Respiratory diseases like pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and lung infections remain leading causes of death worldwide. The tiny air sacs in our lungs, called alveoli, rely on a natural stretch-recoil cycle for normal function – an essential process often disrupted in respiratory disease. Our goal is to develop a ‘breathing’, stem cell-derived model of the human alveolus to investigate how lung tissue responds to mechanical stretch in an array of disease-like environments.
Impact
Respiratory diseases continue to have a significant global burden, yet effective treatment options remain limited, underscoring the urgent need for more advanced models. While existing alveolar models incorporate mechanical stretch to simulate breathing, they often fall short due to limited scalability and reliance on cell types that sacrifice either physiological accuracy or long-term viability. To overcome these limitations, our model uses stem cell–derived alveolar cells, which uniquely offer both relevance and viability, combining the advantages of primary and immortalised cells used in previous systems. In addition, our 96-well stretchable platform enables high-throughput testing across multiple experimental conditions, making it more scalable, reproducible, and versatile than traditional single-chamber systems. By mimicking the dynamic microenvironment of the human alveolus, our flexible model allows for the study of both healthy function and pathological changes seen in acute and chronic respiratory diseases. This next-generation model is a powerful tool to deepen understanding of disease mechanisms and accelerate the development of effective therapies.
reNEW research
To date, we have successfully engineered our flexible alveolar model capable of applying mechanical stretch to stem cell-derived alveolar epithelial cells over extended periods, without inducing significant cytotoxicity. We have analysed expression of key alveolar cell markers to uncover how these cells respond to mechanical stress at the molecular level. Looking ahead, we plan to tune the stiffness of our stretchable membrane to replicate the altered elasticity characteristic of chronic respiratory diseases such as pulmonary fibrosis and COPD. Additionally, we explore how stretch-recoil influences immune responses to acute respiratory viral infections.
Image description
Diffraction of light through one of the flourescently stained 96 wells in our flexible alveolar model. The stem cell-derived alveolar cells sit on an oxygen permeable, transparent membrane made out of polydimethylsiloxane (PDMS). This PDMS membrane can stretch and recoil in response to applied dynamic air pressure.
Credits
Tamaia Dandeniya, Masters Student, Werder Lab, reNEW Melbourne.
