COMPOSITIONS AND METHODS FOR JOINING NON-CONJOINED LUMENS

• US 20080045985A1
• Filed: 06/21/2007
• Published: 02/21/2008
• Est. Priority Date: 06/21/2006
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Gurtner, Geoffrey, Fuller, Gerald, Rajadas, Jayakumar, Longaker, Michael
• Granted Patent: US 8,216,259 B2
• Time in Patent Office: Days
• US Class Current: 606/154
• CPC Class Codes: A61B 17/00491 Surgical glue applicators surgical adhesives A61L24/00; two-component delivery syringes A61M5/19
• CPC Class Codes: A61B 17/04 for suturing wounds; Holders or packages for needles or suture materials suture materials A61L17/00
• CPC Class Codes: A61B 17/11 for performing anastomosis; Buttons for anastomosis
• CPC Class Codes: A61B 17/12022 Occluding by internal devices, e.g. balloons or releasable wires plugging an opening in the wall of an organ A61B17/0057; occluders for the cervical canal A61F6/146; vas deferens occluders A61F6/20
• CPC Class Codes: A61B 17/1204 temporary occlusion
• CPC Class Codes: A61B 17/12109 in a blood vessel
• CPC Class Codes: A61B 17/12186 liquid materials adapted to be injected
• CPC Class Codes: A61B 17/1219 expandable in contact with liquids
• CPC Class Codes: A61B 17/122 Clamps or clips , e.g. for the umbilical cord for the vas deferens A61F6/206
• CPC Class Codes: A61B 2017/1103 Approximator
• CPC Class Codes: A61B 2017/1107 for blood vessels

Abstract

Disclosed are compositions, methods, and kits for joining together non-conjoined lumens in a patient'"'"'s body including vascular lumens. More particularly, in various aspects, this invention provides compositions, methods, and kits for joining such non-conjoined lumens, including small lumens typically requiring microsurgical technique

Claims

1. A method for joining at least two non-conjoined lumens in a patient which method comprises:

a) providing a biocompatible solid mass in at least the distal portion of at least one of the lumens;

b) aligning the lumens;

c) closing the aligned lumens to form a conduit; and

d) removing the solid mass thereby establishing flow through the conduit.

2. The method of claim 1, wherein the solid mass is placed in the distal portion of each lumen to be joined.

3. The method of claim 1, wherein the solid mass is placed in the distal portion of a first lumen in a manner in which the solid mass protrudes from the distal portion such that this protrusion can be used as a male mating functionality with the distal portion of the second lumen which acts as a female mating functionality.

4. The method of claim 1, wherein the solid mass is sterile.

5. The method of claim 1, wherein the solid mass comprises a composition selected from among a sol-gel composition, a wax and a thixotropic agent.

6. The method of claim 5, wherein the sol-gel is a phase-reversible sol-gel.

9. The method of claim 1, wherein the solid mass further comprises a biologically active agent.

10. The method of claim 9, wherein the biologically active agent is selected from among one or more of:

an antithrombotic moiety, an anti-anginal moiety, an anti-coagulant, an antiinfective, an analgesic, an antiinflammatory moiety, an antiarrhythmic moiety, an antihypertensive moiety, a heart failure agent, a wound healing agent, an antiasthmatic agent, an antidiuretic agent, an antineoplastic agent, an antipyretic agent, and antispasmodic agent, and anticholinergic agent, an immunosuppressive agent, a sympathomimetic agent, a central nervous system stimulant;

a parasympatholytic agent, a hormone, a muscle relaxant, a lipid lowering agent;

an anti-ulcer agent, an anorexic, an antiarthritic, an anticonvulsant;

an antidepressant;

a sedative; and

a tranquilizer.

11. The method of claim 10, wherein the biologically active agent is an anti-coagulant.

12. The method of claim 11, wherein the anti-coagulant is heparin.

13. The method of claim 1, wherein the solid mass further comprises one or both moieties selected from a biocompatible dye and a contrast agent.

15. The method of claim 1, wherein the solid mass is removed by a method selected from melting, phase change, change in viscosity, dissolution in the body fluid and combinations thereof.

48. The method of claim 1, wherein the first lumen is a vessel of the cardiovascular system of a human.

49. The method of claim 48, wherein the second lumen is selected from the group consisting of a vessel of the cardiovascular system of a human, an arteriovenous graft, an arteriovenous shunt, an allograft, a xenograft, and a synthetic graft.

51. The method of claim 49, wherein the second lumen is a cadaver xenograft.

52. The method of claim 1, wherein at least one of the lumens has a diameter of less than 1 mm.

53. The method of claim 1, wherein the two lumens are selected from the group consisting of human fallopian tubes, vasa deferentia, tubes in the alimentary canal, pancreatic ducts, bile ducts, tear ducts, and mammary ducts.

54. The method of claim 1, wherein joining of the lumens is conducted using a biocompatible adhesive or with sutures.

55. The method of claim 54, wherein the biocompatible adhesive is selected from among a cyanoacrylate-based adhesive, a fibrin-based adhesive, a polyurethane-based adhesive, and a polyisocyanate-based adhesive.

