可用于肝脏芯片构建的自组装生物材料的研究(（二）组装体的功能与集成)

An Organ-on-a-Chip is a multi-channel 3D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems. In the construction of the Organ-on-a-Chip, the interaction of cells and materials is one of the most important issues. Self-assembly technologies have attracted increasing interest due to their advantages in constructing three-dimensional micro-and nano- hierarchical structure of materials. Several biological and abiological materials, such as DNA and proteins, as well as colloidal particles and block copolymer, have been successfully used as the basic elements to self-assemble the nano- and micro-structured biomaterials. However, it is still a challenge to combine the artificially controllable self-assembly biomaterials and the complicated organ chip systems, and thus to realize the regulation and control of the organic cell culture on the desired chip by using the self-assembly materials. Moreover, it is necessary to develop a biotechnology for cell research to real-time and accurately monitor the interaction of cells and the self-assembly biomaterials, which could effectively reveal the biological mechanism of the organic cell behavior and the reactions of the organic cells and drugs. In this research, we propose to carry out liver-on-a-chip research based on the self-assembly hierarchical structured materials. We will investigate the interaction between organic cells and the self-assembled biomaterials, and sensing mechanism of the biomaterials in the liver-on-a-chip system. Based on these researches, we will construct a novel platform that with the function of real-time monitoring organic cells for the study of the interaction between organic cells, biomaterials and drugs. This research will provide effective techniques for rapid assessment of drugs.

在器官芯片的构建中，细胞与材料的相互作用是一个重要的话题。自组装方法由于其能够在纳米到微米尺度上有效地构筑三维微纳分级结构材料而日益受到人们的重视。生物分子(DNA和多肽)、胶体微球、嵌段共聚物等多种物质都被成功用于组建自组装微纳米材料的构建单元。但是如何将这种人为可控的自组装材料和复杂的器官芯片相结合，实现可控自组装体系对芯片内器官细胞的调控，同时，通过自组装传感体系实现这些细胞的实时、准确监测，并在此基础上揭示细胞与药物的相互作用规律，仍然是一个具有探索性和挑战性的问题。在本项目中，我们将针对这一课题，从自组装微纳分级结构材料制备及调控，到微纳分级结构材料/肝脏芯片构建，再到肝脏芯片实时监测开展系统的研究，构建肝脏芯片调控/检测一体化解决方案，为药物的快速评估提供新型的技术手段。

构建具有生物学功能的肝脏芯片对药物评估具有重要意义。目前国际上有多个研究组都在进行肝脏芯片的构建及应用研究。尽管相关的研究取得了一定的进展，然而，目前的肝脏芯片仍面临着细胞的三维培养、功能再现、以及细胞代谢过程的在线监测等多个科学和技术瓶颈问题。在本项目的资助下，我们利用自组装方法，结合微流控技术来构建功能生物材料，并将其用于解决肝脏芯片的技术瓶颈问题，取得了系列进展。在细胞的培养研究方面，我们提出并实现了利用胶体自组装获取的聚合物反蛋白石材料来进行细胞培养，这种材料可被拉升为不同的比例，进而使其表面具有可以诱导细胞取向及梯度的微结构，而通过向材料的孔洞内灌注不同的生物相容性水凝胶，还可有效的控制细胞在材料表面的生长密度，相关研究为细胞的可控生长提供了新型的基底材料。在仿生微器官的功能构建方面，我们利用组装毛细管的方法构建了具有可扩展微流道结构的微流控装置，制备了一系列具有复杂空间结构和可控组分的海藻酸钙微纤维，通过在微纤维凝胶内部包裹多细胞体系，我们还获得了类似于微血管等结构的纤维组织和器官，该研究为在体外构建人造血管和其他细胞三维组织结构提供了新方法。在细胞及代谢过程的在线监测方面，我们利用微流控液滴模板限域组装方法制备了多种适合于肝脏芯片的流动编码微载体，通过使用树枝状大分子等具有放大效应的偶联分子来优化微载体表面，我们实现了探针的高效固定、生物分子的高灵敏检测、以及循环肿瘤细胞的多元捕获，这些研究为在肝脏芯片中研究药物代谢提供了较好的技术途径。这些研究成果多次发表于JACS和Adv. Mater.等杂志。基于本研究产生的国际影响，我们还应邀在Acc. Chem. Res.和Small等杂志上撰写相关综述论文。