Methods for making biomaterials for augmentation of soft and hard tissues, kits containing precursors for forming the biomaterials, and the resulting biomaterials are described herein. The biomaterials are formed from at least a first and a second precursor component. The first precursor component c
Methods for making biomaterials for augmentation of soft and hard tissues, kits containing precursors for forming the biomaterials, and the resulting biomaterials are described herein. The biomaterials are formed from at least a first and a second precursor component. The first precursor component contains at least two nucleophilic groups, and the second precursor component contains at least two electrophilic groups. The nucleophilic and electrophilic groups of the first and second precursor components form covalent linkages with each other at physiological temperatures. The precursors are selected based on the desired properties of the biomaterial. In the preferred embodiment, the first precursor is a siloxane. Optionally, the biomaterials contain additives, such as thixotropic agents, radiopaque agents, or bioactive agents. In the preferred embodiment, the biomaterials are used to augment at least one vertebra of the spine (vertebroplasty).
대표청구항▼
We claim: 1. A method for augmenting hard tissue, comprising applying to the tissue a composition comprising at least a first and a second precursor component having a functionality of at least three on each precursor component, wherein the first precursor component comprises at least m nucleophili
We claim: 1. A method for augmenting hard tissue, comprising applying to the tissue a composition comprising at least a first and a second precursor component having a functionality of at least three on each precursor component, wherein the first precursor component comprises at least m nucleophilic groups and the second precursor component comprises at least n electrophilic groups, wherein m+n is at least six, and wherein at least one of the first and second precursor components are selected from the group of monomers and oligomers, wherein the oligomers contain between two and ten monomer units, consisting of siloxane derivatives containing amino and/or thiol groups, cyclohexyl derivatives having formula where n=6, R1=H or alkyl, R2"=alkyl; and X=--SH, tetra(3-mercaptopropyl)silane, derivatives of pentaerithritol that contain at least two alkyl chains with end-standing thiol and/or amine groups; derivatives of 1,1,1-tris-(hydroxy-methyl)propane that contain at least two alkyl chains with end-standing thiol and/or amine groups; derivatives of 1,1,1 tris-(hydroxymethyl)propanol that contain at least two alkyl chains with end-standing thiol and/or amine groups, derivatives of 1,1,1 tris(hydroxymethyl)propane that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, derivatives of pentaerithritol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, and derivatives of triglycerol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, wherein the first and second precursor components crosslink at physiological temperatures over a period of time following application to form a biomaterial comprising a polymeric network having a Young's modulus E of at least 15 MPa measured at 0.35 mm/s and 10% strain 10 days after mixing the first and second precursor components and storage at 37° C. 2. The method of claim 1 wherein the hard tissue is at least one vertebra. 3. The method of claim 1 wherein the first and second precursor components are oligomers. 4. The method of claim 1, wherein the first and the second precursor components are monomers. 5. The method of claim 1 wherein the first precursor component and the second precursor component form the covalent linkages by a Michael addition reaction. 6. The method of claim 1 wherein the nucleophilic groups of the first precursor component are selected from the group consisting of thiols and amines. 7. The method of claim 1 wherein the electrophilic groups of the second precursor comprise conjugated unsaturated groups. 8. The method of claim 1 wherein the first precursor component is a siloxane derivative containing amino and/or thiol groups. 9. The method of claim 8 wherein the siloxane derivative is a cyclosiloxane of formula wherein n=3-6, R1=alkyl, R2"=alkyl, and X=--SH or--NH2. 10. The method of claim 9 wherein the cyclosiloxane is 2,4,6,8-Tetra(2-mercaptoethyl)-2,4,6,8-tetramethylcyclotetrasiloxane. 11. The method of claim 7 wherein the conjugate unsaturated group comprises at least one acrylate group. 12. The method of claim 11, wherein the first component comprises a siloxane derivative having at least one thiol as a nucleophilic group. 13. The method of claim 1 wherein the second precursor component is selected from the group consisting of derivatives of 1,1,1 tris(hydroxymethyl)propane that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, derivatives of pentaerithritol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, and derivatives of triglycerol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups. 14. The method of claim 13 wherein the second precursor component is trimethylolpropane triacrylate. 