面向肠道多模态运动与形貌分化、功能形成及菌落共存的腔体肠器官芯片研究

Human intestinal organ-model is a hot research area in the field of Micro-nano sensors. 95% of the drugs, which were screened from animal models, are not suitable for human beings. As a result, drug screening costs sharply rise. The unsuitability is related to the specific intestinal digestion, absorptivity, and drug permeability in different species. Existing two-dimensional intestine-on-chips lack inherent multi-modal motions (e.g. segmental radial contraction, peristalsis), the values of indicators (e.g. specific surface area, trans-membrane resistance) are different from those of the living intestinal villi. To this end, we propose a tubular intestine-on-a-chip integrated with mechanical parameters for exploring the relationships among the chip with cellular metabolism, absorption, and permeability. Under the real condition, we will reveal the mechanisms between intestinal morphology differentiation and colony coexisting that are induced by multimodal motions. This study is the beneficial exploration in constructing human small intestinal environment by using micro-electro-mechanical system (MEMS). The obtained conclusion will provide a platform for bionic research and drug development, and also provide important data and theoretical support.

基于人类肠器官模型的研究是当前微纳传感领域的热点之一。依赖动物模型筛选的药物对人类的不适性高达95%，这种不适与不同物种间肠道及内部菌落对药物代谢、吸收、渗透的差异性有关。现有的人类肠器官芯片模型，缺乏对肠道固有多模态运动(分节径向收缩、蠕动波等)的有效模拟；在形貌与功能的衡量指标（比表面积、渗透率等）与活体肠器官相比存在较大差异。为此，申请者将基于一种腔体肠器官芯片集成多机械控制参数，探索其与肠器官代谢能力、吸收效率、以及跨膜渗透率的关系；揭示真实条件下，多模态运动与肠器官形貌分化、功能形成及菌落共存的内在机制。本课题是微机电系统（MEMS）在构造人体微肠道环境的有益探索，所获结论将为平台性的肠道生理研究和药物开发，提供重要的理论依据及支持。

为了克服传统动物模型和体外肠道模型的局限性。本课题研究了肠道多模态运动与肠形貌分化、功能形成及细菌共存之间的关系。通过MEMS技术制备一种集成多机械参数的三维腔体结构的肠器官芯片。在培养Caco-2 细胞的过程中，通过控制磁场力与微气泵使腔体结构发生多模态形变。模拟肠道纵行肌、环形肌引起的分节径向收缩、蠕动和群量收缩。利用培养液缓慢灌流模拟微流体在腔体内的环向与轴向剪应力。所设计的芯片与对照组（二维肠器官芯片、Transwell 模型）进行形成肠道微环境指标（小肠绒毛表面积、跨膜电阻、渗透率）的统计分析，确定多机械参数可促进肠道形貌与功能的分化。最后，通过引入菌落失衡，探究肠道炎症的相关指标变化，并探索药物（左氧氟沙星）对肠道功能的修复能力。本课题针对临床医学药物筛选过程中遇到实际问题，用微机电系统（MEMS）的方法研究模拟体外器官的功能实现及疾病模型构建，所获结论为高效提升口服类药物吸收/肠炎疾病药物筛选提供理论及实验依据。.在项目执行期间，发表了高水平学术论文11篇（SCI收录）；申请国家发明/实用新型专利4项，已授权1项；获得其他奖项3项；培养了硕士研究生14名。所设计的器官芯片已在山大儿童医院，山东省立医院、齐鲁制药有限公司开展示范应用。