SCAFFOLDS AND METHODS OF FORMING THE SAME

• US 20110311746A1
• Filed: 06/02/2011
• Published: 12/22/2011
• Est. Priority Date: 06/02/2010
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Ma, Peter X., Ma, Haiyun
• Granted Patent: US 9,066,997 B2
• Time in Patent Office: Days
• US Class Current: 428/36.91
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2240/004 Using a positive or negative model, e.g. moulds
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: Y10T 428/139 Open-ended, self-supporting conduit, cylinder, or tube-type article
• CPC Class Codes: Y10T 428/1393 Multilayer [continuous layer]

Abstract

Various embodiments of scaffolds are disclosed herein. In one embodiment, the scaffold includes a tubular polymeric structure, and a controlled gradient of solid-walled microtubules oriented radially or axially in the tubular polymeric structure. In another embodiment, the scaffold includes a nano-fibrous tubular polymeric structure, and an oriented and interconnected microtubular porous network formed in the nano-fibrous tubular polymeric structure. In still another embodiment, a composite scaffold is formed including a polymeric structure having an inner wall and an outer wall, and at least one electrospun layer positioned along at least one of the inner wall, or the outer wall, or in a middle of the porous polymeric structure.

Claims

1. A scaffold, comprising:

a tubular polymeric structure; and

a controlled gradient of solid-walled microtubules oriented radially or axially in the tubular polymeric structure.

2. The scaffold as defined in claim 1 wherein the controlled gradient of solid-walled microtubules is axially oriented in the tubular polymer structure, wherein a porosity of the scaffold ranges from about 70% to about 99% of a total volume of the scaffold, and wherein each of the microtubules has an average pore diameter ranging from about 20 μ

m to about 200 μ

m.

3. The scaffold as defined in claim 2 wherein a cross-section of each of the solid-walled microtubules is a polygon with a number of sides ranging from 3 to 7.

4. The scaffold as defined in claim 1 wherein the controlled gradient of solid-walled microtubules is radially oriented in the tubular polymeric structure, and wherein a diameter of each solid-walled microtubule decreases from an outer surface of the tubular polymeric structure to an inner surface of the tubular polymeric structure.

5. The scaffold as defined in claim 1 wherein the controlled gradient of solid-walled microtubules is radially oriented in the tubular polymeric structure, and wherein a diameter of each solid-walled microtubule decreases from an inner wall of the tubular polymeric structure to an outer wall of the tubular polymeric structure.

6. A method of making a scaffold, comprising:

pouring a polymer solution into a mold formed of at least two materials having different thermal conductivities such that a predetermined temperature gradient can be formed in the mold;

exposing the mold and the polymer solution therein to a temperature ranging from −

200°

C. to 20°

C. to form the temperature gradient and to thermally induce phase separation of the polymer solution into a polymer/solvent system; and

freeze-drying the polymer/solvent system to form the vessel scaffold having a polymeric structure and a controlled gradient of microtubules oriented radially or axially therein.

7. The method as defined in claim 6 wherein the mold is a cylinder having a wall, a removable top, a removable bottom, and an insertable shaft, and wherein pouring the polymer solution into the mold includes pouring the polymer solution in a space formed between the wall and the insertable shaft.

8. The method as defined in claim 7 wherein the wall is formed of a first material, wherein the removable top, the removable bottom, and the insertable shaft are each formed of a second material having a lower conductivity than the first material, and wherein the predetermined temperature gradient is formed in a radial direction where a warmer portion of the temperature gradient is adjacent the insertable shaft and a colder portion of the temperature gradient is adjacent the wall.

9. The method as defined in claim 7 wherein the wall is formed of a first material, wherein the removable top, the removable bottom, and the insertable shaft are each formed of a second material having a higher thermal conductivity than the first material, and wherein the predetermined temperature gradient is formed in a radial direction where a warmer portion of the temperature gradient is adjacent the wall and a colder portion of the temperature gradient is adjacent the insertable shaft.

10. The method as defined in claim 7 wherein the removable bottom is formed of a first material, wherein the removable top, the wall, and the insertable shaft are each formed of a second material having a lower thermal conductivity than the first material, and wherein the predetermined temperature gradient is formed in an axial direction where a warmer portion of the temperature gradient is adjacent the removable top and a colder portion of the temperature gradient is adjacent the removable bottom.

11. The method as defined in claim 7, further comprising controlling at least one of a size of the microtubules, a porosity of the vessel scaffold, or an orientation of the microtubules by at least one of i) altering a concentration of polymer in the polymer solution, ii) altering the temperature, or iii) altering the at least two materials of the mold.

