Method for making a porous polymeric material

• US 20040267354A1
• Filed: 06/09/2004
• Published: 12/30/2004
• Est. Priority Date: 05/13/1994
• Status: Abandoned Application

• Current Assignee: Kensey Nash Corporation (DSM-Firmenich AG)
• Original Assignee: Kensey Nash Corporation (DSM-Firmenich AG)
• Inventors: Ringeisen, Timothy A., Goldman, Scott M.
• Application Number:
  US10/864,143
• Publication Number:
  US 20040267354A1
• Time in Patent Office: Days
• US Class Current: 623/1.42
• CPC Class Codes: A61L 2300/114 Nitric oxide, i.e. NO
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 2300/802 Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/48 with macromolecular fillers
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• 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: C08J 2201/054 Precipitating the polymer by adding a non-solvent or a different solvent
• CPC Class Codes: C08J 9/28 by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
• CPC Class Codes: C08L 75/04 Polyurethanes
• CPC Class Codes: Y10T 428/1386 Natural or synthetic rubber or rubber-like compound containing
• CPC Class Codes: Y10T 428/139 Open-ended, self-supporting conduit, cylinder, or tube-type article

Abstract

Porous polymers having a plurality of openings or chambers that are highly convoluted, with each chamber being defined by multiple, thin, flat partitions are produced by a new gel enhanced phase separation technique. In a preferred embodiment, a second solvent is added to a polymer solution, the second solvent causing the solution to gel. The gel can then be shaped as needed. Subsequent solvent extraction leaves the porous polymeric body of defined shape. The porous polymers have utility as medical prostheses, the porosity permitting ingrowth of neighboring tissue. A second polymer material may be incorporated into the chambers, thereby creating a microstructure filling the voids of the macrostructure. A porous polymeric body manufactured by this process may serve to deliver biologically active agents in a time-staged delivery manner, where differing drugs may be delivered over differing periods.

Claims

1. A porous body suitable for implant in a living being comprising a microstructure, a macrostructure, a first biologically active agent, and a second biologically active agent, said microstructure being arranged to cause a first response upon exposure of the living being to the first biologically active agent, and said macrostructure being arranged to cause a second, and opposing, response upon exposure of the living being to the second biologically active agent.

2. The porous body of claim 1, wherein said macrostructure comprises a polymer.

3. The porous body of claim 1, wherein said microstructure comprises a polymer.

4. The porous body of claim 1, wherein said microstructure comprises a coating inside a plurality of void spaces contained within said macrostructure.

5. The porous body of claim 1, wherein said first and second biologically active agents are delivered sequentially.

6. The porous body of claim 1, wherein said first and second responses cause biological responses opposing each other.

7. The porous body of claim 1, wherein said microstructure comprises said first biologically active agent.

8. The porous body of claim 1, wherein said macrostructure comprises said second biologically active agent.

9. The porous body of claim 1, wherein said first response comprises an increase in activity and said second response comprises a reduction in said activity.

10. The porous body of claim 1, wherein said first response promotes a first tissue type and said second response promotes a second tissue type.

11. The porous body of claim 1, said macrostructure being manufactured by a process comprising the steps of:

a. selecting a polymer;

b. identifying a first solvent that is capable of substantially dissolving a solid form of the polymer;

c. identifying a second solvent that does not substantially dissolve the polymer in solid form, but instead merely swells the solid polymer;

d. providing at least sufficient first solvent to said polymer as to substantially dissolve the polymer in the first solvent to form a solution;

e. adding a quantity of the second solvent to the solution, whereupon the solution begins to gel without forming a precipitate;

f. continuing the adding of the second solvent until a viscosity of the gel increases to a point where the gel is suitable for shape-forming;

g. shape-forming the gel; and

h. removing the first and second solvents from the gel.

12. The porous body of claim 1, wherein said first biologically active agent is at least one of VEGF, PDGF, retinoic acid, ascorbic acid, aFGF, bFGF, TGF-alpha, TGF-beta, Epidermal GF, Hepatocyte GF, IL-8, Platelet Activating Factor, Granulocyte-colony stimulating Factor, Placental GF, Ploriferin, B61, Soluble Vascular Cell Adhesion Molecule, Soluble E-selectin, 12-hydroxyeicosatetraenoic acid, Angiogenin, TNF-alpha, Prostaglandin, Fas ligand.

13. The porous body of claim 1, wherein said second biologically active agent is at least one of sirolimus, cyclosporin, tacrolimus, paclitaxel, cisplatin, Actinomycin-D, L-nitro arginine methyl ester, mycophenolate mofetil, TP53, RB, VHL, Thrombospondin-1, Angiostatin, Endostatin, spliced HGH, PF4, Interferon-gamma, inducible protein 10, gro-beta, IL-12, Heparinase, Proliferin related protein, or 2-methoxyoestradiol.

14. The porous body of claim 1, wherein said macrostructure is at least partially non-resorbable.

15. The porous body of claim 1, wherein said microstructure is at least partially resorb able.

16. The porous body of claim 1, wherein said microstructure comprises a chemotactic ground substance.

17. The porous body of claim 1, wherein said first biologically active agent is chemically bound to said microstructure.

18. The porous body of claim 1, wherein said second biologically active agent is physically entrapped in said macrostructure.

19. The porous body of claim 1, wherein said implant is capable of being terminally sterilized, wherein said terminal sterilization comprises at least one of high energy irradiation, gas sterilization, plasma gas sterilization, heat sterilization, or chemical sterilization.

20. The porous body of claim 1 wherein said microstructure is arranged to insulate said living being from exposure to said second biologically active agent for a period of time after implantation in said living being.

