In this in vitro lung models publication, PhysioMimix users at the University of Sydney, outline their work to accelerate novel therapeutic development by designing and validating lung-on-a-chip models with enhanced human relevance.

For the first time, they provide a comprehensive comparison between different in vitro lung models (healthy and COPD) with varying complexity and their applicability for drug development and disease modeling. Their review covers several topics including:

Why are more human-relevant lung models required?

It is a well-known fact that respiratory diseases are the second leading cause of death globally and that current treatments are purely supportive. Over the last 40 years, very few novel therapeutics have been delivered caused by a lack of reliable in vitro and in vivo animal models for research and development.

Traditional in vitro models offer limited physiological relevance and animal models differ in anatomy, immune and inflammatory response to humans.

Through comparative studies, the authors conclude that current in vitro models of COPD have limited predictive power for efficacy and regeneration endpoints. To do this, a model must emulate the 3D complexity of tissue and the dynamic nature of the lung microenvironment e.g., its microcirculation.

The fundamentals of lung-on-a-chip design?

The publication provides a thorough explanation of the core design principles behind the design of healthy and Chronic obstructive pulmonary disease (COPD) lung-on-a-chip models, also known as microphysiological systems.

The paper outlines their step-by-step development process from simple (cell line mono-cultures) to more complex in vitro co-culture models using primary human lung cells to replicate physiological conditions. They cite the impact of each iteration on the tissues in terms of pathophysiology, and human-relevance and highlight the benefits of microfluidics in dynamically perfused models versus static cultures.

The authors provide a list of the design components required:

• cell selection
• membrane structure/constitution
• environmental condition
• cellular arrangement
• substrate/matrix composition

And the quality control strategy:

Integrated real-time and end-point measurements of:

• cellular barrier function
• permeability
• tight junctions
• tissue structure and composition
• cytokine secretion

The competitive advantages of Lung-on-a-chip compared to existing in vitro lung models

Healthy and COPD Lung-on-a-chip models were cultured using the PhysioMimix System and open-well Multi-chip Barrier plates, which provide dynamic perfusion and ALI to mimic lung physiology. Their model incorporates primary human epithelial cells and pulmonary endothelial cells. The validation data generated by the study demonstrates the following advantages of the Lung-on-a-chip versus existing in vitro models in comparative studies.

• An extracellular matrix proteins interface promotes physiological cell adhesion and differentiation
• Media circulation mimics the dynamic conditions in human lungs
• The model’s macroscale enables multimodal and correlative characterization
• The perfused PhysioMimix COPD model better recapitulates human‑relevant tissue features and responses
• Use of cells derived from patients enables personalized medicine

Why You Should Read It

• Learn practical approaches to modeling respiratory disease in using in vitro cultured human lung tissues—key for translational research applications.
• If you’re involved in drug discovery, or modeling respiratory disease, this study demonstrates how perfused lung-on-chip models deliver more predictive insights for efficacy and safety testing new therapeutics
• In addition the authors cite the model’s potential for testing the toxicity and injury induced by inhaled pollution or pathogens.

Read the full preprint

Advanced pathophysiology mimicking lung models for accelerated drug discovery -published by Phan et al. (2023) in Biomater Res DOI: 10.1186/s40824-023-00366-x

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