88 Chapter 4 Table 3: Main challenges associated with the four different in vitro culture systems for modelling lung environment in health and disease Precision Cut Lung Slices (PCLS) Organoids Lung Extracellular matrix (ECM)- derived hydrogels Lung-on-chip • Patient-to-patient variations • Heterogeneity in number and sizes (due to intra- and inter-patient variations and various culture modalities) • Patient-to-patient variations influencing ECM hydrogel properties • Challenges associated with incorporation of cells (only for closed lung-on-chip systems) • Heterogeneity in the diseased regions, resulting in intra and interslice differences • Closed architecture with limited access to the lumen, which is filled with liquid instead of air • Heterogeneity in the diseased regions and in decellularisation methods • Restriction of the morphogenesis to predefined geometry • Absence of easy air-liquid interface setting • Presence of necrotic cores • Macroscopic architecture differing from native lung • Non-permissive environment that cannot be remodelled • Need for fresh starting material that limits lifespan of various cells and the tissue in vitro • Difficult to obtain fully differentiated lung cell types • Pepsin removal currently not possible • Non-physiological stiffness of the device • Snapshot of the cell populations in the tissue and absence of access to infiltrating cells, • Lack of vascularisation and difficult to introduce perfusion or immune cells • Incorporation of cells is challenging • Challenges associated with translation of observations from microscale to in vivo systems • Difficult to preserve arteriole morphology and function • Limited inclusion of mechanical forces associated with breathing • Limited inclusion of mechanical forces associated with breathing • For non-commercialised lung-onchips: rather long production time of the microfluidic devices with a small throughput • Cellular behaviour likely impacted by processing and agarose embedding • Limitations in hydrogel types to develop organoid culture systems • Lack of vascularization and difficult to introduce perfusion
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