Production of tissue engineered digits and limbs

• US 9,039,782 B2
• Filed: 04/18/2014
• Issued: 05/26/2015
• Est. Priority Date: 03/11/2005
• Status: Active Grant

• Current Assignee: Wake Forest University Health Sciences
• Original Assignee: Wake Forest University Health Sciences
• Inventors: Atala, Anthony, Yoo, James J., Lim, Grace, Lee, Sang Jin
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US14/256,643
• Publication Number:
  US 20140371869A1
• Time in Patent Office: 403 Days
• Field of Search: None
• US Class Current: 623/23.61
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61K 35/34 Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes vascular smooth muscle A61K35/44
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3817 Cartilage-forming cells, e.g. pre-chondrocytes
• CPC Class Codes: A61L 27/3821 Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells
• CPC Class Codes: A61L 27/3826 Muscle cells, e.g. smooth muscle cells
• CPC Class Codes: A61L 27/383 Nerve cells, e.g. dendritic cells, Schwann cells
• CPC Class Codes: A61L 27/3891 as distinct cell layers
• CPC Class Codes: A61L 27/48 with macromolecular fillers
• 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

Abstract

The invention pertains to methods of producing artificial composite tissue constructs that permit coordinated motion. Biocompatable structural matrices having sufficient rigidity to provide structural support for cartilage-forming cells and bone-forming cells are used. Biocompatable flexible matrices seeded with muscle cells are joined to the structural matrices to produce artificial composite tissue constructs that are capable of coordinated motion.

Claims

1. A biocompatible composite scaffolding system capable of providing structural support for engineered bone tissue comprising:

a first biodegradable matrix comprising a synthetic polymer and a naturally derived collagen matrix, wherein the first matrix has a porosity greater than about 50%; and

comprises about 25% to about 75% synthetic polymer;

a population of cells selected from the group consisting of cartilage-forming cells, bone-forming cells and combinations thereof seeded onto the first matrix;

a second matrix comprising a flexible, collagen-containing matrix; and

a population of muscle progenitor cells seeded onto the second matrix;

wherein the seeded second matrix is preconditioned to induce muscle fiber orientation;

wherein the first matrix and the second matrix are joined thereby forming a biocompatible composite scaffolding system.

2. The biocompatible composite scaffolding system of claim 1, wherein the synthetic polymer is selected from the group comprising poly(lactide-co-glycolide) (PLGA), poly(lactide) (PLA), poly(glycolic acid) (PGA), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyortho esters, polyacetals, polycyanoacrylates, degradable polyurethanes, hydroxyapatite (HA), tricalcium phosphate (TCP), and calcium sulfate.

3. The biocompatible composite scaffolding system of claim 1, wherein the naturally derived collagen matrix is submucosa.

4. The biocompatible composite scaffolding system of claim 3, wherein the submucosa is bladder submucosa (BSM).

5. The biocompatible composite scaffolding system of claim 1, wherein the composite scaffolding system is fabricated using a solvent casting/particulate leaching process.

6. The biocompatible composite scaffolding system of claim 1, wherein the biocompatible composite scaffolding system has substantially uniform porous structures having an average pore diameter ranging from about 50 to about 250 μ

m.

7. The biocompatible composite scaffolding system of claim 6, wherein the average pore diameter ranges from about 90 to about 150 μ

m.

8. The biocompatible composite scaffolding system of claim 6, wherein the porosity is greater than about 80%.

9. The biocompatible composite scaffolding system of claim 1, wherein the first matrix and the second matrix are joined using one or more sutures, heat sealing, or gluing.

10. The biocompatible composite scaffolding system of claim 1, wherein the first matrix and the second matrix further comprise a biological agent selected from the group consisting of nutrients, growth factors, cytokines, extracellular matrix components, inducers of differentiation, products of secretion, immunomodulators, proteins, antibodies, nucleic acids molecules, carbohydrates, and biologically-active compounds which enhance or allow growth of the cellular network or nerve fibers.

11. The biocompatible composite scaffolding system of claim 10, wherein the biological agent is a growth factor selected from the group consisting of transforming growth factor-alpha (TGF-α

), transforming growth factor-beta (TGF-β

), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), nerve growth factor (NGF), brain derived neurotrophic factor, cartilage derived factor, bone growth factor (BGF), basic fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G-CSF), hepatocyte growth factor, glial neurotrophic growth factor (GDNF), stem cell factor (SCF), keratinocyte growth factor (KGF), and skeletal growth factor.