Real‐Time Measurement of Cell Mechanics as a Clinically Relevant Readout of an In Vitro Lung Fibrosis Model Established on a Bioinspired Basement Membrane

Abstract

Lung fibrosis, one of the major post‐COVID complications, is a progressive and ultimately fatal disease without a cure. Here, an organ‐ and disease‐specific in vitro mini‐lung fibrosis model equipped with noninvasive real‐time monitoring of cell mechanics is introduced as a functional readout. To establish an intricate multiculture model under physiologic conditions, a biomimetic ultrathin basement (biphasic elastic thin for air–liquid culture conditions, BETA) membrane (<1 µm) is developed with unique properties, including biocompatibility, permeability, and high elasticity (<10 kPa) for cell culturing under air–liquid interface and cyclic mechanical stretch conditions. The human‐based triple coculture fibrosis model, which includes epithelial and endothelial cell lines combined with primary fibroblasts from idiopathic pulmonary fibrosis patients established on the BETA membrane, is integrated into a millifluidic bioreactor system (cyclic in vitro cell‐stretch, CIVIC) with dose‐controlled aerosolized drug delivery, mimicking inhalation therapy. The real‐time measurement of cell/tissue stiffness (and compliance) is shown as a clinical biomarker of the progression/attenuation of fibrosis upon drug treatment, which is confirmed for inhaled Nintedanib—an antifibrosis drug. The mini‐lung fibrosis model allows the combined longitudinal testing of pharmacodynamics and pharmacokinetics of drugs, which is expected to enhance the predictive capacity of preclinical models and hence facilitate the development of approved therapies for lung fibrosis.

Cell-Specific Response of NSIP- and IPF-Derived Fibroblasts to the Modification of the Elasticity, Biological Properties, and 3D Architecture of the Substrate

“…and 70 deg. [ 70 , 88 , 89 ], which are close to the values reported for proteins [ 90 , 91 , 92 , 93 ]. Therefore, the observed increase in the number of cells on substrates decorated with proteins may be related also to modified nonspecific hydrophobic/hydrophilic interactions.…”

“…On the other hand, the macroscopic image of the fibrotic lung tissue in IPF is characterized by the presence of honeycomb lesions, which are abnormal dilated airspaces with walls composed of fibrotic tissue [ 60 ], rarely observed for other ILDs [ 13 , 16 , 17 , 18 , 28 , 61 , 62 ]. The impact of different nano- and microscale structural and topographical cues on cellular behavior is widely considered, mainly when developing materials for applications such as medical implants, cell culture systems, scaffolds for tissue engineering, or ‘organs-on-chip’ devices [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ], showing a great variety of cellular responses, depending on the specific topographic pattern [ 63 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Similarly, to in vitro conditions, the topography of the cell environment within organs and tissue may influence their functions, such as adhesion, differentiation, and migration [ 67 , 71 , 72 , 78 ].…”

Critical Review on Toxicological Mechanisms Triggered by Inhalation of Alumina Nanoparticles on to the Lungs

“…A recent literature review highlights the benefits of using 3D co-culture models to investigate the complexity of cellular interactions during pulmonary inflammation [ 62 ]. A specific in vitro mini-lung fibrosis model equipped with non-invasive real-time monitoring of cell mechanics was developed [ 63 ]. This in vitro model combined a co-culture of three cell types: epithelial and endothelial cell lines incubated with primary fibroblasts from idiopathic pulmonary fibrosis patients.…”

Lung Organoids for Hazard Assessment of Nanomaterials

“…In addition, the porous membranes used as substrate for the cell medium interface usually exceed realistic dimensions. Notably, well-working approaches to overcome this problem with advanced biomimetic membranes already exist [ 32 ].…”