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.

项目总结/摘要 先天性心脏病（CHD）是美国最常见的出生缺陷，有一半的新生儿患有CHD 需要手术干预。许多CHD的手术治疗涉及植入合成导管， Gore-Tex™，因为它们成本低，易于手术处理，并且缺乏替代品。这方面的一个例子 应用是用于单心室畸形的心外Fontan导管，其连接下腔静脉 肺动脉然而，在儿童中使用合成移植物作为管道， 阻碍和缺乏增长潜力。组织工程血管移植物（TEVG）是一种潜在的解决方案， 其中具有自体细胞的生物可降解支架成熟为功能性血管作为支架 退化最近的工作表明，TEVG支架孔隙率是细胞浸润所必需的。当前TEVG 然而，生产方法仅能够生产简单的管状结构， CHD患儿的一系列解剖结构使用计算流体设计的患者专用Fontan导管 在模拟中，已显示出流体动力学（CFD）可改善其血流动力学曲线，从而获得更好的流动 分布，提高能量效率和降低壁剪切应力。因此，仍然迫切需要 患者特异性导管是生物相容的并随患者生长。Feinberg实验室开发了一种3D 生物打印平台称为悬浮水凝胶的自由形式可逆嵌入（FRESH）， 将高强度和微孔胶原基ECM转化为功能性的患者特异性组织支架， 前所未有的分辨率（20 µm）和结构复杂性。我假设FRESH的微孔性 打印的胶原基血管导管将驱动体内细胞浸润， 重塑朝向新组织形成，并且FRESH可以产生符合几何形状的导管。 对CHD儿童的需求。在目标1中，我将新鲜生物打印简单的直导管，植入它们 进入大鼠IVC，并通过重复的体内超声纵向监测其作为管道的功能。在预- 在确定的时间点，我将取出这些TEVG并评估生物力学和组织学变化 是由体内细胞重塑引起的在目标2中，我将使用计算模型来确定壁面剪力 对患者特定Fontan导管施加应力，从患者MRI扫描中分割，并加强高壁区域 通过增加区域或周向壁厚产生剪切应力。然后我将FRESH 3D生物打印这些患者 特定的Fontan管道，测量其准确性并对其进行生物力学测试。完成这些 aims是朝着我们创造患者特异性组织工程化Fontan管道的能力迈出的重要一步， 适用于CHD患者中观察到的解剖几何结构阵列， 动力学，以改善其长期血液动力学性能，是生物相容性的，并可以随着 病人这项工作将使我们能够继续进行TEVG大型动物移植的下一步工作。