Three-dimensional fabrication of biocompatible structures in anatomical shapes and dimensions for tissue engineering and organ replacement

• US 7,718,351 B2
• Filed: 03/14/2006
• Issued: 05/18/2010
• Est. Priority Date: 03/14/2006
• Status: Expired due to Fees

• Current Assignee: Agency For Science Technology and Research
• Original Assignee: Agency For Science Technology and Research
• Inventors: Hsieh, James Tseng-Ming, Hock, Jeremy Loh Ming, Schumacher, Karl, Ying, Jackie Y., Kan, Shyi-Herng
• Primary Examiner(s): Ford; Allison M.
• Application Number:
  US11/375,375
• Publication Number:
  US 20070218544A1
• Time in Patent Office: 1,526 Days
• Field of Search: None
• US Class Current: 430/322
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: C12N 2533/30 Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06

Abstract

Methods and apparatuses involving biocompatible structures for tissue engineering and organ replacement and, more specifically, biocompatible structures formed by three-dimensional fabrication, are described. In some embodiments, the biocompatible structures are scaffolds for cells that can be used as tissue engineering templates and/or as artificial organs. The structures may be three-dimensional and can mimic the shapes and dimensions of tissues and/or organs, including the microarchitecture and porosities of the tissues and organs. Pores in the structure may allow delivery of molecules across the structure, and may facilitate cell migration and/or generation of connective tissue between the structure and its host environment. Structures of the invention can be implanted into a mammal and/or may be used ex vivo as bioartificial assist devices.

Claims

1. An article for use as a template for cell growth, comprising:

a structure formed by a multi-photon lithographic process and comprising a photocurable polymer, the structure comprising at least one wall defining a cavity; and

a plurality of pores having a cross-sectional dimension of less than 40 microns formed in at least a portion of the wall and permeating the wall, thereby enabling exchange of a component between a portion interior to the cavity and a portion exterior to the cavity,

wherein at least a portion of the structure comprises a cell-adhering substance and at least a portion of the structure comprises a cell-inhibiting substance, and

wherein the structure is constructed and arranged for use as a template for cell growth.

2. An article as in claim 1, wherein the plurality of pores have a cross-sectional dimension of less than or equal to 20 microns.

3. An article as in claim 1, wherein the plurality of pores have a cross-sectional dimension of less than or equal to 1 micron.

4. An article as in claim 1, wherein at least a portion of the wall has a thickness of less than 30 microns.

5. An article as in claim 1, wherein the cavity has an inner diameter of less than 300 microns.

6. An article as in claim 1, wherein the article is formed by a process comprising two-photon lithography.

7. An article as in claim 1, wherein the plurality of pores and the structure are fabricated by the same process.

8. An article as in claim 1, wherein the structure comprises a first cavity portion having a first inner diameter and a second cavity portion contiguous with the first cavity portion and having a second inner diameter.

9. An article as in claim 8, wherein the ratio of the first inner diameter to the second inner diameter is greater than 10:

1.

10. An article as in claim 1, wherein the structure comprises a first substance that induces growth of a first cell type, and a second substance that induces growth of a second cell type.

11. An article as in claim 10, wherein at least a portion of the structure is modified with the first substance that induces growth of the first cell type, the article further comprising a substructure positioned within at least a portion of the cavity of the structure, the substructure including at least one portion modified with the second substance that induces growth of the second cell type, wherein the ratio between an inner diameter of the structure to an inner diameter of the substructure is greater than 10:

1.

12. An article as in claim 11, wherein the substructure comprises a wall defining a cavity.

13. An article as in claim 12, wherein the wall of the substructure comprises a plurality of pores formed in at least a portion of the wall and permeating the wall, thereby enabling exchange of a component between a portion interior to the cavity of the substructure and a portion exterior to the cavity of the substructure.

14. An article as in claim 13, wherein the portion exterior to the cavity of the substructure comprises the portion interior to the cavity of the structure.

15. An article as in claim 1, wherein the structure comprises overlapping pores having a total pore size formed by the overlapping pores of less than 40 microns.

16. An article as in claim 1, wherein the structure is adapted to allow cell growth within the pores of the structure.

17. An article as in claim 1, wherein the article is a template for growing an artificial tissue or organ.

18. An article as in claim 17, wherein the artificial tissue or organ is selected from the group consisting of tissues or organs of the circulatory system, tissues or organs of the blood vessel system, tissues or organs of the digestive track, tissues or organs of the gut-associated glands, tissues or organs of the respiratory system, or tissues or organs of the urinary system.

19. An article as in claim 1, wherein the photocurable polymer comprises a crosslinking density that is varied within different portions of the structure.

20. An article as in claim 1, wherein the structure comprises an elastic material.

21. An article as in claim 1, wherein the photocurable polymer comprises an acrylate-based photopolymer.

22. An article as in claim 1, wherein the photocurable polymer comprises pentaerythritol triacrylate.

23. An article as in claim 1, wherein the photocurable polymer comprises an organic-inorganic hybrid material.

24. An article for use as a template for cell growth, comprising:

a structure formed by a multi-photon lithographic process and comprising a photocurable polymer, the structure comprising at least one wall defining a cavity, the cavity having an inner diameter of less than 300 microns; and

a plurality of pores formed in at least a portion of the wall and permeating the wall, thereby enabling exchange of a component between a portion interior to the cavity and a portion exterior to the cavity,

wherein at least a portion of the structure comprises a cell-adhering substance and at least a portion of the structure comprises a cell-inhibiting substance, and

wherein the structure is constructed and arranged for use as a template for cell growth.