The overriding aim of this proposal is to investigate the cellular and molecular mechanisms of vascular neotissue formation in tissue engineered vascular grafts (TEVG), with special emphasis placed on the mechanisms contributing to post-implantation TEVG stenosis. We have designed and developed a TEVG specifically for use in congenital heart surgery. Our TEVG is created by seeding autologous bone marrow derived-mononuclear cells (BM-MNC) onto a biodegradable tubular scaffold and briefly incubating the seeded scaffolds in autologous serum prior to implantation as a vascular conduit. We have performed the first clinical trial evaluating the use of our TEVG as a conduit connecting the inferior vena cava to the pulmonary artery in children requiring modified Fontan surgery. This pilot study demonstrated that our method is both safe and effective. This study also demonstrated that stenosis is the primary mode of graft failure. The rational design of improved "second-generation" vascular grafts will be predicated on our understanding of the mechanisms underlying TEVG stenosis. This research is based upon our preliminary data obtained using a murine model that faithfully recapitulates human vascular neotissue formation and the development of TEVG stenosis as exhibited in our human clinical trial. We hypothesize that BM-MNC seeded onto a tubular biodegradable scaffold and implanted as a vascular interposition graft produce monocyte chemoattractant protein-1 (MCP-1), which recruits circulating monocytes to the implanted TEVG. The monocytes differentiate into macrophages and infiltrate the graft. Subsequently, these macrophages recruit smooth muscle cells from the adjacent vessel wall through a platelet derived growth factor (PDGF)-dependent mechanism and endothelial cells via a vascular endothelial growth factor (VEGF)-dependent mechanism. Alterations in these processes can be used to modulate neotissue formation and to either promote or inhibit the formation stenosis. We will use transgenic mouse models to test these hypotheses in order to investigate the following specific aims:
Aim 1 : Determine if circulating monocytes are the cellular targets of MCP-1/CCR2 signaling and if the resulting macrophage infiltrate in TEVG is critical to the formation of vascular neotissue and development of TEVG stenosis.
Aim 2 : Determine the source of the smooth muscle cells that form the medial layer of the TEVG;determine the role of macrophage production of PDGF-B in mediating this process;and determine if modulation of macrophage production of PDGF will affect the formation of TEVG stenosis.
Aim 3 : Determine the source and identity of the cells that form the intimal layer of the neovessel;determine the role of macrophage production of VEGF-A in mediating this process;and determine if modulation of macrophage production of VEGF-A will affect TEVG stenosis.

Public Health Relevance

Congenital cardiac anomalies are the most common birth defect and a leading cause of death in the newborn period. The most effective treatment for congenital cardiac anomalies is reconstructive surgery. Unfortunately, complications arising from the use of currently available vascular conduits are a significant cause of postoperative morbidity and mortality. The development of a tissue engineered vascular graft, created from an individual's own cells, with the ability to grow, repair, and remodel, holds great promise for advancing the field of congenital heart surgery and improving the outcomes of infants requiring surgical intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098228-05
Application #
8609589
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2010-01-19
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$299,903
Indirect Cost
$77,153
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Sugiura, Tadahisa; Tara, Shuhei; Nakayama, Hidetaka et al. (2016) Fast-degrading bioresorbable arterial vascular graft with high cellular infiltration inhibits calcification of the graft. J Vasc Surg :
Best, Cameron; Onwuka, Ekene; Pepper, Victoria et al. (2016) Cardiovascular Tissue Engineering: Preclinical Validation to Bedside Application. Physiology (Bethesda) 31:7-15
Sugiura, Tadahisa; Tara, Shuhei; Nakayama, Hidetaka et al. (2016) Novel Bioresorbable Vascular Graft With Sponge-Type Scaffold as a Small-Diameter Arterial Graft. Ann Thorac Surg 102:720-7
Sugiura, Tadahisa; Hibino, Narutoshi; Breuer, Christopher K et al. (2016) Tissue-engineered cardiac patch seeded with human induced pluripotent stem cell derived cardiomyocytes promoted the regeneration of host cardiomyocytes in a rat model. J Cardiothorac Surg 11:163
Lee, Yong-Ung; Mahler, Nathan; Best, Cameron A et al. (2016) Rational design of an improved tissue-engineered vascular graft: determining the optimal cell dose and incubation time. Regen Med 11:159-67
Kristofik, Nina; Calabro, Nicole E; Tian, Weiming et al. (2016) Impaired von Willebrand factor adhesion and platelet response in thrombospondin-2 knockout mice. Blood 128:1642-50
Hibino, Narutoshi; Mejias, Dane; Pietris, Nicholas et al. (2015) The innate immune system contributes to tissue-engineered vascular graft performance. FASEB J 29:2431-8
Khosravi, Ramak; Miller, Kristin S; Best, Cameron A et al. (2015) Biomechanical diversity despite mechanobiological stability in tissue engineered vascular grafts two years post-implantation. Tissue Eng Part A 21:1529-38
Duncan, Daniel R; Chen, Pei-Yu; Patterson, Joseph T et al. (2015) TGFβR1 inhibition blocks the formation of stenosis in tissue-engineered vascular grafts. J Am Coll Cardiol 65:512-4
Tara, Shuhei; Kurobe, Hirotsugu; de Dios Ruiz Rosado, Juan et al. (2015) Cilostazol, Not Aspirin, Prevents Stenosis of Bioresorbable Vascular Grafts in a Venous Model. Arterioscler Thromb Vasc Biol 35:2003-10

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