56. The method of claim 54, wherein the adhesive is applied to the cross-sectional surfaces of the lumens.

57. The method of claim 54, wherein the adhesive is applied around the circumference of the joined lumens.

59. The method of claim 1, wherein the lumens are joined end to end.

60. The method of claim 1, wherein the lumens are joined end to side.

61. The method of claim 1, wherein the lumens are joined side to side.

7-8. -8. (canceled)

14. (canceled)

16. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a phase-reversible sol-gel inside at least a portion of the distal end of the first lumen in a manner which imparts structural integrity to said portion of the first lumen;

b) providing a phase-reversible sol-gel inside at least a portion of the distal end of a second lumen in a manner which imparts structural integrity to said portion of the second lumen;

c) aligning the distal portions of the first and second lumens;

d) joining said lumens so as to provide for a conduit;

e) inducing a phase change in the phase-reversible sol-gel in said conduit wherein said gel phase changes to a liquid phase;

f) allowing flow through said conduit.

18. The method of claim 16, wherein at least one of step a) or step b) comprises the step:

a1) placing the phase-reversible sol-gel in a gel phase inside at least a portion of the distal end of the first and/or the second lumen in a manner which imparts structural integrity to said portion of the first and/or the second lumen.

19. The method of claim 16, wherein at least one of step a) and step b) comprises the steps:

a2) placing the phase-reversible sol-gel in a liquid phase inside at least a portion of the distal end of the first and/or the second lumen; and

a3) inducing a phase transition change in the phase-reversible sol-gel in said first and/or second lumen wherein said liquid phase changes to a gel phase which imparts structural integrity to said portion of the first and/or the second lumen.

21. The method of claim 16, wherein phase-reversible sol-gel has an elastic modulus (G′

) of at least about 100 to about 500,000 Pascals when in a gel phase.

22. The method of claim 21, wherein the elastic modulus (G′

) is from about 100 to about 20,000 Pascals.

23. The method of claim 16, wherein the phase-reversible sol-gel is a thermoreversible sol-gel.

24. The method of claim 23, wherein the thermoreversible sol-gel has a transition temperature of from about 35°

C. to about 42°

C.

27. The method of claim 23, wherein the phase transition of the thermoreversible sol-gel occurs due to a change in temperature of about ±

1°

C. to about ±

10°

C.

28. The method of claim 23, wherein the thermoreversible sol-gel comprises a polymer and a solvent.

29. The method of claim 28, wherein the solvent is water.

30. The method of claim 29, wherein the polymer is a copolymer of poly(ethylene oxide) and poly(propylene oxide).

31. The method of claim 30, wherein the copolymer has a molecular weight of from about 8,000 to about 16,000.

34. The method of claim 30, wherein the copolymer is present in an amount of about 15% to about 20% by weight.

35. The method of claim 30, wherein the thermoreversible sol-gel further comprises a protein.

36. The method of claim 35, wherein the copolymer is present in an amount of about 15% to about 20% by weight, the protein is present in an amount of about 0.5% to about 2.0% by weight.

37. The method of claim 35, wherein the copolymer is present in an amount of about 17% by weight ±

20% of the 17%, the protein is present in an amount of about 1% by weight ±

20% of the 1% and water in an amount of about 82% by weight ±

20% of the 82%.

38. The method of claim 35, wherein said protein is an albumin.

39. The method of claim 38, wherein the albumin is selected from the group consisting of bovine serum albumin and human serum albumin.

17. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a phase-reversible sol-gel in a gel phase inside at least a portion of the distal end of a first lumen in a manner which imparts structural integrity to said portion of the first lumen;

b) providing a phase-reversible sol-gel in a gel phase inside at least a portion of the distal end of a second lumen in a manner which imparts structural integrity to said portion of the second lumen;

c) aligning the distal portions of the first and second lumens;

d) joining said lumens so as to provide for a conduit;

e) inducing a phase change in the phase-reversible sol-gel in said conduit wherein said gel phase changes to a liquid phase;

f) allowing flow through said conduit.

20. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a phase-reversible sol-gel in a gel phase inside at least a portion of the distal end of a first lumen in a manner which imparts structural integrity to said portion of the first lumen wherein said sol-gel protrudes from the distal end;

b) mating the distal end of a second lumen with said protrusion from the first lumen thereby aligning the first and second lumens;

c) joining said lumens so as to provide for a conduit;

d) inducing a phase change in the phase-reversible sol-gel in said conduit wherein said gel phase changes to a liquid phase;

e) allowing flow through said conduit.

25-26. -26. (canceled)

32-33. -33. (canceled)

40. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a solid biocompatible wax inside at least a portion of the distal end of the first lumen in a manner which imparts structural integrity to said portion of the first lumen;

b) providing a solid biocompatible wax inside at least a portion of the distal end of a second lumen in a manner which imparts structural integrity to said portion of the second lumen;

c) aligning the distal portions of the first and second lumens;

d) joining said lumens so as to provide for a conduit;

e) converting the wax from a solid to a dissolved and/or liquid form such that flow is established through said conduit.

42. The method of claim 40 or claim 41, wherein the wax has a melting point of between about 38°

C. to about 45°

C.

