Fabrication of a vascular system using sacrificial structures

Patent metadata

Field	Value
Publication number	US-9242027-B2
Application number	US-200913054450-A
Country	US
Kind code	B2
Filing date	Jul 16, 2009
Priority date	Jul 18, 2008
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

The first aspect of the present invention is directed to a method of producing a vascular network preform (VNP). This method involves forming a network of elongate fibers and at least one elongate structure from a sacrificial material. The diameter of the elongate structure is greater than that of the elongate fibers. The network of elongate fibers is placed in contact with at least one elongate structure either following or during forming the network of elongate fibers or forming the at least one elongate structure. A matrix is applied around the network of elongate fibers, in contact with the at least one elongate structure. The network of elongate fibers and elongate structure, within the matrix is sacrificed to form a preform. The resulting preform contains a vascular network of fine diameter tubes in contact with at least one elongate passage having a diameter greater than that of the fine diameter tubes. The resulting solid preform and methods of using it are also disclosed.

First claim

What is claimed:

1. A method of producing a vascular network preform, said method comprising:
forming a network of elongate fibers randomly extending in a non-repeating pattern from a sacrificial material;
forming at least one elongate structure from a sacrificial material, wherein the elongate structure has a diameter greater than that of the elongate fibers;
placing the network of elongate fibers and the at least one elongate structure in contact with one another following or during said forming a network of elongate fibers or said forming at least one elongate structure;
applying a matrix around the network of elongate fibers in contact with the at least one elongate structure; and
sacrificing the network of elongate fibers and the at least one elongate structure within the matrix to form a preform containing a vascular network of fine diameter tubes in fluid communication with at least one elongate passage having a diameter greater than that of the fine diameter tubes.

2. The method of claim 1 , wherein said forming at least one elongate structure comprises forming at least two elongate structures, whereby said method produces a preform containing a vascular network of fine diameter tubes in contact with at least two elongate passages.

3. The method of claim 1 , wherein the at least one elongate structure is branched.

4. The method of claim 1 wherein the elongate fibers are enmeshed with one another.

5. The method of claim 1 , wherein the diameter of the elongate fibers is 1 to 100 microns.

6. The method of claim 1 , wherein the diameter of the at least one elongate structure is 500 microns or greater.

7. The method of claim 1 , wherein said forming a network of elongate fibers is carried out by melt-spinning, wet-spinning, dry-spinning, dry-jet wet spinning, electrospinning, or extrusion.

8. The method of claim 1 , wherein the sacrificial material is selected from the group consisting of sucrose, polyethylene oxide, polyvinyl acetate, nylon, cellulose, polymethyl methacrylate, and other polymers.

9. The method of claim 1 , wherein said sacrificing is carried out by solubilizing in a solvent, heat decomposition, reactive gas decomposition, light decomposition, enzymatic degradation, and/or catalytic degradation.

10. The method of claim 1 , wherein the sacrificial materials used to form the network of elongate fibers and the at least one elongate structure are the same.

11. The method of claim 1 , wherein the sacrificial materials used to form the network of elongate fibers and the at least one elongate structure are different.

12. The method of claim 1 , wherein the matrix is a polymer.

13. The method of claim 12 , wherein the polymer is selected from the group consisting of polydimethylsiloxane, polyglycerol sebacate, polycaprolactone, polylactic acid, polyglycolic acid, cellulose, alginate, agar, agarose, collagen I, collagen IV, hyaluronic acid, fibrin, poly-L-lactide, and poly(lactic-co-glycolic acid).

14. The method of claim 1 further comprising:
orienting the network of elongate fibers and the at least one elongate structure after said placing them in contact with one another.

15. The method of claim 1 further comprising:
connecting the network of elongate fibers and the at least one elongate structure, which are in contact with another, together.

16. The method of claim 1 , wherein said applying a matrix comprises:
applying a flowable material around the network of elongate fibers in contact with the at least one elongate structure and
solidifying the flowable material to form a solid matrix.

17. The method of claim 16 further comprising:
adding a porogen to the matrix before or after said solidifying under conditions effective to introduce pores into the preform.

18. The method of claim 1 further comprising:
incorporating one or more drugs and/or biochemical agents into the matrix.

19. The method according to claim 18 , wherein the drug or biochemical agent is selected from the group consisting of nutrients, growth factors, inducers of differentiation or de-differentiation, products of secretion, immunomodulators, inhibitors of inflammation, regression factors, and biological factors which enhance or allow ingrowth of the vascular, muscular, lymphatic or neural tissue.

20. The method of claim 1 further comprising:
seeding the preform containing a vascular network of fine diameter tubes in contact with at least one elongate passage with cells and
incubating the cells seeded in the preform.

21. The method of claim 20 , wherein the cells are endothelial cells.

22. A solid preform comprising:
a solid matrix;
a vascular network of fine diameter tubes randomly extending in a non-repeating pattern within the solid matrix; and
at least one elongate passage having a diameter greater than that of the fine diameter tubes, said at least one elongate passage extending within the solid matrix and in fluid communication with the vascular network of fine diameter tubes.

23. The solid preform of claim 22 , wherein the fine diameter tubes are enmeshed.

24. The solid preform of claim 22 , wherein the at least one elongate passage is branched.

25. The solid preform of claim 22 , wherein the diameter of the fine diameter tubes is 1 to 100 microns.

26. The solid preform of claim 22 , wherein the diameter of the at least one elongate passage is 500 microns or greater.

27. The solid preform of claim 22 , wherein the solid matrix is a polymer.

28. The solid preform of claim 27 , wherein the polymer is selected from the group consisting of polydimethylsiloxane, polyglycerol sebacate, polycaprolactone, polylactic acid, polyglycolic acid, cellulose, alginate, agar, agarose, collagen I, collagen IV, hyaluronic acid, fibrin, poly-L-lactide, and poly(lactic-co-glycolic acid).

29. The solid preform of claim 22 further comprising:
a polymerization catalyst in the solid preform suitable to convert a healing agent to a filler at sites of injury or cracking in the solid preform.

30. The solid preform of claim 29 , wherein the healing agent is located in the vascular network within the solid preform.

31. The solid preform of claim 22 , wherein the solid preform is configured such that there is transfer of heat between the solid matrix and a fluid present in the vascular network.

32. The solid preform of claim 22 , wherein the solid matrix is sealed so that fluids can only enter the solid preform through the at least one elongate passage.

33. The solid preform of claim 22 , wherein the solid preform is porous.

34. The solid preform of claim 22 , wherein said solid preform comprises at least two elongate passages, with at least one of the elongate passages being configured to permit entry of fluid in said vascular network and at least one of the elongate passages being configured to permit fluid to be withdrawn from said vascular network.

35. A cell seeded monolith comprising:
the solid preform of claim 22 and
cells seeded in the solid preform.

36. The cell seeded monolith of claim 35 , wherein the cells are endothelial cells.

37. The cell seeded monolith of claim 35 , wherein the monolith comprises one or more drugs and/or biochemical agents.

3

Assignees

• Bellan Leon M
• Craighead Harold
• Spector Jason A
• Univ Cornell

Inventors

• Bellan Leon M
• Craighead Harold
• Spector Jason A

Classifications

• A61L27/58

  Materials at least partially resorbable by the body · CPC title

• A61L2300/414

  Growth factors · CPC title

• A61L2300/426

  Immunomodulating agents, i.e. cytokines, interleukins, interferons · CPC title

• A61L2300/602

  Type of release, e.g. controlled, sustained, slow · CPC title

• A61L27/54

  Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} · CPC title