Cartilage growth from cell seeded ceramic compositions

• US 6,277,151 B1
• Filed: 02/13/1998
• Issued: 08/21/2001
• Est. Priority Date: 05/19/1995
• Status: Expired due to Term

• Current Assignee: Life Science Enterprises , INC.
• Original Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Inventors: Rey, Christian, Aiolova, Maria, Lee, Dosuk D.
• Primary Examiner(s): Isabella, David J
• Application Number:
  US09/023,848
• Time in Patent Office: 1,285 Days
• Field of Search: 623/11, 623/12, 623/66, 623/16, 424/549, 424/423, 424/426, 530/838, 530/840, 523/115, 423/305, 423/308, 423/311, 128/898
• US Class Current: 623/23.61
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30762 Means for culturing cartilage
• CPC Class Codes: A61F 2002/4648 Means for culturing bone graft
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• 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 2300/64 Animal cells
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/3821 Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells
• CPC Class Codes: A61L 27/3847 Bones
• CPC Class Codes: A61L 27/3852 Cartilage, e.g. meniscus
• CPC Class Codes: A61L 27/425 of phosphorus containing material, e.g. apatite
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 : Materials at least partially resorbable by the body
• CPC Class Codes: C01B 25/16 : Oxyacids of phosphorus; Salts thereof peroxyacids or salts thereof C01B15/00
• CPC Class Codes: C01B 25/32 : Phosphates of magnesium, calcium, strontium, or barium
• CPC Class Codes: C01B 25/321 : Methods for converting an alkaline earth metal ortho-phosphate into another ortho-phosphate by reaction, e.g. of phosphate rock with phosphoric acid C01B25/322
• CPC Class Codes: C01B 25/325 : Preparation by double decomposition
• CPC Class Codes: C04B 2111/00836 : for medical or dental applications
• CPC Class Codes: C04B 28/344 : the phosphate binder being present in the starting composition solely as one or more phosphates
• CPC Class Codes: Y10S 623/919 : Bone

Abstract

The present invention provides a synthetic, poorly-crystalline apatitic (PCA) calcium phosphate material seeded with cells. Preferably, the cells are tissue-forming or tissue-degrading cells. The compositions provided by the present invention are useful for a variety of applications, including in vivo and in vitro tissue growth (preferably bone or cartilage), osseous augmentation, and methods of diagnosing disease states by assaying tissue-forming potential of cells isolated from a host. The invention also provides in vitro cell culture systems and cell encapsulation matrices.

Claims

1. A method of growing cartilage in vivo comprising:

a. providing a hydrated precursor comprising;

i. at least one amorphous calcium phosphate (ACP);

ii. at least one cartilage-forming cell or precursor thereof; and

iii. a sufficient amount of aqueous solution so that the hydrated precursor has a consistency selected from the group consisting of a paste consistency and a putty consistency, the aqueous solution being compatible with the at least one cartilage-forming cell or precursor thereof;

b. introducing the hydrated precursor into a site in vivo; and

c. after step a, allowing the hydrated precursor to harden.

3. The method of claim 1, wherein the hydrated precursor further comprises a biologically active agent that attracts cartilage-forming cells or precursors thereof so that, after implantation, cartilage-forming cells or precursors thereof migrate into the implanted material.

4. The method of claim 1, wherein the hydrated precursor is characterized by a tendency to harden at 22°

C. after a time longer than one hour.

5. The method of claim 1, wherein the hydrated precursor is characterized by a tendency to harden at 37°

C. after a time shorter than one hour.

6. The method of claim 1, further comprising the step of promoting the conversion of the hydrated precursor into a hardened poorly crystalline apatitic calcium phosphate.

7. The method of claim 1, wherein the hydrated precursor further comprises a therapeutic agent.

8. The method of claim 1, wherein the hydrated precursor further comprises a second calcium phosphate.

9. The method of claim 1, wherein the amorphous calcium phosphate has a Ca/P ratio between 1.1-1.9.

10. The method of claim 8, wherein the second calcium phosphate is selected from the group consisting of calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium decaphosphate, tricalcium phosphates, calcium pyrophosphate dihydrate, poorly crystalline apatitic calcium phosphate, calcium pyrophosphate, octacalcium phosphate, tetracalcium phosphate, and amorphous calcium phosphate.

11. The method of claim 8, wherein the second calcium phosphate is dicalcium phosphate dihydrate.

12. The method of claim 8, wherein the second calcium phosphate is calcium deficient hydroxyapatite.

13. The method of claim 6, wherein the step of promoting conversion involves exposing the hydrated precursor to appropriate conditions for a time sufficient that a poorly crystalline apatitic calcium phosphate characterized by a calcium to phosphate ratio of less than about 1.5 is produced.

14. The method of claim 1, further comprising the step of shaping the hydrated precursor into a predetermined form prior to hardening.

15. The method of claim 8, wherein the hydrated precursor further comprises a supplementary material selected to change a physical parameter of the paste or the hardened product, said parameter selected from the group consisting of strength, resorption time, adherence, injectability, frictional characteristics, release kinetics, tensile strength, hardness, fracture toughness, elasticity, imaging capability, flow properties and setting times.

16. The method of claim 1, wherein said cartilage-forming cell is introduced into said hydrated precursor by allowing said cell to enter the hydrated precursor.

2. A method of growing cartilage in vivo comprising:

a. providing a hydrated precursor comprising;

i. at least one amorphous calcium phosphate (ACP); and

ii. a sufficient amount of aqueous solution so that the hydrated precursor has a consistency selected from the group consisting of a paste consistency and a putty consistency;

b. introducing the hydrated precursor into a site in vivo;

c. promoting conversion of the ACP into a poorly crystalline apatitic (PCA) calcium phosphate after the step of introducing; and

d. allowing cartilage-forming cells or precursors thereof to enter the implanted material.

17. The method of claim 2, wherein the hydrated precursor further comprises a biologically active agent that attracts cartilage-forming cells or precursors thereof so that, after implantation, cartilage-forming cells or precursors thereof migrate into the implanted material.

18. The method of claim 2, wherein the hydrated precursor is characterized by a tendency to harden at 22°

C. after a time longer than one hour.

19. The method of claim 2, wherein the hydrated precursor is characterized by a tendency to harden at 37°

C. after a time shorter than one hour.

20. The method of claim 2, wherein the hydrated precursor further comprises a therapeutic agent.

21. The method of claim 2, wherein the hydrated precursor further comprises a second calcium phosphate.

22. The method of claim 2, wherein the amorphous calcium phosphate has a Ca/P ratio between 1.1-1.9.

23. The method of claim 21, wherein the second calcium phosphate is selected from the group consisting of calcium metaphosphate, dicalcium phosphate, dihydrate, heptacalcium decaphosphate, tricalcium phosphates, calcium pyrophosphate, octacalcium phosphate, tetracalcium phosphate, and amorphous calcium phosphate.

24. The method of claim 21, wherein the second calcium phosphate is dicalcium phosphate dihydrate.

25. The method of claim 21, wherein the second calcium phosphate is calcium deficient hydroxyapatite.

26. The method of claim 2, further comprising the step of shaping the hydrated precursor into a predetermined form prior to hardening.

27. The method of claim 21, wherein the hydrated precursor further comprises a supplementary material selected to change a physical parameter of the paste or the hardened product, said parameter selected from the group consisting of strength, resorption time, adherence, injectability, frictional characteristics, release kinetics, tensile strength, hardness, fracture toughness, elasticity, imaging capability, flow properties and setting times.