USRE38158EExpiredUtility
Adhesive sealant composition
Est. expiryJul 27, 2014(expired)· nominal 20-yr term from priority
Y10S530/83A61L 24/10A61L 24/043A61L 24/106A61L 24/046C09J 189/00
75
PatentIndex Score
45
Cited by
142
References
154
Claims
Abstract
This invention is related to an adhesive composition which may be used to bond or seal tissue in vivo. The adhesive composition is readily formed from a two component mixture which includes a first part of a protein, preferably a serum albumin protein, in an aqueous buffer having a pH in the range of about 8.0-11.0 and a second part of a water-compatible or water-soluble bifunctional crosslinking agent. When the two parts of the mixture are combined, the mixture is initially a liquid which cures in vivo on the surface of tissue in less than about one minute to give a strong, flexible, pliant substantive composition which bonds to the tissue and is absorbed in about four to sixty days. The adhesive composition may be used either to bond tissue, to seal tissue or to prevent tissue adhesions caused by surgery.
Claims
exact text as granted — not AI-modifiedWe claim:
1. An adhesive composition consisting essentially of
i) a first aqueous mixture of about 20-60 wt/vol % serum albumin in about 0.01-0.25 molar buffer at a pH in a range of about 8.0-11.0,
ii) a second aqueous mixture of about 50-800 mg/ml of a crosslinking agent having a molecular weight in a range of about 1,000-15,000, wherein the crosslinking agent is of the formula
G—LM—PEG—LM—G
wherein —PEG— is a diradical fragment represented by the formula
—O—(CH 2 —CH 2 —O—) a —
where a is an integer from 20-300;
wherein —LM— is a diradical fragment selected from the group consisting of a carbonate diradical of the formula, —C(O)—, a monoester diradical of the formula, —(CH 2 ) b C(O)— where b is an integer from 1-5, a diester diradical of the formula, —C(O)—(CH 2 ) c —C(O)— where c is an integer from 2-10 and where the aliphatic portion of the diradical may be saturated or unsaturated, a dicarbonate diradical of the formula —C(O)—O—(CH 2 ) d —O—C(O)— where d is an integer from 2-10, and an oligomeric diradical represented by the formulas —R—C(O)—, —R—C(O)—(CH 2 ) c —C(O)—, or —R—C(O)—O—(CH 2 ) d —O—C(O)— where c is an integer from 2-10, d is an integer from 2-10, and R is a polymer or copolymer having 1-10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone and p-dioxanone; and
wherein —G is a leaving group selected from the group consisting of succinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenyl, or and tresyl, ; and
wherein a combination of the first and second mixtures is initially liquid and then cures on the surface of tissue to give a flexible, substantive matrix which bonds to the tissue and has a burst strength greater than about 10 mmHg.
2. The adhesive mixture composition of claim 1 wherein the protein in the first mixture is about 35-45 wt/vol % serum albumin.
3. The adhesive composition of claim 1 wherein the serum albumin is human serum albumin.
4. The adhesive composition of claim 1 wherein the buffer is 0.05-0.15 molar carbonate/bicarbonate buffer at a pH of about 9.0-10.5.
5. The adhesive composition of claim 1 wherein the second aqueous mixture is about 50-300 mg/ml of a crosslinking agent having a molecular weight in a range of about 1,000-5,000.
6. The adhesive composition of claim 1 wherein the ratio of a volume of the first mixture to a volume of the second mixture is in a range of about 1:10 to about 10:1.
7. The adhesive composition of claim 1 wherein —LM— is an oligomeric diradical —R—C(O)—(CH 2 ) c —C(O)— where c is an integer from 2-10 and R is a polymer or copolymer having 1-10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone and p-dioxanone.
8. The adhesive composition of claim 1 wherein —G is succinimidyl.
9. An in vivo method of adhering tissue comprising the steps of topically applying and bonding an adhesive mixture composition of claim 1 to the tissue.
10. An in vivo method of sealing air leaks in pulmonary tissues comprising the step of topically applying and curing the adhesive mixture composition of claims claim 1 to an air leak site in the pulmonary tissue.
11. An in vivo method to prevent post-surgical adhesions comprising the step of topically applying and curing the adhesive mixture composition of claims claim 1 to tissue surrounding a surgical site.
12. An in vivo method to seal tissue comprising the step of topically applying and bonding the adhesive mixture composition of claims claim 1 to tissue to prevent or control blood or other fluid leaks.
