Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects

• US 20070202084A1
• Filed: 12/13/2006
• Published: 08/30/2007
• Est. Priority Date: 12/14/2005
• Status: Abandoned Application

• Current Assignee: Anika Therapeutics Incorporated
• Original Assignee: Anika Therapeutics Incorporated
• Inventors: Sadozai, Khalid, Sherwood, Charles, Joth, Carol
• Application Number:
  US11/638,103
• Publication Number:
  US 20070202084A1
• Time in Patent Office: Days
• US Class Current: 424/93.700
• 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 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/729 Agar; Agarose; Agaropectin
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in 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: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 2430/06 for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 27/20 Polysaccharides
• 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 27/3817 Cartilage-forming cells, e.g. pre-chondrocytes
• CPC Class Codes: A61L 27/3834 Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
• CPC Class Codes: A61L 27/3843 Connective tissue
• CPC Class Codes: A61L 27/48 with macromolecular fillers
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/56 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61M 5/178 : Syringes
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: C08L 5/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

A method for treating an osteochondral defect or a chondral defect in a subject includes implanting a composite in a site of the osteochondral or chondral defect. The composite includes a hyaluronic acid derivative; and at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor, which is impregnated in, or coupled to, the hyaluronic acid derivative. In one embodiment, carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. In another embodiment, the hyaluronic acid derivative is prepared by reacting an uncrosslinked hyaluronic acid with a biscarbodimide in the presence of a pH buffer in a range of between about 4 and about 8. The composite can be used for regenerating or stimulating regeneration of meniscal tissues in a subject in need thereof.

Claims

1. A method for treating an osteochondral defect or a chondral defect in a subject, comprising implanting a composite in a site of the osteochondral or chondral defect, the composite including:

a) a hyaluronic acid derivative, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea; and

b) at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor, which is impregnated in, or coupled to, the hyaluronic acid derivative.

2. The method of claim 1, wherein the composition includes at least one member selected from mesenchymal stem cells, fibrochondrocytes, osteochondrocytes, chondrocytes, TGFβ

supergene family members, tissue growth hormones, encoding genes thereof, and synthetic peptide analogues thereof.

3. The method of claim 2, wherein the composite includes a cartilage chondrocyte, osteochondrocyte or mesenchymal stem cell.

4. The method of claim 1, further including the step of stabilizing the composite within the site of the osteochondral or chondral defect so that the composite does not move during the regeneration or repair of the osteochondral or chondral defect.

5. The method of claim 1, wherein at least about 1% by mole of the carboxyl functionalities have been derivatized.

6. The method of claim 5, wherein at least about 25% by mole of the derivatized carboxyl functionalities are O-acyl isoureas and/or N-acylureas.

7. The method of claim 5, wherein the hyaluronic acid derivative includes at least one crosslink represented by the following structural formula:

HA′

—

U—

R₂—

U—

HA′

wherein;

each HA′

is the same or a different hyaluronic acid molecule;

each U is independently an optionally substituted O-acyl isourea or N-acyl urea; and

each R₂ is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms.

8. The method of claim 1, wherein the composite has interconnected pores of sizes that can provide molecular cuing for the impregnated or coupled cell to migrate through, or a path for migration of the impregnated or coupled cellular growth or differentiation factor.

9. The method of claim 1, wherein the composite further includes a biocompatible, biodegradable support, wherein the hyaluronic acid derivative is at the support.

10. The method of claim 9, wherein the support includes at least one member selected from the group consisting of crosslinked alginates, gelatin, collagen, crosslinked collagen, collagen derivatives, crosslinked hyaluronic acid, chitosan, chitosan derivatives, cellulose and derivatives thereof, dextran derivatives, polyanionic polysaccharides and derivatives thereof, polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of a polylactic acid and a polyglycolic acid (PLGA), lactides, glycolides, polyoxanones, polyoxalates, copolymer of poly(bis(p-carboxyphenoxy)propane)anhydride (PCPP) and sebacic acid, poly(l-glutamic acid), poly(d-glutamic acid), polyacrylic acid, poly(dl-glutamic acid), poly(l-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid), polyethylene glycol, copolymers of polyamino acids with polyethylene glycol, polypeptides, polycaprolactone, poly(alkylene succinates), poly(hydroxy butyrate) (PHB), poly(butylene diglycolate), nylon-2/nylon-6-copolyamides, polydihydropyrans, polyphosphazenes, poly(ortho ester), poly(cyano acrylates), polyvinylpyrrolidone and polyvinylalcohol.

11. The method of claim 1, wherein the composition further includes a material that enhances adherence of the composite to tissue.