15. The method of claim 1, wherein the composition further comprises one or more additives selected from the group consisting of thixotropic agents and radiopaque agents. 16. The method of claim 15, wherein the additive is selected from the group consisting of barium sulfate, silica, and zirconium oxide. 17. The method of claim 1, wherein the composition further comprises a base. 18. The method of claim 6, wherein the first precursor is pentaerythritol tetrakis(3-mercaptopropyl)ether. 19. The method of claim 16, wherein the additive is barium sulfate. 20. The method of claim 17, wherein the base is selected from the group consisting of tributylamine, triethylamine, ethyldiisopropylamine, N,N-dimethylbutylamine, diethanolamine, ethanolamine, piperdine, morpholine, triethanolamine, and N-Boc-ethanolamine. 21. The method of claim 20, wherein the base is tributylamine. 22. The method of claim 1, wherein the first and second precursor components crosslink at physiological temperatures over a period of time following application to form a biomaterial comprising a polymeric network having a Young's modulus E ranging from 15 MPa to 160 MPa measured at 0.35 mm/s and 10% strain 10 days after mixing the first and second precursor components and storage at 37° C. 23. The method of claim 1, wherein the first precursor is tetra(3-mercaptopropyl)silane. 24. The method of claim 1, wherein the derivatives of 1,1,1 tris(hydroxymethyl)propane, pentaerithritol, or triglycerol contain at least three acrylate groups, itaconoate groups, or itaconamide groups. 25. A biomaterial for augmenting hard tissue comprising a polymeric network formed from a composition comprising at least a first and a second precursor component having a functionality of at least three on each precursor component, wherein the first component comprises at least m nucleophilic groups and the second component comprises at least n conjugated unsaturated groups, wherein m+n is at least six, and wherein at least one of the first and second precursor components are selected from the group of monomers and oligomers, wherein the oligomers contain between two and ten monomer units, consisting of siloxane derivatives containing amino and/or thiol groups, cyclohexyl derivatives having formula where n=6, R1=H or alkyl, R2"=alkyl; and X=--SH, tetra (3-mercaptopropyl)silane, derivatives of pentaerithritol that contain at least two alkyl chains with end-standing thiol and/or amine groups; derivatives of 1,1,1-tris-(hydroxy-methyl)propane that contain at least two alkyl chains with end-standing thiol and/or amine groups; derivatives of 1,1,1 tris-(hydroxy-methyl)propanol that contain at least two alkyl chains with end-standing thiol and/or amine groups, derivatives of 1,1,1 tris(hydroxymethyl)propane that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, derivatives of pentaerithritol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, and derivatives of triglycerol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, wherein the polymeric network formed by the first and second precursor component has a Young's modulus E of at least 15 MPa measured at 0.35 mm/s and 10% strain 10 days after mixing the first and second precursor components and storage at 37° C. 26. The biomaterial of claim 25, wherein the first component comprises a siloxane derivative having at least one thiol as the nucleophilic group, and wherein the conjugated unsaturated groups comprise at least one acrylate. 27. The biomaterial of claim 26 wherein the siloxane derivative containing amino and/or thiol groups is a cyclosiloxane of formula wherein n=3-6; R1=alkyl; R2"=alkyl; and X=--SH or--NH2. 28. The biomaterial of claim 27 wherein the cyclosiloxane derivative is 2,4,6,8-Tetra(2-mercaptoethyl)-2,4,6,8-tetramethylcyclotetrasiloxane. 29. The biomaterial of claim 26 wherein the second precursor component is selected from the group consisting of derivatives of 1,1,1 tris(hydroxymethyl)propane that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, derivatives of pentaerithritol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, and derivatives of triglycerol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups. 30. The biomaterial of claim 29 wherein the second precursor component is trimethylolpropane triacrylate. 31. The biomaterial of claim 26, wherein the composition further comprises one or more additives selected from the group consisting of thixotropic agents and radiopaque agents. 32. The biomaterial of claim 31, wherein the additive is selected from the group consisting of barium sulfate, silica, and zirconium oxide. 33. The biomaterial of claim 31, wherein the additive is barium sulfate. 