13. The adhesive composition of claim 1 wherein the second aqueous mixture is about 300-800 mg/ml of a crosslinking agent having a molecular weight in a range of about 5,000-15,000.
14. The adhesive composition of claim 13 wherein —LM— is a diester diradical of the formula —C(O)—(CH 2 ) 2 —C(O)—.
15. The adhesive mixture composition of claim 1 wherein —LM— is a diester diradical of the formula, —C(O)—(CH 2 ) c —C(O)— where c is an integer from 2-10 and where the aliphatic portion of the diradical may be saturated or unsaturated.
16. The adhesive composition of claim 15 1 wherein —LM— is a an oligomeric diradical derived from polyglycolic acid.
17. A method of making a tissue adhesive consisting of the step of forming a mixture of
i) a first aqueous mixture of about 20-60 wt/vol % serum albumin in about 0.01-0.25 molar buffer at a pH in a range of about 8.0-11.0,
ii) a second aqueous mixture of about 50-800 mg/ml of a crosslinking agent having a molecular weight in a range of about 1,000-15,000, wherein the crosslinking agent is of the formula
G—LM—PEG—LM—G
wherein —PEG— is a diradical fragment represented by the formula
—O—(CH 2 —CH 2 —O—) a —
where a is an integer from 20-300;
wherein —LM— is a diradical fragment selected from the group consisting of a carbonate diradical of the formula, —C(O)—, a monoester diradical of the formula, —(CH 2 ) b C(O)— where b is an integer from 1-5, a diester diradical of the formula, —C(O)—(CH 2 ) c —C(O)— where c is an integer from 2-10 and where the aliphatic portion of the diradical may be saturated or unsaturated, a dicarbonate diradical of the formula —C(O)—O—(CH 2 ) d —O—C(O)— where d is an integer from 2-10, and an oligomeric diradical represented by the formulas —R—C(O)—, —R—C(O)—(CH 2 ) c —C(O)—, or —R—C(O)—O—(CH 2 ) d —O—C(O)— where c is an integer from 2-10, d is an integer from 2-10, and R is a polymer or copolymer having 1-10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone and p-dioxanone; and
wherein —G is a leaving group selected from the group consisting of succinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenyl or , and tresyl, ; and
wherein a combination of the first and second mixtures is initially liquid and then cures on the surface of tissue to give a flexible, substantive matrix which bonds to the tissue and has a burst strength greater than about 10 mmHg.
18. A method of treating tissue to prevent or control air or fluid leaks comprising:
providing a composition to tissue, said composition including a serum albumin protein at about 20 - 60 wt/vol % and a crosslinking agent at about 50 - 800 mg/ml, said crosslinking agent having a polyoxyethylene chain portion and an activated leaving group which allows the crosslinking agent to react with said protein and having a molecular weight in a range of about 1 , 000 - 15 , 000 ; and
curing said composition on the tissue to bond said composition to the tissue and to provide a substantive cured matrix that has a burst strength greater than about 10 mm Hg.
19. The method of claim 18 wherein said composition is cured to produce the matrix in less than about 10 minutes.
20. The method of claim 18 wherein said composition is cured to produce the matrix in less than about one minute.
21. The method of claim 18 wherein said composition is cured to produce the matrix in about ten seconds.
22. The method of claim 18 comprising providing the composition to the tissue using a syringe.
23. The method of claim 18 comprising providing the composition to the tissue using a dual syringe.
24. The method of claim 18 comprising providing the composition to the tissue using a spray apparatus.
25. The method of claim 18 wherein the matrix is resorbed.
26. The method of claim 25 wherein the matrix is resorbed in about four to sixty days.
27. The method of claim 18 comprising curing the composition such that the peel strength of the matrix is about 0 . 08 lb/in or more.
28. The method of claim 18 wherein the matrix has a burst pressure of about 34 mmHg or greater.
29. The method of claim 28 wherein the matrix has a burst pressure of about 90 mmHg or greater.
30. The method of claim 29 wherein the matrix has a burst pressure of about 130 mmHg or greater.
31. The method of claim 18 comprising providing a composition wherein the crosslinking agent has a molecular weight in a range of about 1 , 000 - 5 , 000 .
32. The method of claim 18 comprising providing a composition wherein the activated leaving group is an N- hydroxy imide.
33. The method of claim 32 comprising providing a composition wherein the activated leaving group is N- hydroxy succinimide.