21. The porous body of claim 1, wherein said porous body is arranged to be a vascular graft implant.

22. The porous body of claim 21, wherein said vascular graft implant is arranged to bypass a vessel of said living being, and further wherein said vascular graft implant has a compliance approximating that of the bypassed vessel.

23. The porous body of claim 21, wherein said macrostructure comprises a plurality of pores of an average pore size between about 10 microns and about 300 microns.

24. The porous body of claim 21, wherein at least one end of said vascular graft implant has a shape that encourages optimal fluid flow therethrough.

25. The porous polymeric body of claim 24, wherein said macrostructure is arranged to slow the flow of blood therethrough, whereupon said vascular graft implant is self-sealing after suturing.

26. The porous body of claim 21, wherein said vascular graft implant is capable of being bent and made resistant to kinking.

27. The porous body of claim 21, wherein said microstructure is arranged to provide increased resistance to fluid flow through said macrostructure.

28. The porous body of claim 21, wherein said vascular graft implant is arranged to be delivered laparoscopically.

29. A porous body suitable for implant in a living being comprising a microstructure and a macrostructure, and a biologically active agent, said macrostructure being arranged to cause a response upon exposure of the living being to said biologically active agent, and said microstructure being arranged to insulate said living being from exposure to said biologically active agent for a period of time after implantation in said living being.

30. The porous body of claim 29, wherein said macrostructure comprises a polymer.

31. The porous body of claim 29, wherein said microstructure comprises a polymer.

32. The porous body of claim 29, wherein said microstructure comprises a coating inside a plurality of void spaces contained within said macrostructure.

33. The porous body of claim 29, wherein said macrostructure comprises said biologically active agent.

34. The porous body of claim 29, said macrostructure being manufactured by a process comprising the steps of:

a. selecting a polymer;

b. identifying a first solvent that is capable of substantially dissolving a solid form of the polymer;

c. identifying a second solvent that does not substantially dissolve the polymer in solid form, but instead merely swells the solid polymer;

d. providing at least sufficient first solvent to said polymer as to substantially dissolve the polymer in the first solvent to form a solution;

e. adding a quantity of the second solvent to the solution, whereupon the solution begins to gel without forming a precipitate;

f. continuing the adding of the second solvent until a viscosity of the gel increases to a point where the gel is suitable for shape-forming;

g. shape-forming the gel; and

h. removing the first and second solvents from the gel.

35. The porous body of claim 29, wherein said biologically active agent is selected from at least one of VEGF, PDGF, retinoic acid, ascorbic acid, aFGF, bFGF, TGF-alpha, TGF-beta, Epidermal GF, Hepatocyte GF, IL-8, Platelet Activating Factor, Granulocyte-colony stimulating Factor, Placental GF, Ploriferin, B61, Soluble Vascular Cell Adhesion Molecule, Soluble E-selectin, 12-hydroxyeicosatetraenoic acid, Angiogenin, TNF-alpha, Prostaglandin, Fas ligand, sirolimus, cyclosporin, tacrolimus, paclitaxel, cisplatin, Actinomycin-D, L-nitro arginine methyl ester, mycophenolate mofetil, TP53, RB, VHL, Thrombospondin-1, Angiostatin, Endostatin, spliced HGH, PF4, Interferon-gamma, inducible protein 10, gro-beta, IL-12, Heparinase, Proliferin related protein, or 2-methoxyoestradiol.

36. The porous body of claim 29, wherein said macrostructure is at least partially non-resorbable.

37. The porous body of claim 29, wherein said microstructure is at least partially resorbable.

38. The porous body of claim 29, wherein said microstructure comprises a chemotactic ground substance.

39. The porous body of claim 29, wherein said biologically active agent is physically entrapped in said macrostructure.

40. The porous body of claim 29, wherein said implantable porous body is capable of being terminally sterilized, and said terminal sterilization comprises at least one of high energy irradiation, gas sterilization, plasma gas sterilization, heat sterilization, or chemical sterilization.

41. The porous body of claim 29, wherein said porous body is arranged to be a vascular graft implant.

42. The porous body of claim 41, wherein said vascular graft implant is arranged to bypass a vessel of said living being, and further wherein said vascular graft implant has a compliance approximating that of the bypassed vessel.

43. The porous body of claim 41, wherein at least one end of said vascular graft implant has a shape that encourages optimal fluid flow therethrough.

44. The porous polymeric body of claim 43, wherein said macrostructure is arranged to slow the flow of blood therethrough, whereupon said vascular graft implant is self-sealing after suturing.

45. The porous body of claim 41, wherein said vascular graft implant is capable of being bent and is resistant to kinking.

46. The porous body of claim 41, wherein said microstructure is arranged to provide increased resistance to fluid flow through said macrostructure.

47. A porous body suitable for implant in a living being comprising a microstructure, a macrostructure, a first biologically active agent, and a second biologically active agent, said microstructure being arranged to cause a first response upon exposure of the living being to the first biologically active agent, and said macrostructure being arranged to cause a second response upon exposure of the living being to the second biologically active agent, wherein said first biologically active agent is an anti-coagulant, and wherein said second biologically active agent is an anti-proliferative.

48. The porous body of claim 47, wherein said second biologically active agent is at least one of sirolimus, cyclosporin, tacrolimus, paclitaxel, cisplatin, Actinomycin-D, L-nitro arginine methyl ester, mycophenolate mofetil, TP53, RB, VHL, Thrombospondin-1, Angiostatin, Endostatin, spliced HGH, PF4, Interferon-gamma, inducible protein 10, gro-beta, IL-12, Heparinase, Proliferin related protein, or 2-methoxyoestradiol.

49. The porous body of claim 47, wherein said first biologically active agent is heparin.