34. The biomaterial of claim 25, wherein the polymeric network formed by the first and second precursor component has a Young's modulus E ranging from 15 MPa to 160 MPa measured at 0.35 mm/s and 10% strain 10 days after mixing the first and second precursor components and storage at 37° C. 35. The biomaterial of claim 25, wherein the first precursor is pentaerythritol tetrakis(3-mercaptopropyl)ether. 36. The biomaterial of claim 25, wherein the first precursor is tetra(3-mercaptopropyl)silane. 37. The biomaterial of claim 25, wherein the composition further comprises a base selected from the group consisting of tributylamine, triethylamine, ethyldiisopropylamine, N,N-dimethylbutylamine, diethanolamine, ethanolamine, piperdine, morpholine, triethanolamine, and N-Boc-ethanolamine. 38. The biomaterial of claim 37, wherein the base is tributylamine. 39. The biomaterial of claim 25, wherein the derivatives of 1,1,1 tris(hydroxymethyl)propane, pentaerithritol, or triglycerol contain at least three acrylate groups, itaconoate groups, or itaconamide groups. 40. A kit for forming in situ crosslinkable composition for augmenting hard tissue comprising at least a first precursor component and a second precursor component having a functionality of at least three on each precursor component, wherein the first precursor component comprises at least m nucleophilic groups and the second precursor component comprises at least n electrophilic groups, wherein m+n is at least six, wherein at least one of the first and second precursor components are selected from the group of monomers and oligomers, wherein the oligomers contain between two and ten monomer units, consisting of siloxane derivatives containing amino and/or thiol groups, cyclohexyl derivatives having formula where n=6, R1=H or alkyl, R2"=alkyl; and X=--SH, tetra(3-mercaptopropyl)silane, derivatives of pentaerithritol that contain at least two alkyl chains with end-standing thiol and/or amine groups; derivatives of 1,1,1-tris-(hydroxy-methyl)propane that contain at least two alkyl chains with end-standing thiol and/or amine groups; derivatives of 1,1,1 tris-(hydroxy-methyl)propanol that contain at least two alkyl chains with end-standing thiol and/or amine groups, derivatives of 1,1,1 tris(hydroxymethyl)propane that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, derivatives of pentaerithritol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, and derivatives of triglycerol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, wherein the first and second precursor components crosslink at physiological temperatures to form a biomaterial comprising a polymeric network having a Young's modulus E of at least 15 MPa measured at 0.35 mm/s and 10% strain 10 days after mixing the first and second precursor components and storage at 37° C. 41. The kit of claim 40 wherein the first precursor component is a siloxane derivative containing amino and/or thiol groups. 42. The kit of claim 41 wherein the siloxane derivative is a cyclosiloxane of formula wherein n=3-6; R1=alkyl; R2=alkyl; and X=--SH or--NH2. 43. The kit of claim 42 wherein the cyclosiloxane derivative is 2,4,6,8-Tetra(2-mercaptoethyl)-2,4,6,8-tetramethylcyclotetrasiloxane. 44. The kit of claim 40 wherein the second precursor component is selected from the group consisting of derivatives of 1,1,1 tris(hydroxymethyl)propane that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, derivatives of pentaerithritol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups, and derivatives of triglycerol that contain at least two acrylate groups, itaconoate groups, or itaconamide groups. 45. The kit of claim 44 wherein the second precursor component is trimethylolpropane triacrylate. 46. The kit of claim 40, further comprising one or more additives selected from the group consisting of thixotropic agents and radiopaque agents. 47. The kit of claim 46, wherein the additive is selected from the group consisting of barium sulfate, silica, and zirconium oxide. 48. The kit of claim 47, wherein the additive is barium sulfate. 49. The kit of claim 40, wherein the first and second precursor components crosslink at physiological temperatures to form a biomaterial comprising a polymeric network having a Young's modulus E ranging from 15 MPa to 160 MPa measured at 0.35 mm/s and 10% strain 10 days after mixing the first and second precursor components and storage at 37° C. 50. The kit of claim 40, wherein the composition further comprises a base selected from the group consisting of tributylamine, triethylamine, ethyldiisopropylamine, N,N-dimethylbutylamine, diethanolamine, ethanolamine, piperdine, morpholine, triethanolamine, and N-Boc-ethanolamine. 51. The kit of claim 50, wherein the base is tributylamine. 52. The kit of claim 40, wherein the first precursor is pentaerythritol tetrakis(3-mercaptopropyl)ether. 53. The kit of claim 40, wherein the first precursor is tetra(3-mercaptopropyl)silane. 54. The kit of claim 40, wherein the derivatives of 1,1,1 tris(hydroxymethyl)propane, pentaerithritol, or triglycerol contain at least three acrylate groups, itaconoate groups, or itaconamide groups.
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