Advanced pathophysiology mimicking lung models for accelerated drug discovery

Thanh Huyen Phan; Huaikai Shi; Christopher E Denes; Alexander J Cole; Yiwei Wang; Yuen Yee Cheng; Daniel Hesselson; Susan H Roelofs; Graham Gregory Neely; Jun-Hyeog Jang; Wojciech Chrzanowski

doi:10.1186/s40824-023-00366-x

Advanced pathophysiology mimicking lung models for accelerated drug discovery

Biomater Res. 2023 Apr 26;27(1):35. doi: 10.1186/s40824-023-00366-x.

Authors

Thanh Huyen Phan¹, Huaikai Shi^{2

3}, Christopher E Denes⁴, Alexander J Cole^{5

6}, Yiwei Wang^{2

7}, Yuen Yee Cheng^{3

8}, Daniel Hesselson^{5

6}, Susan H Roelofs⁹, Graham Gregory Neely^{4

5}, Jun-Hyeog Jang¹⁰, Wojciech Chrzanowski¹¹

Affiliations

¹ The University of Sydney, Sydney Nano Institute, Faculty of Medicine and Health, Sydney School of Pharmacy, Pharmacy and Bank Building A15, Camperdown, NSW, 2006, Australia.
² Burns Research and Reconstructive Surgery, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, Australia.
³ Asbestos Disease Research Institute, Concord Hospital, Sydney, Australia.
⁴ The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.
⁵ Centenary Institute, The University of Sydney, Sydney, NSW, 2006, Australia.
⁶ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
⁷ Jiangsu Provincial Engineering Research Centre of TCM External Medication Development and Application, Nanjing University of Chinese Medicine, Nanjing, China.
⁸ Institute for Biomedical Materials and Devices (IBMD), School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Broadway, NSW, 2007, Australia.
⁹ Locsense B.V., Locsense B.V., Enschede, The Netherlands.
¹⁰ Department of Biochemistry, College of Medicine, Inha University, Incheon, 400-712, South Korea.
¹¹ The University of Sydney, Sydney Nano Institute, Faculty of Medicine and Health, Sydney School of Pharmacy, Pharmacy and Bank Building A15, Camperdown, NSW, 2006, Australia. wojciech.chrzanowski@sydney.edu.au.

Abstract

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.

Keywords: Extracellular matrix; Lung-mimicking models; Microcirculation; Multimodal characterisation; Patient-derived cell lines; Personalised medicine; Physiological relevance.