147 3D lung models – 3D extracellular matrix models vitro models. In addition, the possibility of fine-tuning mechanical properties either by reinforcing the solution with additional biopolymers or functionalization with chemical groups leads the way to de-couple the contribution of biochemical and biomechanical changes in the progression of chronic lung diseases. Another interesting method to prepare 3D in vitro models using solubilized decellularized lung ECM is electrospinning, a versatile scaffold preparation method that allows fine-tuning the size and the alignment of the produced fibers [174]. Utilizing the possibility of modulating the stiffness, fiber alignment and other mechanical properties as well as combinations of them in 3D in vitro cultures would enhance the capacity for mimicry of the in vivo lung ECM environment of these models. CHALLENGES Excitingly, ECM-based 3D culture systems for the in vitro modeling of lung diseases have advanced significantly in the last decade. While these 3D culture systems indicated the limitations of 2D culturing, there are many challenges that must be faced before these culture models can become mainstream tools (Figure 4). Single ECM protein models such as collagen or gelatin bring a reductionist approach for research on lung diseases. The possibility of fine-tuning the mechanical properties of such hydrogels allows mimicking many different stages of lung development and disease, yet they lack the complex composition of the native lung ECM. Especially in chronic lung diseases such as asthma, COPD or IPF, the composition of ECM is radically altered, and such changes are not reflected in these models. The altered number and availability of cell binding domains are another limitation of single-protein-based culture systems, mimicking the altered ECM in this aspect is not always possible with these models. The 3D culture systems derived from the whole lung ECM provide advantages over the single-protein counterparts, especially in providing a more physiological composition and structural arrangement of the ECM in health and disease. Using decellularized matrices in various forms such as tissue pieces or PCLS for disease modeling will advance our understanding of many different disease underlying mechanisms; however, the current procedures for decellularization of lung tissue limit the retention of the total composition of the ECM. Especially GAGs have been recognized to be lost during these harsh processes, and the potential impact of their loss in these culture systems has yet to be fully explored. Using the whole tissue ECM 6
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