Organ Model: Respiratory System

Organ Model: Lung (Alveolus)

Application: Infectious Disease

Highlights

In this study, researchers used a human Alveolus Lung-Chip to test CRISPR-Cas13 RNA therapeutics targeting conserved regions of the influenza A virus genome. The chip model showed that these crRNAs potently suppressed viral replication and also reduced inflammatory cytokine release and immune cell recruitment, effects not easily captured in animal models. Transcriptomic analyses revealed minimal off-target activity, indicating strong specificity in human primary lung tissue. These findings highlight Organ-Chips as a valuable preclinical platform for evaluating both efficacy and safety of CRISPR-based antiviral therapies.

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Organ Model: Lung (airway)

Application: Methodology development

Highlights

The authors developed new methods to process and analyze Emulate Organ-Chips by trimming and paraffin-embedding Chip-S1 consumables, which enabled routine histology, immunohistochemistry, and in situ hybridization on chip cross-sections. They also applied electron microscopy workflows to assess ultrastructural features, allowing identification of cell types and organelles and localization of marker proteins. Using these approaches, they compared Airway Lung-Chips and Colon Intestine-Chips to other culture formats, showing how chips influenced differentiation trajectories and cellular composition relative to primary tissue.

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Organ Model: Lung (Airway)

Application: ADME

Highlights

In pursuit of a more reliable method for predicting the permeability of inhaled compounds during the development of new and generic drugs, the authors in this study used a small airway Lung-Chip to recapitulate the pulmonary air-liquid interface (ALI) with primary epithelial and vascular endothelial cell layers. This study showed that the small airway Lung-Chip recapitulated relevant cell types and many morphological features in the lung. The apparent permeabilities measured indicated that albuterol sulfate and formoterol fumarate would be categorized as highly permeable, while olodaterol HCl would be categorized as a low permeable drug.

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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.

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Organ Model: Lung (airway)

Application: Immunology & Inflammation, Cancer

Highlights

The authors of this study leveraged Organ-Chips to model cystic fibrosis airways. The researchers used CRISPR/Cas9 to knock out CFTR in human bronchial epithelial cells, then grew them in Chip-S1 Organ-Chips to study how CFTR loss drives inflammation, immune cell recruitment, and epithelial invasiveness — key features of CF lung disease. Compared to wild-type controls, CFTR-deficient chips showed increased recruitment of polymorphonuclear neutrophils and greater migration of epithelial cells into the endothelial channel, reflecting a pro-inflammatory, EMT-associated phenotype. These chip-based functional assays complemented proteomic findings, linking CFTR loss to pathways involved in cancer progression and immune cell recruitment.

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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.