Method of tissue repair II

1. A biomolecular solder made by a method comprising

(b) providing a composition comprising a proteinaceous substance in a solvent; and

(b) pre-denaturing the proteinaceous substance before placing the composition in situ by at least partially denaturing the proteinaceous substance while moist with the solvent such that at least a portion of the proteinaceous substance bonds together.

2. A solder according to claim 1 wherein the proteinaceous substance comprises a protein.

3. A solder according to claim 2 wherein the protein comprises an albumin, a collagen an elastin, a fibrinogen, or any combination thereof.

4. A solder according to claim 1 , further comprising a dye.

5. A solder according to claim 4 wherein the dye comprises an indocyanine green, a methylene blue or a fluorescein isothiocyanate or any combination thereof.

6. A solder according to claim 1 , further comprising an adjuvant.

7. A solder according to claim 1 further comprising a growth factor, a sodium hyaluronate, a hormone and an anti-coagulant.

8. A solder according to claim 1 further comprising a material for improving the strength of the solder.

9. A solder according to claim 8 wherein the material comprises a polytetrafluoroethylene fibre or a ceramic fibre.

10. A kit comprising a biomolecular solder according to claim 1 .

11. A method of preparing a biomolecular solder ex vivo, the method comprising:

(a) providing a composition comprising a proteinaceous substance and a solvent;

(b) shaping the composition into a desired shape, wherein the composition is shaped before, during or after the pre-denaturing of step (c), or a combination thereof; and

(c) pre-denaturing the proteinaceous substance before placing the composition in situ by at least partially denaturing the proteinaceous substance while the composition is moist such that at least a portion of the proteinaceous substance bonds together, thereby preparing a biomolecular solder.

12. A method according to claim 11 wherein the proteinaceous substance is pre-denatured by exposing the solder to an energy for a time period that is sufficient to allow the energy to at least partially denature the proteinaceous substance.

13. A method according to claim 12 wherein the energy comprises a thermal energy.

14. A method according to claim 13 wherein the proteinaceous substance is pre-denatured by heating the solder at a temperature of greater than 40° C. for a time period of about 30 seconds or longer.

15. A method according to claim 14 wherein in the pre-denaturing step the solder is heated in a hot liquid bath or in pressurized steam.

16. A method according to claim 11 wherein the proteinaceous substance is pre-denatured by exposure to a denaturing agent for a time period that is sufficient to allow the denaturing agent to homogenously and completely denature the proteinaceous substance.

17. A method according to claim 11 wherein the biomolecular solder further comprises a dye.

18. A method according to claim 17 wherein the dye is in an amount between 0.1 to 2.5% w/w of the solder.

19. A method according to claim 17 wherein the dye is mixed with the solvent, prior to mixing the solvent with the proteinaceous substance.

20. A method according to claim 11 wherein the pre-denaturing step further comprises drying the composition, wherein a majority of the solvent is removed from the composition during the drying of the composition.

21. The method of claim 11 wherein in the pre-denaturing step the composition is applied to a support structure before the proteinaceous substance is pre-denatured.

22. The method of claim 21 wherein the support structure is a mesh, a stiffener or a graft material.

23. The method of claim 11 further comprising the step of sterilizing the biomolecular solder following the pre-denaturing of the proteinaceous substance.

24. A method of welding or joining a biological tissue together, the method comprising:

(a) applying a biomolecular solder according to claim 1 to the biological tissue to be welded or joined together; and

(b) exposing the biomolecular solder to an energy for a time sufficient to cause the solder to weld or join the biological tissue together.

25. The method of claim 24 wherein the pre-denatured solder is moistened before application to the biological tissue.

26. The biomolecular solder of claim 1 wherein the proteinaceous substance is denatured ex vivo such that it is essentially insoluble in the physiological fluid at body temperature.

27. The biomolecular solder of claim 1 wherein the pre-denatured solder has been shaped from a composition comprising the proteinaceous substance in an amount of at least 40% w/w of the composition.

28. The biomolecular solder of claim 1 wherein the proteinaceous substance comprises at least one substance selected from the group consisting of a protein, a polypeptide, a mixture of proteins, a biodegradable protein, a fibrous material, a synthetic polypeptide and any combination thereof.

29. The method of claim 11 further comprising drying the pre-denatured solder.

30. The method of claim 11 wherein the pre-denatured solder, shaped into the predetermined shape, comprises the proteinaceous substance in an amount of at least 40% w/w or greater of the solder.

31. The method of claim 11 , wherein the solder initially comprises a proteinaceous substance in an amount in the range from 50% w/w to 80% w/w of the solder.

32. The method of claim 30 or 31 wherein the solder initially comprises a solvent in an amount up to 60% w/w of the solder.

