91 Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research All of these methodologies have the potential to be applied for examining PCLS, organoids, cultures with ECM-derived hydrogels and decellularised lung matrices, or LOC. Generation of such information will further our understanding of how altered mechanical conditions in lung disease impact cellular behaviour in the 3D environment [169]. TRANSLATIONAL POTENTIAL OF IN VITRO MODELS The high number of failures of new drugs for respiratory diseases in clinical trials might be related to limitations in preclinical studies [170, 171]. Many of these trials fail in phase III: while the therapy is not toxic, its efficacy cannot be demonstrated. One of the main problems with the preclinical models that are currently used, is the lack of attention given to the physical aspects that are characteristic of the lung and (spatial) organization of different cells [172, 173]. Because 3D models can be implemented with human cells, they can more closely resemble human physiology, which has resulted in a growing number of studies using 3D models to study lung development and lung disease pathogenesis. Furthermore, these models have the potential as screening tools for pharmacological drugs being developed to treat pathologies such as lung fibrosis and other rare lung diseases. Figure 2 illustrates currently available models for most common lung diseases while highlighting the models that have yet to be developed for these diseases. Mechanopharmacology is emerging as one of the key fields associated with the development of 3D models and harvesting their potential in translational research, as it investigates the effects of mechanics in dictating the efficacy of drugs and vice versa. Pioneering studies on healthy and asthmatic subjects [174, 175] highlighted the difference on the mechanical properties of the airways and the relation with strains produced by deep inhalations [176-178]. In IPF, it has been shown that transforming growth factor (TGF)-β signalling [179] is involved in an aberrant feedback loop, as the composition of ECM [180], and stiffening of the microenvironment activates TGF-β, which further promotes production and cross-linking of fibrillar collagen [181]. Experiments performed with IPF fibroblasts cultured on either stiff tissue culture plastic, in CytoSoft® plates (2 kPa) or in soft spheroids (0.4 kPa) showed that softer materials induced expression of cycloxygenase-2 (COX-2), suggesting that higher stiffness reduced COX-2 expression while activating TGF-β [182]. Human airway organoids have been explored with respect to their translational potential for cell therapy [93]. However, dissociating such organoids into single4
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