34. The method of claim 18 further comprising mixing a first mixture and a second mixture to form the composition and applying said composition to the tissue,
wherein the first mixture includes about 20 - 60 wt/vol % of the protein in about 0 . 01 - 0 . 25 molar buffer at pH in a range of about 8 . 0 - 11 . 0 and the second mixture includes about 50 - 800 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 15 , 000 .
35. The method of claim 34 wherein the crosslinking agent is of the formula
—G—LM—PEG—LM—G
wherein:
—PEG— is a diradical fragment represented by the formula
—O— ( CH 2 —CH 2 —O— ) a —
where a is an integer from 20 - 300 ;
—LM— is a diradical fragment selected from the group consisting of a carbonate diradical of the formula —C ( O ) —, a monoester diradical of the formula — ( CH 2 ) b C ( O ) — where b is an integer from 1 - 5 , a diester diradical of the formula —C ( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated, a dicarbonate diradical of the formula —C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where d is an integer from 2 - 10 , and an oligomeric diradical represented by the formulas —R—C ( O ) —, —R—C ( O ) — ( CH 2 ) c —C ( O ) —, or —R—C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where c is an integer from 2 - 10 , d is an integer from 2 - 10 , and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone; and
—G is the leaving group selected from the group consisting of succinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenyl, and tresyl.
36. The method of claim 35 wherein the protein in the first mixture is about 35 - 45 wt/vol % serum albumin.
37. The method of claim 36 wherein the buffer is 0 . 05 - 0 . 15 molar carbonate/bicarbonate buffer at a pH of about 9 . 0 - 10 . 5 .
38. The method of claim 35 wherein the second mixture is about 50 - 300 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 5 , 000 .
39. The method of claim 35 wherein the ratio of a volume of the first mixture to a volume of the second mixture is in a range of about 1 : 10 to about 10 : 1 .
40. The method of claim 35 wherein —LM— is an oligomeric diradical —R—C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone.
41. The method of claim 35 wherein —G is succinimidyl.
42. The method of claim 35 wherein the second mixture includes about 300 - 800 mg/ml of a crosslinking agent having a molecular weight in a range of about 5 , 000 - 15 , 000 .
43. The method of claim 35 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) 2 —C ( O ) —.
44. The method of claim 35 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated.
45. The method of claim 35 wherein —LM— is an oligomeric diradical derived from polyglycolic acid.
46. The method of claim 18 comprising treating tissue to prevent or control a fluid leak.
47. The method of claim 46 wherein the fluid leak is a blood leak.
48. The method of claim 18 wherein the tissue includes an air leak.
49. The method of claim 48 wherein the air leak is in a pulmonary system.
50. A method of treating tissue to prevent formation of an adhesion comprising:
providing a composition to tissue, said composition including a serum albumin protein at about 20 - 60 wt/vol % and a crosslinking agent of about 50 - 800 mg/ml, said crosslinking agent having a polyoxyethylene chain portion and an activated leaving group which allows the crosslinking agent to react with said protein and having a molecular weight in the range of about 1 , 000 - 15 , 000 ; and
curing said composition on the tissue to bond said composition to the tissue and to provide a substantive cured matrix that has a burst strength greater than about 10 mm Hg.
51. The method of claim 50 wherein said composition is cured to produce the matrix in less than about 10 minutes.
52. The method of claim 50 wherein said composition is cured to produce the matrix in less than about one minute.
53. The method of claim 50 wherein said composition is cured to produce the matrix in about ten seconds.
54. The method of claim 50 comprising providing the composition to the tissue using a syringe.
55. The method of claim 50 comprising providing the composition to the tissue using a dual syringe.
56. The method of claim 50 comprising providing the composition to the tissue using a spray apparatus.
57. The method of claim 50 wherein the matrix is resorbed.
58. The method of claim 57 wherein the matrix is resorbed in about four to sixty days.
59. The method of claim 50 comprising curing the composition such that the peel strength of the matrix is about 0 . 08 lb/in or more.
60. The method of claim 50 wherein the matrix has a burst pressure of about 34 mmHg or greater.
61. The method of claim 60 wherein the matrix has a burst pressure of about 90 mmHg or greater.
62. The method of claim 61 wherein the matrix has a burst pressure of about 130 mmHg or greater.
63. The method of claim 50 comprising providing a composition wherein the crosslinking agent has a molecular weight in a range of about 1 , 000 - 5 , 000 .
64. The method of claim 50 comprising providing a composition wherein the activated leaving group is an N- hydroxy imide.
65. The method of claim 64 comprising providing a composition wherein the activated leaving group is N- hydroxy succinimide.
