Rapid 3D bioprinting of biomimetic vascularized tissue constructs

项目总结 包括立体光刻和喷嘴生物打印在内的快速成型方法的最新进展 能够制造具有受控架构和可调特性的复杂结构。带着他们的 针对患者的设计和精密工程的能力，这些技术已经影响了许多领域 例如组织工程和再生医学。在组织工程中，高度透明的材料的制造 有组织、有功能的三维(3D)结构，模拟各种器官的复杂结构 是非常重要的。为了实现这一目标，不同的基于光固化技术的快速成型策略和 生物打印已经被证明。尽管取得了重大进展，但以下关键挑战 生物打印仿生组织构建物仍然存在：a)用于制造3D细胞负载构建体的当前方法 与临床相关的精确度需要诱导细胞死亡的时间尺度。B)多组分/多细胞 具有生物相关结构和特征的组织结构很难或不可能 目前正在进行生物打印。 为了同时应对这两个挑战，我们计划开发一种快速、多材料的生物打印 (人民币)技术。新的人民币打印方法比传统的3D生物打印和 使用不同的细胞负载生物材料连续生产多组分的复杂架构。因此， 这种新的3D生物打印系统可以用来构建仿生组织，例如预血管化的心脏 血管从较大的可吻合血管到较小的毛细血管的组织。我们将整合一个 具有动态光学打印方法以输送不同细胞类型和凝胶的可编程微流控系统 用于模拟心脏组织的生物力学特性和成分的前体。具体来说，我们 将iPS细胞来源的人心肌细胞(ICM)和内皮细胞(ECs)与设计的 工程化组织结构中的空间分布。然后，我们将评估前- 体外血管化的心脏组织，并检测生物打印的生物相容性和功能 裸鼠皮下植入模型中的血管网络。这项工作的完成将是一个 范式转变和血管心脏临床治疗的里程碑式成就 组织。

PROJECT SUMMARY Recent advances in rapid prototyping methods including stereolithography and nozzle-based bioprinting have enabled manufacturing of complex structures with controlled architectures and tunable properties. With their capability of patient-specific design and precision engineering, these technologies have impacted many areas such as tissue engineering and regenerative medicine. In tissue engineering, the fabrication of highly organized, functional three-dimensional (3D) constructs that mimic the complex architecture of various organs is of great importance. Towards this goal, different rapid prototyping strategies based on stereolithography and bioprinting have been demonstrated. Despite significant advances, however, the following key challenges for bioprinting biomimetic tissue constructs still remain: a) Current methods for fabricating 3D cell-laden constructs with clinically-relevant precision require time-scales that induce cell death. b) Multicomponent/multicellular tissue constructs with biologically-relevant architectures and characteristics are difficult or impossible to bioprint at present. To address both of these challenges simultaneously, we plan to develop a Rapid, Multimaterial Bioprinting (RMB) technology. The novel RMB approach is significantly faster than conventional 3D bioprinting and produces multicomponent complex architectures using diverse cell-laden biomaterials continuously. Therefore, this novel 3D bioprinting system can be used to build biomimetic tissues, such as pre-vascularized cardiac tissue with blood vessels ranging from larger anastomosable vessels to smaller capillaries. We will integrate a programmable microfluidic system with a dynamic optical printing method to deliver different cell types and gel precursors to mimic the biomechanical characteristics and compositions of the cardiac tissue. Specifically, we will incorporate iPS cell-derived human cardiomyocytes (iCMs) and endothelial cells (ECs) with designed spatial distributions in the engineered tissue constructs. We will then assess the maturation of the pre- vascularized cardiac tissues in vitro and examine the biocompatibility and functionality of the bioprinted vascular networks in a subcutaneous implantation model in nude rats. The completion of this work will be a paradigm shift and a landmark achievement in efforts towards clinical treatments of vascularized cardiac tissue.