Programmable multimaterial bioprinting of 3D vascularized tissue constructs

项目摘要 高度组织化和血管化的三维(3D)组织结构的体外开发具有重要意义 在组织工程中的重要性，因为天然肌肉组织表现出高度组织化的3D复合体 由细胞外基质(ECM)、不同细胞类型以及化学和物理组成的体系结构 信号提示。生物打印已经成为一种开发高度复杂的3D结构的新技术； 然而，仍然存在许多挑战，例如需要精确定位/切换 不同的细胞类型和材料，以创建不同大小的多细胞3D结构，并创建图案 类似于活体环境的物理特性。为了应对这些挑战，我们计划开发 嵌入式多材料生物打印(EMB)技术，采用自愈支持水凝胶和 一种可编程微流控装置。多材料生物打印(MB)系统可通过以下方式开发 将直写3D生物打印系统与高精度、可编程微流控打印头集成在一起， 它可以在不同的材料、试剂和细胞之间轻松快速地切换。多轴挤压 系统能够为肌束和可灌流的血管网络创建多尺度微纤维，以 模仿其在空间上有组织的自然对应物的机械特性和建筑。虽然它是 很难精确地控制材料在Z方向上的位置以创建独立的水凝胶结构， 我们将通过结合嵌入式3D生物打印技术来提高MB系统的打印保真度 通过使用一种自我修复的支持性水凝胶。此外，配套的水凝胶将能够快速实现 无需额外的凝胶处理即可在X-Y-Z方向沉积所需的预聚体溶液。通过 将这种嵌入式打印策略与结合了MB技术的微流控设备相结合，它将允许 美国将打印具有生物相关结构的多组分/多细胞组织结构和 目前很难或不可能进行生物打印的特征。此外，使用细胞负载的生物墨水， 它模仿肌肉组织的机械和生物特性，可以作为一个平台来促进 肌肉前体的分化和成熟，以及改善的收缩活动。它是被设想的 这个项目的成功开发将对肌肉的康复能力产生重大影响 并推动肌肉组织工程领域的发展。此外，这一过程可以很容易地 应用于再生医学的其他领域，以产生新的器官。

Project Summary In vitro development of highly organized and vascularized three-dimensional (3D) tissue constructs is of great importance in tissue engineering, since native muscle tissues exhibit highly organized 3D complex architectures composed of an extracellular matrix (ECM), different cell types, and chemical and physical signaling cues. Bioprinting has emerged as a new technology to develop highly complex, 3D structures; however, there are many remaining challenges, such as the necessity for precise positioning/switching of different cell-types and materials to create multi-cellular 3D structures with various sizes, and creating patterns that resemble the physical properties of in vivo environments. To address these challenges, we plan to develop an embedded multi-material bioprinting (EMB) technology that employs a self-healing supporting hydrogel and a programmable microfluidic device. The multi-material bioprinting (MB) system can be developed by integration of a direct-write 3D bioprinting system with a high precision, programmable microfluidic printhead, which can easily and quickly switch between different materials, reagents and cells. The multi-axial extrusion systems are able to create multi-scale microfibers for muscle bundles and perfusable blood vessel networks to mimic the mechanical properties and architecture of their spatially organized natural counterparts. While it is difficult to precisely control the materials’ position in Z directions to create freestanding hydrogel architectures, we will improve the high print fidelity of the MB system by combining an embedded 3D bioprinting technology by using a self-healing supporting hydrogel. In addition, the supporting hydrogel will be able to achieve fast deposition of the desired pre-polymer solution in X-Y-Z directions without additional gelation processing. By combining this embedded printing strategy with the microfluidic device incorporated MB technology, it will allow us to print multi-component/multi-cellular tissue constructs with biologically relevant architectures and characteristics that are difficult or impossible to bioprint at present. Furthermore, the use of a cell-laden bioink, which mimics the mechanical and biological properties of muscle tissue, can act as a platform to promote differentiation and maturation of muscle precursors, as well as improved contractile activity. It is envisioned that the successful development of this project will have a significant impact on the ability to heal muscle trauma as well as to advance the field of muscle tissue engineering. Furthermore, this process can be readily applied to other areas of regenerative medicine to generate new organs.