Rapid 3D bioprinting of biomimetic vascularized tissue constructs

项目摘要 包括立体光刻和基于生物打印的快速成型方法的最新进展已经 能够制造具有受控结构和可调特性的复杂结构。与他们的 由于具有患者特定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。在组织工程学中， 有组织的、功能性的三维（3D）结构，其模拟各种器官的复杂结构 非常重要。为了实现这一目标，不同的快速成型策略的基础上立体光刻和 生物打印已经被证实。然而，尽管取得了重大进展， 生物打印仿生组织构建体仍然存在： 具有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 具有生物学相关结构和特征的组织构建体难以或不可能 生物打印目前 为了同时应对这两个挑战，我们计划开发一种快速、多材料的生物打印技术， (RMB)技术.新的RMB方法比传统的3D生物打印快得多， 连续使用不同的载有细胞的生物材料产生多组分复杂结构。因此，我们认为， 这种新型的3D生物打印系统可用于构建仿生组织，例如预血管化的心脏， 具有血管的组织，从较大的可扩张血管到较小的毛细血管。我们将整合一个 具有动态光学印刷方法的可编程微流体系统以递送不同细胞类型和凝胶 前体来模拟心脏组织的生物力学特性和组成。我们特别 将iPS细胞衍生的人心肌细胞（iCM）和内皮细胞（EC）与设计的 在工程化组织构建体中的空间分布。我们将在未来的时间里， 体外血管化心脏组织，并检查生物打印的生物相容性和功能性。 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 范式转变和临床治疗血管化心脏病的里程碑式成就 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.