Osteogenic devices

• US 5,108,753 A
• Filed: 09/07/1990
• Issued: 04/28/1992
• Est. Priority Date: 04/08/1988
• Status: Expired due to Term

• Current Assignee: Stryker Corporation
• Original Assignee: Creative Biomolecules
• Inventors: Rueger, David C., Kuberasampath, Thangavel
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/579,865
• Time in Patent Office: 599 Days
• Field of Search: 424/422, 424/423, 424/424, 424/426, 514/2, 514/21, 530/350, 530/840, 530/327, 530/326
• US Class Current: 424/422
• CPC Class Codes: A61C 8/0006 Periodontal tissue or bone regeneration support means for endoprosthetic bone substitute or bone graft implants A61F2/2846
• 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: 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: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/3608 Bone, e.g. demineralised bone matrix [DBM], bone powder
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: C07K 14/51 Bone morphogenetic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: Y10S 530/84 Bones; tendons; teeth; cartilage
• CPC Class Codes: Y10S 623/908 Bone

Abstract

Disclosed are osteogenic devices comprising a matrix containing substantially pure mammalian osteogenic protein and methods of inducing endochondral bone growth in mammals. A partial amino acid sequence, amino acid composition, solubility properties, and various other data characterizing osteogenic protein are also disclosed, as well as a nucleic acid sequences encoding a consensus osteogenic protein.

Claims

1. An osteogenic device for implantation in a mammal, said device comprising:

a biocompatible, porous, insoluble particulate matrix defining pores of a dimension sufficient to permit influx, differentiation, a proliferation of migratory progenitor cells from the body of said mammal; and

substantially pure osteogenic protein disposed on the surface of said matrix, said protein comprising a pair of polypeptide chains disulfide bonded to produce a dimeric species having a conformation such that said pair of polypeptide chains is capable of inducing endochondral bone formation in said mammal when disposed in said matrix and accessible to said cells.

2. The device of claim 1 wherein said matrix comprises close-packed particulate matter having a particle size within the range of 70-850 μ

m.

3. The device of claim 2 wherein said particulate matter has a particle size within the range of 70-420 μ

m.

4. The device of claim 1 wherein said matrix comprises demineralized, protein extracted, particulate bone.

5. The device of claim 1 wherein said matrix comprises a material selected from the group consisting of collagen, hydroxyapatite, tricalcium phosphate, polymers comprising lactic acid monomer units, polymers comprising glycolic acid monomer units, demineralized, guanidine-extracted allogenic bone, and mixtures thereof.

6. The device of claim 1 wherein said matrix is shaped to span a non-union fracture in said mammal.

7. The device of claim 1 disposed within the marrow cavity of allogeneic bone.

8. The device of claim 1 wherein said osteogenic protein has a molecular weight of about 30 kD when oxidized as determined by comparison to molecular weight standards in SDS-polyacrylamide gel electrophoresis.

9. The device of claim 1 wherein said osteogenic protein is glycosylated.

10. The device of claim 1 wherein one of said pair of polypeptide chains has a molecular weight of about 16 kD and the other has a molecular weight of about 18 kD, both as determined after reduction by comparison to molecular weight standards in SDS-polyacrylamide gel electrophoresis.

11. The device of claim 1 wherein said osteogenic protein comprises the following amino acid sequence:

space="preserve" listing-type="equation">D-F-D-A-Y-Y-C-S-G-A-C-Q-F-P-S.

12. The device of claim 1 wherein said osteogenic protein comprises the following amino acid sequence:

space="preserve" listing-type="equation">S-L-K-P-S-N-Y-A-T-I-Q-S-I-V.

13. The device of claim 1 wherein said osteogenic protein comprises the following amino acid sequence:

space="preserve" listing-type="equation">E-L-S-A-I-S-M-L-Y-L-D-E-N.

14. The device of claim 1 wherein said osteogenic protein comprises the following amino acid sequence:

space="preserve" listing-type="equation">M-S-S-L-S-I-L-F-F-D-E-N.

15. The method of inducing local cartilage and bone formation in a mammal comprising the step of implanting the device of claim 1 in said mammal at a locus accessible to migratory progenitor cells of said mammal.

16. A method of inducing endochondral bone formation in a mammal comprising the step of implanting the device of claim 1 in said mammal at a locus accessible to migratory progenitor cells of said mammal.

17. A method of inducing endochondral bone formation in a non union fracture in a mammal comprising the step of implanting in the fracture in said mammal the device of claim 6.

18. The device of claim 1 wherein said osteogenic protein has a half maximum activity of at least about 25 to 50 ng per 25 mg of said matrix.

19. The osteogenic device of claim 1 for use in periodontal or dental reconstructive procedures.

20. The method of claim 16 comprising the step of implanting the device of claim 1 in said mammal at a locus accessible to migratory progenitor cells of said mammal wherein said locus in a mammalian jaw bone for use in periodontal or dental reconstructive procedures.

21. The method of claims 15 or 16 for use in craniofacial reconstructive procedures.