Shin Yong Cheol, Shin Woojung, Koh Domin, Wu Alexander, Ambrosini Yoko M, Min Soyoun, Eckhardt S Gail, Fleming R Y Declan, Kim Seung, Park Sowon, Koh Hong, Yoo Tae Kyung, Kim Hyun Jung
Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
Micromachines (Basel). 2020 Jul 7;11(7):663. doi: 10.3390/mi11070663.
The regeneration of the mucosal interface of the human intestine is critical in the host-gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn's disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic-oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host-microbiome crosstalk to target a patient-specific disease modeling.
人类肠道黏膜界面的再生在与胃肠道疾病相关的宿主-肠道微生物群相互作用中至关重要。活检衍生的肠道类器官提供了具有生理细胞分化的患者的遗传信息。然而，封闭的管腔和静态培养条件极大地限制了患者来源的类器官在微生物群相关疾病建模中的应用。在此，我们报告了一种患者特异性的三维（3D）生理动态芯片上黏膜界面（PMI芯片），它在特定生物力学条件下提供了一个微观生理肠道环境。PMI芯片的实时成像和计算模拟验证了对非线性管腔和微血管血流的重现，该血流模拟了活人体肠道中的流体动力学。在一个盘绕的微通道中的多轴变形不仅诱导了动态细胞应变，还增强了管腔微通道中的颗粒混合。在这种生理动态条件下，从被诊断患有克罗恩病、溃疡性结肠炎或结直肠癌的患者获得的类器官衍生上皮独立形成了具有疾病特异性分化的3D上皮层。此外，在缺氧-有氧界面与人类粪便微生物群共培养导致了随机微菌落的形成，而不会丧失上皮屏障功能。我们设想，传达个体患者遗传、表观遗传和环境因素的患者特异性PMI芯片将有可能展示病理生理动力学和复杂的宿主-微生物群相互作用，以实现针对患者特异性的疾病建模。
