Tissue regeneration matrices by solid free-form fabrication techniques

• US 6,530,958 B1
• Filed: 06/05/1995
• Issued: 03/11/2003
• Est. Priority Date: 10/18/1993
• Status: Expired due to Term

• Current Assignee: Aprecia Pharmaceuticals Company
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Cima, Michael J., Cima, Linda G.
• Primary Examiner(s): Prebilic, Paul B.
• Application Number:
  US08/463,203
• Time in Patent Office: 2,836 Days
• Field of Search: 623/11.11, 623/23.56, 623/23.51, 623/23.58, 623/23.61, 623/23.57, 623/901, 623/911, 264/401
• US Class Current: 623/23.51
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• 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 of bone tissue onto implantable joints A61F2002/3093
• CPC Class Codes: A61F 2002/009 for hindering or preventing attachment of biological tissue of bone tissue onto implantable joints A61F2002/30932
• 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 2002/3028 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: A61F 2310/00359 : Bone or bony tissue
• CPC Class Codes: A61K 9/0024 : Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0097 : Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips intradermal microneedle arrays A61K9/0021; MEMS in general B81B7/02
• CPC Class Codes: A61K 9/1647 : Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 : resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61L 27/34 : Macromolecular materials
• 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 64/00 : Additive manufacturing, i.e. manufacturing of three-dimensional [3D] objects by additive deposition, additive agglomeration or additive layering, e.g. by 3D printing, stereolithography or selective laser sintering
• 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 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
• CPC Class Codes: Y10S 623/901 : Method of manufacturing prosthetic device
• CPC Class Codes: Y10T 428/249953 : Composite having voids in a component [e.g., porous, cellular, etc.]
• CPC Class Codes: Y10T 428/249954 : With chemically effective material or specified gas other than air, N, or carbon dioxide in void-containing component
• CPC Class Codes: Y10T 428/249961 : With gradual property change within a component
• CPC Class Codes: Y10T 428/249978 : Voids specified as micro
• CPC Class Codes: Y10T 428/249986 : Void-containing component contains also a solid fiber or solid particle
• CPC Class Codes: Y10T 428/249994 : Composite having a component wherein a constituent is liquid or is contained within preformed walls [e.g., impregnant-filled, previously void containing component, etc.]
• CPC Class Codes: Y10T 428/249999 : Differentially filled foam, filled plural layers, or filled layer with coat of filling material

Abstract

Solid free-form (SSF) techniques for making medical devices for implantation and growth of cells from polymers or polymer/inorganic composites using computer aided design are described. 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). The devices can incorporate inorganic particles to improve the strength of the walls forming the pores within the matrix and to provide a source of mineral for the regenerating tissue. The devices can contain tissue adhesion peptides, or can be coated with materials which reduce tissue adhesion. The macrostructure and porosity of the device can be manipulated by controlling printing parameters. Most importantly, these features can be designed and tailored using computer assisted design (CAD) for individual patients to optimize therapy.

Claims

1. A medical device for tissue regeneration formed using a solid free-form fabrication method comprising a matrix of successive layers of biocompatible polymeric material having interconnected pores extending throughout the matrix suitable for seeding or ingrowth of cells wherein the method is three dimensional printing, comprising:

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

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

c) repeating steps a and b until the desired matrix is made.

3. The device of claim 1 or claim 2 wherein the powder size is less than 40 microns in diameter.

7. The device of claim 1 or claim 2 further comprising surface-active agents that are printed into the regions or lines of the powder bed in between where the binder or biocompatible polymer is printed.

2. A medical device for bone regeneration formed using three dimensional printing comprising a matrix of successive layers of biocompatible composite material having interconnected pores extending throughout the matrix suitable for seeding or ingrowth of cells, having a pore size of at least five to forty microns in diameter

wherein the method comprises

a) spreading a first dispersion of a resorbable powder selected from the group consisting of calcium phosphate, hydroxyapatite, and calcium carbonate onto a bed,

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

c) repeating steps a and b until the desired matrix is made.

4. The device of claim 2 wherein the walls are less than 100 microns thick.

5. The device of claim 2 wherein the binder or biocompatible polymer is a resorbable polymer selected from the group consisting of polyhydroxyacids, polyorthoesters, polyanhydrides, and copolymers and blends thereof.

6. The device of claim 2 wherein the polymer or biocompatible polymer includes a biodegradable latex.

8. The device of claim 2 wherein a surface of the polymer or composite material is modified with a surface active agent which prevents adhesion of cells.

9. The device of claim 2 wherein an exogenously fabricated device is incorporated into the matrix by printing layers of binder around the exogenously fabricated device.

10. The device of claim 2 wherein the composite or polymeric material includes a bioactive agent.

11. The device of claim 10 wherein the biocompatible material is polymeric particles and the bioactive agent is added to the polymeric particles and dispersed in the polymer layers.

12. The device of claim 10 wherein the bioactive agent is added to a solvent or binder for polymeric particles used to form the polymer layers.

13. The device of claim 12 wherein the solvent for the bioactive agent is not a solvent for the polymer, wherein three dimensional printing is used to form discrete regions of bioactive agent within a polymeric matrix.

14. The device of claim 2 that incorporates a non-biodegradable material into the device to form structural elements maintaining the integrity of the device when formed of a biodegradable material.

15. A rectangular device for bone regeneration of approximate size 2 cm×

1 cm×

1 cm, comprising;

a) a first layer comprising;

(i) lines approximately 100 microns wide spaced approximately 300 microns center-to-center along the length of the 2 cm axis, wherein each line is 200 microns in depth, totaling 30 lines, and

(ii) triplets of approximately 100 micron wide lines with approximate 100 micron spacing in between printed along the 1-cm axis, for a total of 25 triplets;

b) a second layer comprising lines approximately 100 microns Wide spaced approximately 300 microns center-to-center along the length of the 2-cm axis, wherein the lines are approximately 200 microns in depth and placed directly above the lines in the first layer;

c) a third layer comprising lines approximately 100 microns wide with approximate 100 micron spacing printed along the 1 cm axis with approximate 100 micron spacing in between with an approximate 200 micron depth, and wherein the lines are printed on top of each of the outside lines in each triplet in the layer below;

d) a second-to-last layer that is the same as the second layer;

e) a layer between the second-to-last layer and the last layer that is the same as the third layer; and

f) a last layer that is the same as the first layer.