75 Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research models along with a comprehensive overview of the advantages and disadvantages of each model are presented. Furthermore, the translational potential of in vitro systems supplemented with potential challenges are reviewed. GENERATION OF (3D) INNOVATIVE IN VITRO LUNG MODELS Currently, translation of respiratory therapies from bench to bedside remains limited in part due to the lack of relevant in vitro and in vivo models. The need for more accurate and physiologically representative models of the lung is thus clearly established. Various approaches to develop new models range from models using exclusively the source material of the lung like precision cut lung slices (PCLS) to fully engineered environments like the lung-on-chip (LOC). This article will focus on disease modelling in four main types of in vitro lung models: PCLS, organoids, lung ECM-derived hydrogels, and LOC. Each of these models have their strengths and weaknesses as presented in Figure 1. The common ground in the above-mentioned models is the development of a cellular environment away from stiff and non-physiological plastic culture dishes, proposing instead a transition towards softer materials, with the possibility of inclusion of ECM proteins and/or reproduction of the structural arrangement, biochemical, and biomechanical properties of the lung. To recapitulate the lung microenvironment, several different factors are important. The main factors are biomechanics (mechanics of breathing and stiffness), lung ECM (structure and composition), and lung cell composition (cell types and cell source). Other factors that may be added include, but are not limited to, an immune component, hypoxic and normoxic regions, and blood flow (perfusion). These in vitro models can be used to investigate the influence of individual mechanical parameters and immune cell interactions on disease origin and progression, along with screening for druggable targets and developing therapies. Animal models remain an indispensable tool for research as in vitro models cannot yet mimic the complex structures of tissues and systemic effects. However, there is an evolving role for these preclinical systems for modelling in vivo conditions and screening therapeutics to reduce the burden on in vivo systems. Each model has different advantages and disadvantages, and the choice of model is highly dependent on the research question to be addressed and the availability of source material. This review section will highlight some of the innovative in vitro lung models and their recent developments. 4
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