Organ Model: Respiratory System

Originally presented at the MPS World Summit 2025 Annual Meeting in Brussels, Belgium.

Authors

Bárbara F. Fonseca¹, Jérôme Wong-Ng¹, Michael Connor², Héloïse Mary¹, Min Hee Kim¹, Rémy Yim¹, Lisa A. Chakrabarti³, Samy Gobaa¹

¹Institut Pasteur, Université Paris Cité, Biomaterials and Microfluidics core facility, C2RT, Paris, France. ²Institut Pasteur, Université Paris Cité, Chromatin and Infection Laboratory, Paris, France. ³Institut Pasteur, Université Paris Cité, Control of Chronic Viral Infections Group, Virus and Immunity Unit, Paris, France.

Abstract

The development of complex in vitro models, such as organoids, gastruloids and organ-on-chips systems, allow a better understanding of human biological processes that are otherwise difficult to address with classical in vitro 2D culture and/or with animal models. Elucidating how pathogens invade human cells by evading the immune system and how this could be modulated by the host microbiota has been greatly facilitated by the advancement of 3D cell culture techniques. Our Team is working on establishing unique advanced microphysiological systems that can mimic the interaction between human epithelial barriers with the surrounding tissues, such as blood vessels, mesenchyme and immune cells. We relay both on the use of organoids derived from human tissues and microfluidic chips.

Originally presented at the MPS World Summit 2025 Annual Meeting in Brussels, Belgium.

Authors

Naomi S. Coombes¹, Tanja Šuligoj², Rhiannon Davies¹, Tessa Prince², Lisa Luu², Conner Norris¹, Julian Hiscox², Yper Hall¹, Simon GP Funnell³, Kevin R. Bewley¹

¹UK Health Security Agency, Porton Down, Salisbury, UK; ²Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; ³Gut Microbes and Health, Quadram Institute Bioscience, Norwich, UK

Abstract

The SARS-CoV-2 pandemic caused significant worldwide disruption to economies and healthcare systems. It is predicted that the frequency at which new pandemics occur in the future will increase due to factors such as climate change, global population increase, intensification of agriculture and closer contact with wildlife. All but one of the pathogens on the current WHO R&D emergency context priority disease list are viruses which require work to be performed at containment level 3 or 4 (BSL3 or BSL4). There is a need for physiologically relevant in vitro systems to assist pre-clinical research in preparedness for the next pandemic. For example, Disease X which by definition will be a human disease, may not infect current cell lines or animal models commonly used in virus research.

Here the authors present the results from infections with SARS-CoV-2, SARS-CoV-1 and MERS-CoV of an alveolar model using the commercially available Emulate system at BSL3. They also describe the results from antiviral assessment in this model.

Organ Model: Lung (Airway)

Application: Infectious Disease, Immunology & Inflammation

Highlights

In this study, the researchers created an Airway Lung-Chip that contains primary human airway epithelial cells (from either healthy donors or COPD patients) cultured at an air–liquid interface above a channel lined with pulmonary endothelial cells. This chip faithfully reproduces many features of the human airway, including differentiation into multiple cell lineages, mucus production, and barrier integrity. By infecting the Airway Lung-Chips with influenza virus, they could directly compare how healthy versus COPD airway cells respond to infection and drug treatments in a more physiologically relevant environment. Notably, they showed that COPD Airway Lung-Chips exhibit heightened viral replication and inflammation, mirroring the exacerbated disease states seen in patients. The Airway Lung-Chip experiments consistently showed higher viral replication and more pronounced inflammatory responses compared to static Transwell cultures, suggesting that the dynamic microenvironment on the chip better recapitulates in vivo airway physiology.

Products Used In This Publication

Dr. Vivek Thacker’s presentation explores the innovative use of Organ-Chip models in studying tuberculosis (TB) pathogenesis and treatment. Highlighting his work at EPFL and Heidelberg University, Dr. Thacker details the integration of in vitro Organ-Chip systems with traditional mouse models to bridge the gap between simplistic cell culture and complex animal models. These systems provide high-resolution insights into TB’s early stages, bacterial interactions with pulmonary surfactant, and immune responses.

Key learnings from this presentation include how:

• 3D bacterial architectures, such as cords, play a role in bacterial resilience, immune evasion, and dissemination.
• These structures compress host cell nuclei and alter immune responses.
• Organ-Chips can be used to model antibiotic delivery, showing that bacterial cords impede drug efficacy—a finding validated in mouse models.

Dr. Thacker’s findings demonstrate the utility of Organ-Chips in developing more predictive and physiologically relevant platforms for studying TB, advancing both therapeutic approaches and fundamental understanding of the disease. This pioneering work underscores the potential of bioengineered systems in infectious disease research.

In this session from Heidelberg MPS Day, Yuncheng Man, PhD, discusses how he used a microfluidic Alveolus Lung-Chip to study the impact of macrophages on influenza H3N2 infection. The presence of macrophages reduced viral levels but increased inflammation and tissue damage. This included higher levels of inflammatory signals, immune cell recruitment, and cell death, leading to weakened lung tissue barriers. The inflammation was partly driven by pyroptosis (a form of inflammatory cell death) in macrophages, linked to the release of IL-1β. Blocking pyroptosis reduced lung damage, highlighting potential therapeutic targets for conditions like viral pneumonia and acute respiratory distress syndrome (ARDS).

