Biocompatible phase invertable proteinaceous compositions and methods for making and using the same
View Patent ↗Biocompatible phase invertable proteinaceous compositions and methods for making and using the same are provided. The subject phase invertable compositions are prepared by combining a proteinaceous substrate and a cross-linker. The proteinaceous substrate includes one or more proteins and an adhesion modifier, and may also include one or more of: a pasticizer, a carbohydrate, or other modification agent. In certain embodiments, the cross-linker is a heat-treated dialdehyde, e.g., heat-treated glutaraldehyde. Also provided are kits for use in preparing the subject compositions. The subject compositions, kits and systems find use in a variety of different applications.
1. A fluid phase invertible composition that goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow, wherein said composition is produced by combining:
(a) a fluid substrate comprising a proteinaceous material, wherein said proteinaceous material comprises one or more of: albumin, elastin, fibrin and soluble and insoluble forms of collagen and combinations thereof, and
(b) a heat stabilized dialdehyde crosslinking agent that has been produced by maintaining an initial dialdehyde crosslinking composition at a temperature ranging from about 45 to about 55° C. for a period of time ranging from about 1 to about 20 days, wherein said heat stabilized crosslinking agent has been heat stabilized prior to contacting said substrate;
wherein said fluid phase invertible composition goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow in a period of time ranging from about 10 seconds to about 10 minutes following crosslinking-of said substrate by said heat stabilized dialdehyde crosslinking agent.
2. The phase invertible composition according to claim 1 , wherein said substrate further comprises an adhesion modifier.
3. The phase invertible composition according to claim 2 , wherein said adhesion modifier is chosen from polyethyleneimine, gelatin and carboxymethylcellulose.
4. The phase invertible composition according to claim 1 , wherein said substrate further comprises a plasticizer.
5. The phase invertible composition according to claim 3 , wherein the plasticizer is chosen from polyethylene glycol, glycerin, a fatty acid, butylhydroxytoluene, and combinations thereof.
6. The phase invertible composition according to claim 1 , wherein said substrate further comprises a carbohydrate.
7. The phase invertible composition according to claim 1 , wherein said substrate further comprises a filler.
8. The phase invertible composition according to claim 1 , wherein said substrate further comprises a polyblend.
9. The phase invertible composition according to claim 1 , wherein said substrate further comprises a biologically active agent.
10. The phase invertible composition according to claim 1 , wherein said substrate further comprises a foaming agent.
11. The phase invertible composition according to claim 1 , wherein said crosslinking agent comprises glutaraldehyde.
12. A fluid phase invertible composition that goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow, wherein said composition is produced by combining:
(a) a fluid substrate comprising:
(i) a proteinaceous material, wherein said proteinaceous material comprises one or more of: albumin, elastin, fibrin and soluble and insoluble forms of collagen and combinations thereof, and
(ii) an adhesion modifier; and
(b) a heat stabilized dialdehyde crosslinking agent that has been produced by maintaining an initial dialdehyde crosslinking composition at a temperature ranging from about 45 to about 55° C. for a period of time ranging from about 1 to about 20 days, wherein said heat stabilized crosslinking agent has been heat stabilized prior to contacting said substrate;
wherein said fluid phase invertible composition goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow in a period of time ranging from about 10 seconds to about 10 minutes following crosslinking of said substrate by said heat stabilized dialdehyde crosslinking agent.
13. A fluid phase invertible composition that goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow, wherein said composition is produced by combining:
(a) a fluid substrate comprising:
(i) a proteinaceous material, wherein said proteinaceous material comprises one or more of: albumin, elastin, fibrin and soluble and insoluble forms of collagen and combinations thereof;
(ii) an adhesion modifier; and
(iii) a plasticizer; and
(b) a heat stabilized dialdehyde crosslinking agent that has been produced by maintaining an initial dialdehyde crosslinking composition at a temperature ranging from about 45 to about 55° C. for a period of time ranging from about 1 to about 20 days, wherein said heat stabilized crosslinking agent has been heat stabilized prior to contacting said substrate;
wherein said fluid phase invertible composition is goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow in a period of time ranging from about 10 seconds to about 10 minutes following crosslinking of said substrate by said heat stabilized dialdehyde crosslinking agent.
14. A method comprising:
(i) producing a fluid phase invertible composition in a step consisting essentially of mixing:
(a) a fluid substrate comprising a proteinaceous material, wherein said proteinaceous material comprises one or more of: albumin, elastin, fibrin and soluble and insoluble forms of collagen and combinations thereof; and
(b) a heat stabilized dialdehyde crosslinking agent that has been produced by maintaining an initial dialdehyde crosslinking composition at a temperature ranging from about 45 to about 55° C. for a period of time ranging from about 1 to about 20 days;
to produce said fluid phase invertible composition that goes from a first fluid state to a second non-fluid state in which said composition is incapable of fluid flow in a period of time ranging from about 10 second to about 10 minutes following combination of said substrate and said crosslinking agent; and
(ii) delivering said phase invertible composition to a site of a subject before said composition goes from said first fluid state to said second non-fluid state so that said phase invertible composition is delivered to said site of said subject in said first fluid state.
