Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure

• US 5,736,372 A
• Filed: 04/16/1990
• Issued: 04/07/1998
• Est. Priority Date: 11/20/1986
• Status: Expired due to Term

• Current Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Original Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Inventors: Langer, Robert S., Vacanti, Joseph P., Vacanti, Charles A.
• Primary Examiner(s): Naff, David M.
• Application Number:
  US07/509,952
• Time in Patent Office: 2,913 Days
• Field of Search: 435/174, 435/177, 435/178, 435/180, 435/182, 435/395, 435/398, 435/402, 623/10, 623/16, 623/18, 424/93.7, 424/548, 424/549, 424/422, 424/426, 514/21, 530/840
• US Class Current: 435/180
• 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 2/062 Apparatus for the production of blood vessels made from natural tissue or with layers of living cells prostheses made from natural tissue or living cells A61L27/507
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61L 2430/06 for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/60 Materials for use in artificial skin
• CPC Class Codes: C12N 2533/18 Calcium salts, e.g. apatite, Mineral components from bones, teeth, shells
• CPC Class Codes: C12N 2533/30 Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 2533/40 Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06
• CPC Class Codes: C12N 5/0655 Chondrocytes; Cartilage

Abstract

Methods and artificial matrices for the growth and implantation of cartilaginous structures and surfaces and bone are disclosed. In the preferred embodiments, chondrocytes are grown on biodegradable, biocompatible fibrous polymeric matrices. Optionally, the cells are proliferated in vitro until an adequate cell volume and density has developed for the cells to survive and proliferate in vivo. One advantage of the matrices is that they can be cast or molded into a desired shape, on an individual basis, so that the final product closely resembles a patient'"'"'s own ear or nose. Alternatively, flexible matrices can be used which can be manipulated at the time of implantation, as in a joint, followed by remodeling through cell growth and proliferation in vivo. The cultured cells can also be maintained on the matrix in a nutrient media for production of bioactive molecules such as angiogenesis inhibiting factor. Examples are provided showing the growth of hyaline cartilage for joint relinings, the growth of elastic cartilage for plastic or reconstructive replacement of cartilage structures, and repair of large bone defects.

Claims

1. A cell-scaffold composition for growing cells to produce a functional cartilaginous structure in vivo, comprising:

a fibrous three-dimensional scaffold composed of fibers of a biocompatible, biodegradable, synthetic polymer; and

cartilage-producing cells attached to the surface of the fibers of the scaffold uniformly throughout the scaffold;

wherein the fibers of the scaffold are spaced apart such that the average interfiber distance is between approximately 100 and 300 microns;

wherein the fibers of the scaffold provide sufficient surface area to permit attachment of a density of cells effective to produce the functional cartilaginous structure in vivo; and

wherein the diffusion in the scaffold provides free exchange of nutrients, gases and waste to and from the cells uniformly attached to the fibers and proliferating throughout the scaffold in an amount effective to maintain cell viability throughout the scaffold prior to the formation of the functional cartilage in vivo.

2. The cell-scaffold composition of claim 1 wherein the polymer is selected from the group consisting of polyanhydrides, polyorthoesters, polyglycolic acids, polylactic acids, copolymers, and blends thereof.

3. The cell-scaffold composition of claim 1 wherein the scaffold is formed of a combination of biodegradable and non-biodegradable materials.

4. The cell-scaffold composition of claim 3 wherein the non-degradable material is selected from the group consisting of polytetrafluoroethylene, nylon, ethylene vinyl acetate, polyesters and combinations thereof.

5. The cell-scaffold composition of claim 1 further comprising a coating(s) on the fibers selected from the group consisting of basement membrane components, agar, agarose, gelating, gum arabic, collagens, fibronectin, laminin, hyaluronic acid, glycosaminoglycans, attachment peptides and mixtures thereof.

6. The cell-scaffold composition of claim 1 wherein the scaffold forms a rigid structure.

7. The cell-scaffold composition of claim 1 wherein the scaffold forms a flexible structure conformable to a joint surface.

8. The cell-scaffold composition of claim 1 wherein the cells are chondrocyte cells.

9. The cell-scaffold composition of claim 1 wherein the structure is a joint lining.

10. The cell-scaffold composition of claim 1 wherein the cartilage-producing cells are fibroblasts capable of differentiation into chondrocytes.

11. The cell-scaffold composition of claim 1 wherein the cartilage precursor cells are bone precursor cells capable of differentiation into chondrocytes.

12. The cell-scaffold composition of claim 1 wherein the fibers form an open-cell sponge containing voids interconnected with the surface of the scaffold.

13. The cell-scaffold composition of claim 1 wherein the polymer is selected from the group consisting of polymers degrading by hydrolysis and polymers degrading enzymatically, and

the scaffold fibers are separated by a distance sufficient to allow multiple layers of cells to adhere to the surface of the fibers and to provide free exchange by diffusion of nutrients and waste to the attached cells throughout the scaffold when the cells on the scaffold are cultured in a nutrient media.

14. A cell-scaffold composition comprising a fibrous three-dimensional scaffold composed of fibers of a biocompatible, synthetic polymer and cartilage-producing cells uniformly attached to the surface of the fibers throughout the scaffold,

wherein the scaffold fibers are separated by a distance sufficient to allow multiple layers of cells to adhere to the surface of the fibers and to provide free exchange by diffusion of nutrients and waste to the attached cells throughout the scaffold when the cells on the scaffold are cultured in a nutrient media, and wherein the scaffold is in the form of an ear or a component thereof.

15. A cell-scaffold composition comprising a fibrous three-dimensional scaffold composed of fibers of a biocompatible, synthetic polymer and cartilage-producing cells uniformly attached to the surface of the fibers throughout the scaffold,

wherein the scaffold fibers are separated by a distance sufficient to allow multiple layers of cells to adhere to the surface of the fibers and to provide free exchange by diffusion of nutrients and waste to the attached cells throughout the scaffold when the cells on the scaffold are cultured in a nutrient media, and wherein the scaffold is in the form of a nose or a component thereof.