Tissue engineered blood vessels

• US 20060240061A1
• Filed: 03/10/2006
• Published: 10/26/2006
• 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, Soker, Shay, Yoo, James J.
• Granted Patent: US 8,491,457 B2
• Time in Patent Office: Days
• US Class Current: 424/422
• CPC Class Codes: A61F 2/06 Blood vessels
• 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: A61K 35/44 Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices artificial blood vessels A61L27/507
• 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 27/3808 Endothelial cells
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• 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

Abstract

The invention is directed to methods for preparing artificial blood vessels by preconditioning a matrix seeded with endothelial cells to fluid flow conditions that mimic blood flow.

Claims

1. A method for producing a preconditioned blood vessel, comprising:

providing a biocompatible matrix shaped in a tubular configuration seeded with a cultured population of endothelial cells on the inside surface of the matrix;

attaching a first and second end of the tubular matrix to a first and second attachment element in a preconditioning chamber, wherein the first and second attachment elements have a channel that is fluidly coupled to fluid flow system;

gently rotating the preconditioning chamber such that the endothelial cells attach to the inside surface of the tubular matrix; and

preconditioning the seeded tubular matrix with the flow system in which a biological fluid is moved through the seeded tubular matrix, wherein the flow-rate and pulse-rate of the biological fluid is controlled such that a preconditioned blood vessel is produced.

2. The method of claim 1, wherein biocompatible matrix is selected from the group consisting of a decellularized matrix, an electrospun matrix and a synthetic polymer matrix.

3. The method of claim 1, wherein the preconditioning chamber is a container with dimensions suitable for attaching a length of tubular matrix.

4. The method of claim 1, wherein the step of preconditioning the matrix comprises moving the biological fluid through the inside surface of the attached matrix in a closed fluid flow system.

5. The method of claim 1, wherein the step of preconditioning the matrix comprises moving the biological fluid through the inside surface of the attached matrix as a continuous flow.

6. The method of claim 5, wherein the continuous flow has a flow-rate that is incremented over time to induce a wall shear in the range of about 1 dyne/cm² to about 30 dynes/cm².

7. The method of claim 1, wherein the step of preconditioning the matrix comprises moving the biological fluid through the inside surface of the attached matrix as a pulsed flow.

8. The method of claim 7, wherein the pulsed flow has a pulse-rate that is incremented over time to induce a wall shear in the range of about 10 dynes/cm² to about 45 dynes/cm².

9. The method of claim 7, wherein the pulsed flow has a pulse-rate that is incremented over time to induce a wall pressure distribution in the range of about 60 to about 200 mmHg.

10. The method of claim 1, wherein the biological fluid is moved through the seeded tubular matrix by a pump.

11. The method of claim 1, wherein the biological fluid has a composition and viscosity that is equivalent to blood.

12. The method of claim 1, wherein the biological fluid is selected from the group consisting of culture medium, buffer medium, and physiological medium.

13. The method of claim 1, further comprising adding a volume of biological fluid to the preconditioning chamber such that the outside surface of the tubular matrix is exposed to the biological fluid.

14. The method of claim 1, wherein the matrix is an electrospun matrix comprising at least one natural component and at least one synthetic polymer component and a therapeutic agent coupled to a nanoparticle.

15. The method of claim 14, wherein the natural component is collagen and the synthetic polymer component is poly(lactide-co-glycolides) (PLGA).

16. The method of claim 14 further comprising elastin.

17. The method of claim 14, wherein the therapeutic agent is heparin and the nanoparticle is a quantum dot.

18. The method of claim 17, wherein the heparin and quantum dot are encapsulated in a polymer.

19. The method of claim 18, wherein the release of heparin from the nanoparticle is controlled by the application of radiation at a wavelength in the range of about 700 nm to about 1000 nm.

20. The method of claim 19, wherein the heparin is locally released from the nanoparticle by heating the nanoparticle so that it alters the ultrastructure of the polymer.

21. The method of claim 14, wherein the nanospun matrix further comprises an image enhancing agent.

22. The method of claim 21, wherein the image enhancing agent is gadolinium.

23. The method of claim 1, wherein the endothelial cells are isolated from a human saphenous vein.

24. The method of claim 1, wherein the endothelial cells are derived from progenitor cells isolated from peripheral blood or bone marrow.