Purpose and impact

The purpose of the Theme group Lung-on-Chip is to promote interaction, share knowledge, and provide opportunities for collaboration. Bundling our expertise and technology will accelerate the development of tissue-level chip models that include (differentiated) epithelium, vessels, stromal cells and ECM. This would allow the development of chip models that emulate more representatively healthy and diseased lung tissues. Ideally the different anatomical regions will be furthermore connected to form a true Lung-on-Chip and Lung-on-Chips should be connected to other co-morbidity-related organs, such as cardiac or skeletal muscle.

Program coordinators

Chair
Anne van der Does
LUMC

Vice-chair
Reinoud Gosens
University of Groningen

Upcoming meetings

  • 21 February (10-16, LUMC)
  • 2 October (10-16h, RUG)

Previous meetings

 

Challenges

To achieve tissue level representation in the chips, integrate lung-specific features such as airflow and stretch, and ideally combine chips to represent the different anatomical regions of the lungs, the following challenges need to be resolved:

  1. For application of lung-relevant mechanobiological cues:
    1. Application of bi-directional airflow
    2. Development of stretchable membranes
    3. Biomimetic culture substrates/porous membranes concerning substrate microtopography and elasticity
    4. Integrate application of stretch
  2. Inclusion of lung-specific ECM
  3. Inclusion of immune cells, e.g. alveolar macrophages in the alveolar models
  4. Generation of sufficient cell numbers for especially alveolar epithelial cells
  5. Controlled and optimal differentiation of cell cultures matching the anatomical location of the lung that is represented.
  6. More efficient generation of airway and alveolar type-2 cells from hiPSCs

Collaboration partners

  • National: MERLN, LUMC, UMCU, ErasmusMC, UMCG, Stichting Proefdiervrij, Longfonds, Ncardia, Stichting Astmabestrijding, Stichting Taai; Prof. Andries v/d Meer – Universiteit Twente
  • International: 300MICRONS GmbH (Karlsruhe, Germany; Microengineered 3D cell culture solutions); STEMCELL Technologies; dr. Janna Nawroth, Munich, Germany
  • Organs-on-Chips companies: Emulate Inc.; Dynamic42; Ibidi; TissUse
Thesis Thijs Pasman (UTwente): Poly(trimethylene carbonate)-based membranes for biomimetic lung epithelial-endothelial models

On December 8th 2021 Thijs Pasman successfully defended his thesis ‘Poly(trimethylene carbonate)-based membranes for biomimetic...

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Background

Patients with chronic lung diseases, including those with asthma, Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD), currently have no treatment available that can cure their disease, despite decades of research. Importantly, early insults to the lung, such as those occurring in congenital and perinatal lung diseases like congenital diaphragmatic hernia (CDH), congenital pulmonary airway malformation (CPAM) or Bronchopulmonary Dysplasia (BPD) , frequently lead to long term chronic lung diseases, such as COPD. One contributing factor to this problem has been the lack of representative culture models of the human lung that include sufficient tissue representation to reliably reproduce or predict mechanisms involved or of therapy tested, respectively.

Lung tissue composition is constantly changing throughout the lungs and in addition, mechanical forces as a result of breathing are continuously present. This complexity creates numerous challenges on both design level and for the biology in chip models.

The respiratory epithelium that lines the lung mucosa acts as a barrier between the environment and inside of the body and is constantly exposed to in- and exhaled air. In the upper and lower airways, the epithelium supports neutralization and removal of inhaled agents via a variety of host defence functions, including mucociliary clearance. Inspired air is transported via the airways before it arrives in the alveoli. Alveoli are lined with different (alveolar) epithelial cells including those that support the gas exchange function. Epithelial cell types lining the lumen of the airways vary in composition depending on their anatomical location in the lungs. Predominant cell-types in the epithelium of the larger airways include mucus-producing goblet cells and ciliated cells expressing hair-like structures that together with goblet cells contribute to mucociliary clearance. Also progenitor basal cells and multifunctional club cells are present in varying ratios, together with more rare subsets such as neuroendocrine cells, ionocytes and tuft cells. When descending deeper into the (smaller) airways, basal progenitor and goblet cell populations become less frequent or even disappear with a concomitant increase in the number of club cells that share the progenitor role of the basal cells. Finally the airways transition into the alveoli that are lined with alveolar epithelial type-1 and -2 cells that reside in close contact with microvascular endothelial cells supporting gas exchange. The epithelial lining is surrounded by immune cells, structural cells and endothelium, embedded in a complex extracellular matrix and continuously exposed to breathing-related forces such as airflow and stretch.

To represent such complex biology in vitro, challenges on chip platform design and biology have to be resolved. So far, a variety of chip models have been developed on both commercial and in-house platforms with various designs supporting the research question driving the chip development. These platforms allow culturing of multiple cell-types in presence or absence of mechanical stimuli such as stretch and/or airflow. Currently however a choice still has to be made between features, such as inclusion of a representative ECM or application of stretch or between including multiple cell types and duration of the culture.

The ideal Lung-on-Chip model should not be limited by these choices and should represent a complete tissue cross-section of the region that is modelled and ideally could be coupled if the mechanism or therapy studied spans more regions (i.e. large vs small airway, or airway vs alveoli). Key for these developments is regular cross-talk between engineering and biological teams to promote synergy and facilitate knowledge exchange.

Key Publications

Grant applications.

  • TKI-LSH-T2019-P4O2: Precision Medicine for more Oxygen (Heijink, van der Does, Hiemstra, Langen)
  • ZonMw Covid-19 MKMD: Use of patient-relevant human lung epithelial cell models to study acute and long-term effects of COVID-19 (Hiemstra).
  • ZonMw Covid-19 Program: A Fibrosis Lung-Chip model to study development and therapy of COVID-19 post-ARDS pulmonary fibrosis (van der Does)
  • NWO Perspectief: RecovAir: repairing lung damage via recovery of stromal health to restore respiratory function (Heijink, van der Does, Hiemstra, Gosens).
  • NWO – ENW. Modeling mast cell-neuron interactions driving neuroplasticity. 2021-2026 (Gosens).
  • Health Holland PPP. Targeting the exacerbation as a window for lung repair in COPD (Gosens).
  • Lung Foundation Netherlands 4.1.19.021. The dark side of the lung: the instructive role of the endothelial cell in COPD. 2019-2024 (Gosens, Hiemstra, van der Meer, van der Does).
  • ZonMW Covid19: Employing a physiological microfluidic lung bioreactor to improve understanding of SARS-CoV2 biology and testing of therapeutics (Rottier, Truckenmuller)
  • Lung Foundation Netherlands grant 4.1.18.226 ‘TORCA’ (Hendriks)
  • NWO-ZonMw VENI grant: “Danger signals released from damaged lung cells trigger extra-pulmonary co-morbidities in COPD patients” (Pouwels).
  • UMCG PPP-allowance grant “Identification of non-invasive small airway-lining fluid biomarkers for the early detection and progression of COPD” (Pouwels).
  • ZonMW Open Competitie– MitoReg: Targeting mitochondrial dysfunction to enhance lung tissue repair in COPD: muscles to the rescue (Heijink, Langen, Gosker, Verpoorte)
  • Lung Foundation Netherlands: Microengineered 3D analogues of alveolar tissue for lung regeneration, 2014-2020 (Hiemstra, Rottier, Stamatialis, Truckenmüller)
  • ZonMW-2020-09120012010088: Targeting mitochondrial dysfunction to enhance lung tissue repair in COPD: muscles to the rescue’ (Heijink, Langen, Gosker).