@article{d118558b129b4c78bfac4457c7bc44e2,
title = "Spontaneous reversal of stenosis in tissue-engineered vascular grafts",
abstract = "We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)–approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.",
author = "Drews, {Joseph D.} and Pepper, {Victoria K.} and Best, {Cameron A.} and Szafron, {Jason M.} and Cheatham, {John P.} and Yates, {Andrew R.} and Hor, {Kan N.} and Zbinden, {Jacob C.} and Chang, {Yu Chun} and Mirhaidari, {Gabriel J.M.} and Ramachandra, {Abhay B.} and Shinka Miyamoto and Blum, {Kevin M.} and Onwuka, {Ekene A.} and Jason Zakko and John Kelly and Cheatham, {Sharon L.} and Nakesha King and Reinhardt, {James W.} and Tadahisa Sugiura and Hideki Miyachi and Yuichi Matsuzaki and Julie Breuer and Heuer, {Eric D.} and {Aaron West}, T. and Toshihiro Shoji and Darren Berman and Boe, {Brian A.} and Jeremy Asnes and Mark Galantowicz and Goki Matsumura and Narutoshi Hibino and Marsden, {Alison L.} and Pober, {Jordan S.} and Humphrey, {Jay D.} and Toshiharu Shinoka and Breuer, {Christopher K.}",
note = "Funding Information: We thank our Data Safety Monitoring Board (R. Shaddy, G. Wernovsky, R. Burke, D. Mooney, and J. Burns), the Nationwide Children's Hospital Animal Research Core (H. Pisharath, L. Goodchild, A. Morrison, A. Artrip, A. Ashbrook, K. Nelson, J. Hamilton, and C. Haller), Interventional Cardiology staff (J. Chisolm, A. Latham, J. Swinning, P. Lawrence, and A. Harrison), and A. Lee for their assistance completing the work described here. This research was supported by U.S. NIH grants: R01HL098228, R01HL128602, R01HL128847, and R01HL139996, in addition to the Department of Defense Application ID PR170976 Award Number W81XWH-18-1-0518. Funding was also provided by the NIH (TL1TR001069 to J.D.D. from the National Center for Advancing Translational Sciences; 2T32GM068412-11A1 to C.A.B. from the National Institute of General Medical Sciences; T32AI106704 to E.A.O. and TL1TR002735 to J.Z. from the National Center for Advancing Translational Sciences; Diversity Supplement Grant 3R01HL098228-06S1 to N.K.; T32HL098039-06A1 to J.W.R. and T32HL098039 to J.K. from the National Heart, Lung, and Blood Institute). J.M.S. was supported by NSF Graduate Research Fellowship DGE1122492. J.W.R. was supported, in part, by the American Heart Association under Award Number 18POST33990231. Publisher Copyright: Copyright {\textcopyright} 2020 The Authors,",
year = "2020",
month = apr,
day = "1",
doi = "10.1126/scitranslmed.aax6919",
language = "English (US)",
volume = "12",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "537",
}