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 先天性心脏病是美国最常见的出生缺陷，有一半的新生儿患有先天性心脏病 需要外科手术治疗。许多先天性心脏病的外科治疗需要植入合成导管，如 作为戈尔-特克斯™，因为它们的低成本，易于手术处理，并且缺乏替代方案。这方面的一个例子 连接下腔静脉的心外Fontan导管在单室畸形中的应用 到了肺动脉。然而，在儿童中使用合成移植物作为管道，由于进展而变得复杂。 阻碍和缺乏增长潜力。组织工程血管移植物(TEVGs)是一种潜在的解决方案， 其中含有自体细胞的可生物降解支架成熟为功能性血管作为支架 会退化。最近的研究表明，TEVG支架的孔隙率对于细胞渗透是必不可少的。当前TEVG 然而，生产方法只能生产与宽度不匹配的简单管状结构 先天性心脏病儿童的解剖阵列。使用计算流体设计的患者专用Fontan导管 动力学(CFD)在模拟中已被证明可以改善他们的血流动力学曲线，从而产生更好的流动 分布，提高能效，降低壁面剪应力。因此，仍然迫切需要 患者特定的导管，具有生物兼容性，并与患者一起生长。范伯格实验室已经开发出一种3D 一种可实现打印的生物打印平台，称为悬浮水凝胶(Fresh)的自由形式可逆嵌入 将高强度和微孔的胶原基ECM植入患者特定的功能性组织支架中 前所未有的分辨率(20微米)和结构复杂性。我假设新鲜的微孔率 打印的、以胶原蛋白为基础的血管管道将促进体内细胞的渗透，并促进强大的细胞 对新组织的形成进行重塑，新鲜的可以产生符合几何形状的管道 对先天性心脏病儿童的需求。在目标1中我将新鲜的生物打印简单的直管，植入他们 进入大鼠下腔静脉，并通过重复的体内超声纵向监测其作为管道的功能。在Pre- 确定的时间点我将植入这些TEVG，并评估生物力学和组织学变化 由体内细胞重塑引起。在目标2中，我将使用计算模型来确定墙体剪力 对患者特定的Fontan导管施加应力，从患者的MRI扫描中分割出来，并加固高壁区域 通过增加区域或周向壁厚而产生的剪切应力。然后我会对这些病人进行新鲜的3D生物打印 特定的Fontan导管，测量精确度并对其进行生物力学测试。完成这些工作 AIMS是我们在创建患者特有的组织工程化Fontan管道方面迈出的重要一步 适合于冠心病患者中看到的解剖几何阵列，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，具有生物兼容性，并可与 有耐心的。这项工作将使我们能够继续进行大动物植入我们的TEVGs的下一步。