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Updated: Aug 1, 2025
Generation of Human 3D Lung Tissue Cultures 3D-LTCs for Disease Modeling
Published on: February 12, 2019
Advanced pathophysiology mimicking lung models for accelerated drug discovery
Thanh Huyen Phan1, Huaikai Shi2,3, Christopher E Denes4
1The University of Sydney, Sydney Nano Institute, Faculty of Medicine and Health, Sydney School of Pharmacy, Pharmacy and Bank Building A15, Camperdown, NSW, 2006, Australia.
Background:
Respiratory diseases are the 2nd leading cause of death globally. The current treatments for chronic lung diseases are only supportive. Very few new classes of therapeutics have been introduced for lung diseases in the last 40 years, due to the lack of reliable lung models that enable rapid, cost-effective, and high-throughput testing. To accelerate the development of new therapeutics for lung diseases, we established two classes of lung-mimicking models: (i) healthy, and (ii) diseased lungs - COPD.
Methods:
To establish models that mimic the lung complexity to different extents, we used five design components: (i) cell type, (ii) membrane structure/constitution, (iii) environmental conditions, (iv) cellular arrangement, (v) substrate, matrix structure and composition. To determine whether the lung models are reproducible and reliable, we developed a quality control (QC) strategy, which integrated the real-time and end-point quantitative and qualitative measurements of cellular barrier function, permeability, tight junctions, tissue structure, tissue composition, and cytokine secretion.
Results:
The healthy model is characterised by (i) continuous tight junctions, (ii) physiological cellular barrier function, (iii) a full thickness epithelium composed of multiple cell layers, and (iv) the presence of ciliated cells and goblet cells. Meanwhile, the disease model emulates human COPD disease: (i) dysfunctional cellular barrier function, (ii) depletion of ciliated cells, and (ii) overproduction of goblet cells. The models developed here have multiple competitive advantages when compared with existing in vitro lung models: (i) the macroscale enables multimodal and correlative characterisation of the same model system, (ii) the use of cells derived from patients that enables the creation of individual models for each patient for personalised medicine, (iii) the use of an extracellular matrix proteins interface, which promotes physiological cell adhesion and differentiation, (iv) media microcirculation that mimics the dynamic conditions in human lungs.
Conclusion:
Our model can be utilised to test safety, efficacy, and superiority of new therapeutics as well as to test toxicity and injury induced by inhaled pollution or pathogens. It is envisaged that these models can also be used to test the protective function of new therapeutics for high-risk patients or workers exposed to occupational hazards.
Insights
Researchers developed novel lung models to accelerate the discovery of new treatments for respiratory diseases. These advanced models mimic healthy and diseased lungs, enabling faster and more reliable drug testing.
Area of Science:
- Biotechnology
- Respiratory Medicine
- In Vitro Models
Background:
- Respiratory diseases are a leading global cause of death, with limited therapeutic options due to a lack of effective lung models.
- Current treatments for chronic lung diseases are primarily supportive, highlighting the urgent need for novel therapeutic development.
Purpose of the Study:
- To establish advanced, reliable, and reproducible in vitro lung models that mimic both healthy and diseased (COPD) lung complexity.
- To accelerate the development and high-throughput testing of new therapeutics for respiratory diseases.
Main Methods:
- Utilized five key design components: cell type, membrane structure, environmental conditions, cellular arrangement, and substrate/matrix composition.
- Implemented a quality control strategy with real-time and end-point measurements of cellular barrier function, permeability, tight junctions, tissue structure, composition, and cytokine secretion.
Main Results:
- Developed a healthy lung model with continuous tight junctions, physiological barrier function, a multi-layered epithelium, and presence of ciliated/goblet cells.
- Created a COPD model exhibiting dysfunctional barrier function, depleted ciliated cells, and goblet cell overproduction, mimicking human disease.
- Highlighted competitive advantages including macroscale for multimodal characterization, patient-derived cells for personalized medicine, extracellular matrix for cell adhesion, and microcirculation for dynamic conditions.
Conclusions:
- The developed lung models are suitable for evaluating the safety, efficacy, and superiority of new therapeutics.
- Models can assess toxicity and injury from inhaled pollutants or pathogens, and test protective therapeutics for high-risk individuals.
