Department of Internal Medicine, Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, Yale School of Medicine, 300 George Street, New Haven, CT 06511, United States; Yale Stem Cell Center, 10 Amistad street, New Haven, CT 06511, United States; Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06510, United States.
Department of Internal Medicine, Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, Yale School of Medicine, 300 George Street, New Haven, CT 06511, United States; Yale Stem Cell Center, 10 Amistad street, New Haven, CT 06511, United States; Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06510, United States; Department of Pathology, Yale University, New Haven, CT 06510, United States.
Acta Biomater. 2020 Jan 15;102:220-230. doi: 10.1016/j.actbio.2019.10.019. Epub 2019 Oct 19.
Single ventricle heart defects (SVDs) are congenital disorders that result in a variety of complications, including increased ventricular mechanical strain and mixing of oxygenated and deoxygenated blood, leading to heart failure without surgical intervention. Corrective surgery for SVDs are traditionally handled by the Fontan procedure, requiring a vascular conduit for completion. Although effective, current conduits are limited by their inability to aid in pumping blood into the pulmonary circulation. In this report, we propose an innovative and versatile design strategy for a tissue engineered pulsatile conduit (TEPC) to aid circulation through the pulmonary system by producing contractile force. Several design strategies were tested for production of a functional TEPC. Ultimately, we found that porcine extracellular matrix (ECM)-based engineered heart tissue (EHT) composed of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary cardiac fibroblasts (HCF) wrapped around decellularized human umbilical artery (HUA) made an efficacious basal TEPC. Importantly, the TEPCs showed effective electrical and mechanical function. Initial pressure readings from our TEPC in vitro (0.68 mmHg) displayed efficient electrical conductivity enabling them to follow electrical pacing up to a 2 Hz frequency. This work represents a proof of principle study for our current TEPC design strategy. Refinement and optimization of this promising TEPC design will lay the groundwork for testing the construct's therapeutic potential in the future. Together this work represents a progressive step toward developing an improved treatment for SVD patients. STATEMENT OF SIGNIFICANCE: Single Ventricle Cardiac defects (SVD) are a form of congenital disorder with a morbid prognosis without surgical intervention. These patients are treated through the Fontan procedure which requires vascular conduits to complete. Fontan conduits have been traditionally made from stable or biodegradable materials with no pumping activity. Here, we propose a tissue engineered pulsatile conduit (TEPC) for use in Fontan circulation to alleviate excess strain in SVD patients. In contrast to previous strategies for making a pulsatile Fontan conduit, we employ a modular design strategy that allows for the optimization of each component individually to make a standalone tissue. This work sets the foundation for an in vitro, trainable human induced pluripotent stem cell based TEPC.
单心室心脏缺陷 (SVD) 是一种先天性疾病,会导致多种并发症,包括心室机械应变增加和氧合血与脱氧血混合,导致心力衰竭,如果不进行手术干预。SVD 的矫正手术传统上由 Fontan 手术处理,需要血管导管完成。尽管有效,但目前的导管受到其无法帮助血液泵入肺循环的限制。在本报告中,我们提出了一种创新且多功能的组织工程搏动导管 (TEPC) 设计策略,通过产生收缩力来辅助肺系统循环。测试了几种设计策略来生产功能性 TEPC。最终,我们发现由人诱导多能干细胞衍生的心肌细胞 (hiPSC-CMs) 和原代心肌成纤维细胞 (HCF) 组成的基于猪细胞外基质 (ECM) 的工程心脏组织 (EHT) 包裹在脱细胞人脐动脉 (HUA) 周围,构成了有效的基本 TEPC。重要的是,TEPC 显示出有效的电和机械功能。我们的体外 TEPC 的初始压力读数 (0.68 mmHg) 显示出有效的导电性,使它们能够跟随电起搏达到 2 Hz 的频率。这项工作代表了我们目前 TEPC 设计策略的原理验证研究。对这种有前途的 TEPC 设计进行改进和优化将为未来测试该构建体的治疗潜力奠定基础。这项工作共同代表了朝着为 SVD 患者开发改进治疗方法的一个进步步骤。
单心室心脏缺陷 (SVD) 是一种先天性疾病,预后不良,如果不进行手术干预。这些患者通过 Fontan 手术治疗,该手术需要血管导管完成。Fontan 导管传统上由稳定或可生物降解的材料制成,没有泵送活性。在这里,我们提出了一种用于 Fontan 循环的组织工程搏动导管 (TEPC),以减轻 SVD 患者的过度应变。与之前制作搏动 Fontan 导管的策略不同,我们采用了模块化设计策略,允许单独优化每个组件,以制造独立的组织。这项工作为体外可训练的基于人诱导多能干细胞的 TEPC 奠定了基础。