Gradient Template for Angiogensis During Large Organ Regeneration

• US 20100145473A1
• Filed: 11/07/2006
• Published: 06/10/2010
• Est. Priority Date: 11/07/2005
• Status: Abandoned Application

• Current Assignee: Brendan Harley, Christpher J. Zagorski, Harry K. Reddy, Ioannis V. Yannas
• Original Assignee: Brendan Harley, Christpher J. Zagorski, Harry K. Reddy, Ioannis V. Yannas
• Inventors: Reddy, Harry K., Harley, Brendan, Zagorski, Christpher J., Yannas, Ioannis V.
• Application Number:
  US12/084,569
• Publication Number:
  US 20100145473A1
• Time in Patent Office: Days
• US Class Current: 623/23.720
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• 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

This invention relates to highly porous scaffolding and methods of producing the same. Specifically, the scaffolding comprises a pore volume fraction of no less than 80% (v/v) of the total volume of the scaffold and interconnecting pores forming channels in the scaffold.

Claims

1. A solid, porous biodegradable scaffold for implantation in a subject, comprising at least one polymer, and having a pore volume fraction of at least 80% of the total volume of said scaffold, comprising interconnected pores which form channels in said scaffold, wherein

a. said channels have a diameter of between 1-200 μ

m,

b. a negative gradient exists in said channel diameter along an axis of said scaffold; and

c. branching of said channels along said axis is proportional to said negative gradient

2. The scaffold of claim 1, wherein said channel diameter is inversely proportional to the distance of said channel from the host tissue.

3. The scaffold of claim 1, wherein said polymer comprises at least one synthetic or natural polymer, ceramic, metal, extracellular matrix protein or an analogue thereof.

4. The scaffold of claim 3, wherein said extracellular matrix proteins comprise a collagen, a glycosaminoglycan, or a combination thereof.

5. The scaffold of claim 1, wherein said scaffold varies in its cross-link density, which may be modified by any crosslinking technology known in the art.

6. The scaffold of claim 5, wherein said cross-linking agent is glutaraldehyde, formaldehyde, paraformaldehyde, formalin, (1 ethyl 3-(3dimethyl aminopropyl)carbodiimide (EDAC), or UV light, or a combination thereof.

7. The scaffold of claim 1, wherein said scaffold further comprises cells, extracellular matrix components, growth factors, cytokines, hormones, inflammatory stimuli, angiogenic factors, or a combination thereof.

8. The scaffold of claim 1, wherein the size and shape of said scaffold is a function of the tissue into which the scaffold is to be implanted.

9. The scaffold of claim 1, wherein said scaffold, when implanted, promotes angiogenesis within, or proximal to the scaffold.

10. The scaffold of claim 1, wherein said scaffold is comprised of a material whose stiffness is sufficient to resist compressive forces of tissue proximal to a site of implantation.

11. The scaffold of claim 1, wherein said pores have a diameter ranging from 30 μ

m-200 μ

m.

12. The scaffold of claim 11, wherein said scaffold is oriented such that regions of said scaffold with a larger pore diameter are placed proximally and regions with a smallest pore diameter are placed more distally to a site of said implantation in said subject.

13. The scaffold of claim 1, wherein said scaffold has a surface area of about 20,000 mm²/cm³, with an average pore diameter of about 35 μ

m and a pore volume fraction of over 90%.

17. A method of organ or tissue engineering in a subject, comprising the step of implanting a scaffold of claim 1 in said subject.

18. The method of claim 17, further comprising the step of implanting cells in said subject.

19. The method of claim 18, wherein said cells are seeded on said scaffold.

20. The method of claim 19, wherein said scaffold is cultured for a period of time prior to implantation in said subject.

21. The method of claim 19, wherein said cells are seeded at the periphery of said scaffold.

22. The method of claim 19, wherein said cells are stem or progenitor cells.

23. The method of claim 19, wherein said cells are engineered to express extracellular matrix components, growth factors, cytokines, hormones, inflammatory stimuli, angiogenic factors, or a combination thereof.

24. The method of claim 17, wherein said engineering is of an organ or tissue comprised of heterogeneous cell types.

25. The method of claim 17, wherein angiogenesis is stimulated within said scaffold.

26. The method of claim 17, wherein said scaffold comprises pores having a diameter ranging from 30 μ

m-200 μ

m.

27. The method of claim 25, wherein said scaffold is implanted proximally to a host tissue surface, with an orientation such that regions of said scaffold with a larger pore diameter are placed proximally and regions with a smallest pore diameter are placed more distally to said host tissue surface.

28. The method of claim 25, wherein at about 20 mm away from said host tissue surface, said pore diameter is about 100 μ

m.

29. The method of claim 25, wherein at about 40 mm away from said host tissue surface, said pore diameter is about 30 μ

m.

30. The method of claim 17, wherein said scaffold has a surface area of 20,000 mm²/cm³, with an average pore diameter of about 35 μ

m and a pore volume fraction of over 90%.

31. A method of organ or tissue repair or regeneration in a subject, comprising the step of implanting a scaffold of claim 1 in said subject.

32. The method of claim 31, further comprising the step of implanting cells in said subject.

33. The method of claim 32, wherein said cells are seeded on said scaffold.

34. The method of claim 32, wherein said scaffold is cultured for a period of time prior to implantation in said subject.

35. The method of claim 32, wherein said cells are seeded at the periphery of said scaffold.

36. The method of claim 32, wherein said cells are stem or progenitor cells.

37. The method of claim 32, wherein said cells are engineered to express extracellular matrix components, growth factors, cytokines, hormones, inflammatory stimuli, angiogenic factors, or a combination thereof.

38. The method of claim 31, wherein said engineering is of an organ or tissue comprised of heterogeneous cell types.

39. The method of claim 31, wherein angiogenesis is stimulated within said scaffold.

40. The method of claim 31, wherein said scaffold comprises pores having a diameter ranging from 30 μ

m-200 μ

m.

41. The method of claim 40, wherein said scaffold is implanted proximally to a host tissue surface, with an orientation such that regions of said scaffold with a larger pore diameter are placed proximally and regions with a smallest pore diameter are placed more distally to said host tissue surface.

42. The method of claim 41, wherein at about 20 mm away from said host tissue surface, said pore diameter is about 100 μ

m.

43. The method of claim 41, wherein at about 40 mm away from said host tissue surface, said pore diameter is about 30 μ

m.

44. The method of claim 31, wherein said scaffold has a surface area of 20,000 mm²/cm³, with an average pore diameter of about 35 μ

m and a pore volume fraction of over 90%.

14. A process for preparing a solid, porous, biodegradable scaffold having branched channels of decreasing diameter, the process comprising the steps of

a) applying a polymeric suspension to a mold comprised of a conductive material, wherein said mold has conical projections disposed at an angle to an axis, said conical projections having diameter between 1-200 μ

m;

b) super-cooling the suspension-filled mold in (a) in a refrigerant, for a period of time until said suspension is solidified, whereby ice crystals are formed in said solidified polymeric suspension; and

c) removing the conical projections from said solidified polimeric suspension, thereby exposing said polimeric suspension to sublimation conditions.

15. A scaffold, prepared according to the process of claim 14.

16. The scaffold of claim 15, wherein said pore volume is no less than 80%