COMPOSITIONS AND METHODS FOR JOINING NON-CONJOINED LUMENS

• US 20100204718A1
• Filed: 02/06/2009
• Published: 08/12/2010
• Est. Priority Date: 02/06/2009
• Status: Active Grant

• Current Assignee: Tautona Group LP
• Original Assignee: Synvascular, Inc.
• Inventors: Rimsa, Joseph, Rappleye, C. Travis, Hoffmann, Drew A.
• Granted Patent: US 8,563,037 B2
• Time in Patent Office: Days
• US Class Current: 606/153
• CPC Class Codes: A61L 24/001 Use of materials characterised by their function or physical properties
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: C08L 71/02 Polyalkylene oxides

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 thermoreversible sol-gel composition for surgical use comprising poloxamer 188 or poloxamer 407 or a mixture thereof, which composition has a transition temperature of from about 0°

C., to about 40°

C., and a gel phase elastic modulus of at least about 40,000 Pascals.

2. The composition of claim 1, wherein the transition temperature is about 20°

C. to 35°

C.

3. The composition of claim 1, wherein the gel phase elastic modulus of at least about 50,000 Pascals.

16. The composition of claim 1 or 4, further comprises a biologically active agent, a biocompatible dye and/or a biocompatible contrasting agent.

19. The composition of claim 16, wherein the biologically active agent is selected from the group consisting of anti-coagulants, anti-spasm agents, anti-restenosis agents, pro-angiogenic agents and combinations thereof, which biologically active agent is optionally formulated in sustained release or in gene vectors.

20. The composition of claim 19, wherein the biologically active agent is selected from the group consisting of heparin, fibroblast growth factor, insulin-like growth factor, vascular endothelial growth factor, hepatocyte growth factor, monocyte chemotactic protein-1, nitroglycerine, everolimus, sirolimus, paclitaxel, rapamycin, biolimus and combinations thereof.

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

(a) applying a composition of claim 1 or 4 in at least the distal portion of at least one of the lumens in a manner which imparts structural integrity to said portion of the lumen; and

(b) joining the lumens to form a conduit.

26. A method for joining at least two non-conjoined lumens in a patient, wherein at least one of the lumens has a clamp to arrest the flow of the fluid therein, which method comprises:

(a) providing a biocompatible phase-reversible sol-gel composition of claim 1 or 4 in a gel phase in at least the distal portion of at least of the lumen having the clamp;

(b) aligning the lumens;

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

(d) inducing a phase transition of the sol-gel wherein the sol-gel changes from the gel phase to a liquid phase;

(e) confirming substantial completion of the phase transition; and

(f) removing the clamp(s) thereby establishing flow through the conduit.

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

(a) approximating the lumens in a connecting position;

(b) providing a biocompatible phase-reversible sol-gel composition of claim 1 or 4 in a gel phase in the distal portion of both lumens;

(c) closing the lumens to form a conduit;

(d) inducing a phase transition of the sol-gel wherein the sol-gel changes from the gel phase to a liquid phase; and

(e) establishing flow through the conduit.

28. The method of claim 27, further comprises a step before step (a), which step comprises arresting the flow of body fluid in the lumens.

29. The method of claim 28, wherein the arresting the flow of body fluid in the lumen comprises clamping at least one of the lumens or by applying a pressure on at least one of the lumens.

31. The method of claim 27, wherein step (e) comprises (e1) and (e2), wherein (e1) comprises confirming substantial completion of the phase transition, and wherein (e2) comprises removing the clamps thereby establishing flow through the conduit and removing the sol-gel composition.

32. The method of claim 27, wherein the approximating the lumens in a connecting position comprises partially suturing the lumens.

33. The method of claim 26, further comprising flushing the distal potion of the clamped lumen with a biocompatible liquid prior to step (a).

34. A method for joining at least two non-conjoined lumens in a patient, wherein at least one of the lumens is clamped to arrest the flow of body fluid therein, which method comprises:

flushing the distal potion of the clamped lumen with a biocompatible liquid;

approximating the lumens in a connecting position, which approximating comprises partially suturing the lumens;

providing a biocompatible phase-reversible sol-gel composition of claim 1 or 4 in a gel phase in the distal portion of both lumens;

closing the lumens to form a conduit with a biocompatible adhesive;

inducing a phase transition of the sol-gel wherein the sol-gel changes from the gel phase to a liquid phase;

confirming substantial completion of the phase transition; and

removing the clamps thereby establishing flow through the conduit and removing the sol-gel composition.

