Hybrid matrix implants and explants

• US 6,472,181 B1
• Filed: 05/14/1999
• Issued: 10/29/2002
• Est. Priority Date: 10/25/1995
• Status: Expired due to Fees

• Current Assignee: Shire Human Genetic Therapies, Inc. (Shire plc)
• Original Assignee: Transkaryotic Therapies Incorporated (Shire plc)
• Inventors: Mineau-Hanschke, Rochelle
• Primary Examiner(s): Nguyen, Dave T.
• Assistant Examiner(s): Nguyen, Quang
• Application Number:
  US09/312,246
• Time in Patent Office: 1,264 Days
• Field of Search: 424/93.21, 424/422, 424/423, 435/69.1, 435/70.1, 435/382, 435/455, 435/320, 435/325, 435/70.3, 935/6, 935/9, 935/10-15, 935/66, 935/70, 935/71
• US Class Current: 435/70.3
• CPC Class Codes: A61F 2310/00365 Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/428 Vitamins, e.g. tocopherol, riboflavin
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3839 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/44 having a macromolecular matrix
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: C07K 14/61 Growth hormone [GH], i.e. somatotropin

Abstract

An implantable device having a body of matrix material made up of insoluble collagen fibrils, and disposed therewithin

(a) a plurality of vertebrate cells; and

(b) a plurality of microspheres each of which consists primarily of one or more of the following materials: collagen, polystyrene, dextran, polyacrylamide, cellulose, calcium alginate, latex, polysulfone, or glass.

Claims

1. A method of producing a polypeptide in vitro, comprising:

providing a composition comprising a body of matrix material comprising insoluble collagen fibrils, there being embedded within the body of matrix material (a) a plurality of cultured vertebrate cells which express the polypeptide and (b) a plurality of microspheres;

maintaining the composition under conditions whereby the cultured vertebrate cells express and secrete the polypeptide;

contacting the composition with a liquid such that the cells secrete the polypeptide into the liquid; and

obtaining the polypeptide from the liquid.

2. The method of claim 1, wherein the cultured vertebrate cells are genetically engineered to express the polypeptide.

3. The method of claim 2, wherein the polypeptide is selected from the group consisting of enzymes, hormones, cytokines, colony stimulating factors, vaccine antigens, antibodies, clotting factors, regulatory proteins, transcription factors, receptors, and structural proteins.

4. The method of claim 2, wherein the polypeptide is an angiogenesis factor.

5. The method of claim 1, wherein the composition is anchored to a surface and is bathed by the liquid.

6. The method of claim 1, wherein the composition floats freely in the liquid.

7. The method of claim 1, wherein the cultured vertebrate cells are selected from the group consisting of adipocytes, astrocytes, cardiac muscle cells, chondrocytes, endothelial cells, epithelial cells, fibroblasts, gangliocytes, glandular cells, glial cells, hematopoietic cells, hepatocytes, keratinocytes, myoblasts, neural cells, osteoblasts, pancreatic beta cells, renal cells, smooth muscle cells, striated muscle cells, and precursors of any of the above.

8. The method of claim 1, wherein the cultured vertebrate cells are human cells.

9. The method of claim 1, wherein the cultured vertebrate cells are transfected cells containing exogenous DNA encoding a medically useful polypeptide.

10. The method of claim 9, wherein the polypeptide is selected from the group consisting of human growth hormone, Factor VIII, Factor IX, erythropoietin, and insulin.

11. The method of claim 1, wherein the cultured vertebrate cells are transfected cells containing exogenous DNA which includes a regulatory sequence that activates expression of a gene encoding a medically useful polypeptide, said gene being endogenous to said vertebrate cells both prior to and after they are transfected.

12. The method of claim 11, wherein the polypeptide is selected from the group consisting of human growth hormone, Factor VIII, Factor IX, erythropoietin, and insulin.

13. The method of claim 1, wherein the polypeptide is selected from the group consisting of alpha-1 antitrypsin, calcitonin, glucocerebrosidase, low density lipoprotein (LDL) receptor, IL-2 receptor, globin, immunoglobulin, catalytic antibodies, the interleukins, insulin-like growth factor 1 (IGF-1), parathyroid hormone (PTH), leptin, the interferons, the nerve growth factors, basic fibroblast growth factor (bFGF), acidic FGF (aFGF), epidermal growth factor (EGF), endothelial cell growth factor, platelet derived growth factor (PDGF), transforming growth factors, endothelial cell stimulating angiogenesis factor (ESAF), angiogenin, tissue plasminogen activator (t-PA), granulocyte colony stimulating factor (G-CSF), and granulocyte-macrophage colony stimulating factor (GM-CSF).

14. The method of claim 1, wherein the microspheres are beads of type I collagen.

15. The method of claim 1, wherein the matrix material additionally comprises a substance selected from the group consisting of a second type of collagen, agarose, alginate, fibronectin, laminin, hyaluronic acid, heparan sulfate, dermatan sulfate, sulfated proteoglycans, fibrin, elastin, and tenascin.

16. The method of claim 1, additionally comprising noncollagen fibers dispersed within the body of matrix material.

17. The method of claim 16, wherein the noncollagen fibers comprise a material selected from the group consisting of nylon, dacron, polytetrafluoroethylene, polyglycolic acid, polylactic/polyglycolic acid mixture, polystyrene, polyvinylchloride copolymer, cat gut, cotton, linen, polyester and silk.

18. The method of claim 1, wherein each of the plurality of microspheres consists primarily of one or more substances selected from the group consisting of collagen, polystyrene, dextran, polyacrylamide, cellulose, calcium alginate, latex, polysulfone, and glass.

19. The method of claim 1, wherein the microspheres have a diameter between approximately 0.1 and approximately 2 mm.

20. The method of claim 1, wherein the collagen in the matrix material is type I.