12. A scaffold, comprising:

a nano-fibrous tubular polymeric structure; and

an oriented and interconnected microtubular porous network formed in the nano-fibrous tubular polymeric structure.

13. A method of making a scaffold, comprising:

preparing a polymer solution including a predetermined amount of polymer in at least one solvent that dissolves the polymer;

pouring the polymer solution into a mold;

inducing a solid-liquid phase separation by exposing the mold and the polymer solution therein to a temperature ranging from −

200°

C. to 20°

C.;

inducing a liquid-liquid phase separation at the same temperature or a different temperature as the temperature of the solid-liquid phase separation, thereby forming a solidified solvent phase and a nano-fibrous polymer-rich phase;

immersing the mold, the solidified solvent phase, and the nano-fibrous polymer-rich phase into a bath of a non-solvent of the polymer, thereby extracting the at least one solvent and forming a nano-fibrous polymer scaffold in the non-solvent;

removing the nano-fibrous polymer scaffold; and

freezing the nano-fibrous polymer scaffold to achieve a substantially solvent-free nano-fibrous polymer scaffold.

14. The method as defined in claim 13 wherein the at least one solvent is a solvent mixture including a predetermined ratio of benzene to tetrahydrofuran, and wherein the predetermined ratio of benzene to tetrahydrofuran ranges from 8:

2 (v/v) to 6;

4 (v/v).

15. The method as defined in claim 13 wherein the mold is formed of at least two materials having different thermal conductivities such that a predetermined temperature gradient can be formed in the mold during the solid-liquid phase separation.

16. The method as defined in claim 13 wherein each step is performed in the absence of a porogen material.

17. The method as defined in claim 13, further comprising:

adding porogen material to the mold prior to introducing the polymer solution into the mold; and

leaching the porogen material after the freezing of the polymer scaffold.

18. The method as defined in claim 13, further comprising exchanging the non-solvent for a different non-solvent after a predetermined time and prior to removing the nano-fibrous polymer scaffold.

19. A composite scaffold, comprising:

a porous polymeric structure having an inner surface and an outer surface; and

at least one electrospun layer positioned along at least one of the inner surface, or the outer surface, or in a middle of the porous polymeric structure.

20. The composite scaffold as defined in claim 19 wherein the porous polymer structure is selected from a solid-wall porous polymeric structure or a nano-fibrous wall porous polymeric structure.

21. The composite scaffold as defined in claim 20 wherein the solid-wall porous polymeric structure or the nano-fibrous wall porous polymeric structure has a controlled gradient of microtubules oriented radially or axially therein.

22. The composite scaffold as defined in claim 19, further comprising a plurality of additional porous polymeric structures adjacent to the porous polymeric structure or adjacent to the at least one electrospun layer.

23. The composite scaffold as defined in claim 19 wherein the porous polymeric structure and the at least one electrospun layer are configured as flat films, three-dimensional scaffolds, or tubular scaffolds.

24. The composite scaffold as defined in claim 19, further comprising:

a second porous polymeric structure having an inner surface and an outer surface; and

wherein the at least one electrospun layer is positioned along the outer surface of the porous polymeric structure and along the inner surface of the second porous polymeric structure.

25. A method for making a graded macroporous nano-fibrous scaffold, comprising:

introducing porogen materials of different sizes into a mold such that a predetermined size gradient of the porogen materials is obtained;

heat treating the porogen materials to form a porogen template having the predetermined size gradient;

introducing a polymer solution into the mold such that interspaces of the porogen template are filled with the polymer solution;

inducing phase separation by exposing the porogen template and the polymer solution to a predetermined temperature ranging from −

200°

C. to 20°

C., thereby initiating formation of the graded macroporous nano-fibrous scaffold;

performing a solvent exchange process;

freeze-drying the porogen template and the graded macroporous nano-fibrous scaffold; and

leaching the porogen template.

26. The method as defined in claim 25, further comprising forming the porogen materials of different sizes by:

melting d-fructose to form a molten sugar;

emulsifying the molten sugar in an oil to form an emulsion; and

cooling the emulsion to solidify sugar spheres therein, wherein the sugar spheres are the porogen materials of different sizes.

27. The method as defined in claim 25, further comprising controlling individual sections of the graded macroporous nano-fibrous scaffold by adding different amounts of the porogen materials of different sizes.

28. The method as defined in claim 25, further comprising controlling a size of macropores in the graded macroporous nano-fibrous scaffold by varying sizes of the porogen materials of different sizes.