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.

我们开发了一种用于儿童的组织工程血管移植物 (TEVG)，并展示了美国食品和药物管理局 (FDA) 批准的临床试验结果，该试验在单心室心脏异常患者中评估了这种移植物。TEVG 被用作 Fontan 导管连接下腔静脉和肺动脉，但在前 6 个月内出现了高发生率的移植物狭窄，并通过血管成形术成功治疗。为了阐明这种早期狭窄的潜在机制，我们使用了一个数据知情的计算模型来执行 TEVG 发展的硅参数研究。模拟预测了在我们的临床试验中观察到的早期狭窄，但进一步表明这种狭窄可以通过炎症驱动的机械介导机制自发逆转。我们测试了这出乎意料的，通过将 TEVG 植入绵羊下腔静脉插入移植模型中，模型生成的假设证实了 TEVG 狭窄自发解决并且通常耐受性良好的预测。这些发现对我们的转化研究具有重要意义，因为它们表明无症状早期狭窄患者可以安全地避免血管成形术，尽管仍然需要适当的医学监测。模拟进一步预测，可以通过改变支架设计来减轻早期炎症并增加合成细胞的机械感应来减轻可逆变窄的程度，从而为优化下一代 TEVG 提供了新的范例。