41. The method of any one of claims 23, wherein the phase transition change of the composition is induced by raising the temperature of the lumen to above the transition temperature of the composition.

42. The method of any one of claims 23, wherein the composition is removed by lowering the temperature of the lumen to below the transition temperature of the composition.

43. The method of any one of claims 23, wherein the composition is removed by dissolution with body fluid.

44. The method of any one of claims 23, wherein the lumens are joined by applying a biocompatible 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.

45. The method of claim 44, wherein the biocompatible adhesive is selected from among a cyanoacrylate-based adhesive, a fibrin-based adhesive, a polyurethane-based adhesive, an ultraviolet curable gel, a protein based glue and a polyisocyanate-based adhesive.

48. The method of claim 45, wherein the adhesive further forms an external stent.

49. The method of claim 48, wherein adhesive forming the external stent comprising an anti-proliferative drug.

50. The method of claim 49, wherein the anti-proliferative drug is paclitaxel or rapamycin.

51. The method of any one of claims 23, wherein the joining of the lumens comprises sutures, applying a biocompatible adhesive, applying laser, electrocautery or combinations thereof.

54. The method of any one of claims 23, wherein the first lumen is a vessel of the cardiovascular system of a human.

55. The method of claim 54, wherein the second lumen is selected from the group consisting of a vessel of the cardiovascular system of a human, an arteriovenous graft and an arteriovenous shunt.

56. The method of claim 54, wherein the second lumen is selected from the group consisting of an allograft, a xenograft, a cadaver xenograft and a synthetic graft.

58. The method of any one of claims 23, wherein at least one of the lumens has a diameter of less than 1 mm.

59. The method of any one of claims 23, wherein the two lumens are selected from the group consisting of human fallopian tubes, vas deferens, tubes in the alimentary canal, pancreatic ducts, bile ducts, tear ducts, and mammary ducts.

60. The method of any one of claims 23, wherein the lumens are joined end to end, or end to side, or side to side.

63. A vessel of a cardiovascular system of a mammal, wherein the vessel has a composition of claim 1 or 4 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.

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

a delivering device; and

a composition of claim 1 or 4.

65. The kit of claim 64, wherein the delivering device is a syringe optionally coupled with a heating or cooling component and optionally loaded with the composition, a catheter or a laparoscopic tool.

69. The kit of claim 64, further comprising at least one clamp for closing at least one of the non-conjoined lumen, a biocompatible adhesive for sealing the lumens, or a heat source, or a combination thereof.

4. A thermoreversible sol-gel composition comprising:

a) greater than 35% w/w to about 48% w/w of poloxamer 188 or poloxamer 407 or a mixture thereof, and

b) an aqueous salt solution having an ionic strength of 0.05 M to 0.4 M.

5. The composition of claim 4, wherein the composition has a gel phase elastic modulus of at least about 20,000 Pascals.

6. The composition of claim 5, wherein the gel phase elastic modulus is at least about 40,000 Pascals.

7. The composition of claim 6, wherein the gel phase elastic modulus is at least about 50,000 Pascals.

8. The composition of claim 4, comprising about 45% w/w of poloxamer 188.

9. The composition of claim 4, comprising about 36% w/w of a mixture of poloxamer 188 and poloxamer 407 in a ratio of about 1.5:

1.

10. The composition of claim 4, wherein the salt is selected from the group consisting of sodium chloride, potassium chloride, sodium sulfate, sodium bisulfate, sodium phosphate, monosodium phosphate, disodium phosphate, potassium phosphate, monopotassium phosphate, dipotassium phosphate, calcium chloride, magnesium chloride, and a combination thereof.

11. The composition of claim 4, wherein the aqueous salt solution has an ionic strength that is equal to the ionic strength of a solution having a pH of about 7.4 and comprising about 68 mM to 274 mM of sodium chloride, about 1.3 mM to 5.4 mM of potassium chloride and about 5 mM to 20 mM of phosphate ion.

12. The composition of claim 11, wherein the aqueous salt solution is a solution having a pH of about 7.4 and comprising about 68 mM and 274 mM of sodium chloride, about 1.3 mM to 5.4 mM of potassium chloride, and about 5 mM to 20 mM of phosphate ion.

13. The composition of claim 12, wherein the aqueous salt solution is phosphate buffered saline.

14. The composition of claim 4, comprising

about 14.4% w/w of poloxamer 407;

about 21.6% w/w of poloxamer 188;

and about 64% w/w of phosphate buffered saline solution.

15. The composition of claim 4, comprising

about 45% w/w of poloxamer 188;

and about 55% w/w of phosphate buffered saline solution.

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