In vivo delivery of neurotransmitters by implanted, encapsulated cells

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.

We claim: 
     
       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.