Spontaneous reversal of stenosis in tissue-engineered vascular grafts
Joseph D. Drews, Victoria K. Pepper, Cameron A. Best, Jason M. Szafron, John P. Cheatham, Andrew R. Yates, Kan N. Hor, Jacob C. Zbinden, Yu-Chun Chang, Gabriel Mirhaidari, Abhay B. Ramachandra, Shinka Miyamoto, Kevin M. Blum, Ekene Onwuka, Jason Zakko, John Kelly, John P. Cheatham, Nakesha King, James W. Reinhardt, Tadahisa Sugiura, Hideki Miyachi, Yuichi Matsuzaki, Julie Breuer, Eric Heuer, T. Aaron West, Toshihiro Shoji, Darren P. Berman, Brian A. Boe, Jeremy D. Asnes, Mark Galantowicz, Goki Matsumura, Narutoshi Hibino, Alison L. Marsden, Jordan S. Pober, Jay D. Humphrey, Toshiharu Shinoka, Christopher K. Breuer
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.