298 Chapter 10 far target cells and cellular components [51], but a recent study illustrated the possibility of targeting the ECM itself [52]. It remains undiscovered whether these methods, alone or in combination, can be used to monitor the changes in the ECM organization and topography, especially during clinical assessments. It is intriguing to speculate on possibilities of utilization of some of the specific parameters regarding ECM organization investigated in this thesis for the assessment of the disease progression. Assessment of more micro-scale changes in ECM structure and organization during lung fibrosis before it translates to macro-scale changes in the whole lung tissue can bring an advantage for monitoring disease progression, both alone and in combination with other clinical parameters. Realigning our perspectives for considering (the changes in) the ECM more than just collagens and structural support and realizing its potential for being monitored for disease progression and for being targeted for treatment strategies may bring new possibilities for patients Further developing innovative models, described in this thesis, is possible through several different paths, all of which have their own forests and mountains to conquer. Recapitulating physiological ECM composition in (alveolar) organoid cultures derived from primary human cells remains still challenging, even with the use of lung ECMderived hydrogels. The same hydrogels also have limitations in capturing the complex biomechanical nature of native tissue; specifically, stress relaxation behavior of the tissue is currently missing in lung ECM-derived hydrogels. Lastly, introducing perfusion and breathing dynamics to these in vitro models also needs more attention, as the primary function of lungs is providing gas exchange through intricate blood vessels surrounding alveolar structure. Together with the recent encouraging changes in the legislations with respect to in vitro studies being considered enough for taking pre-clinical studies to clinical trials [53], future opportunities for using such models can only go further. CLOSING REMARKS “Not all those who wander are lost.” – J.R.R. Tolkien. Understanding the complex interactions between the dynamic ECM and resident cells in lung fibrosis is the essence of understanding the disease mechanisms. Even though there still remains a whole different world of possibilities to discover, it is now high time to wander along the edges of knowledge. Only through these steps, we can hope to first uncloud, then conquer the whole realm of influence of ECM in lung fibrosis, which rules them all.
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