Composites for tissue regeneration and methods of manufacture thereof

• US 6,454,811 B1
• Filed: 10/12/1999
• Issued: 09/24/2002
• Est. Priority Date: 10/12/1998
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology, Theken Spine LLC (Orthofix Medical Inc.)
• Original Assignee: Massachusetts Institute of Technology, Therics Inc.
• Inventors: Brown, Scott, Sherwood, Jill K., Griffith, Linda G.
• Primary Examiner(s): McDermott, Corrine
• Assistant Examiner(s): STEWART, ALVIN J
• Application Number:
  US09/416,346
• Time in Patent Office: 1,078 Days
• Field of Search: 623/23.76, 623/17
• US Class Current: 623/23.76
• 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 2/468 Testing instruments for artificial joints for testing non-implantable prostheses A61F2/76
• CPC Class Codes: A61F 2002/0086 for preferentially controlling or promoting the growth of specific types of cells or tissues of bone tissue onto implantable joints A61F2002/3093
• CPC Class Codes: A61F 2002/2817 Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
• CPC Class Codes: A61F 2002/2835 Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
• CPC Class Codes: A61F 2002/30004 the prosthesis being made from materials having different values of a given property at different locations within the same prosthesis
• CPC Class Codes: A61F 2002/30011 differing in porosity
• 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 2002/30301 saddle-shaped
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2002/30762 Means for culturing cartilage
• CPC Class Codes: A61F 2002/30766 Scaffolds for cartilage ingrowth and regeneration
• CPC Class Codes: A61F 2002/3093 for promoting ingrowth of bone tissue
• CPC Class Codes: A61F 2002/30952 using CAD-CAM techniques or NC-techniques
• CPC Class Codes: A61F 2002/30962 using stereolithography
• CPC Class Codes: A61F 2002/30968 Sintering
• CPC Class Codes: A61F 2002/3097 using laser
• CPC Class Codes: A61F 2002/30971 : Laminates, i.e. layered products
• CPC Class Codes: A61F 2002/4648 : Means for culturing bone graft
• CPC Class Codes: A61F 2210/0004 : bioabsorbable
• CPC Class Codes: A61F 2230/0063 : Three-dimensional shapes
• CPC Class Codes: A61F 2230/0095 : Saddle-shaped
• CPC Class Codes: A61F 2240/001 : Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0014 : having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
• CPC Class Codes: A61F 2250/0023 : differing in porosity
• CPC Class Codes: A61F 2310/00179 : Ceramics or ceramic-like structures
• CPC Class Codes: A61F 2310/00203 : containing alumina or aluminium oxide
• CPC Class Codes: A61F 2310/00293 : containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61F 2310/00365 : Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61L 27/46 : with phosphorus-containing inorganic fillers
• 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: A61L 27/58 : Materials at least partially resorbable by the body
• 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: B29L 2031/7532 : Artificial members, protheses
• CPC Class Codes: B33Y 70/00 : Materials specially adapted for additive manufacturing
• CPC Class Codes: B33Y 70/10 : Composites of different types of material, e.g. mixtures of ceramics and polymers or mixtures of metals and biomaterials
• CPC Class Codes: B33Y 80/00 : Products made by additive manufacturing

Abstract

Composite devices for tissue engineering are provided having a gradient of one or more of the following: materials, macroarchitecture, microarchitecture, or mechanical properties, which can be used to select or promote attachment of specific cell types on and in the devices prior to and/or after implantation. In various embodiments, the gradient forms a transition zone in the device from a region composed of materials or having properties best suited for one type of tissue to a region composed of materials or having properties suited for a different type of tissue. The devices are made in a continuous process that imparts structural integrity as well as a unique gradient of materials in the architecture. The gradient may relate to the materials, the macroarchitecture, the microarchitecture, the mechanical properties of the device, or several of these together. The devices disclosed herein typically are made using solid free form processes, especially three-dimensional printing process (3DP™). The device can be manufactured in a single continuous process such that the transition from one form of tissue regeneration scaffold and the other form of tissue regeneration scaffold have no “seams” and are not subject to differential swelling along an axis once the device is implanted into physiological fluid.

