In vivo delivery of active factors by co-cultured cell implants

• US 5,182,111 A
• Filed: 06/28/1991
• Issued: 01/26/1993
• Est. Priority Date: 11/17/1987
• Status: Expired due to Term

• Current Assignee: Brown University, Neurotech S.A. (LivaNova Plc)
• Original Assignee: Boston University Research Foundation
• Inventors: Aebischer, Patrick, Winn, Shelley R.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US07/722,894
• Time in Patent Office: 578 Days
• Field of Search: 424/422-424, 435/177, 435/240.1, 435/240.2, 435/240.22, 435/180, 435/182, 435/284, 604/890.1, 604/891.1, 604/93, 604/36, 623/11, 623/12, 530/399
• US Class Current: 424/424
• 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 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• 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 2230/005 Parameter used as control input for the apparatus
• 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 2533/74 Alginate
• CPC Class Codes: C12N 5/0012 Cell encapsulation
• CPC Class Codes: C12N 5/0614 Adrenal gland
• CPC Class Codes: C12N 5/0619 Neurons
• CPC Class Codes: C12N 5/0676 Pancreatic cells
• CPC Class Codes: C12P 1/00 : Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes

Abstract

Methods and devices are disclosed for the delivery of an active factor from an implanted co-culture of an active factor-secreting cell obtained from a first source and an augmentary substance-secreting cell obtained from a second source different from the first source, to a target region in a subject. The co-culture is maintained within a biocompatible, semipermeable membrane in which the augmentary substance secreted by the augmentary substance-producing cells stimulates the active factor-producing cells to secrete active factor. The semipermeable membrane permits the diffusion of the active factor therethrough while excluding detrimental agents present in the extenral environment from gaining access to the co-culture.

Claims

1. A cell culture device for implantation within a subject for the delivery of an active factor to said subject, said device comprising:

a semipermeable membrane permitting the diffusion of an active factor therethrough, while excluding agents present at the site of implantation which are detrimental to cells;

at least one specific active factor-secreting cell disposed within the membrane, said active factor-secreting cell being isolated from a first tissue or cell line; and

at least one specific augmentary substance-producing cell disposed within said membrane, said augmentary substance being a molecule which induces the active factor-producing cell to produce active factor, said augmentary substance-secreting cell being isolated from a second tissue or cell line different from said first tissue or cell line, and secreting an augmentary substance that is different from said active factor and that stimulates aid active factor-producing cell to secrete active factor.

2. The device of claim 1 wherein said semipermeable membrane is permeable to solutes having a molecular weight of up to about 150,000 daltons.

3. The device of claim 1 wherein said semipermeable membrane comprises a material selected from the group consisting of polyvinylchloride, polyvinylidene fluoride, polyurethane isocyanates, polyalginate, cellulose acetate, cellulose nitrate, polysulfone, polystyrene, polyurethane, polyvinyl alcohols, polyacrylonitrile, polyamides, polymethylmethacrylate, polyethylene oxide, and mixtures thereof.

4. The device of claim 1 wherein said active factor-producing cell or said augmentary substance-producing cell is allospecific.

5. The device of claim 1 wherein said active factor-producing cell or said augmentary substance-producing cell is xenospecific.

6. The device of claim 1 wherein said active factor-producing cell or said augmentary substance-producing cell or said augmentary substance-producing cell has been genetically engineered to produce said active factor or said augmentary substance.

7. The device of claim 1 wherein said active factor-producing cell is a cell which produces an active factor selected from the group consisting of a neurotransmitter, neuromodulator, growth factor, trophic factor, and hormone.

8. The device of claim 1 wherein said active factor is dopamine, and said active factor-secreting cell is isolated from a tissue or culture selected from the group consisting of adrenal medulla tissue, chromaffin cells, ventral mesencephalic embryonic tissue, neuroblastoid tissue, and a cell genetically engineered to produce dopamine.

9. The device of claim 1 wherein said augmentary substance-producing cell produced an augmentary substance selected from the group consisting of nerve growth factor (NGF), epidermal growth factor (EGF), brain derived neutrophic factor (BDNF), neurotrophin-3 (NT-3), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and combinations thereof.

10. The device of claim 1 further comprising a retrievable, nonresorbable, and biocompatible guide wire attached to said semipermeable membrane, so as to enable the removal of said device from said subject.

11. The device of claim 1 wherein said semipermeable membrane is tubular, having at least one end with a removable and reattachable cap element.

12. The device of claim 1 wherein said active factor-secreting cell and said augmentary substance-producing cell are disposed within said semipermeable membrane in a removable fashion, said membrane being tubular, having at least one end with a removable and reattachable cap element, so as to enable extraction of said cells therein.

13. The device of claim 1 wherein said active factor is a neurotransmitter selected from the group consisting of dopamine, norepinephrine, epinephrine, acetylcholine, enkephalins, dynorphin, substance P, gamma aminobutyric acid, glutamic acid, agonists, precursors, analogs, and fragments thereof having neurotransmitter activity.

14. The device of claim 13 wherein said neurotransmitter precursor is L-dopa.

15. The device of claim 13 wherein said neurotransmitter analog is bromocriptine.