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Front. Bioeng. Biotechnol., 22 October 2021
Sec. Biomaterials
Volume 9 - 2021 |

Editorial: Innovative In Vitro Models for Pulmonary Physiology and Drug Delivery in Health and Disease

  • 1Helmholtz Center for Infection Research (HZI), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Saarbrücken, Germany
  • 2Department of Pharmacy, Saarland University, Saarbrücken, Germany
  • 3School of Engineering, Royal Melbourne Institute of Technology, Melbourne, VIC, Australia
  • 4Departments of Biomedical Engineering, Technion – Israel Institute of Technology, Haifa, Israel

Respiratory diseases continue to exemplify a global leading cause of disability and mortality (Wisnivesky and De-Torres, 2019), with little signs of receding. In the midst of it, there is an ongoing and unmet need in treating such respiratory conditions. The situation has only been further exacerbated with the current COVID-19 pandemic and ensuing therapeutic challenges following the transmission of respiratory viruses (Scheuch, 2020; Leung, 2021; Wang et al., 2021). Concurrently, Chronic Obstructive Pulmonary Disease (COPD), with over 200 M patients, stands as one of the top five leading causes of death worldwide (Barnes and Stockley, 2005; Barnes et al., 2015a). All the meanwhile, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), idiopathic pulmonary fibrosis (IPF) as well as other infectious diseases (e.g., pneumonia, tuberculosis) are either fatal diseases or pathologies exhibiting high mortality rates. Few new compounds that are safe have shown efficacy and have eventually emerged as new therapeutic options; rather, approved treatments have mainly consisted in improvements or repurposing of existing classes of drug (Barnes et al., 2015b), thus falling short of addressing existing the breadth of therapeutic needs. One critical issue lies in the existing discrepancy between the performance of therapeutic candidates in preclinical in vivo animal models and their high failure rate for safety and/or efficacy in reaching clinical trials. More generally, the efforts advocating for improved human-relevant in vitro lung models are intimately tied to current discussions on alternatives to in vivo animal experiments (Bonniaud et al., 2018) and have been further underlined with major hurdles faced with animal experiments regarding the extent to which these shed light on human pulmonary physiology and diseases (van der Worp et al., 2010; Benam et al., 2015; Artzy-Schnirman et al., 2021).

The present Special Issue exemplifies a timely snapshot of new research efforts aimed at delivering innovative and human-relevant pulmonary in vitro models, thereby overcoming the enduring disconnect between predictive capacities of pre-clinical in vivo animal models and novel respiratory therapeutics, as highlighted in the new review of Cidem et al. on the challenges and advances of in vitro models and the implementation of ex vivo inhaled drug screening models. In the field of lung-on-chips, this special volume first highlights new pulmonary platforms that are advancing more realistic in vitro inhalation assays with endpoints geared at assessing properties of the airway epithelium, including pharmacokinetics and barrier properties (Elias-Kirma et al.; Doryab et al.). Of particular interest, one new review covers advances in generating complex 3D culture systems that emulate the microarchitecture and pathophysiology of the human lungs using organotypic systems for host-environment and pathogen interaction (Jimenez-Valdes et al.). Concurrently, Yang et al. discuss in another review opportunities for organ-on-chip platforms to accelerate in vitro studies elucidating the cytotoxic effects of inhaled particulate matter (PM).

The Special Issue also exemplifies a number of state-of-the-art methodologies for research in respiratory physiology. This includes for example the use of high-precision cut lung slices subject to cyclic stretching in an effort to mimic physiological breathing (Mondoñedo et al.), in particular in cytotoxic studies on exposure to cigarette smoke, as well as the introduction of new fibroblast cell lines for in vitro disease modeling of pulmonary fibrosis at an air-liquid interface (Nemeth et al.). In parallel, Lingampally et al. summarize the current knowledge and limitations of strategies aiming to carry out methodical pre-clinical drug screening in pertinent in vitro, ex vivo, and in vivo models of pulmonary fibrosis, with a focus on relevant therapeutics that to date only reduce the expression of fibrotic markers. In recreating phenotypes of fibrotic lung tissue, Yamanishi et al. have combined a technique of printing microscale collagen gels embedded with fibroblast cells together with live cell imaging and automated image analysis to enable high-throughput analysis of the kinetics of cell-mediated contraction of this collagen matrix. Meanwhile, Hortsmann et al. describe a straightforward custom-made device, allowing connection to commercially available nebulizers with standard in vitro pulmonary cell culture plates for reproducibly depositing pre-metered doses of nebulized drugs. Finally, Majoral et al. have also aimed to develop and evaluate a new method using cascade impactor to measure particle size at human physiological temperature and humidity taking into account ambient air conditions.

To conclude, this volume highlights perhaps most importantly innovative proof-of-concept efforts geared at drug screening of potential drug candidates for pulmonary therapies. For example, Garcia-Mouton et al. focus on the potential use of pulmonary surfactant (PS) to deliver full-length recombinant human surfactant protein SP-D (rhSP-D) using the respiratory air-liquid interface as a shuttle, demonstrating that PS may transport rhSP-D long distances over air-liquid interfaces, and thus opening opportunities to empower the current clinical surfactants and surfactant replacement therapy (SRT). In parallel, Tang et al. have explored the anti-inflammatory properties of Poloxamer 188 (P188) in ischemia/reperfusion (IR)-induced acute lung injury models that can help to maintain plasma membrane function by suppressing multiple signaling pathways and maintaining cell membrane integrity. Finally, Wu et al. have explored the promising therapeutic potential of the dual pharmacological inhibition of two isoforms of rho-associated coiled-coil-forming protein kinase (ROCK 1 and 2) to counteract growth factor (TGF)-β-induced myofibroblast transformation and remodeling in mesenchymal-epithelial interactions that are known to contribute to chronic lung diseases (i.e., COPD, lung fibrosis) and defective lung repair.

Author Contributions

C-ML, LY, and JS drafted and edited the editorial.

Conflict of Interest

C-ML is co-founder, scientific advisor and shareholder of PharmBioTec GmbH, Saarbrücken, Germany.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


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Keywords: in vitro, organ on chips, lung on a chip, lungs, therapeutics, respiratory disease, drug screening and delivery

Citation: Lehr C-M, Yeo L and Sznitman J (2021) Editorial: Innovative In Vitro Models for Pulmonary Physiology and Drug Delivery in Health and Disease. Front. Bioeng. Biotechnol. 9:788682. doi: 10.3389/fbioe.2021.788682

Received: 03 October 2021; Accepted: 07 October 2021;
Published: 22 October 2021.

Edited and reviewed by:

Nihal Engin Vrana, Sparta Medical, France

Copyright © 2021 Lehr, Yeo and Sznitman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Josué Sznitman,