Claims

1. A porous device for tissue engineering formed by solid free form fabrication comprising

a first region having a first pore size, porosity, macroarchitecture, microarchitecture, and composition selected to promote attachment, proliferation, and/or differentiation of a first cell type;

and

a second region seamlessly joined to the first region by a transition zone, wherein the second region has a second pore size, porosity, macroarchitecture, microarchitecture, and/or composition selected to (i) promote attachment, proliferation, and/or differentiation of a second cell type, or (ii) limit attachment or proliferation of either the first or second cell type,

wherein the transition zone has gradients of pore size, porosity, macroarchitecture, microarchitecture, and/or composition effective to avoid delanination of the first or second regions.

2. The device of claim 1 wherein the transition zone comprises a gradient of pore sizes, porosities, and/or compositions between and seamlessly joining the first region and the second region.

3. The device of claim 1 wherein the first region and second region are fabricated from a polymeric material in the form of a powder using three dimensional printing.

4. The device of claim 1 wherein the porosity in at least one region is greater than about 90%.

5. The device of claim 1 wherein at least one region or a gradient within a region comprises osteogenic, osteoinductive, and/or osteoconductive materials.

6. The device of claim 1 further comprising a bioactive agent, diagnostic agent, or non-polymeric particles enhancing cell attachment or providing structural properties.

7. The device of claim 6 wherein the bioactive agent enhances differentiation, proliferation, and/or attachment of cells or specific cell types.

8. The device of claim 1 further comprising particles of leachable salt having a defined diameter dispersed in at least one region.

14. The device of claim 1 wherein at least one of the region has a cross-sectional design substantially in a form selected from the group consisting of tubes, coils, clovers, inverted clovers, honeycombs, and slots.

15. The device of claim 1 wherein the microarchitecture of at least one region promotes the incorporation of cells and/or ingrowth of tissue.

16. The device of claim 1 wherein the microarchitecture of at least one region limits the incorporation of cells and/or ingrowth of tissue.

17. The device of claim 1 wherein the surfaces of at least one region are modified by surfactants, cell attachment peptides, or bloactive agents.

18. The device of claim 2 wherein at least one region, the transition zone, or both, comprise layers of mixtures of two or more materials, wherein the layers together provide within the at least one region, transition zone, or both, gradients of two or more of the materials.

19. The device of claim 18 wherein one of the materials is leachable and another of the materials is non-leachable.

20. The device of claim 19 wherein the leachable material is sodium chloride.

21. The device of claim 18 wherein the mixtures further comprise inorganic particles.

22. The device of claim 21 wherein the inorganic particles are selected from the group consisting of bone, tricalcium phosphate, hydroxyapatite, and combinations thereof.

23. The device of claim 1 wherein the polymeric material comprises a polymer selected from the group consisting of poly(alpha)esters, poly(ε

-caprolactone)s, polyanhydrides, polyarylates, polyphosphazenes, polyhydroxyalkanoates, and polysaccharides.

24. The device of claim 23 wherein the polymer is poly(lactic acid-co-glycolic acid) or poly(lactic acid).

25. The device of claim 24 wherein the poly(lactic acid-co-glycolic acid) has free acidic side chains to increase the rate of degradation of the polymer.

26. The device of claim 1 wherein the polymeric material is formed from coacervated particles.

27. The device of claim 26 wherein the coacervated particles are non-polymeric particles coated with a polymer.

28. The device of claim 27 wherein the non-polymeric particles are selected from the group consisting of bone particles, hydroxyapatite particles, and calcium phosphate particles.

29. The device of claim 27 wherein particles are coated with a poly(lactic acid-co-glycolic acid).

30. The device of claim 1 wherein the first region is a bone regeneration region and the second region is a cartilage regeneration region.

31. The device of claim 30 wherein the porosity of the cartilage region is about 90% or more and the pore size of the cartilage region is 38 μ

m or more.

32. The device of claim 31 wherein the pore size of the cartilage region is between about 106 and 150 μ

m.

33. The device of claim 30 wherein the porosity of the bone region is between about 35 and 55%, and the pore size is between about 125 and 150 μ

m.

34. The device of claim 30 wherein the bone region has a clover shape.

35. The device of claim 30 wherein the bone region has a honeycomb or hollow cylinder shape.

36. The device of claim 30 wherein the bone region comprises a 3:

1 ratio of poly(lactic acid-co-glycolic acid) to tricalcium phosphate or hydroxyapatite.