In this session from Heidelberg MPS Day, Dr. Irina Shalashova presents her work on developing and applying an Alveolus Lung-Chip model to study idiopathic pulmonary fibrosis (IPF) and improve drug discovery efforts. She describes how her team isolates and cultures primary human alveolar epithelial cells, expanding them into organoids before seeding them on the chip’s epithelial compartment. Endothelial cells line the opposite channel, and mechanical stretching simulates breathing. Over time, the alveolar type II cells partially differentiate into type I-like cells, creating a physiologically relevant, dynamic environment. By treating these chips with fibrotic stimuli, the team can observe biomarker changes, gas exchange issues, and drug responses. Ultimately, this platform enables more accurate modeling of human lung pathology and holds promise for identifying novel therapeutics.

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CFTR gene (Cystic fibrosis transmembrane conductance regulator), a protein with chloride channel function. Key consequences of a CFTR dysfunction include imbalance in ion transport, mucus accumulation, and chronic inflammation as well as infection in the airways of CF patients. 

In this webinar, Roberto Plebani, PhD, described how he used the Chip-S1® Stretchable Chip to develop the first CF Airway Lung-Chip using primary cells derived from patients’ airways and lung microvascular endothelial cells. The chip not only allowed the reconstruction of a CF bronchial unit, with increased mucus production and inflammation, but also enabled the perfusion of immune cells and infection with pathogens to better model inflammation and infection in CF.

Key highlights from the webinar include:

• Development of the first CF Airway Lung-Chip and potential enhancements for its use as a preclinical CF model.
• How the chip replicates a CF bronchial unit with increased mucus, inflammation, immune cell perfusion, and pathogen infection to better model CF.
• Future studies that will use the chip for drug testing and aim to improve it by adding CF endothelium and stroma.

Heidelberg MPS Day, held on October 1st, 2024, was a one-day Organ-Chip User Group Meeting centered around the theme of “Disease-on-Chip: Insights from Cancer, Infectious Disease & Respiratory Models.”

At this event, Organ-Chip users and enthusiasts from across Europe came together to attend expert-led sessions, network, and discuss the latest advancements in the field.

Featured talks include:

“The Human Emulation System – Advancing Research in Cancer and Infectious Diseases” by Christine Lansche, PhD, Scientific Liaison, Emulate

“Alveolus Lung-Chip for Studying Alveolar Niche and Lung Repair” by Irina Shalashova, PhD, Postdoctoral Researcher, Boehringer Ingelheim

“Cord Formation and Alveolar Immunity – Harnessing Microphysiological Models to Study Humanity’s Oldest Foe” by Vivek Thacker, PhD, Group Leader, Heidelberg University Medical Faculty

“Cancer-Bone Crosstalk in an Organ-Chip Model of Breast Cancer Metastases” by Stefaan Verbruggen, PhD, Assistant Professor of Medical Technology, Queen Mary University of London

“Modelling Cancer-Microbe Interactions with Organoids and Organs-on-Chips” by Jens Puschhof, PhD, Principal Investigator, DKFZ

“Microbial Insights in Oncology” by Rafik Fellague-Chebra, MD, Msc, Executive Global Group Medical Director, Novartis

“Exacerbation of Influenza Virus Induced Lung Injury by Alveolar Macrophages and Its Suppresion by Pyroptosis Blockade in a Human Lung Alveolus Chip” by Yuncheng Man, PhD, Postdoctoral Research Fellow, Wyss Institute & Boston Children’s Hospital

Organ Model: Lung (Alveolus)

Application: Infectious Disease

Abstract: Lung disease due to non-tuberculous mycobacteria (NTM) is rising in incidence. While both two dimensional cell culture and animal models exist for NTM infections, a major knowledge gap is the early responses of human alveolar and innate immune cells to NTM within the human alveolar microenvironment. Here we describe development of a humanized, three-dimensional, alveolus lung-on-a-chip (ALoC) model of Mycobacterium fortuitum lung infection that incorporates only primary human cells such as pulmonary vascular endothelial cells in a vascular channel, and type I and II alveolar cells and monocyte-derived macrophages in an alveolar channel along an air-liquid interface. M. fortuitum introduced into the alveolar channel primarily infected macrophages, with rare bacteria inside alveolar cells. Bulk-RNA sequencing of infected chips revealed marked upregulation of transcripts for cytokines, chemokines and secreted protease inhibitors (SERPINs). Our results demonstrate how a humanized ALoC system can identify critical early immune and epithelial responses to M. fortuitum infection. We envision potential application of the ALoC to other NTM and for studies of new antibiotics.

Organ Model: Lung (Alveolus)

Application: Infectious Disease

Abstract: Alveolar macrophages (AMs) are the major sentinel immune cells in human alveoli and play a central role in eliciting host inflammatory responses upon distal lung viral infection. Here, we incorporated peripheral human monocyte-derived macrophages within a microfluidic human Lung Alveolus Chip that recreates the human alveolar-capillary interface under an air-liquid interface along with vascular flow to study how residential AMs contribute to the human pulmonary response to viral infection. When Lung Alveolus Chips that were cultured with macrophages were infected with influenza H3N2, there was a major reduction in viral titers compared to chips without macrophages; however, there was significantly greater inflammation and tissue injury. Pro-inflammatory cytokine levels, recruitment of immune cells circulating through the vascular channel, and expression of genes involved in myelocyte activation were all increased, and this was accompanied by reduced epithelial and endothelial cell viability and compromise of the alveolar tissue barrier. These effects were partially mediated through activation of pyroptosis in macrophages and release of pro-inflammatory mediators, such as interleukin (IL)-1β, and blocking pyroptosis via caspase-1 inhibition suppressed lung inflammation and injury on-chip. These findings demonstrate how integrating tissue resident immune cells within human Lung Alveolus Chip can identify potential new therapeutic targets and uncover cell and molecular mechanisms that contribute to the development of viral pneumonia and acute respiratory distress syndrome (ARDS).

Products Used in This Publication