Fabrication of a vascular system using sacrificial structures

• US 9,242,027 B2
• Filed: 07/16/2009
• Issued: 01/26/2016
• Est. Priority Date: 07/18/2008
• Status: Active Grant

• Current Assignee: Cornell University
• Original Assignee: Cornell University
• Inventors: Bellan, Leon M., Craighead, Harold, Spector, Jason A.
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Singh, Randeep
• Application Number:
  US13/054,450
• Publication Number:
  US 20110270412A1
• Time in Patent Office: 2,385 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/3808 Endothelial cells
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body

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.

Claims

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.

38. The cell seeded monolith of claim 37, 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.

39. A method of treating a patient for a condition requiring vascularization, said method comprising:

providing a cell seeded monolith according to claim 35;

selecting a subject with a condition requiring vascularization; and

implanting the cell seeded monolith into the selected subject.

40. The method of claim 39, wherein said condition is selected from the group consisting of wound healing, organ transplantation, tissue transplantation, and burn treatment.

41. A method of forming a self healing material system, said comprising:

providing the solid preform of claim 30;

allowing for release of the healing agent from the vascular network upon injury to or cracking of the solid preform, whereby the injury or crack is filled.

42. The method according to claim 41, wherein the healing agent is contained either in a plurality of microcapsules dispersed in the solid matrix or flows within the vascular network.

43. A method of transferring heat to a surface or volume comprising:

providing the solid preform of claim 31 and

passing a fluid through the vascular network whereby the solid preform heats or cools the fluid or the fluid heats or cools the solid preform.

44. A method of carrying out a biological reaction comprising:

providing the cell seeded monolith of claim 35 and

passing a fluid through the vascular network under conditions effective to carry out the biological reaction.

45. The method according to claim 44, wherein the biological reaction produces a biochemical agent or molecule.

46. The method according to claim 44, where the biological reaction is an assay to determine the effect of a drug or biochemical agent on the cells seeded within the monolith.

47. The method according to claim 44, wherein the fluid comprises cells or cellular materials.