Chronic deep venous insufficiency remains a major health problem in the United States. Subacute thrombosis and intimal hyperplasia limit the usefulness of bioprosthetic venous valves. While some improvements have been reported with allograft valves seeded or coated with endothelial cells (EC), the harvesting of ECs from autologous sources, e.g. veins or adipose tissue, remains problematic. More recently, endothelial progenitor cells (EPCs) have been considered a promising source of ECs because EPCs are readily isolated from whole blood and rapidly expanded in vitro. However, for bioprosthetic venous valves the therapeutic potential of EPCs has not been demonstrated. Accordingly, the central hypothesis of this proposal is that modification of the surface of small intestinal submucosa (SIS) leaflets will enable the capture and growth of functional EPCs in order to modulate the in vivo biologic responses of limited intimal hyperplasia formation on SIS bioprosthetic venous valves in an ovine model. To test this hypothesis we will conduct the project with ovine EPCs in vitro, ex vivo, and in vivo in a ovine model with percutaneous delivery of venous valves to the jugular vein of sheep. We propose to: 1) Determine the ability of SIS valve leaflets coated with oriented antibodies to capture EPCs. We propose to modify the SIS valve leaflet surface by conjugating oriented capture antibodies directed at cell surface markers (KDR, CD34, and CD133) to specifically capture EPCs. Capture will be evaluated both in vitro and ex vivo. 2) Determine the ability of differentiated EPCs to limit intimal hyperplasia on SIS valve leaflets. We propose to seed differentiated ovine EPCs onto SIS leaflets of bioprosthetic venous valves, implant the endothelialized valves into sheep, and evaluate both the degree of intimal hyperplasia and the functionality of the valves. 3) Determine the ability of captured EPCs to limit intimal hyperplasia on SIS valve leaflets in an ovine animal model. We hypothesize that captured EPCs will rapidly endothelialize the SIS leaflets, which will result in the reduction of intimal hyperplasia and improved functionality of the bioprosthetic venous valve.

Public Health Relevance

Chronic deep venous insufficiency is a major health problem worldwide. Bioprosthetic venous valves represent an innovative experimental concept and have the potential to revolutionize patient treatment by percutaneously replacing diseased valves. The endothelialization of the leaflets of the bioprosthetic valves will alter the healing response and improve the function of the bioprosthetic venous valves.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Lundberg, Martha
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Oregon Health and Science University
Engineering (All Types)
Schools of Medicine
United States
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Glynn, Jeremy J; Hinds, Monica T (2016) Bioactive Anti-Thrombotic Modification of Decellularized Matrix for Vascular Applications. Adv Healthc Mater 5:1439-46
Glynn, Jeremy J; Hinds, Monica T (2015) Endothelial outgrowth cells regulate coagulation, platelet accumulation, and respond to tumor necrosis factor similar to carotid endothelial cells. Tissue Eng Part A 21:174-82
Cutiongco, Marie F A; Anderson, Deirdre E J; Hinds, Monica T et al. (2015) In vitro and ex vivo hemocompatibility of off-the-shelf modified poly(vinyl alcohol) vascular grafts. Acta Biomater 25:97-108
Glynn, Jeremy J; Polsin, Elizabeth G; Hinds, Monica T (2015) Crosslinking decreases the hemocompatibility of decellularized, porcine small intestinal submucosa. Acta Biomater 14:96-103
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Anderson, Deirdre E J; McKenna, Kathryn A; Glynn, Jeremy J et al. (2014) Thrombotic responses of endothelial outgrowth cells to protein-coated surfaces. Cells Tissues Organs 199:238-48
Anderson, Deirdre E J; Glynn, Jeremy J; Song, Howard K et al. (2014) Engineering an endothelialized vascular graft: a rational approach to study design in a non-human primate model. PLoS One 9:e115163
Glynn, Jeremy J; Hinds, Monica T (2014) Endothelial outgrowth cells: function and performance in vascular grafts. Tissue Eng Part B Rev 20:294-303
McKenna, Kathryn A; Hinds, Monica T; Sarao, Rebecca C et al. (2012) Mechanical property characterization of electrospun recombinant human tropoelastin for vascular graft biomaterials. Acta Biomater 8:225-33
Jones, Casey M; Hinds, Monica T; Pavcnik, Dusan (2012) Retention of an autologous endothelial layer on a bioprosthetic valve for the treatment of chronic deep venous insufficiency. J Vasc Interv Radiol 23:697-703

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