Bone filling complex and method for fabricating the same

• US 8,183,229 B2
• Filed: 08/27/2007
• Issued: 05/22/2012
• Est. Priority Date: 08/31/2006
• Status: Active Grant

• Current Assignee: Megagen Implant Co., Ltd., Pohang University of Science and Technology (Posco Holdings Incorporated)
• Original Assignee: Megagen Implant Co., Ltd., Pohang University of Science and Technology Dept of Advanced Materials Science & Engineering
• Inventors: Hahn, Sei Kwang, Oh, Eun Ju, Park, Jung Kyu, Park, Kwang Bum, Ryoo, Kyoung Ho, Choi, Seok Kyu, Yang, Dong Jun, An, Hyun Wook
• Primary Examiner(s): Peselev, Elli
• Application Number:
  US12/438,628
• Publication Number:
  US 20100249059A1
• Time in Patent Office: 1,730 Days
• Field of Search: 536/55.1, 536/55.2
• US Class Current: 514/54
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Provided is a bone filling complex and method of preparing the same. The bone filling complex includes a matrix including a hydrogel-type hyaluronic acid derivative; and a bone derivative filling the matrix For example, the bone filling complex can be used to regenerate an injured alveolar bone.

Claims

1. A bone filling complex comprising:

a matrix comprising a hydrogel-type hyaluronic acid derivative, wherein the hydrogel-type hyaluronic acid derivative is obtained by reacting a hyaluronic acid with a bis(sulfosuccinimmidyl)suberate or a dithiol-based crosslinker, wherein the dithiol-based derivative is a peptide which has cysteine at its opposite ends and an arginine-glycine-aspartic acid sequence interposed between the ends; and

a bone derivative, wherein the bone derivative is a calcium phosphate-based compound, filling the matrix.

2. The bone filling complex of claim 1, wherein the hydrogel-type hyaluronic acid derivative is obtained by reacting a hyaluronic acid with the bis(sulfosuccinimmidyl)suberate.

3. The bone filling complex of claim 2, wherein the suberate is bonded to a carbonyl group of the hyaluronic acid through a linker.

4. The bone filling complex of claim 3, wherein the linker comprises at least two amino groups, wherein one amino group of the amino groups is bonded to the carboxylic group of the hyaluronic acid and another amino group of the amino groups is bonded to a carbonyl group of the suberate.

5. The bone filling complex of claim 4, wherein the matrix comprises at least one unit represented by Formula 1:

6. The bone filling complex of claim 5, wherein each of R₁ and R₂ is hydrogen atom and R₃ is —

NHCO—

(CH₂)y-CONH—

.

7. The bone filling complex of claim 1, wherein the hydrogel-type hyaluronic acid derivative is obtained by reacting a hyaluronic acid to which a methacrylic anhydride is introduced with a dithiol-based crosslinker, wherein the dithiol-based crosslinker is a peptide which has cysteine at its opposite ends and an arginine-glycine-aspartic acid sequence interposed between the ends.

8. The bone filling complex of claim 7, wherein the methacrylic anhydride is bonded to a carboxylic group of the hyaluronic acid through a linker.

9. The bone filling complex of claim 8, wherein the linker comprises at least two amino groups, wherein one amino group of the amino groups is bonded to the carboxylic group of the hyaluronic acid and another amino group of the amino groups is bonded to a carbonyl group of the methacrylic anhydride.

10. The bone filling complex of claim 7, wherein the matrix comprises at least one unit represented by Formula 2:

11. The bone filling complex of claim 10, wherein each of R₁ and R₂ is hydrogen atom and R₃ is —

NHCO—

(CH₂)y-CONH—

.

12. The bone filling complex of claim 1, wherein the matrix has a network structure.

13. The bone filling complex of claim 1, wherein the bone filling complex is formulated into blocks, granules, or an injectable form.

14. A method of preparing a bone filling complex, the method comprising:

forming a matrix comprising a hydrogel-type hyaluronic acid derivative, wherein the forming of a matrix comprises reacting a hyaluronic acid with a bis(sulfosuccinimmidyl)suberate or a dithiol-based crosslinker, wherein the dithiol-based crosslinker is a peptide which has cysteine at its opposite ends and an arginine-glycine-aspartic acid sequence interposed between the ends; and

filling the matrix with a bone derivative, wherein the bone derivative is a calcium phosphate-based compound.

15. The method of claim 14, wherein the forming of a matrix comprises reacting a hyaluronic acid with the bis(sulfosuccinimmidyl)suberate.

16. The method of claim 15, wherein the suberate is bonded to a carbonyl group of the hyaluronic acid through a linker.

17. The method of claim 16, wherein the linker comprises at least two amino groups, wherein one amino group of the amino groups is bonded to the carboxylic group of the hyaluronic acid and another amino group of the amino groups is bonded to a carbonyl group of the suberate.

18. The method of claim 17, wherein the matrix comprises at least one unit represented by Formula 1:

19. The method of claim 18, wherein each of R₁ and R₂ is hydrogen atom and R₃ is —

NHCO—

(CH₂)y-CONH—

.

20. The method of claim 16, wherein the linker is bonded to the carboxylic group of the hyaluronic acid in a solution comprising at least one organic solvent in an amount ranging from 0 to 60 vol %.

21. The method of claim 20, wherein the organic solvent is ethanol.

22. The method of claim 14, wherein the forming of the matrix further comprises:

introducing methacrylic anhydride to a hyaluronic acid; and

reacting the hyaluronic acid to which the methacrylic anhydride is introduced with a dithiol-based crosslinker, wherein the dithiol-based crosslinker is a peptide which has cysteine at its opposite ends and an arginine-glycine-aspartic acid sequence interposed between the ends.

23. The method of claim 22, wherein the methacrylic anhydride is bonded to a carboxylic group of the hyaluronic acid through a linker.

24. The method of claim 23, wherein the linker comprises at least two amino groups, wherein one amino group of the amino groups is bonded to the carboxylic group of the hyaluronic acid and another amino group of the amino groups is bonded to a carbonyl group of the methacrylic anhydride.

25. The method of claim 22, wherein the matrix comprises at least one unit represented by Formula 2:

26. The method of claim 25, wherein each of R₁ and R₂ is hydrogen atom and R₃ is —

NHCO—

(CH₂)y-CONH—

.

27. The method of claim 23, wherein the linker is bonded to the carboxylic group of the hyaluronic acid in a solution comprising at least one organic solvent in an amount ranging from 0 to 60 vol %.

28. The method of claim 27, wherein the organic solvent is ethanol.

29. The method of claim 14, wherein the forming of the matrix and the filling with the bone derivative are performed substantially in situ.