37. The device of claim 36 wherein the bone region further comprises 55% salt.

38. The device of claim 30 wherein the cartilage region comprises a 1:

1 ratio of poly(lactic acid-co-glycolic acid) and poly(lactic acid).

39. The device of claim 38 wherein the cartilage region comprises 90% salt.

40. The device of claim 30 further comprising a transition region between the first region and the second region.

41. The device of claim 40 wherein the transition region includes a gradient of a salt from 85% to 65%, a gradient of 1:

1 poly(lactic acid-co-glycolic acid) (50;

50);

poly(lactic acid) from 10% to 5%, and a gradient of poly(lactic acid-co-glycolic acid) (85;

15) from 5% to 30%, from the cartilage region to the bone region.

42. The device of claim 2 wherein one or more of the regions and transition zone further comprise one or more macroscopic channels suitable for cell seeding and proliferation.

43. The device of claim 42 having two or more layers of channels, wherein the channels of one layer are in a staggered orientation, an offset orientation, or both, with respect to the channels of adjacent layers.

44. The device of claim 43 wherein the channels in the layers form flow paths that extend completely through the device.

45. The device of claim 43 wherein the channels in the layers form flow paths that do not extend completely through the device.

46. The device of claim 43 wherein the channels are offset about 90°

with respect an axis perpendicular to the layers.

47. The device of claim 1 wherein cells are selectively excluded in vitro from one or more regions of the device by means of the pore size and/or porosity of said one or more regions.

48. The device of claim 47 wherein cells proliferate in vivo in said one or more regions.

49. The device of claim 1 wherein at least one region is treated with a substance to prevent cell attachment in vitro, but in which cells will grow into in vivo.

50. The device of claim 1 wherein the first region is a suitable for weight bearing loads and the second region is a suitable for soft tissue regeneration.

53. The device of claim 50 further comprising chondrocytes seeded within the channels.

9. A method of making a porous device for tissue engineering comprising at least two regions, the method comprising

(a) making, by solid free form fabrication of a material, a first region having a pore size, porosity, macroarchitecture, microarchitecture, and composition selected to promote attachment, proliferation, and/or differentiation of a first cell type,

(b) making, by solid free form fabrication of a material, a transition zone next to the first region;

and

(c) making next to the transition zone, by solid free form fabrication of a material, a second region having a pore size, porosity, macroarchitecture, microarchitecture, and/or composition selected to (i) promote attachment proliferation, and/or differentiation of a second cell type, or (ii) limit attachment or proliferation of either the first or second cell type,

wherein the transition zone has gradients of pore size, porosity, macroarchitecture, microarchitecture, and/or composition effective to avoid delamination of the first or send regions.

10. The method of claim 9 wherein the transition zone comprises a gradient of pore sizes, porosities, and/or compositions between and seamlessly joining the first region and the second region.

11. The method of claim 9 wherein the solid free form fabrication is three dimensional printing.

12. The method of claim 9 wherein the material forming the first region, the second region, or both comprises a polymeric material.

13. The method of claim 9 wherein the forming in (a) and/or (b) comprises incorporating a coacervate of non-polymeric particles coated with polymer.

54. The method of claim 13 further comprising leaching the leachable particles from the device.

55. The method of claim 54 wherein residual solvent is removed from the device using liquid or supercritical carbon dioxide prior to the leaching.

56. The method of claim 9 wherein the polymeric material in step (a) and/or step (b) is a coacervate of non-polymeric particles coated with polymer.

57. The method of claim 9 further comprising seeding one or more regions of the device with cells.

58. The method of claim 9 wherein the device has at least two regions, one of which is a bone regeneration region and one of which is a cartilage regeneration region.

59. The method of claim 58 further comprising selectively seeding the cartilage region with cells in vitro, while simultaneously excluding cell attachment in the bone region.

60. The method of claim 59 wherein the selective seeding is achieved as a function of the relative porosity of the two regions.

61. The method of claim 57 wherein the cells are chondrocytes.

62. The method of claim 9 wherein the solid free form fabrication method is selected from stereo-lithography, selective laser sintering, ballistic particle manufacturing, and fusion deposition modeling.

51. A device for regeneration of cartilage comprising

a porous matrix formed by three dimensional printing of a polymer,

wherein the matrix contain staggered channels and has a porosity of 90% or more.

52. The device of claim 51 wherein the matrix comprises primary pores having a size greater than 100 μ

m and secondary pores having a size less than 10 μ

m.