Development of a 3D-printed anisotropic heart-on-a-chip for drug screening applications

在心血管药物开发的背景下，工程化的体外心脏组织已经得到了越来越多的关注。它们作为一线工具提供了巨大的希望，可以补充甚至用作动物药物评估的代理。然而，开发更接近自然心肌组织的3D工程化体外心肌模型仍然是一个持续的挑战。这种组织由各向异性的多层结构组成，在调节心脏独特的生物力学行为方面发挥着关键作用。相比之下，目前大多数的单芯片心脏模型在2D平面衬底上使用单一的心脏细胞层。在这个项目(HEARTCHIP)中，我们建议开发一种3D打印的各向异性芯片上的心脏，作为心血管疾病药物筛选的体外急性缺氧模型。我们将制备一种基于磁控纳米短纤维纱线和光固化水凝胶的远程导磁生物墨水，以诱导hPSC来源的心肌细胞的组织和分化。然后，我们将使用凝胶中3D生物打印方法来构建3D各向异性、多层心肌组织。此外，为了提供对培养条件的自动控制和对细胞生理反应的实时测量，我们打算将制成的组织集成到微流控芯片中。有了这种芯片上的心脏，我们的目标是在急性缺氧条件下进行高通量药物测试。因此，本项目旨在为快速、高通量、自动化控制和实时分析的药物筛选提供一个新的心脏组织平台。

Engineered ex vivo cardiac tissues have garnered increasing attention in the context of cardiovascular drug development. They offer great promise as first-line tools that can complement or even be used as proxies for some of the drug evaluations carried out with animals. However, it remains an ongoing challenge to develop 3D engineered ex vivo cardiac muscle models that more closely recapitulate native cardiac tissue. This tissue consists of an anisotropic multilayer structure, which plays a key role in regulating the unique biomechanical behaviour of the heart. In contrast, most of the current heart-on-a-chip models employ a single cardiac cell layer on a 2D flat substrate. In this project (HEARTCHIP), we propose to develop a 3D printed anisotropic heart-on-a-chip as an ex vivo acute hypoxia model for CVD drug screening. We will prepare a remote magnetic conductive bioink based on magnetic-control of short nanofiber yarns and photocurable hydrogels to induce the organization and differentiation of hiPSC-derived cardiomyocytes. We will then use a gel-in-gel 3D bioprinting approach to fabricate a 3D anisotropic, multi-layered cardiac muscle tissue. In addition, to provide automated control of culture conditions and real-time measurement of cell physiological responses, we intend to integrate the as-fabricated tissue into a microfluidic chip. With this heart-on-a-chip, we aim to perform high-throughput drug tests in the condition of acute hypoxia. Hence, this project aims to provide a new platform of cardiac tissue for rapid, high-throughput drug screening with automated control and real-time analysis.