Bioprinted Vascularized Tissue Constructs

项目摘要 烧伤、创伤和糖尿病引起的急慢性损伤常常导致无法闭合的开放。 可能会造成永久性损伤、毁容甚至可能死亡的伤口。这是一个特别的 具有挑战性的问题，这种侮辱横跨相对较大的区域，几乎没有潜在的地点 自体组织采集。因此，替代块状组织等效物的开发是一种 主要对组织工程和再生医学领域感兴趣。市面上有售 产品只针对皮肤。无论是全厚的还是只有真皮层的，这些表面皮肤移植 不能满足重建手术的大量需求。当应用于患者时，这些 移植物常常因为不能在这些困难的伤口床上形成血管而失败。一种高效的血液动力学， 血管网未闭是决定移植物植入和长期存活的最重要因素 任何替换的组织。目前将血管网络整合到工程材料中的方法 组织只成功地生成了微尺度的均匀毛细血管丛(&lt；1 cm3)。 组织元素。这些网络具有有限的血流动力学控制，高血管阻力，以及 如果它们能够扩大规模，很可能不会蓬勃发展。我们已经率先使用组织生物制造 开发具有不同大小的管腔的可灌流的血管组织等效物的策略， 它模仿了天然的微血管结构。这项提案将测试规定的宏观规模如何 血管网络几何形状控制局部微血管新生血管反应和整个组织 灌流和植入。这项提议有三个目标。第一个目标是确定具体到什么程度 3D打印血管通道内的局部流动模式影响内皮细胞滞留和 新生血管萌发。第二个目标是测试植入的大量间充质干细胞 在特定的血流动力学环境中增加内皮细胞的保留和发芽。第三个目标 应用前面目标的结果并测试合理设计的Living 3D打印的效果 体内的血管化组织等价物。开发了一种创新的啮齿动物吻合模型，以 回答这些问题。这项提议将建立和验证一个新的临床可翻译的 血管网状移植物制作技术。这一结果还将带来重大的新的 血管反应中内皮细胞和间充质细胞之间相互作用的信息 在体外和体内的几何形状和流体流动。

Project Summary Acute and chronic injuries resulting from burns, trauma, and diabetes often result in uncloseable open wounds subject to permanent damage, disfigurement, and potentially death. This is an especially challenging problem where such insults span a relatively large area leaving few sites for potential autologous tissue harvest. The development of replacement bulk tissue equivalents is therefore a major interest in the fields of tissue engineering and regenerative medicine. Commercially available products only address the skin. Whether full-thickness or dermal layer-only, these surface skin grafts cannot fulfill the substantial volume needs of reconstructive surgery. When applied to patients, these grafts often fail due to inability to vascularize in these difficult wound beds. A hemodynamically efficient, patent vascular network is the most important factor governing the engraftment and long-term survival of any replacement tissue. Current approaches to incorporate a vascular network in engineered bulk tissues have succeeded only in generating homogeneous capillary plexuses in microscale (<1 cm3) tissue elements. These networks possess limited hemodynamic control, high vascular resistance, and likely will not thrive if they could be scaled up. We have pioneered the use of tissue biofabrication strategies to develop perfusable vascularized tissue equivalents with heterogeneously sized lumens, which mimics the native microvascular architecture. This proposal will test how prescribed macro-scale vascular network geometries control local microvascular angiogenic response and overall tissue perfusion and engraftment. This proposal has three aims. The first aim is to determine how specific local flow patterns within 3D printed vascular channels influence endothelial cell retention and angiogenic sprouting. The second aim tests whether embedded bulk mesenchymal stem cells augments endothelial retention and sprouting in defined hemodynamic environments. The third aim applies the results of the previous aims and tests the efficacy of rationally designed living 3D printed vascularized tissue equivalents in vivo. An innovative rodent anastomosis model is developed to answer these questions. This proposal will establish and validate a new clinically translatable technology for vascular network graft fabrication. The results will also contribute significant new information about the interplays between endothelial and mesenchymal in response to vessel geometries and fluid flows in vitro and in vivo.