Modeling Pulmonary Cystic Fibrosis in a Human Lung Airway-on-a-chip

Abstract

Background: 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. Methods: 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. Results: The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus production, 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. Conclusions: The human CF Airway Chip may provide a valuable preclinical tool for pathophysiology studies as well as for drug testing and personalized medicine.

Engineering Organoids for in vitro Modeling of Phenylketonuria

“…Indeed, a patient-derived, organoid-based, high-throughput drug screening system could be engineered to model treatment responses to conventional and developing treatments, possibly helping to decrease the number of pre-clinical trial failure. Also, the addition of circulating immune cells in the vascular channels would be helpful to predict adverse effects ( Armstrong et al, 2021 ; Plebani et al, 2021 ) regarding therapeutic options, such as enzyme substitution by administration of pegylated phenylalanine ammonia lyase (PEG-PAL), known to have significant immunogenicity ( Hausmann et al, 2019 ). Combinations between healthy- and PKU-derived liver and brain organoids could also be a strategy to modulate the interplay between the metabolic impairment and neuronal damage.…”

Imaging-Guided Bioreactor for De-Epithelialization and Long-Term Cultivation ofEx VivoRat Trachea

“…10,13 Recent synergistic advances in tissue engineering, biomaterials, and stem cell technologies have shown great potential for modeling different lung diseases, 14 repairing damaged tissues or organs, 15 studying human lung development, 16 and developing therapeutic materials without the use of animals. 17 For example, faithful in vitro models of diseases, such as cystic fibrosis, 18,19 COPD, 20 asthma, 21 surfactant protein B deficiency, 22 pulmonary fibrosis, 23,24 and viral infection, 25 have been generated using primary epithelial cells and induced pluripotent stem cells (iPSCs). Furthermore, recent establishment of innovative protocols for guided differentiation of airway stem cells, in particular basal cells, [26][27][28] allowed emergence of cell replacement therapy as a promising approach to repairing airway tissues of live patients that are severely injured or diseased beyond their intrinsic repairable limits, 29 or donor lungs that are refused for transplantation due to substantial tissue damage.…”