Nationwide Children's Hospital, Columbus, OH (T.B., M.J., T.S., C.K.B.).
Yale University, School of Engineering and Applied Science, New Haven, CT (J.D.H.).
Arterioscler Thromb Vasc Biol. 2023 Mar;43(3):399-409. doi: 10.1161/ATVBAHA.122.318236. Epub 2023 Jan 12.
For over 25 years, our group has used regenerative medicine strategies to develop improved biomaterials for use in congenital heart surgery. Among other applications, we developed a tissue-engineered vascular graft (TEVG) by seeding tubular biodegradable polymeric scaffolds with autologous bone marrow-derived mononuclear cells. Results of our first-in-human study demonstrated feasibility as the TEVG transformed into a living vascular graft having an ability to grow, making it the first engineered graft with growth potential. Yet, outcomes of this first Food and Drug Administration-approved clinical trial evaluating safety revealed a prohibitively high incidence of early TEVG stenosis, preventing the widespread use of this promising technology. Mechanistic studies in mouse models provided important insight into the development of stenosis and enabled advanced computational models. Computational simulations suggested both a novel inflammation-driven, mechano-mediated process of in vivo TEVG development and an unexpected natural history, including spontaneous reversal of the stenosis. Based on these in vivo and in silico discoveries, we have been able to rationally design strategies for inhibiting TEVG stenosis that have been validated in preclinical large animal studies and translated to the clinic via a new Food and Drug Administration-approved clinical trial. This progress would not have been possible without the multidisciplinary approach, ranging from small to large animal models and computational simulations. This same process is expected to lead to further advances in scaffold design, and thus next generation TEVGs.
25 多年来，我们的团队一直利用再生医学策略来开发改良的生物材料，用于先天性心脏病手术。在其他应用中，我们通过将自体骨髓来源的单核细胞接种到管状可生物降解聚合物支架上来开发组织工程血管移植物 (TEVG)。我们的首例人体研究结果证明了其可行性，因为 TEVG 转化为具有生长能力的活血管移植物，成为第一个具有生长潜力的工程移植物。然而，这项首次获得美国食品和药物管理局批准的临床试验的安全性评估结果显示，早期 TEVG 狭窄的发生率高得令人望而却步，这阻碍了这项有前途的技术的广泛应用。在小鼠模型中的机制研究为狭窄的发展提供了重要的见解，并能够进行先进的计算模型。计算模拟表明，存在一种新型的炎症驱动、机械介导的体内 TEVG 发展过程，以及一种意想不到的自然史，包括狭窄的自发逆转。基于这些体内和计算机模拟的发现，我们能够合理设计抑制 TEVG 狭窄的策略，这些策略已经在临床前大型动物研究中得到验证，并通过新的美国食品和药物管理局批准的临床试验转化为临床应用。如果没有从小型到大型动物模型和计算模拟的多学科方法，就不可能取得这一进展。这一过程有望在支架设计方面取得进一步进展，从而开发出下一代 TEVG。
