Bioprinted Vascularized Tissue Constructs

项目摘要 由烧伤、创伤和糖尿病引起的急性和慢性损伤经常导致无法闭合的开放性伤口。 伤口会造成永久性损伤，毁容，甚至可能死亡。这是一个特别 具有挑战性的问题，其中这种损伤跨越相对较大的区域， 自体组织收获。因此，替代散装组织等效物的开发是 对组织工程和再生医学领域有浓厚的兴趣。市售 产品只针对皮肤。无论是全层还是真皮层， 不能满足重建手术的大量需求。当应用于患者时， 移植物经常由于不能在这些困难的伤口床中血管化而失败。血液动力学有效， 通畅的血管网是决定植入和长期生存的最重要因素 任何替代组织。目前在工程体中纳入血管网络的方法 组织仅成功地在微尺度（<1cm 3）产生均匀的毛细血管丛 组织成分这些网络具有有限的血流动力学控制，高血管阻力， 如果他们能扩大规模，他们可能不会蓬勃发展。我们率先使用组织生物织物 开发具有不同尺寸管腔的可灌注血管化组织等同物的策略， 它模仿了天然的微血管结构。这一建议将测试如何规定宏观尺度 血管网络几何形状控制局部微血管血管生成反应和整体组织 灌注和植入。这项建议有三个目的。第一个目标是确定 3D打印血管通道内的局部流动模式影响内皮细胞保留， 血管生成发芽。第二个目标是测试包埋的大量间充质干细胞是否 在确定的血液动力学环境中增强内皮保留和发芽。第三个目标 应用先前目标的结果，并测试合理设计的活体3D打印的功效。 体内血管化组织等同物。开发了一种创新的啮齿动物吻合模型， 回答这些问题该提案将建立并验证一种新的临床可翻译的 血管网移植物制造技术。这些成果还将为新的 关于内皮细胞和间充质细胞之间的相互作用的信息， 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.