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.

项目概要/摘要 先天性心脏病 (CHD) 是美国最常见的出生缺陷，一半的新生儿患有先天性心脏病 许多先心病的手术治疗需要植入合成导管，例如 例如 Gore-Tex™，因为其成本低、易于手术操作且缺乏替代品。 应用是用于单心室异常的心外 Fontan 导管，连接下腔静脉 然而，使用合成移植物作为儿童的导管由于进行性进展而变得复杂。 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可生物降解支架作为支架成熟为功能性血管 最近的研究表明，TEVG 支架的孔隙度对于当前的 TEVG 细胞浸润至关重要。 然而，生产方法只能生产简单的管状结构，与宽范围的结构不匹配。 使用计算流体设计的针对患有 CHD 的儿童的一系列解剖结构。 模拟表明，动力学 (CFD) 可以改善其血流动力学特征，从而实现更好的流动 因此，仍然迫切需要。 Feinberg 实验室开发了一种具有生物相容性并可随患者生长的患者特定导管。 称为自由形式可逆嵌入悬浮水凝胶（FRESH）的生物打印平台，可实现打印 将高强度和微孔的基于胶原蛋白的 ECM 转化为功能性的、患者特异性的组织支架 前所未有的分辨率（20 µm）和结构复杂性。 基于胶原蛋白的印刷血管导管将驱动体内细胞浸润并促进强大的细胞 重塑新组织形成，并且 FRESH 可以产生符合几何形状的导管 患有先心病的儿童的要求 在目标 1 中，我将新鲜生物打印简单的直导管，并将其植入。 进入大鼠 IVC 并通过重复的体内超声纵向监测其作为导管的功能。 确定的时间点我将外植这些 TEVG 并评估生物力学和组织学变化 在目标 2 中，我将使用计算模型来确定壁剪切力。 对患者特定的 Fontan 导管施加压力，从患者 MRI 扫描中分段，并加固高墙区域 然后，我将通过增加局部或周向壁厚度来产生剪切应力，然后对这些患者进行 FRESH 3D 生物打印。 特定的 Fontan 导管，测量准确性并对其进行生物力学测试。 目标是朝着我们创造患者特异性、组织工程 Fontan 导管的能力迈出的重要一步 适合先心病患者的一系列解剖几何形状，并用计算流体进行修改 动力学以改善其长期血流动力学性能，具有生物相容性，并且可以与 这项工作将使我们能够继续进行 TEVG 大型动物植入的下一步。