Research ArticleTissue Engineering

Spontaneous reversal of stenosis in tissue-engineered vascular grafts

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Science Translational Medicine  01 Apr 2020:
Vol. 12, Issue 537, eaax6919
DOI: 10.1126/scitranslmed.aax6919

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Lessons in graft remodeling

Tissue-engineered grafts have the capacity to grow and remodel after implantation, which could confer considerable benefit to individuals with congenital heart disease. After a promising clinical trial in Japan, Drews et al. implanted tissue-engineered vascular grafts (TEVGs) as cardiac conduits in children with single-ventricle anomalies in the United States. The grafts, polymeric scaffolds seeded with autologous bone marrow–derived cells, showed surprising evidence of stenosis within 8 months after implantation, halting the clinical trial. Computational studies predicted the early stenosis, which was also observed after TEVG implantation in sheep. In silico and in vivo studies confirmed that early stenosis resolved via inflammation-driven graft remodeling without surgical intervention within 1 year after implantation. Results uncover a mechanism of reversible stenosis in TEVGs and support the value of computational modeling for informing graft design and accelerating safe translation of cardiovascular tissue–engineered products.

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.

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