66. The method of claim 50 further comprising mixing a first mixture and a second mixture to form the composition and applying said composition to the tissue,
wherein the first mixture includes about 20 - 60 wt/vol % of the protein in about 0 . 01 - 0 . 25 molar buffer at a pH in a range of about 8 . 0 - 11 . 0 and the second mixture includes about 50 - 800 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 15 , 000 .
67. The method of claim 66 wherein the crosslinking agent is of the formula
G—LM—PEG—LM—G
wherein:
—PEG— is a diradical fragment represented by the formula
—O— ( CH 2 —CH 2 —O— ) a —
where a is an integer from 20 - 300 ;
—LM— is a diradical fragment selected from the group consisting of a carbonate diradical of the formula —C ( O ) —, a monoester diradical of the formula — ( CH 2 ) b C ( O ) — where b is an integer from 1 - 5 , a diester diradical of the formula —C ( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated, a dicarbonate diradical of the formula —C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where d is an integer from 2 - 10 , and an oligomeric diradical represented by the formulas —R—C ( O ) —, —R—C ( O ) — ( CH 2 ) c —C ( O ) —, or —R—C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where c is an integer from 2 - 10 , d is an integer from 2 - 10 , and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone; and
—G is the leaving group selected from the group consisting of succinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenyl, and tresyl.
68. The method of claim 67 wherein the protein in the first mixture is about 35 - 45 wt/vol % serum albumin.
69. The method of claim 68 wherein the buffer is 0 . 05 - 0 . 15 molar carbonate/bicarbonate buffer at a pH of about 9 . 0 - 10 . 5 .
70. The method of claim 67 wherein the second mixture is about 50 - 300 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 5 , 000 .
71. The method of claim 67 wherein the ratio of a volume of the first mixture to a volume of the second mixture is in a range of about 1 : 10 to about 10 : 1 .
72. The method of claim 67 wherein —LM— is an oligomeric diradical —R—C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone.
73. The method of claim 67 wherein —G is succinimidyl.
74. The method of claim 67 wherein the second mixture includes about 300 - 800 mg/ml of a crosslinking agent having a molecular weight in a range of about 5 , 000 - 15 , 000 .
75. The method of claim 67 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) 2 —C ( O ) —.
76. The method of claim 67 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated.
77. The method of claim 67 wherein —LM— is an oligomeric diradical derived from polyglycolic acid.
78. The method of claim 50 wherein the composition is provided to tissue at a surgical site.
79. The method of claim 50 wherein the composition is provided on a surface of an internal organ.
80. A method of treating tissue to bind layers of tissue together comprising:
providing a composition to tissue, said composition including a serum albumin protein at about 20 - 60 wt/vol % and a crosslinking agent at about 50 - 800 mg/ml, said crosslinking agent having a polyoxyethylene chain portion and an activated leaving group which allows the crosslinking agent to react with said protein and having a molecular weight in the range of about 1000 - 15 , 000 ; and
curing said composition on the tissue to bond said composition to the tissue and to provide a substantive cured matrix that has a burst strength of greater than about 10 mm Hg.
81. The method of claim 80 wherein said composition is cured to produce the matrix in less than about 10 minutes.
82. The method of claim 80 wherein said composition is cured to produce the matrix in less than about one minute.
83. The method of claim 80 wherein said composition is cured to produce the matrix in about ten seconds.
84. The method of claim 80 comprising providing the composition to the tissue using a syringe.
85. The method of claim 80 comprising providing the composition to the tissue using a dual syringe.
86. The method of claim 80 comprising providing the composition to the tissue using a spray apparatus.
87. The method of claim 80 wherein the matrix is resorbed.
88. The method of claim 87 wherein the matrix is resorbed in about four to sixty days.
89. The method of claim 80 comprising curing the composition such that the peel strength of the matrix is about 0 . 08 lb/in or more.
90. The method of claim 80 wherein the matrix has a burst pressure of about 34 mmHg or greater.
91. The method of claim 90 wherein the matrix has a burst pressure of about 90 mmHg or greater.
92. The method of claim 91 wherein the matrix has a burst pressure of about 130 mmHg or greater.
93. The method of claim 80 comprising providing a composition wherein the crosslinking agent has a molecular weight in a range of about 1 , 000 - 5 , 000 .
94. The method of claim 80 comprising providing a composition wherein the activated leaving group is an N- hydroxy imide.
95. The method of claim 94 comprising providing a composition wherein the activated leaving group is N- hydroxy succinimide.
