The search for a biologically based arterial graft that could function at small diameters has gone on for several decades, and multiple hurdles have been overcome during that time. In recent years, the previous limitation of inadequate mechanical strength has been overcome by several investigators, but extended times for autologous artery culture have limited widespread adaption or experimentation. Niklason reported in 2003 the feasibility of decellularizing engineered arteries, and we showed in the previous granting period that tissue engineered and decellularized grafts can function long-term in vivo, thereby shortening the required culture time to 4 weeks of autologous endothelial cell culture. Hence, one of the last significant hurdles in vascular tissue engineering is to produce tissue-based grafts that require no culture time, and that can resist thrombosis without having an autologous endothelial cell layer. The overall goal of this proposal is to develop non-cell-based means of inhibiting coagulation and platelet activation on decellularized engineered arteries, so that functional arterial grafts may be available "off the shelf". In this revised, competitive renewal, our approach is to inhibit both the coagulation cascade and platelet adhesion by intervening at multiple points. By incorporating a high density of covalently bound heparin onto the graft surface, we should inhibit coagulation factors XIIa, Xa, and IIa, and thereby reduce clot formation and platelet adhesion and aggregation. By coating the graft lumen with thrombospondin2- null matrix, platelet adhesion should be reduced, which in combination with thrombin inhibition by heparin should inhibit clot formation. Thrombospondin2-null matrix may also support endothelial adhesion and growth more than native collagen matrix that contains thrombospondin2, enabling better host endothelialization. These novel anti-coagulation strategies will be compared, using a comprehensive set of in vitro assays as well as large animal in vivo studies, with autologous endothelium for their ability to inhibit thrombosis of decellularized, engineered arterial grafts.

Public Health Relevance

Development of engineered arteries has advanced substantially over the past several decades, but progress has stopped short of a fully functional, off-the-shelf arterial conduit. Work in this application will build upon our progress in the last granting period, wherein we developed acellular tissue engineered matrices for use as vascular grafts. In this application, we will study the efficacy of several non-cellular modifications of the graft surface to reduce thrombogenicity, with the aim of creating a completely off-the-shelf vascular graft.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL083895-06A1
Application #
8237548
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2006-09-01
Project End
2015-11-30
Budget Start
2012-02-15
Budget End
2012-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$601,832
Indirect Cost
$183,297
Name
Yale University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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