93 Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research be considered when developing NAMs are: (1) a detailed methodological description; (2) consideration of the diseased organ anatomy, control of the cell/cell ratio; (3) overcome the uncertainty due to interspecies differences, by using human cells, no animal-derived proteins, and including the microbiome; (4) exposure conditions and time points [188, 189]. Primarily driven from cancer research, these lessons can be applied to develop innovative 3D in vitro models described here to investigate disease pathogenesis, progression, and therapeutic targets for chronic lung diseases. CONCLUSIONS In vitro models with 3D structures are powerful tools that provide variability and versatility for both basic and translational research in lung diseases. PCLS, organoids, lung ECM-derived hydrogels and LOC systems present a wide spectrum of tuneability and biomimicry. Each of these models have advantages and limitations, and selection and application of the models for different studies requires a thorough understanding of their strengths and disadvantages. The future of these models, moving towards increased complexity to better represent the lung physiological conditions, will be built upon refinement of the currently developed model versions, by defining best practices for the materials used, the characterisation methods applied, and how the reported readouts can be compared. Similarly, combinations of these models to create increasingly tailored models for specific research questions would also increase the lung mimicking capacity of the models. By improving the currently existing models, generating new and innovative alternatives, as well as developing creative combinations of these systems, the translational capacity of in vitro research for lung preclinical studies will be greatly enhanced. The path to achieve more applicable and accepted models lies in open communication, clear descriptions of all materials/components used, and methods applied, as well as educating all parts of the scientific community. It is not unlikely that in the near future advanced in vitro models will replace several animal models that do not accurately reflect the diseased microenvironment of some lung diseases. Points for Future Research: • Exploring opportunities for combining elements from precision-cut lung slices, organoids, lung ECM-derived hydrogels and lung-on-chip models to expand 3D models for mimicking lung homeostasis and pathogenesis will advance the field. • Establishing best practices for reporting the materials used, methods applied for generation of in vitro models, and the end points tested, based on the research question and model used, would greatly benefit the field. Thorough and cross4
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