83 Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research Table 2: Overview of the use of the different 3D in vitro systems to model healthy and diseased human lungs. Precision Cut Lung Slices (PCLS) Organoids# Lung Extracellular Matrix (ECM)-derived hydrogels* Lung-on-chip Healthy Both alveolar and airway: Bronchoconstriction assay [18, 88], Response to drugs or industrial chemicals [89], Long-term (14 days) [90, 91], Indacaterol efficacy [92] Airway: From adult stem cells [93, 94] From PSCs [49, 95], With bronchial epithelial cells, lung fibroblasts and endothelial cells [96] Alveolar: From PSCs [97-99] Both alveolar and airway: Human foetal-lung derived organoids [100] Both alveolar and airway: Human lung ECM hydrogels and comparison to native tissue [54] Airway: With epithelial cells only [101], epithelial-vascular interface [102], With fibroblast compartment [103], Epithelial-ECM-smooth muscle interface [104], Epithelial-ECM-vascular interface [105], Cell extravasation [106] Alveolar: Alveolar-capillary interface [70], Alveolar acini with immune compartment [107], With micro-diaphragm [76], With inverse opal gelatine hydrogel [108], With biological and stretchable membrane [79], With fibroblast compartment [75] Asthma Airway only: Effect of soluble guanylate cyclase on bronchodilation [109], asthma mediators [110], ẞ2-agonist efficacy modulated by steroids [111], Rhinovirus infection: increased IL-13, IL-25 and thymic stromal lymphopoietin [112] Airway only: Notch2 role in goblet cell metaplasia [113] Airway only: IL-13 induced asthma [102], IL-13 and viral-induced exacerbations [114] Chronic Obstructive Pulmonary Disease Alveolar only: CS model +/- viral exacerbations FZD4 inhibitor efficiency in COPD patients PCLS [115], Wnt/β-catenin signal activation efficiency [22] Alveolar only: COPD-patient derived epithelial cell organoids [116], Emphysematous alveolar epithelial cells [42] Both alveolar and airway: COPD lung ECM hydrogels and comparison to native tissue [54] Airway: With COPD epithelial cells, poly-ICinduced [102], Cigarette smoke-induced [73, 117] Alveolar: Cigarette smoke-induced [108], With emphysematous cells [42] 4
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