Production of tissue engineered heart valves

• US 9,801,713 B2
• Filed: 01/04/2016
• Issued: 10/31/2017
• Est. Priority Date: 03/11/2005
• Status: Active Grant

• Current Assignee: Wake Forest University Health Sciences
• Original Assignee: Wake Forest University Health
• Inventors: Atala, Anthony, Yoo, James
• Primary Examiner(s): Noble, Marcia S
• Application Number:
  US14/987,601
• Publication Number:
  US 20160199179A1
• Time in Patent Office: 666 Days
• CPC Class Codes: A61F 2/2415 Manufacturing methods
• 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 27/3641 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3808 Endothelial 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 27/3839 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3886 comprising two or more cell types
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C12N 2533/90 Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06
• CPC Class Codes: C12N 5/069 Vascular Endothelial cells

Abstract

The invention is directed to methods for preparing artificial heart valves by preconditioning a matrix seeded with endothelial cells and smooth muscle cells differentiated from isolated progenitor cells. These cell seeded matrices are exposed to fluid conditions that mimic blood flow through the heart to produce tissue engineered heart valves that are analogous to native heart valves.

Claims

1. A preconditioned tissue engineered heart valve, comprising:

a biocompatible matrix seeded with at least one population of endothelial cells differentiated from progenitor cells ex vivo, wherein the seeded cells form at least one cell layer on the biocompatible matrix;

a population of smooth muscle cells differentiated from progenitor cells and seeded onto the endothelial cell layer,

wherein the biocompatible matrix is selected from the group consisting of a decellularized matrix, an electrospun matrix, and a synthetic polymer matrix, and

wherein at least one cell of the population of endothelial cells, the population of smooth muscle cells, or a combination thereof comprise(s) an exogenous nucleic acid encoding an anti-inflammatory factor operably linked to a promoter.

2. The heart valve of claim 1, wherein the anti-inflammatory factor is selected from the group consisting of anti-GM-CSF, anti-TNF, anti-IL-1 and anti-IL2.

3. The heart valve of claim 1, wherein biocompatible matrix is a decellularized heart valve.

4. The heart valve of claim 1, wherein the electrospun matrix is a crosslinked matrix.

5. The heart valve of claim 4, wherein the electrospun matrix comprises poly(lactide-co-glycolides) (PLGA).

6. The heart valve of claim 4, wherein the electrospun matrix comprises nanofibers having a diameter of about 50 nanometers to about 1000 nanometers and wherein the distance between the fibers is about 50 nanometers to about 500 nanometers.

7. The heart valve of claim 4, wherein the electrospun matrix has a pore size of about 0.1 μ

m² to about 100 μ

m².

8. The heart valve of claim 1, wherein the biocompatible matrix is coated with a basement membrane component.

9. The heart valve of claim 8, wherein the basement membrane component is selected from the group consisting agar, agarose, gelatin, gum arabic, collagens, fibronectin, laminin, glycoaminoglycans, and mixtures thereof.