BONE PASTE SUBJECTED TO IRRADIATIVE AND THERMAL TREATMENT

• US 20020076429A1
• Filed: 09/16/1998
• Published: 06/20/2002
• Est. Priority Date: 01/28/1998
• Status: Abandoned Application

• Current Assignee: Regeneration Technologies Incorporated (Surgalign Holdings, Inc.)
• Original Assignee: Regeneration Technologies Incorporated (Surgalign Holdings, Inc.)
• Inventors: JAW, REBECCA, FELTON, PHILIP A., WIRONEN, JOHN F.
• Application Number:
  US09/154,400
• Publication Number:
  US 20020076429A1
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/2875 Skull or cranium A61F2/2803 and A61F2/3099 take precedence
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2310/00383 Gelatin
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/222 Gelatin
• 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 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/48 with macromolecular fillers
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

A thermally sterilized bone paste useful in the orthopedic arts, for example in the repair of non-union fractures, periodontal ridge augmentation, craniofacial surgery, implant fixation, impaction grafting, or any other procedure in which generation of new bone is deemed necessary, is provided by a composition comprising a substantially bioabsorbable osteogenic compound in a matrix of 11-19%, and preferably about 15-19% (w/w) or thermally sterilized gelatin. In various embodiments, the osteogenic compound is selected from (i) demineralized bone matrix (DBM); (ii) bioactive glass ceramic, BIOGLASS®, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, tricalcium phosphate, or like material; bone marrow extracts, vascular proliferation or regeneration growth factors, bone morphogenetic protein, TGF-β, PDGF, or mixtures thereof, natural or recombinant; and (iv) mixtures of (i)-(iii). The thermally sterilized gelatin may be a commercially available grade of gelatin which is both thermally and irradiatively sterilized.

Claims

1. An implantable bone paste composition comprising thermally sterilized gelatin as a carrier for substantially bioabsorbable osteogenic components for use in a recipient in need thereof.

2. The bone paste composition of claim 1 when implanted in non-union fractures, periodontal ridge augmentation, craniofacial surgery, arthrodesis of spinal or other joints, spinal fusion procedures, and implant fixation.

3. The composition of claim 1 wherein the gelatin is thermally cross-linkable at or slightly above the temperature of the organism into which it is to be implanted.

4. The composition of claim 3 wherein said composition gels at about 38°

C.

5. The composition of claim 3 wherein said gelatin is present at a concentration of between about 11-19% (w/w) gelatin as a fraction of the weight of the composition.

6. The composition of claim 5 wherein the osteogenic component is selected from the group consisting of:

(i) demineralized bone, preferably derived from the species into which the thermally sterilized bone paste is to be implanted;

or

(ii) bioactive glass ceramic, BIOGLASS®

, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, cortical bone chips, cancellous bone chips, tricalcium phosphate, like material, or mixtures thereof;

or

(iii) bone morphogenetic protein, osteogenic proteins or peptides and the like, TGF-beta, bone marrow extracts, vascular proliferation or regeneration growth factors, PDGF, or mixtures thereof, natural or recombinant;

or

(iv) mixtures of (i)-(iii).

7. The composition of claim 6 wherein the gelatin, the demineralized bone matrix, or both are derived from the species into which the bone paste is to be implanted.

8. The composition of claim 7 wherein DBM is present at between about 1-40% (w/w) of the total composite weight.

9. The composition of claim 8 wherein DBM is present at between about 15-33% (w/w) of the total composite weight.

10. The composition of claim 6 wherein the bioactive glass is BIOGLASS®

.

11. The composition of claim 6 wherein component (ii) is present at between about 0-60% (w/w) of the total composition mass.

12. The composition of claim 6 comprising antibiotics, bone morphogenetic or other proteins, whether derived from natural or recombinant sources, wetting agents, glycerol, carboxymethyl cellulose (CMC), growth factors, steroids, non-steroidal anti-inflammatory compounds, or combinations thereof.

13. The composition of claim 6 comprising between about 0.0001 to 10 mg/ml bone morphogenetic protein, natural or recombinant.

14. The composition of claim 1 which is a frozen solution or is freeze-dried.

15. The composition of claim 1 wherein the gelatin is human, bovine, porcine, ovine, fish, equine, feline, canine or mixtures thereof.

16. The composition of claim 1 wherein the gelatin is derived from human collagen sources via enzymatic, acid or alkaline extraction.

17. The composition of claim 16 wherein said human collagen sources are human skin, bone, cartilage, tendon, connective tissue, or mixtures thereof.

18. The composition of claim 17 produced by:

(a) treating the collagen source with pepsin at about 30°

C., separating a soluble supernatant from an insoluble residue, and retaining the soluble supernatant;

(b) treating the insoluble residue with pepsin at about 330°

C., separating a soluble supernatant from an insoluble residue, and retaining the soluble supernatant;

(c) pooling the thus obtained soluble supernatants;

(d) heat denaturing the pooled supernatants under controlled conditions to produce gelatin;

(e) removing the moisture from the gelatin to produce dry gelatin;

(f) thermally sterilizing the dry gelatin; and

(g) mixing a known mass of the dry gelatin with a known mass of osteogenic compound such that the dry gelatin is present at a final concentration of about 11-19% (w/w).

19. The composition of claim 18 wherein the denaturation is achieved by heating to at least 60°

C.

