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.

The Real Need for Regenerative Medicine in the Future of Congenital Heart Disease Treatment

“…Our model predicted the early stenosis as observed in clinical trials, but surprisingly it suggested that the stenosis would spontaneously reverse though an inflammatory-driven, mechano-mediated mechanism [ 107 ]. Further validation of this model occurred through implanting TEVGs in a sheep inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis would resolve spontaneously [ 108 ]. These results suggested that although the need for appropriate medical monitoring remains important, angioplasty could have been safely avoided in patients with asymptomatic initial stenosis.…”

A Novel Restorative Pulmonary Valve Conduit: Early Outcomes of Two Clinical Trials

“…The dramatic clinical presentation, with acute conduit stenosis and right ventricular failure 9 days after a seemingly normal routine follow-up 9 months post-XPV implantation, defies clear explanation. Tuberous sclerosis can be associated with overexpression of the complement pathways, and a hyperimmune reaction ( 16 ). The patient's current Contegra conduit has experienced the same process of early recurrence of stenosis.…”

“…Stenosis was assessed in the parasternal short axis view, using the continuous wave Doppler technique to measure the peak velocity of flow through the conduit. PI was qualitatively assessed using previously published criteria combining color flow and pulsed Doppler echocardiography ( 16 ). Regurgitation was classified as none, trivial or trace, mild, moderate or severe.…”

Cell signaling model for arterial mechanobiology

“…Many different models focusing on different conditions have been proposed to study arterial growth and remodeling [65][66][67][68][69][70]. Among others, we have found phenomenological models to be useful in generating and testing diverse hypotheses fundamental to arterial adaptations [5,22], in studying arterial disease progression [71,72], and in the design of tissue engineered constructs and their clinical usage [73,74]. Nevertheless, tissue-level manifestations arise from molecular and cellular level changes [75][76][77][78].…”