96. The method of claim 80 further comprising mixing a first mixture and a second mixture to form the composition and applying said composition to the tissue,
wherein the first mixture includes about 20 - 60 wt/vol % of the protein in about 0 . 01 - 0 . 25 molar buffer at a pH in a range of about 8 . 0 - 11 . 0 and the second mixture includes about 50 - 800 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 15 , 000 .
97. The method of claim 96 wherein the crosslinking agent is of the formula
G—LM—PEG—LM—G
wherein:
—PEG— is a diradical fragment represented by the formula
—O— ( CH 2 —CH 2 —O— ) a —
where a is an integer from 20 - 300 ;
—LM— is a diradical fragment selected from the group consisting of a carbonate diradical of the formula —C ( O ) —, a monoester diradical of the formula — ( CH 2 ) b C ( O ) — where b is an integer from 1 - 5 , a diester diradical of the formula —C ( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated, a dicarbonate diradical of the formula —C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where d is an integer from 2 - 10 , and an oligomeric diradical represented by the formulas —R—C ( O ) —, —R—C ( O ) — ( CH 2 ) c —C ( O ) —, or —R—C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where c is an integer from 2 - 10 , d is an integer from 2 - 10 , and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone; and
—G is the leaving group selected from the group consisting of succinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenyl, and tresyl.
98. The method of claim 97 wherein the protein in the first mixture is about 35 - 45 wt/vol % serum albumin.
99. The method of claim 98 wherein the buffer is 0 . 05 - 0 . 15 molar carbonate/bicarbonate buffer at a pH of about 9 . 0 - 10 . 5 .
100. The method of claim 97 wherein the second mixture is about 50 - 300 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 5 , 000 .
101. The method of claim 97 wherein the ratio of a volume of the first mixture to a volume of the second mixture is in a range of about 1 : 10 to about 10 : 1 .
102. The method of claim 97 wherein —LM— is an oligomeric diradical —R—C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone.
103. The method of claim 97 wherein —G is succinimidyl.
104. The method of claim 97 wherein the second mixture includes about 300 - 800 mg/ml of a crosslinking agent having a molecular weight in a range of about 5 , 000 - 15 , 000 .
105. The method of claim 97 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) 2 —C ( O ) —.
106. The method of claim 97 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated.
107. The method of claim 97 wherein —LM— is an oligomeric diradical derived from polyglycolic acid.
108. The method of claim 80 wherein the matrix binds tissue together in addition to a suture, a staple, a tape, or a bandage.
109. The method of claim 80 wherein the composition is provided to attach skin grafts.
110. The method of claim 80 wherein the composition is provided to attach adjacent layers of tissue.
111. The method of claim 80 wherein the composition is provided to position tissue flaps.
112. The method of claim 80 wherein the composition is provided to close gingival flaps.
113. A method of treating tissue comprising:
providing a composition to tissue, said composition including a serum albumin protein at about 20 - 60 wt/vol % and a crosslinking agent at about 50 - 800 mg/ml, said crosslinking agent having a polyoxyethylene chain portion and an activated leaving group which allows the crosslinking agent to react with said protein and having a molecular weight in a range of about 1000 - 15 , 000 ; and
curing said composition on the tissue to bond said composition to the tissue and to provide a substantive cured matrix that has a burst strength greater than about 10 mm Hg.
114. The method of claim 113 wherein said composition is cured to produce the matrix in less than about 10 minutes.
115. The method of claim 113 wherein said composition is cured to produce the matrix in less than about one minute.
116. The method of claim 113 wherein said composition is cured to produce the matrix in about ten seconds.
117. The method of claim 113 comprising providing the composition to the tissue using a syringe.
118. The method of claim 113 comprising providing the composition to the tissue using a dual syringe.
119. The method of claim 113 comprising providing the composition to the tissue using a spray apparatus.
120. The method of claim 113 wherein the matrix is resorbed.
121. The method of claim 120 wherein the matrix is resorbed in about four to sixty days.
122. The method of claim 113 comprising curing the composition such that the peel strength of the matrix is about 0 . 08 lb/in or more.
123. The method of claim 113 wherein the matrix has a burst pressure of about 34 mmHg or greater.
124. The method of claim 123 wherein the matrix has a burst pressure of about 90 mmHg or greater.
125. The method of claim 124 wherein the matrix has a burst pressure of about 130 mmHg or greater.
126. The method of claim 113 comprising providing a composition wherein the crosslinking agent has a molecular weight in a range of about 1 , 000 - 5 , 000 .
