Vascularized tissue regeneration matrices formed by solid free form fabrication techniques

• US 6,139,574 A
• Filed: 08/20/1997
• Issued: 10/31/2000
• Est. Priority Date: 10/18/1993
• Status: Expired due to Fees

• Current Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Original Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Inventors: Cima, Michael J., Vacanti, Joseph P., Cima, Linda G.
• Primary Examiner(s): Willse, David H.
• Assistant Examiner(s): Koh, Choon P.
• Application Number:
  US08/915,409
• Time in Patent Office: 1,168 Days
• Field of Search: 623/1, 623/11, 623/15, 623/66, 623/12, 264/63, 264/69, 264/71, 264/109, 264/113, 264/123, 264/128, 264/308, 424/422, 424/423, 424/424, 424/425, 424/572, 425/130, 425/218, 425/425, 435/1, 435/2, 435/30, 435/240.1, 435/240.2, 435/240.21, 435/240.23, 435/240.243, 435/284, 435/285, 435/287, 435/292, 435/293, 435/297, 435/299, 435/300, 600/36
• US Class Current: 623/1.44
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61F 2/105 Skin implants, e.g. artificial skin
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2/3094 Designing or manufacturing processes
• CPC Class Codes: A61F 2002/0086 for preferentially controlling or promoting the growth of specific types of cells or tissues
• CPC Class Codes: A61F 2002/009 for hindering or preventing attachment of biological tissue
• CPC Class Codes: A61F 2002/30011 differing in porosity
• CPC Class Codes: A61F 2002/30032 differing in absorbability or resorbability, i.e. in absorption or resorption time
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30199 Three-dimensional shapes
• CPC Class Codes: A61F 2002/3028 polyhedral different from parallelepipedal and pyramidal
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2002/3093 for promoting ingrowth of bone tissue
• CPC Class Codes: A61F 2002/30932 for retarding or preventing ingrowth of bone tissue
• CPC Class Codes: A61F 2002/30962 using stereolithography
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2230/0063 Three-dimensional shapes
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0023 differing in porosity
• CPC Class Codes: A61F 2250/003 : differing in adsorbability or resorbability, i.e. in adsorption or resorption time
• CPC Class Codes: A61F 2250/0031 : made from both resorbable and non-resorbable prosthetic parts, e.g. adjacent parts
• CPC Class Codes: A61F 2250/0067 : Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 27/38 : containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3808 : Endothelial cells
• CPC Class Codes: A61L 27/40 : Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
• CPC Class Codes: A61L 27/56 : Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/60 : Materials for use in artificial skin
• CPC Class Codes: B29C 64/135 : the energy source being concentrated, e.g. scanning lasers or focused light sources
• CPC Class Codes: B29C 64/165 : using a combination of solid and fluid materials, e.g. a powder selectively bound by a liquid binder, catalyst, inhibitor or energy absorber
• CPC Class Codes: B29K 2995/0064 : Non-uniform density
• CPC Class Codes: B33Y 10/00 : Processes of additive manufacturing
• CPC Class Codes: B33Y 30/00 : Apparatus for additive manufacturing; Details thereof or accessories therefor
• CPC Class Codes: B33Y 80/00 : Products made by additive manufacturing
• CPC Class Codes: Y10S 623/901 : Method of manufacturing prosthetic device

Abstract

Solid free-form fabrication (SFF) methods are used to manufacture devices for allowing tissue regeneration and for seeding and implanting cells to form organ and structural components, which can additionally provide controlled release of bioactive agents, wherein the matrix is characterized by a network of lumens functionally equivalent to the naturally occurring vasculature of the tissue formed by the implanted cells, and which can be lined with endothelial cells and coupled to blood vessels at the time of implantation to form a vascular network throughout the matrix. The SFF methods can be adapted for use with a variety of polymeric, inorganic and composite materials to create structures with defined compositions, strengths, and densities, using computer aided design (CAD).

Examples of SFF methods include stereo-lithography (SLA), selective laser sintering (SLS), ballistic particle manufacturing (BPM), fusion deposition modeling (FDM), and three dimensional printing (3DP).

Claims

1. A method for making devices for tissue regeneration comprising using a solid free-form fabrication method to sequentially form layers of a biocompatible material into a matrix having

(a) interconnected pores extending throughout the matrix wherein the interconnected pores are for seeding with cells, and

(b) interconnected lumens for fluid flow within the matrix having openings for connection to ducts within tissue in a patient.

2. The method of claim 1 comprising forming interconnected lumens within the matrix which can be connected to blood vessels.

3. The method of claim 1 comprising forming interconnected lumens within the matrix which can be connected to ducts selected from the group consisting of lymph ducts, exocrine function ducts, excretory ducts, and ducts for neural ingrowth.