33. The method of claim 11 wherein the pre-denaturing step comprises heating the solder at a temperature in a range from between about 75° C. to 100° C.

34. The method of claim 33 wherein the pre-denaturing step comprises heating the solder at a temperature in a range from between about 100° C. to 150° C.

35. The method of claim 16 wherein in the pre-denaturing step the denaturing agent comprises a chemical.

36. The method of claim 11 , wherein the proteinaceous substance comprises at least one substance selected from the group consisting of a protein, a polypeptide, a mixture of proteins, a biodegradable protein, a fibrous material, a synthetic polypeptide and any combination thereof.

37. The method of to claim 36 wherein the proteinaceous substance comprises at least one substance selected from the group consisting of human albumin, bovine albumin, horse albumin, ovine albumin, rabbit albumin, rat albumin, and a combination thereof.

38. The method of claim 36 , wherein the proteinaceous substance comprises at least one protein selected from the group consisting of an albumin, an elastin, a collagen and a fibrinogen.

39. The method of claim 25 wherein the moistening of the pre-denatured solder increases flexibility of the solder.

40. The biomolecular solder of claim 1 , wherein the solvent comprises an aqueous solvent.

41. The biomolecular solder of claim 40 , wherein the aqueous solvent comprises water or saline.

42. The method of claim 11 , wherein the solvent comprises an aqueous solvent.

43. The method of claim 42 , wherein the aqueous solvent comprises water or saline.

44. The method of claim 11 , wherein denaturing the protein in situ in step (e) comprises denaturing the proteinaceous substance by exposing the solder to a laser energy.

45. The method of claim 44 , wherein the laser is a diode laser.

46. The method of claim 24 , wherein the biological tissue is welded together to effect a repair.

47. The biomolecular solder of claim 1 , wherein denaturing the protein in situ in step (e) comprises denaturing all of the proteinaceous substance.

48. The biomolecular solder of claim 1 , wherein denaturing the protein in situ in step (e) comprises denaturing a portion of the proteinaceous substance.

49. The method of claim 11 , wherein denaturing the protein in situ in step (e) comprises denaturing all of the proteinaceous substance.

50. The method of claim 11 , wherein denaturing the protein in situ in step (e) comprises denaturing a portion of the proteinaceous substance.

51. The biomolecular solder of claim 1 , wherein the method of making the solder further comprises sterilizing the biomolecular solder before the step (d) placing of the pre-denatured solder in situ.

52. The biomolecular solder of claim 1 , wherein the pre-denatured proteinaceous substance is shaped into a sheet, a tube, a partial tube, a strip, a patch, a hollow tube with a flanged end or a rod before the step (d) placing of the pre-denatured solder in situ, after the step (d) placing the pre-denatured solder in situ, or a combination thereof.

53. The method of claim 11 , the desired shape comprises a sheet, a tube, a partial tube, a strip, a patch, a hollow tube with a flanged end or a rod before the step (d) placing of the pre-denatured solder in situ, after the step (d) placing the pre-denatured solder in situ, or a combination thereof.

54. A biomolecular solder comprising a protein comprising an albumin, an elastin, a collagen, a fibrinogen or a combination thereof, wherein the biomolecular solder is made by the method of claim 1 , and the pre-denatured solder has been at least partially denatured while moist such that the protein bonds together and, when shaped, the shape of the solder is thereby essentially maintained and the solubility of the protein is reduced in a physiological fluid at body temperature.

55. The biomolecular solder of claim 54 , wherein the solder is shaped before pre-denaturing.

56. The biomolecular solder of claim 54 , wherein the solder is shaped after pre-denaturing.

57. The biomolecular solder of claim 54 , wherein the protein comprises a bovine, rabbit, ovine, rat or horse serum albumin.

58. The biomolecular solder of claim 54 , wherein the protein comprises a human albumin, a human elastin, a human fibrinogen, a human collagen or any combination thereof.

59. The biomolecular solder of claim 54 , further comprising a dye for improving energy deposition into the solder when the solder is exposed to energy.

60. The biomolecular solder of claim 54 , wherein the proteinaceous substance has been at least partially denatured while moist with a solvent.

61. The biomolecular solder of claim 60 , wherein the solvent comprises an aqueous solvent.

62. The biomolecular solder of claim 61 , wherein the aqueous solvent comprises water or saline.

63. A biomolecular solder made by a method comprising:

(a) providing a composition comprising a protein in a solvent;

(b) pre-denaturing the protein before placing the composition in situ by at least partially denaturing the protein while moist with the solvent such that at least a portion of the protein bonds together; and,

(c) shaping the pre-denatured protein, wherein the solder is shaped before, during or after the pre-denaturing of step (b), or a combination thereof.

