Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, United States; Center on Advanced Studies and Technology (CAST), Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, United States; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.
J Cyst Fibros. 2022 Jul;21(4):606-615. doi: 10.1016/j.jcf.2021.10.004. Epub 2021 Nov 17.
Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which results in impaired airway mucociliary clearance, inflammation, infection, and respiratory insufficiency. The development of new therapeutics for CF are limited by the lack of reliable preclinical models that recapitulate the structural, immunological, and bioelectrical features of human CF lungs.
We leveraged organ-on-a-chip technology to develop a microfluidic device lined by primary human CF bronchial epithelial cells grown under an air-liquid interface and interfaced with pulmonary microvascular endothelial cells (CF Airway Chip) exposed to fluid flow. The responses of CF and healthy Airway Chips were analyzed in the presence or absence of polymorphonuclear leukocytes (PMNs) and the bacterial pathogen, Pseudomonas aeruginosa.
The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells. The CF chips also secreted higher levels of IL-8, which was accompanied by enhanced PMN adhesion to the endothelium and transmigration into the airway compartment. In addition, CF Airway Chips provided a more favorable environment for Pseudomonas aeruginosa growth, which resulted in enhanced secretion of inflammatory cytokines and recruitment of PMNs to the airway.
The human CF Airway Chip may provide a valuable preclinical tool for pathophysiology studies as well as for drug testing and personalized medicine.
囊性纤维化（CF）是一种由编码囊性纤维化跨膜电导调节因子（CFTR）的基因突变引起的遗传性疾病，导致气道黏液纤毛清除功能受损、炎症、感染和呼吸功能不全。由于缺乏能够重现人类 CF 肺部结构、免疫和生物电学特征的可靠临床前模型，CF 的新疗法的发展受到限制。
我们利用器官芯片技术开发了一种微流控装置，其内壁由在气液界面下生长的原代人 CF 支气管上皮细胞组成，并与暴露于流体流动的肺微血管内皮细胞（CF 气道芯片）相连接。在存在或不存在多形核白细胞（PMN）和细菌病原体铜绿假单胞菌的情况下，分析 CF 和健康气道芯片的反应。
CF 气道芯片忠实地再现了许多人类 CF 气道的特征，包括与由健康支气管上皮细胞衬里的芯片相比，黏液积聚增加、纤毛密度增加和纤毛摆动频率增加。CF 芯片还分泌了更高水平的 IL-8，这伴随着 PMN 与内皮细胞的粘附增强和向气道腔的迁移。此外，CF 气道芯片为铜绿假单胞菌的生长提供了更有利的环境，导致炎症细胞因子的分泌增加和 PMN 向气道募集。
人类 CF 气道芯片可能为病理生理学研究以及药物测试和个性化医疗提供有价值的临床前工具。