12. The method of claim 11, wherein the material that enhances adherence of the composite to tissue is a polymer selected from the group consisting of fibrin, collagen, crosslinked collagen, collagen derivative and a polymer that includes a peptide sequence having arginine, glycine and aspartic acid.

13. The method of claim 1, further including the step of fabricating the composite in the shape of the osteochondral or chondral defect.

14. The method of claim 1, further including the steps of:

forming the composite in a sheet or film; and

cutting, trimming and contouring the sheet or film to fill the osteochondral or chondral defect.

15. A method for regenerating or promoting regeneration of cartilage and/or bone in an osteochondral or chondral defect in a subject, comprising:

a) forming a scaffold that includes a hyaluronic acid derivative and a support, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea;

b) impregnating in, or coupling to, the scaffold at least one member of the group consisting of a cell, and a cellular growth and differentiation factor in the scaffold; and

c) implanting the scaffold that is impregnated or coupled with said at least one member of the group consisting of a cell, and a cellular growth and differentiation factor at a site of the osteochondral or chondral defect of the subject, thereby providing a mechanism for delivery of the cell, cellular growth factor or cellular differentiation factor to the site of the osteochondral or chondral defect to regenerate or promote regeneration of cartilage and bone in the osteochondral or chondral defect.

16. The method of claim 15, wherein the cell, cellular growth factor and cellular differentiation factor include at least one member selected from the group consisting of mesenchymal stem cells, fibrochondrocytes, osteochondrocytes, chondrocytes, TGFβ

supergene family members, and hormones that stimulate tissue growth.

17. The method of claim 16, wherein the scaffold include a cartilage chondrocyte, osteochondrocyte or mesenchymal stem cell.

18. The method of claim 15, further including the step of stabilizing the composite within the osteochondral or chondral defect so that the composite does not move during the regeneration or repair of the osteochondral or chondral defect.

19. The method of claim 15, wherein at least 1% by mole of the carboxyl functionalities have been derivatized.

20. The method of claim 19, wherein at least 25% by mole of the derivatized carboxyl functionalities are O-acyl isoureas and/or N-acylureas.

21. The method of claim 15, wherein the hyaluronic acid derivative includes at least one crosslink represented by the following structural formula:

HA′

—

U—

R₂—

U—

HA′

wherein;

each HA′

is the same or a different hyaluronic acid molecule;

each U is independently an optionally substituted O-acyl isourea or N-acyl urea; and

each R₂ is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms.

22. The method of claim 15, wherein the scaffold has interconnected pores of sizes that can provide molecular cuing for the impregnated or coupled cell to migrate through, or a path for migration of the impregnated or coupled cellular growth factor or cellular differentiation factor.

23. The method of claim 15, wherein the support is a biocompatible and biodegradable support.

24. The method of claim 23, wherein the support includes at least one member selected from the group consisting of crosslinked alginates, gelatin, collagen, crosslinked collagen, collagen derivatives, crosslinked hyaluronic acid, chitosan, chitosan derivatives, cellulose and derivatives thereof, dextran derivatives, polyanionic polysaccharides and derivatives thereof, polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of a polylactic acid and a polyglycolic acid (PLGA), lactides, glycolides, polyoxanones, polyoxalates, copolymer of poly(bis(p-carboxyphenoxy)propane)anhydride (PCPP) and sebacic acid, poly(l-glutamic acid), poly(d-glutamic acid), polyacrylic acid, poly(dl-glutamic acid), poly(l-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid), polyethylene glycol, copolymers of polyamino acids with polyethylene glycol, polypeptides, polycaprolactone, poly(alkylene succinates), poly(hydroxy butyrate) (PHB), poly(butylene diglycolate), nylon-2/nylon-6-copolyamides, polydihydropyrans, polyphosphazenes, poly(ortho ester), poly(cyano acrylates), polyvinylpyrrolidone and polyvinylalcohol.

25. The method of claim 15, wherein the scaffold further includes a material that enhances adherence of the composite to tissue.

26. The method of claim 25, wherein the material that enhances adherence of the composite to tissue is a polymer selected from the group consisting of fibrin, collagen, crosslinked collagen, collagen derivative and a polymer that includes a peptide sequence having arginine, glycine and aspartic acid.

27. The method of claim 15, further including the step of fabricating the scaffold in the shape of the osteochondral or chondral defect.

28. The method of claim 15, further including the steps of:

forming the scaffold in a sheet or film; and

cutting, trimming and contouring the sheet or film to fill the osteochondral or chondral defect.