64. The biomolecular solder of claim 63 , further comprising steps

(d) placing the pre-denatured solder in situ, and

(e) further denaturing the protein in situ such that the final shape of the in situ-denatured solder is essentially maintained and the solubility of the protein is reduced in a physiological fluid at body temperature.

65. The biomolecular solder of claim 63 , wherein the protein comprises albumin.

66. The biomolecular solder of claim 65 , wherein the albumin comprises human albumin, bovine albumin, ovine albumin, horse albumin, rat albumin or a mixture thereof.

67. The biomolecular solder of claim 63 , wherein the protein comprises collagen, elastin, fibrinogen or a combination thereof.

68. The biomolecular solder of claim 63 , wherein pre-denaturing the protein before placing the composition in situ comprises the step of steam heating or immersion into hot water.

69. The biomolecular solder of claim 68 , wherein the steam heating step comprises use of a temperature of between about 100° C. and 150° C.

70. The biomolecular solder of claim 63 , wherein pre-denaturing the protein before placing the composition in situ comprises use of light, heat, radiation, ultrasound or chemicals.

71. The biomolecular solder of claim 63 , wherein the step of denaturing the protein in situ comprises exposing the solder to light, heat, radiation, ultrasound or chemicals.

72. The biomolecular solder of claim 63 , wherein the step of denaturing the protein in situ comprises exposing the solder to a laser energy.

73. The biomolecular solder of claim 72 , wherein the laser energy that denatures the protein in situ comprises a power of about 90 mW and a wavelength of about 805 nm.

74. The biomolecular solder of claim 72 , wherein the laser energy that denatures the protein in situ comprises a spot size at the solder of about 200 μm.

75. The biomolecular solder of claim 63 , wherein further comprising a dye.

76. The biomolecular solder of claim 75 , wherein the dye comprises an indocyanine green, a methylene blue or a fluorescein isothiocyanate.

77. The method of claim 24 , wherein the biological tissue is a human or an animal tissue.

78. The method of claim 24 , wherein a blood vessel, a nerve, a pancreatic duct, a liver vessel or duct, a cystic duct, a tear duct, prostatic duct, a ureter, urethra, an epididymis, a vas deferens, a fallopian tube, a bowel, a bronchi, a gastroenterological tube or duct, a respiratory tube or duct or a brain vessel, tube or duct are welded together.

79. A solder according to claim 1 , wherein in step (b) the proteinaceous substance is fully denatured.

80. The biomolecular solder of claim 1 wherein the composition comprises a proteinaceous substance in a concentration in a range of between about 40% w/w and 80% w/w, or between about 45% w/w and 75% w/w, of the composition.

81. A biomolecular solder made by a method comprising

(a) providing a composition comprising a proteinaceous substance in a solvent;

(b) pre-denaturing the proteinaceous substance before placing the composition in situ by at least partially denaturing the proteinaceous substance while moist with the solvent such that at least a portion of the proteinaceous substance bonds together and the solubility of the proteinaceous substance is reduced in a physiological fluid at body temperature; and,

(c) shaping the proteinaceous substance, wherein the solder is shaped before, during or after the denaturing of step (b), or a combination thereof, and, when shaped, the final shape of the solder is essentially maintained.

82. A sterile biomolecular solder made by a method comprising

(a) providing a composition comprising a proteinaceous substance in a solvent;

(b) pre-denaturing the proteinaceous substance ex vivo by at least partially denaturing the proteinaceous substance while moist with the solvent such that at least a portion of the proteinaceous substance bonds together; and,

(c) sterilizing the pre-denatured solder.

83. A biomolecular solder composition comprising a shaped proteinaceous substance and a solvent, wherein the proteinaceous substance is at least partially denatured ex vivo while moist with the solvent such that at least a portion of the proteinaceous substance bonds together.

84. The composition of claim 83 , wherein the proteinaceous substance is fully denatured.

85. The composition of claim 83 , wherein the protein comprises an albumin, a collagen, an elastin, a fibrinogen, or any combination thereof.

86. A sterile shaped biomolecular solder comprising an at least partially cross-linked proteinaceous substance and a solvent, wherein the proteinaceous substance is at least partially cross-linked while moist with the solvent such that at least a portion of the proteinaceous substance bonds together.

87. A biomolecular solder comprising an at least partially cross-linked protein and a solvent, wherein the protein comprises an albumin, a collagen, an elastin, a fibrinogen, or any combination thereof, and is at least partially cross-linked while moist with the solvent.

88. A kit comprising the sterile biomolecular solder of claim 82 .

89. A kit comprising the sterile shaped biomolecular solder of claim 86 .

90. A kit comprising the biomolecular solder of claim 87 .

91. A kit comprising the sterile biomolecular solder of claim 87 , the sterile shaped biomolecular solder of claim 86 or the biomolecular solder of claim 87 , and instructions for using the solder as set forth in claim 24 .