Modelling cigarette smoke-induced lung vascular dysfunction using an alveolus-on-chip

Materials Today Bio, vol. 39, pp. 103429

Abstract

Abstract The alveolus is central to gas exchange in the lung, and alveolar damage is a characteristics of a variety of lung diseases. Understanding alveolar microvascular dynamics and epithelial-endothelial interactions is essential for accurately modeling alveolar physiology and its dysfunction in lung diseases such as Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis and acute respiratory distress syndrome (ARDS). In this study, we present an open-top, membrane-free alveolus-on-chip platform incorporating self-assembled, perfusable 3D vascular networks by primary human lung endothelial cells and pericytes, co-cultured with alveolar epithelial type 2 (AEC2) cells. These vascular networks were developed within 6 days under continuous flow and remained stable for at least 12 days. The inclusion of pericytes supported capillary-like vessel formation and increased gene expression of EDNRB1 , a gene enriched in alveolar microvascular endothelial cells. Furthermore, CD31 gene expression was higher in 3D endothelial networks compared to 2D endothelial monolayers, suggesting increased cell-cell adhesion. Monocytes could be successfully perfused through the networks, expanding the platform’s potential for studying immune interactions in lung disorders. Culturing AEC2 monolayers directly on the vascularized hydrogel enabled physiologically relevant cell-cell interactions without artificial membranes, while maintaining air-liquid interface conditions. Importantly, exposure of the AEC2 layer to whole cigarette smoke (WCS) led to complete disintegration of the underlying vascular network, an effect not observed in the absence of AEC2. This chip model provides a human-relevant system for investigating vascular-epithelial crosstalk in the alveolus, smoke-induced lung injury, and immune recruitment, offering a valuable platform for future disease modeling and drug testing applications.

Authors 9

1. Abilash Ravi Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands

   Leiden University Medical Center

2. Tarek Gensheimer

   University of Twente

   Affiliation as printed

   Applied Stem Cell Technologies, Department of Bioengineering Technologies, University of Twente, Enschede, 7522 AA, the Netherlands

   University of Twente

3. Xinhui Wu

   University Medical Center Groningen · Aston University · University of Groningen

   Affiliation as printed

   Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, 9713 AV, the Netherlands

   Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, 9713 AV, the Netherlands

   School of Biosciences, College of Health & Life Sciences, Aston University, Birmingham, B15 2TT, United Kingdom

   Aston University

4. Jill R. Johnson

   University Medical Center Groningen · Aston University · University of Groningen

   Affiliation as printed

   School of Biosciences, College of Health & Life Sciences, Aston University, Birmingham, B15 2TT, United Kingdom

   Univeristy of Groningen/UMCG

5. Martin C. Harmsen

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, 9713 AV, the Netherlands

   Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, 9713 GZ, the Netherlands

   University of Groningen

6. Reinoud Gosens Aachen

   University Medical Center Groningen · University of Groningen · Leiden University Medical Center

   Affiliation as printed

   Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, 9713 AV, the Netherlands

   Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, 9713 AV, the Netherlands

   Leiden University Medical Center

7. Pieter Sicco Hiemstra Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center · University of Twente

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands

   University of Twente

8. Andries D. van der Meer Aachen

   Leiden University Medical Center · University of Twente

   Affiliation as printed

   Applied Stem Cell Technologies, Department of Bioengineering Technologies, University of Twente, Enschede, 7522 AA, the Netherlands

   Leiden University Medical Center

9. Anne M. van der Does corresponding Aachen PulmoScience Lab Dept of Pulmonology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, Leiden, 2333 ZA, the Netherlands