Development of a physiomimetic model of acute respiratory distress syndrome by using ECM hydrogels and organ-on-a-chip devices

Abstract

Acute Respiratory Distress Syndrome is one of the more common fatal complications in COVID-19, characterized by a highly aberrant inflammatory response. Pre-clinical models to study the effect of cell therapy and anti-inflammatory treatments have not comprehensively reproduced the disease due to its high complexity. This work presents a novel physiomimetic in vitro model for Acute Respiratory Distress Syndrome using lung extracellular matrix-derived hydrogels and organ-on-a-chip devices. Monolayres of primary alveolar epithelial cells were cultured on top of decellullarized lung hydrogels containing primary lung mesenchymal stromal cells. Then, cyclic stretch was applied to mimic breathing, and an inflammatory response was induced by using a bacteriotoxin hit. Having simulated the inflamed breathing lung environment, we assessed the effect of an anti-inflammatory drug (i.e., dexamethasone) by studying the secretion of the most relevant inflammatory cytokines. To better identify key players in our model, the impact of the individual factors (cyclic stretch, decellularized lung hydrogel scaffold, and the presence of mesenchymal stromal cells) was studied separately. Results showed that developed model presented a more reduced inflammatory response than traditional models, which is in line with what is expected from the response commonly observed in patients. Further, from the individual analysis of the different stimuli, it was observed that the use of extracellular matrix hydrogels obtained from decellularized lungs had the most significant impact on the change of the inflammatory response. The developed model then opens the door for further in vitro studies with a better-adjusted response to the inflammatory hit and more robust results in the test of different drugs or cell therapy.

Fast cycling of intermittent hypoxia in a physiomimetic 3D environment: A novel tool for the study of the parenchymal effects of sleep apnea

“…The results obtained in W = 500-μm hydrogels ( Figure 3 ; Figure 5 ) show that O 2 diffusion through the 3D scaffold was sufficiently fast to allow high-frequency intermittent hypoxia requiring 30-s for raising and decreasing times in O 2 concentration across the 3D sample. Interestingly, ≈500 μm is a commonly used thickness for the research of 3D cell-seeded samples ( De Hilster et al, 2020 ; Falcones et al, 2021 ; Marhuenda et al, 2022 ). The suitability of this thickness for optimal application of 60 hypoxic events/h was expected taking into account that the O 2 coefficient of diffusion D in this type of hydrogel is slightly lower than that of water.…”

What is the need and why is it time for innovative models for understanding lung repair and regeneration?

“…These are powerful systems with which to study cell behaviors, cell-cell interactions, cell-matrix interactions, and the effects of environmental, such as tobacco smoke exposure, and physical forces on cell behaviors ( Huh et al, 2012 ; Benam et al, 2016 ; Nawroth et al, 2020 ; Plebani et al, 2020 ; Bai et al, 2022 ). These, along with organoid model systems, are also powerful tools for evaluating drug effects and also for evaluating inflammatory and immune responses as both immune cells as well as infectious agents can be added to the culture systems ( Huh et al, 2012 ; Benam et al, 2016 ; Nawroth et al, 2020 ; Plebani et al, 2020 ; Bai et al, 2022 ; Marhuenda et al, 2022a ).…”

Current possibilities and future opportunities provided by three-dimensional lung ECM-derived hydrogels

“…The field is now moving forward with the cellular systems that are being explored, taking advantage of the values of lung ECM-derived hydrogels. Multi-cellular culture systems are being developed to enable cellular cross-talk in a 3D microenvironment to be examined ( Park et al, 2018 ), and lung ECM-derived hydrogels are being incorporated into other experimental systems (for example, lung on chip or stretching/mechanical force setups) to bring the cell microenvironment in those systems also ( Park et al, 2021 ; Marhuenda et al, 2022a ). The possibilities for 3D printing lung ECM-derived hydrogels are also being examined, suggesting greater scope for spatial arrangement of cells within their 3D microenvironment will be possible in the future ( De Santis et al, 2021 ; Falcones et al, 2021 ).…”