4. The method of claim 1 wherein the solid free-form fabrication method is three dimensional printing, comprising

a) spreading a first dispersion of a biocompatible polymer or composite powder onto a bed,

b) printing a layer comprising a second dispersion of biocompatible polymer or composite powder in a solvent which binds the first biocompatible polymer or composite powder to the second biocompatible polymer or composite powder at locations where it is desired to have walls, and

c) repeating step b until the desired matrix is made.

5. The method of claim 1 wherein the solid free-form fabrication method is ballistic particle manufacturing or fusion deposition modeling and polymeric material is applied to a platform in layers to form a polymeric device.

6. The method of claim 1 wherein the solid free-form fabrication method is selective laser sintering comprising applying polymeric particles to a platform and fusing selected area of the polymeric particles with a laser.

7. The method of claim 1 wherein the solid free-form fabrication method is stereo-lithography comprising photopolymerizing selected areas of a bath of photopolymerizable prepolymer or monomers.

8. The method of claim 1 wherein the matrix is formed of biodegradable polymer.

9. The method of claim 8 wherein structural elements having a longer rate of degradation than the matrix-forming material or which are not biodegradable are incorporated into the matrix.

10. The method of claim 1 wherein the texture of the matrix is altered or surface active agents are applied to device walls to control cell adhesion to and within the device.

11. The method of claim 10 wherein the matrix is made by three dimensional printing of a binder onto a powder bed where a solution containing surface-active agents is printed into the regions or lines of the powder bed in between where the binder is printed.

12. The method of claim 10 wherein an outer surface of the matrix is modified with a surface active agent which prevents adhesion of cells.

13. The method of claim 1 further comprising seeding the device with dissociated cells.

14. The method of claim 2 further comprising seeding the lumens with dissociated endothelial cells and culturing the device until the cells form a confluent layer on the walls of the lumens.

15. The method of claim 14 further comprising seeding other regions of the matrix with cells forming tissue.

16. A medical device for tissue regeneration formed using a solid free-form fabrication method comprising a matrix of successive layers of a biocompatible material wherein the layers create

(a) interconnected pores or lumens extending throughout the matrix wherein the interconnected pores or lumens are for seeding with cells, and

(b) interconnected lumens for fluid flow within the matrix having openings for connection to ducts within tissue in a patient.

17. The device of claim 16 comprising forming interconnected lumens within the matrix which can be connected to blood vessels.

18. The device of claim 16 comprising interconnected lumens within the matrix which can be connected to ducts selected from the group consisting of lymph ducts, exocrine function ducts, excretory ducts, and ducts for neural ingrowth.

19. The device of claim 16 wherein the solid free-form fabrication method is three dimensional printing, comprising

a) spreading a first dispersion of a biocompatible polymer or composite powder onto a bed,

b) printing a layer comprising a second dispersion of biocompatible polymer or composite powder in a solvent which binds the first biocompatible polymer or composite powder to the second biocompatible polymer or composite powder at locations where it is desired to have walls, and

c) repeating step b until the desired matrix is made.

20. The device of claim 16 wherein the solid free-form fabrication method is ballistic particle manufacturing or fusion deposition modeling and polymeric material is applied to a platform in layers to form a polymeric device.

21. The device of claim 16 wherein the solid free-form fabrication method is selective laser sintering comprising applying polymeric particles to a platform and fusing selected area of the polymeric particles with a laser.

22. The device of claim 16 wherein the solid free-form fabrication method is stereo-lithography comprising photopolymerizing selected areas of a bath of photopolymerizable prepolymer or monomers.

23. The device of claim 16 wherein the matrix is formed of biodegradable polymer.

24. The device of claim 16 wherein structural elements having a longer rate of degradation than the matrix-forming material or which are not biodegradable are incorporated.

25. The device of claim 16 wherein the texture of the matrix is altered or surface active agents are applied to device walls to control cell adhesion to and within the device.

26. The device of claim 25 wherein the matrix is made by three dimensional printing of a binder onto a powder bed where a solution containing surface-active agents is printed into the regions or lines of the powder bed in between where the binder is printed.

27. The device of claim 25 wherein an outer surface of the matrix is modified with a surface active agent which prevents adhesion of cells.

28. The device of claim 16 further comprising bioactive agent.

29. The device of claim 16 wherein the device is formed by a method that builds a complex three dimensional device as a series of two dimensional layers.

30. The device of claim 29 wherein the layers are betwen 2 microns and 1 mm in thickness.

31. The device of claim 16 wherein the pores or lumens have a diameter of between 150 and 300 microns.

32. The device of claim 16 further comprising seeding the device with dissociated cells.

33. The device of claim 17 further comprising dissociated endothelial cells seeded onto the walls of the pores or lumens.

34. The device of claim 33 further comprising cells forming tissue seeded onto other regions of the matrix.

35. The device of claim 18 further comprising cells forming tissues seeded therein.

36. The device of claim 16 wherein the polymeric material includes a bioactive agent.