Compositions and methods for promoting patency of vascular grafts

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.

1 - 10 . (canceled) 
     
     
         11 . A biodegradable polymeric vascular graft or conduit comprising 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. 
     
     
         12 . (canceled) 
     
     
         13 . The polymeric vascular graft or conduit 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. 
     
     
         14 . The polymeric vascular graft or conduit of  claim 13 , wherein the biodegradable or bioabsorbable polymers are formed into a fiber-based mesh. 
     
     
         15 . The polymeric vascular graft or conduit of  claim 14 , wherein the fiber-based mesh is a non-woven mesh. 
     
     
         16 . The polymeric vascular graft or conduit of  claim 15 , wherein the vascular graft further comprises a polymeric sealant. 
     
     
         17 . The polymeric vascular graft or conduit of  claim 16 , wherein the polymeric sealant comprises a co-polymer of ε-caprolactone and L-lactide. 
     
     
         18 . The polymeric vascular graft or conduit of  claim 11 , further comprising a cytokine or chemokine selected from the group consisting 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. 
     
     
         19 . (canceled) 
     
     
         20 . The polymeric vascular graft or conduit of  claim 11 , wherein the vascular graft or conduit further comprises an active agent selected from the group consisting of anti-thrombogenic agents, anti-proliferative agents, anti-inflammatory agents, antiproliferative agents, anesthetic agents, anti-coagulants, cholesterol-lowering agents, vasodilating agents, and agents which interfere with endogenous vasoactive mechanisms. 
     
     
         21 . The polymeric vascular graft or conduit of  claim 11 , wherein the MCP-1 or other cytokine or chemokine is dispersed throughout the vascular graft or conduit. 
     
     
         22 . The polymeric vascular graft or conduit of  claim 21 , wherein the cytokine or chemokine is encapsulated in the form of microspheres, nanospheres, microparticles and/or microcapsules that are seeded into the vascular graft or conduit. 
     
     
         23 . The polymeric vascular graft or conduit of  claim 11 , 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. 
     
     
         24 . The polymeric vascular graft or conduit of  claim 11 , 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. 
     
     
         25 . The polymeric vascular graft or conduit of  claim 11 , wherein the graft or conduit is seeded with human bone marrow mononuclear cells. 
     
     
         26 . The polymeric vascular graft or conduit of  claim 11 , wherein the MCP-1 is provided in microparticles between 1 μm and 20 μm in diameter incorporated into the graft. 
     
     
         27 . The polymeric vascular graft or conduit of  claim 11 , wherein the internal diameter of the graft or conduit is larger relative to the internal diameter of the graft or conduit in the absence of MCP-1 ten weeks after implantation of the graft into the host. 
     
     
         28 . The polymeric vascular graft or conduit of  claim 11 , wherein the wall thickness of the graft or conduit is thinner relative to the wall thickness of the graft or conduit in the absence of MCP-1 ten weeks after implantation of the graft or conduit into the host. 
     
     
         29 . The polymeric vascular graft or conduit of  claim 11 , for implantation into a pediatric patient. 
     
     
         30 . The polymeric vascular graft or conduit of  claim 14  wherein the graft or conduit is formed of knitted or braided fibers. 
     
     
         31 . The polymeric vascular graft or conduit of  claim 14  wherein the graft or conduit is formed of a woven mesh