3D Bioprinted Collagen Vascular Conduits For Use In Patients With Congenital Heart Defects

3D 生物打印胶原血管导管用于先天性心脏病患者

• 批准号: 10763791
• 负责人: Syed Faaz Ashraf
• 金额: $ 8.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10763791
• 关键词: 3-Dimensional; Anastomosis - action; Anatomy; Animal Model; Animals; Area; Autologous; Biomechanics; Biomedical Engineering; Bioreactors; Blood Vessels; Cardiac; Cells; Cellular Infiltration; Characteristics; Child; Clinical; Collagen; Common Ventricle; Complex; Computer Models; Congenital Abnormality; Congenital Heart Defects; Development; Electrospinning; Endothelium; Engineering; Extracellular Matrix; Future; Geometry; Goals; Goretex; Growth; Histologic; Histology; Human; Hydrogels; Immunohistochemistry; Implant; Inferior vena cava structure; Inflammation; Liquid substance; MRI Scans; Measures; Mechanics; Methods; Modification; Monitor; Newborn Infant; Obstruction; Operative Surgical Procedures; Optical Coherence Tomography; Patients; Performance; Polyglycolic Acid; Porosity; Printing; Production; Property; Psychological reinforcement; Pulmonary artery structure; Rattus; Resistance; Resolution; Scientist; Specificity; Sprague-Dawley Rats; Stenosis; Structure; Surgeon; Testing; Thick; Thrombosis; Tissue Engineering; Tissue Viability; Tissues; Training; Tubular formation; Vascular Graft; Venous Pressure level; Work; biodegradable scaffold; biomaterial compatibility; biomechanical test; bioprinting; cost; design; energy efficiency; hemodynamics; immunogenicity; implantation; improved; in vivo; in vivo monitoring; manufacture; mechanical properties; meter; microCT; mouse model; pressure; scaffold; shear stress; simulation; tissue support frame; ultrasound; vascular tissue engineering

PROJECT SUMMARY/ABSTRACT Congenital heart defects (CHDs) are the most common birth defect in the US, with half of all newborns with CHD requiring surgical intervention. Surgical treatment of many CHDs involves implantation of synthetic conduits such as Gore-Tex™ due to their low cost, ease of surgical handling, and lack of alternatives. An example of this application is the extra-cardiac Fontan conduit for single ventricle anomalies, that connects the inferior vena cava to the pulmonary artery. Use of synthetic grafts as conduits in children, however, is complicated by progressive obstruction and lack of growth potential. Tissue engineered vascular grafts (TEVGs) are a potential solution, where a biodegradable scaffold with autologous cells mature into a functional blood vessel as the scaffold degrades. Recent work suggests that TEVG scaffold porosity is essential for cellular infiltration. Current TEVG production methods, however, are only able to produce simple tubular constructs that do not match the wide array of anatomies in children with CHDs. Patient specific Fontan conduits designed using Computational Fluid Dynamics (CFD) have been shown, in simulations, to improve their hemodynamic profile resulting in better flow distribution, improved energy efficiency and reduced wall shear stress. Thus, there remains critical need for patient specific conduits that are biocompatible and grow with the patient. The Feinberg lab has developed a 3D bioprinting platform called freeform reversible embedding of suspended hydrogels (FRESH) that enables printing of high-strength and microporous collagen-based ECM into functional, patient specific tissue scaffolds with unprecedented resolution (20 µm) and structural complexity. I hypothesize that the microporosity of FRESH printed, collagen-based, vascular conduits will drive in-vivo cellular infiltration and facilitate robust cellular remodeling towards neo-tissue formation, and that FRESH can produce conduits that meet the geometric demands required of children with CHD. In Aim 1 I will FRESH bioprint simple straight conduits, implant them into rats IVC and monitor their function as a conduit longitudinally via repeated in-vivo ultrasound. At pre- determined timepoints I will explant these TEVGs and assess the biomechanical and histological changes brought upon by in vivo cellular remodeling. In Aim 2 I will use computational modelling to determine wall shear stress on patient specific Fontan conduits, segmented from patients MRI scans, and reinforce areas of high wall shear stress by increasing regional or circumferential wall thickness. I will then FRESH 3D bioprint these patient specific Fontan conduits, gauge for accuracy and perform biomechanical tests on them. Completion of these aims is an important step towards our ability in creating patient specific, tissue engineered Fontan conduits that are suited to the array of anatomical geometries seen in patients with CHD, are modified with computational fluid dynamics to improve their long-term hemodynamic performance, are biocompatible and can grow with the patient. This work will allow us to move on to the next steps of large animal implantations of our TEVGs.

项目摘要/摘要 先天性心脏缺陷（CHD）是美国最常见的先天缺陷，其中一半的新生儿患有冠心病 需要手术干预。许多CHD的手术治疗涉及植入合成导管 由于Gore-Tex™的成本较低，手术处理的易用性以及缺乏替代方案，因此作为Gore-Tex™。一个例子 应用是单个通风异常的心外fontan导管，它连接下腔静脉 到肺动脉。然而，使用合成移植物作为儿童的导管很复杂 阻塞和缺乏增长潜力。组织工程的血管移植物（TEVG）是潜在的解决方案， 其中具有自体细胞的可生物降解脚手架成熟成功能性血管作为脚手架 退化。最近的工作表明，TEVG支架孔隙度对于细胞浸润至关重要。当前的tevg 但是，生产方法只能产生与宽宽的简单管状结构 冠心病儿童的一系列解剖学。使用计算流体设计的患者特定的方丹导管 在模拟中已经显示了动力学（CFD），以改善其血液动力学特征，从而提高流量 分布，提高能源效率并减少壁剪应力。那仍然仍然需要 具有生物相容性并与患者一起生长的患者特定导管。 Feinberg实验室已经开发了3D 生物印刷平台称为悬浮水凝胶（新鲜）的自由形式可逆嵌入，可实现印刷 具有高强度和微孔胶原蛋白的ECM的功能，特定于患者的组织支架 前所未有的分辨率（20 µm）和结构复杂性。我假设新鲜的微孔度 印刷的，基于胶原蛋白的血管导管将驱动体内细胞浸润并促进可靠的细胞 朝向新组织形成的重塑，新鲜可以产生符合几何形状的导管 冠心病儿童所需的要求。在AIM 1中，我将新鲜的生物构图简单的直管，植入它们 进入大鼠IVC，并通过重复的体内超声监测其作为导管的功能。 确定的时间点我将探索这些TEVG并评估生物力学和组织学变化 由体内蜂窝重塑购买。在AIM 2中，我将使用计算建模来确定墙壁剪切 对患者特定的方丹导管的压力，从患者MRI扫描中分割的压力，并加强高壁区域 剪切应力通过增加区域或圆周壁厚。然后，我将新鲜的3D生物申请这些患者 特定的方坦导管，仪表的准确性并对它们进行生物力学测试。这些完成 Aims是我们迈向创建特定于患者的，组织工程的Fontan导管的重要一步 适用于在冠心病患者中看到的一系列解剖几何形状，用计算流体修饰 改善其长期血液动力学性能的动力学是生物相容性的，并且可以随着 病人。这项工作将使我们能够继续进入TEVG的大型动物植入的后续步骤。