43. The method of claim 42, wherein the wax has a melting point of between about 39°

C. to about 42°

C.

44. The method of claim 40 or claim 41, wherein the wax comprises an agent selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, lignoceric acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, Steedman'"'"'s wax, and combinations thereof.

41. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a solid biocompatible wax inside at least a portion of the distal end of a first lumen in a manner which imparts structural integrity to said portion of the first lumen which wax protrudes from said distal end;

b) mating the distal end of a second lumen with said protrusion from the first lumen thereby aligning the first and second lumens;

c) joining said lumens so as to provide for a conduit;

d) converting the wax from a solid to a dissolved and/or liquid form such that flow is established through said conduit.

45. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a solid biocompatible thixotropic agent inside at least a portion of the distal end of the first lumen in a manner which imparts structural integrity to said portion of the first lumen;

b) providing a solid biocompatible thixotropic agent inside at least a portion of the distal end of a second lumen in a manner which imparts structural integrity to said portion of the second lumen;

c) aligning the distal portions of the first and second lumens;

d) joining said lumens so as to provide for a conduit;

e) converting said thixotropic agent from a solid to a dissolved and/or liquid form such that flow is established through said conduit.

46. A method for joining at least two non-conjoined lumens having distal ends, comprising the steps of:

a) providing a solid biocompatible thixotropic agent inside at least a portion of the distal end of a first lumen in a manner which imparts structural integrity to said portion of the first lumen which agent protrudes from said distal end;

b) mating the distal end of a second lumen with said protrusion from the first lumen thereby aligning the first and second lumens;

c) joining said lumens so as to provide for a conduit;

d) converting said thixotropic agent from a solid to a dissolved and/or liquid form such that flow is established through said conduit.

47. A method of connecting lumens within a living mammal, comprising the steps of:

providing a phase-reversible gel inside a first lumen in a manner which holds the first lumen open;

providing a phase-reversible gel inside a second lumen in a manner which holds the second lumen open;

applying adhesive between an end of the first lumen and an end of the second lumen and allowing the adhesive to form bonds between the first and second lumens;

inducing a phase change in the phase-reversible gel inside the first lumen and inside the second lumen; and

allowing flow through the first lumen to the second lumen.

50. (canceled)

58. The method of 57, wherein the adhesive further forms an external stent.

62. A thermoreversible sol-gel, comprising:

a) a polymer; and

b) water;

wherein said thermoreversible sol-gel having a sol-gel transition temperature of from about 35°

C. to about 42°

C. and a modulus of from at least about 100 to about 500,000 Pascals.

63. The thermoreversible sol-gel of claim 62, wherein the polymer is a block co-polymer of polyoxyethylene and polyoxypropylene or mixtures of such block copolymers.

64. The thermoreversible sol-gel of claim 63, wherein the copolymer has a molecular weight of from about 8,000 to about 16,000.

67. The thermoreversible sol-gel of claim 62, wherein the copolymer is present in an amount of about 15% to about 20% by weight.

68. The thermoreversible sol-gel of claim 62, further comprising a biocompatible protein.

69. The thermoreversible sol-gel of claim 68, wherein said biocompatible protein is selected from bovine serum albumin and human serum albumin.

71. The thermoreversible sol-gel of claim 68, wherein the copolymer is present in an amount of about 15% to about 20% by weight, the protein is present in an amount of about 0.5% to about 2.0% by weight.

72. The thermoreversible sol-gel of claim 68, wherein the copolymer is present in an amount of about 17% by weight ±

20% of the 17%, the protein is present in an amount of about 1% by weight ±

20% of the 1% and water in an amount of about 82% by weight ±

20% of the 82%.

73. The thermoreversible sol-gel of claim 62, further comprising a biologically active drug.

74. The thermoreversible sol-gel of claim 73, wherein the biologically active drug is selected from the group consisting of an antithrombotic moiety, an anti-anginal moiety, an anti-coagulant, an antiinfective, an analgesic, an antiinflammatory moiety, an antiarrhythmic moiety, an antihypertensive moiety, a heart failure agent, a wound healing agent, an antiasthmatic agent, an antidiuretic agent, an antineoplastic agent, an antipyretic agent, and antispasmodic agent, and anticholinergic agent, an immunosuppressive agent, a sympathomimetic agent, a central nervous system stimulant;

a parasympatholytic agent, a hormone, a muscle relaxant, a lipid lowering agent;

an anti-ulcer agent, an anorexic, an antiarthritic, an anticonvulsant;

an antidepressant;

a sedative; and

a tranquilizer.

75. The thermoreversible sol-gel of claim 74, wherein the anticoagulant agent is heparin.

65-66. -66. (canceled)

70. (canceled)

76. A vessel of a cardiovascular system of a mammal, wherein the vessel has a solid mass positioned in the vessel in a manner and in an amount sufficient to hold walls of the vessel open in a fashion similar to when blood flows through the vessel.

77-82. -82. (canceled)

83. A kit for connecting at least two non-conjoined lumens within a living mammal, comprising:

a delivering device; and

a composition selected from a sol-gel, a wax, and a thixotropic material.

84-88. -88. (canceled)