20. The composition of claim 19 wherein the gelatin has a molecular weight of greater than about 50,000 daltons.

21. The composition of claim 20 wherein the step of thermally sterilizing the dry gelatin occurs at between about 121°

C. to 130°

C. for between about five minutes and 18 hours.

22. The composition of claim 1 wherein the osteogenic component is demineralized bone matrix in a powdered form, and is composed of particles in the size range between about 80-850 μ

m in diameter.

23. The composition of claim 22 comprising about 1-40% (w/w) demineralized bone matrix powder, provided that if the demineralized bone matrix powder is absent, then a bone growth factor is present at a concentration of at least 0.0001 mg/ml.

24. The composition of claim 23 wherein said bone growth factor is morphogenetic protein, TGF-β

, osteoinductive factors, osteoconductive factors, or mixtures thereof, natural or recombinant.

25. The composition of claim 6 wherein the bioactive glass is BIOGLASS®

having a diameter of between about 0.5-710 μ

m.

26. The composition of claim 1 further comprising cortical, cancellous or cortical and cancellous bone chips.

27. The composition of claim 26 wherein said bone chips are in the size range of 80 μ

m to 10 mm.

28. The composition of claim 1 which is injection molded, vacuum molded, rotation molded, blow molded, extruded or otherwise formed into a solid form.

29. The composition of claim 28 wherein said form is selected from vertebral disks, acetabular hemispheres, tubes, ellipsoid, oblong, and “

U”

shapes for void filling, intramedullary plug formation, and impaction grafting.

39. The bone paste composition of claim 1 wherein said gelatin is sterilized by exposure to a sterilizing dose of gamma irradiation.

47. The composition according to claim 1 wherein said composition does not dissolve within 5 minutes when placed in distilled water at 38±

0.5 degrees centigrade.

30. A method for inducing bone formation in vivo in a recipient in need thereof which comprises implanting an effective amount of an implantable bone paste composition comprising thermally sterilized gelatin as a carrier for substantially bioabsorbable osteogenic components.

31. The method claim 30 which comprises repairing non-union fractures, achieving periodontal ridge augmentation, conducting craniofacial surgery, securing implants, arthrodesis of spinal or other joints, spinal fusion procedures, or impaction grafting, which comprises implanting said composition at the site in vivo in need of such treatment.

32. The method according to claim 31 which comprises extruding said composition from a syringe at a first temperature at which it remains liquid or highly malleable, and forming a resilient, sticky and easily formable shape from said composition as it gels at a second temperature at or slightly above the body temperature of the organism into which it is implanted.

33. A method for making an implantable graft which comprises preparing thermally sterilized composition comprising a thermally cross-linkable gelatin carrier and suspending therein a substantially bioabsorbable osteogenic component.

34. The method of claim 33 wherein said osteogenic component is selected from:

(i) demineralized bone, preferably derived from the species into which the thermally sterilized bone paste is to be implanted;

or

(ii) bioactive glass ceramic, BIOGLASS®

, bioactive ceramic, calcium phosphate ceramic, hydroxyapatite, hydroxyapatite carbonate, corraline hydroxyapatite, calcined bone, cortical bone chips, cancellous bone chips, tricalcium phosphate, like material, or mixtures thereof;

or

(iii) bone morphogenetic protein, osteogenic proteins or peptides and the like, TGF-beta, bone marrow extracts, vascular proliferation or regeneration growth factors, PDGF, or mixtures thereof, natural or recombinant;

or

(iv) mixtures of (i)-(iii).

35. The method of claim 34 which further comprises injection molding, vacuum molding, rotation molding, blow molding, extruding or otherwise forming said composition into the desired form of a solid graft, and allowing the composition to solidify at a temperature at which the gelatin becomes thermally cross-linked.

36. The method of claim 35 wherein said form is selected from vertebral disks, acetabular hemispheres, tubes, ellipsoid, oblong, and “

U”

shapes for void filling, intramedullary plug formation, and impaction grafting.

37. The method of claim 35 which comprises raising the temperature of the composition above its liquefaction temperature and allowing the composition to gel in a mold of appropriate shape.

38. The method of claim 33 wherein the composition is thermally sterilized by treatment of the dry gelatin at between about 121°

C. to 130°

C. for between about 5 minutes to about 18 hours, prior to suspending therein a substantially bioabsorbable osteogenic component.

40. The composition according to claim 39 comprising, on a volume basis, 60-75% of component (a), and between 0-100% on a volume basis, of component (b), which, if present, because of the substantial void volume thereof, completely absorbs any volume contribution of component (a), wherein component (a) comprises:

about 11-30% (w/w) gelatin, 24-33% (w/w) demineralized bone matrix, with the balance being made of water or an aqueous solution;

and wherein component (b) comprises aseptic corticocancellous bone chips.

41. The composition according to claim 40 wherein component (a) comprises between about 15-19% gelatin.

42. The method according to claim 33 comprising exposing said gelatin to a sterilizing dose of gamma irradiation.

43. The method according to claim 42 wherein said gelatin is thermally sterilized by autoclaving the gelatin.

44. The method according to claim 43 wherein said gelatin is a commercially available grade of porcine gelatin.

45. The method according to claim 44 wherein said gelatin has a bloom number of between about 250 and 300.

46. The composition according to claim I having a melt-flow-index (MFI) from a one cubic-centimeter BD slip-tip syringe of greater than about 0.00719 g/sec, or greater than about 0.03497 g/sec from a five cubic centimeter BD slip-tip syringe at 47±

2 degrees centigrade when 2644±

1 gram of weight is applied to a plunger of a syringe containing said composition.