransmitter-secreting cell, said cell being a tissue allograft.

11. The method of claim 1 wherein said encapsulating step further comprises disposing within said membrane a neurotransmitter-secreting cell, said cell being a tissue xenograft.

12. The method of claim 1 wherein said implanting step further comprises implanting said encapsulated, neurotransmitter-secreting cell in said target region of said subject, said target region being the brain.

13. A cell culture device for implantation within a subject for the constitutive delivery of a neurotransmitter to a target area of said subject, said device comprising:

a semipermeable membrane permitting the diffusion of the neurotransmitter therethrough, while excluding viruses, antibodies, and other detrimental agents present in the external environment; and

at least one neurotransmitter-secreting cell disposed within the membrane, said cell being capable of secreting neurotransmitter without direct neuronal contact with said target area.

14. The device of claim . .14.!. .Iadd.13 .Iaddend.wherein said semipermeable membrane is permeable to solutes having a molecular weight of up to about 50,000 daltons.

15. The device of claim . .14.!. .Iadd.13 .Iaddend.wherein said semipermeable membrane comprises a material selected from the group consisting of acrylic copolymers, polyvinylidene fluoride, polyurethane isocyanates, polyalginate, cellulose acetate, polysulfone, polyvinyl alcohols, polyacrylonitrile, and derivatives and mixtures thereof.

16. The device of claim . .14.!. .Iadd.13 .Iaddend.wherein said neurotransmitter-producing cell further comprises a tissue allograft.

17. The device of claim . .14.!. .Iadd.13 .Iaddend.wherein said neurotransmitter-producing cell further comprises a tissue xenograft.

18. The device of claim . .14.!. .Iadd.13.Iaddend. wherein said neurotransmitter is dopamine, and said neurotransmitter-secreting cell is selected from the group consisting of adrenal medulla tissue, ventral mesencephalic embryonic tissue, and neuroblastoid tissue.

19. The device of claim . .14.!. .Iadd.13 .Iaddend.wherein said neurotransmitter is selected from the group consisting of agonists, precursors, analogs, derivatives, and fragments of a neurotransmitter which have neurotransmitter activity.

20. The device of claim 19 wherein said neurotransmitter precursor is L-dopa.

21. The device of claim 19 wherein said neurotransmitter analog is bromocriptine.

22. The device of claim . .14.!. .Iadd.13 .Iaddend.further comprising a retrievable, nonresorpable, and biocompatible guide wire attached to said semipermeable membrane, so as to enable the removal of said device from said subject.

23. The device of claim . .14.!. .Iadd.13 .Iaddend.wherein said semipermeable membrane is tubular, having at least one end with a cap element reversibly attached thereto.

24. The device of claim 22 wherein said neurotransmitter-secreting cell is disposed within said semipermeable membrane in a removable fashion, said membrane being tubular, having at least one end with a cap element reversibly attached thereto, so as to enable extraction of said cells therein.