Chronic respiratory diseases are among the leading causes of death worldwide, but only symptomatic therapies are available for terminal illness. This in part reflects a lack of biomimetic in vitro models that can imitate the complex environment and physiology of the lung. Here, a copolymeric membrane consisting of poly(ε‐)caprolactone and gelatin with tunable properties, resembling the main characteristics of the alveolar basement membrane is introduced. The thin bioinspired membrane (≤5 μm) is stretchable (up to 25% linear strain) with appropriate surface wettability and porosity for culturing lung epithelial cells under air–liquid interface conditions. The unique biphasic concept of this membrane provides optimum characteristics for initial cell growth (phase I) and then switch to biomimetic properties for cyclic cell‐stretch experiments (phase II). It is showed that physiologic cyclic mechanical stretch improves formation of F‐actin cytoskeleton filaments and tight junctions while non‐physiologic over‐stretch induces cell apoptosis, activates inflammatory response (IL‐8), and impairs epithelial barrier integrity. It is also demonstrated that cyclic physiologic stretch can enhance the cellular uptake of nanoparticles. Since this membrane offers considerable advantages over currently used membranes, it may lead the way to more biomimetic in vitro models of the lung for translation of in vitro response studies into clinical outcome.

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.

As post‐COVID complications, chronic respiratory diseases are one of the foremost causes of mortality. The quest for a cure for this recent global challenge underlines that the lack of predictive in vitro lung models is one of the main bottlenecks in pulmonary preclinical drug development. Despite rigorous efforts to develop biomimetic in vitro lung models, the current cutting‐edge models represent a compromise in numerous technological and biological aspects. Most advanced in vitro models are still in the “proof‐of‐concept” phase with a low clinical translation of the findings. On the other hand, advances in cellular and molecular studies are mainly based on relatively simple and unrealistic in vitro models. Herein, the current challenges and potential strategies toward not only bioinspired but truly biomimetic lung models are discussed.

Background and Purpose: Emphysema is an incurable disease characterized by loss of lung tissue leading to impaired gas exchange. Wnt/β‐catenin signalling is reduced in emphysema, and exogenous activation of the pathway in experimental models in vivo and in human ex vivo lung tissue improves lung function and structure. We sought to identify a pharmaceutical able to activate Wnt/β‐catenin signalling and assess its potential to activate lung epithelial cells and repair.Experimental Approach: We screened 1216 human‐approved compounds for Wnt/β‐catenin signalling activation using luciferase reporter cells and selected candidates based on their computationally predicted protein targets. We further performed confirmatory luciferase reporter and metabolic activity assays. Finally, we studied the regenerative potential in murine adult epithelial cell‐derived lung organoids and in vivo using a murine elastase‐induced emphysema model.Key Results: The primary screen identified 16 compounds that significantly induced Wnt/β‐catenin‐dependent luciferase activity. Selected compounds activated Wnt/β‐catenin signalling without inducing cell toxicity or proliferation. Two compounds were able to promote organoid formation, which was reversed by pharmacological Wnt/β‐catenin inhibition, confirming the Wnt/β‐catenin‐dependent mechanism of action. Amlexanox was used for in vivo evaluation, and preventive treatment resulted in improved lung function and structure in emphysematous mouse lungs. Moreover, gene expression of Hgf, an important alveolar repair marker, was increased, whereas disease marker Eln was decreased, indicating that amlexanox induces pro‐regenerative signalling in emphysema.Conclusion and Implications: Using a drug screen based on Wnt/β‐catenin activity, organoid assays and a murine emphysema model, amlexanox was identified as a novel potential therapeutic agent for emphysema.