Compositions and methods for promoting patency of vascular grafts

• US 9,855,370 B2
• Filed: 01/08/2009
• Issued: 01/02/2018
• Est. Priority Date: 01/08/2008
• Status: Active Grant

• Current Assignee: Yale University
• Original Assignee: Yale University
• Inventors: Breuer, Christopher, Kyriakides, Themis, Roh, Jason
• Primary Examiner(s): Gamett, Daniel C
• Application Number:
  US12/811,676
• Publication Number:
  US 20100303889A1
• Time in Patent Office: 3,281 Days
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61K 38/195 Chemokines, e.g. RANTES
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

Methods for increasing the patency of biodegradable, synthetic vascular grafts are provided. The methods include administering one or more cytokines and/or chemokines that promote outward tissue remodeling of the vascular grafts and vascular neotissue formation. The disclosed methods do not require cell seeding of the vascular grafts, thus avoiding many problems associated with cell seeding. Biodegradable, polymeric vascular grafts which provide controlled release of cytokines and/or chemokines at the site of vascular graft implantation are also provided.

Claims

1. A method for increasing the patency of a vascular graft comprising a biodegradable polymer, the method comprising

incorporating into or onto the graft monocyte chemoattractant protein 1 (MCP-1), wherein the MCP-1 is locally released from the graft in an effective amount following graft implantation to recruit an effective amount of host monocytes to the graft within one week of graft implantation to prevent, inhibit or reduce stenosis, and promote neotissue formation and increase the patency of the graft in the host over time relative to the patency of the graft in the absence of MCP-1.

2. The method of claim 1, wherein the biodegradable or bioabsorbable polymers are selected from the group consisting of poly(lactic acid), poly(glycolic acid), polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxyalkanoates), and poly(lactide-co-caprolactone), or combinations, blends or co-polymers thereof.

3. The method of claim 1, wherein the biodegradable or bioabsorbable polymers are formed into a fiber-based mesh.

4. The method of claim 3, wherein the fiber-based mesh is a non-woven mesh.

5. The method of claim 4, wherein the vascular graft further comprises a polymeric sealant.

6. The method of claim 5, wherein the polymeric sealant comprises a co-polymer of ε

-caprolactone and L-lactide.

7. The method of claim 1, further comprising administering to the host, or incorporating into graft an additional cytokine or chemokine selected from the group consisting of interleukin (IL)1α

, IL-1β

, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IP-10, eotaxin, interferon γ

(IFNγ

), granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1α

(MIP-1α

), RANTES, tumor necrosis factor (TNF)-α

, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, TGF-beta, VEGF, and combinations thereof.

8. The method of claim 7, wherein the cytokine or chemokine is IL-1β

or G-CSF.

9. The method of claim 7 further comprising administering G-CSF to the host.

10. The method of claim 9 wherein the administration of G-CSF occurs prior to implantation of the graft in the host.

11. The method of claim 1 wherein the effective amount of MCP-1 is released from microparticles in the graft over a period of 1 to 3 days after the graft is implanted into the host.

12. The method of claim 1 wherein the MCP-1 is incorporated into or onto the graft by seeding the graft with microparticles comprising MCP-1 before implantation of the graft into the host.

13. The method of claim 1 further comprising seeding the graft with human bone marrow mononuclear cells prior to implantation of the graft.

14. The method of claim 1 wherein the MCP-1 is provided in microparticles between 1 μ

m and 20 μ

m in diameter incorporated into the graft.

15. The method of claim 1 wherein the internal diameter of the graft is larger relative to the internal diameter of the graft in the absence of MCP-1 ten weeks after implantation of the graft into the host.

16. The method of claim 1 wherein the wall thickness of the graft is thinner relative to the wall thickness of the graft in the absence of MCP-1 ten weeks after implantation of the graft into the host.

17. The method of claim 1 wherein the monocytes enhance neotissue formation and reduce stenosis at the site of graft implantation as the graft degrades.

18. The method of claim 1, wherein the host is a pediatric patient.