127. The method of claim 114 comprising providing a composition wherein the activated leaving group is an N- hydroxy imide.
128. The method of claim 127 comprising providing a composition wherein the activated leaving group is N- hydroxy succinimide.
129. The method of claim 113 further comprising mixing a first mixture and a second mixture to form the composition and applying said composition to the tissue,
wherein the first mixture includes about 20 - 60 wt/vol % of the protein in about 0 . 01 - 0 . 25 molar buffer at a pH in a range of about 8 . 0 - 11 . 0 and the second mixture includes about 50 - 800 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 15 , 000 .
130. The method of claim 129 wherein the crosslinking agent is of the formula
G—LM—PEG—LM—G
wherein:
—PEG— is a diradical fragment represented by the formula
—O— ( CH 2 —CH 2 —O— ) a —
where a is an integer from 20 - 300 ;
—LM— is a diradical fragment selected from the group consisting of a carbonate diradical of the formula —C ( O ) —, a monoester diradical of the formula — ( CH 2 ) b C ( O ) — where b is an integer from 1 - 5 , a diester diradical of the formula —C ( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated, a dicarbonate diradical of the formula —C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where d is an integer from 2 - 10 , and an oligomeric diradical represented by the formulas —R—C ( O ) —, —R—C ( O ) — ( CH 2 ) c —C ( O ) —, or —R—C ( O ) —O— ( CH 2 ) d —O—C ( O ) — where c is an integer from 2 - 10 , d is an integer from 2 - 10 , and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone; and
—G is the leaving group selected from the group consisting of succinimidyl, maleimidyl, phthalimidyl, imidazolyl, nitrophenyl, and tresyl.
131. The method of claim 130 wherein the protein in the first mixture is about 35 - 45 wt/vol % serum albumin.
132. The method of claim 131 wherein the buffer is 0 . 05 - 0 . 15 molar carbonate/bicarbonate buffer at a pH of about 9 . 0 - 10 . 5 .
133. The method of claim 130 wherein the second mixture is about 50 - 300 mg/ml of the crosslinking agent having a molecular weight in a range of about 1 , 000 - 5 , 000 .
134. The method of claim 130 wherein the ratio of a volume of the first mixture to a volume of the second mixture is in a range of about 1 : 10 to about 10 : 1 .
135. The method of claim 130 wherein —LM— is an oligomeric diradical —R—C( O ) — ( CH 2 ) c — where c is an integer from 2 - 10 and R is a polymer or copolymer having 1 - 10 monomeric fragments selected from the group consisting of lactide, glycolide, trimethylene carbonate, caprolactone, and p - dioxanone.
136. The method of claim 130 wherein —G is succinimidyl.
137. The method of claim 130 wherein the second mixture includes about 300 - 800 mg/ml of a crosslinking agent having a molecular weight in a range of about 5 , 000 - 15 , 000 .
138. The method of claim 130 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) 2 —C ( O ) —.
139. The method of claim 130 wherein —LM— is a diester diradical of the formula —C( O ) — ( CH 2 ) c —C ( O ) — where c is an integer from 2 - 10 and where the aliphatic portion of the diradical may be saturated or unsaturated.
140. The method of claim 130 wherein —LM— is an oligomeric diradical derived from polyglycolic acid.
141. The method of claim 113 comprising curing the composition on the tissue to seal the tissue.
142. The method of claim 141 comprising treating tissue to prevent or control a fluid leak.
143. The method of claim 142 wherein the fluid leak is a blood leak.
144. The method of claim 141 wherein the tissue includes an air leak.
145. The method of claim 144 wherein the air leak is in a pulmonary system.
146. The method of claim 113 wherein the composition is provided to tissue at a surgical site.
147. The method of claim 113 comprising curing the composition at the tissue to prevent a tissue adhesion.
148. The method of claim 113 wherein the composition is provided on a surface of an internal organ.
149. The method of claim 113 comprising curing the composition to form a matrix to bind tissue.
150. The method of claim 149 wherein the matrix binds tissue together in addition to a suture, a staple, a tape, or a bandage.
151. The method of claim 113 wherein the composition is provided to attach skin grafts.
152. The method of claim 113 wherein the composition is provided to attach adjacent layers of tissue.
153. The method of claim 113 wherein the composition is provided to position tissue flaps.
154. The method of claim 113 wherein the composition is provided to close gingival flaps.Cited by (0)
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