# US 9,039,782 B2 · Production of tissue engineered digits and limbs

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- Number: US 9,039,782 B2
- Document ID: US9039782B2
- Status: Granted
- Kind: B2
- Application number: 14/256,643
- Filed: 2014-04-18
- Published: 2014-12-18
- Granted: 2015-05-26
- Earliest claimed: 2005-03-11
- Assignees: Wake Forest University Health Sciences
- Applicants: Wake Forest University Health Sciences
- Inventors: Anthony Atala; James J. Yoo; Grace Lim; Sang Jin Lee
- Web page: https://patentgrep.com/patent/US9039782B2

## CPC

- A61F 2/28: Bones
- A61K 35/32: Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
- A61K 35/34: Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes (vascular smooth muscle A61K35/44)
- A61K 38/18: Growth factors; Growth regulators
- 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}
- A61L 27/3817: {Cartilage-forming cells, e.g. pre-chondrocytes}
- A61L 27/3821: {Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells}
- A61L 27/3826: {Muscle cells, e.g. smooth muscle cells}
- A61L 27/383: {Nerve cells, e.g. dendritic cells, Schwann cells}
- A61L 27/3891: {as distinct cell layers}
- A61L 27/48: with macromolecular fillers
- A61L 27/56: Porous materials, {e.g. foams or sponges}
- A61L 27/58: Materials at least partially resorbable by the body
- A61L 2430/02: for reconstruction of bones; weight-bearing implants
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)

## 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

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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 μm.

### Claim 7 (depends on 6)

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

### Claim 8 (depends on 6)

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

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 10)

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.