15. The phase invertible composition according to claim 12 , wherein said substrate further comprises a plasticizer.
16. The phase invertible composition according to claim 15 , wherein the plasticizer is chosen from polyethylene glycol, glycerin, a fatty acid, butylhydroxytoluene, and combinations thereof.
17. The phase invertible composition according to claim 12 , wherein said adhesion modifier is chosen from polyethyleneimine, gelatin and carboxymethylcellulose.
18. The phase invertible composition according to claim 12 , wherein said substrate further comprises a carbohydrate.
19. The phase invertible composition according to claim 12 , wherein said substrate further comprises a filler.
20. The phase invertible composition according to claim 12 , wherein said substrate further comprises a polyblend.
21. The phase invertible composition according to claim 12 , wherein said substrate further comprises a biologically active agent.
22. The phase invertible composition according to claim 12 , wherein said substrate further comprises a foaming agent.
23. The phase invertible composition according to claim 12 , wherein said crosslinking agent comprises glutaraldehyde.
24. The phase invertible composition according to claim 13 , wherein the plasticizer is chosen from polyethylene glycol, glycerin, a fatty acid, butylhydroxytoluene, and combinations thereof.
25. The phase invertible composition according to claim 13 , wherein said adhesion modifier is chosen from polyethyleneimine, gelatin and carboxymethylcellulose.
26. The phase invertible composition according to claim 13 , wherein said substrate further comprises a carbohydrate.
27. The phase invertible composition according to claim 13 , wherein said substrate further comprises a filler.
28. The phase invertible composition according to claim 13 , wherein said substrate further comprises a polyblend.
29. The phase invertible composition according to claim 13 , wherein said substrate further comprises a biologically active agent.
30. The phase invertible composition according to claim 13 , wherein said substrate further comprises a foaming agent.
31. The phase invertible composition according to claim 13 , wherein said crosslinking agent comprises glutaraldehyde.
32. The method according to claim 14 , wherein said substrate further comprises an adhesion modifier.
33. The method according to claim 32 , wherein said adhesion modifier is chosen from polyethyleneimine, gelatin and carboxymethylcellulose.
34. The method according to claim 14 , wherein said substrate further comprises a plasticizer.
35. The method according to claim 34 , wherein the plasticizer is chosen from polyethylene glycol, glycerin, a fatty acid, butylhydroxytoluene, and combinations thereof.
36. The method according to claim 14 , wherein said substrate further comprises a carbohydrate.
37. The method according to claim 14 , wherein said substrate further comprises a filler.
38. The method according to claim 14 , wherein said substrate further comprises a polyblend.
39. The method according to claim 14 , wherein said substrate further comprises a biologically active agent.
40. The method according to claim 14 , wherein said substrate further comprises a foaming agent.
41. The method according to claim 14 , wherein said crosslinking agent comprises glutaraldehyde.
42. A solid phase composition produced by the method of claim 14 .
43. A kit for producing a fluid phase invertible composition, said kit consisting essentially of:
(a) a fluid substrate comprising a proteinaceous material, wherein said proteinaceous material comprises one or more of: albumin, elastin, fibrin and soluble and insoluble forms of collagen and combinations thereof;
(b) a heat stabilized dialdehyde crosslinking agent that has been produced by maintaining an initial dialdehyde crosslinking composition at a temperature ranging from about 45 to about 55° C. for a period of time ranging from about 1 to about 20 days; and
(c) a mixing element for thoroughly combining said substrate and said crosslinker with each other to produce said fluid phase invertible composition;
wherein said components (a) and (b) are present in separate containers in said kit.
44. The kit according to claim 43 , wherein said kit further comprises a fluid delivery device.
45. The kit according to claim 43 , wherein said fluid delivery device is a catheter.
46. The kit according to claim 43 , wherein said kit further comprises a guiding element.
47. The method according to claim 14 , wherein said site is a vascular site.
48. The method according to claim 47 , wherein said method comprises producing a structural member from said phase invertible composition at said vascular site.
49. The method according to claim 48 , wherein said structural member is a stent.
50. The method according to claim 49 , wherein said method comprises delivering said phase invertible composition using a fluid delivery device.
51. The method according to claim 50 , wherein said fluid delivery device is a catheter having first and second occlusion members and an expandable mandrel at its distal end.
52. The method according to claim 51 , wherein said method comprises:.
occluding said first and second occlusion members and expanding said mandrel to produce a mold space; and
delivering said phase invertible composition to said mold space when said composition is in said first fluid state.
53. The composition according to claim 1 , wherein said heat stabilized dialdehyde crosslinking agent is produced by maintaining a dialdehyde composition at a at a temperature of from about 35 to about 60° C. for a period of time ranging from about 1 to about 20 days.
54. The composition according to claim 53 , wherein said dialdehyde is a glutaraldehyde.