Microphysiological lung models to evaluate the safety of new pharmaceutical modalities: a biopharmaceutical perspective

Abstract

Drug developers seek specific advancements in the development and qualification of microphysiological lung models for the evaluation of drug safety; here these essential elements are discussed from the perspective of the biopharmaceutical industry.

Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

“…Probably the most famous example of this in vitro, cell-based NAM is the breathing lung-on-chip developed by Huh and co-workers at the Wyss Institute of Harvard University (USA), capable of reproducing both the physiological and pathological responses of the human lung, a rudimentary circulatory system and the mechanical stress associated with breathing [ 118 , 119 , 120 ]. The immediate application of lung-on-chip has been for toxicity testing [ 121 , 122 ]; more recently, this model has been exploited for improving understanding of the complex lung disease processes and their responses to therapeutics [ 123 , 124 , 125 ], with applications extending even to the most recent need of a fast drug discovery for COVID-19 treatment [ 126 ]. Lung-on-chip systems allow, in fact, the in vitro creation of highly tissue-mimetic lung disease models [ 127 , 128 ], thus allowing, for example, to model the human response and the effects of existing and novel therapeutics when the lung is infected by the influenza virus or by viral pseudoparticles expressing spike protein of SARS-CoV-2, the virus responsible for COVID-19 development [ 126 ].…”

Where We Stand: Lung Organotypic Living Systems That Emulate Human-Relevant Host–Environment/Pathogen Interactions

“…Another similar yet distinct preclinical system is organoids; these are cultured organ-specific cell types, which are derived from a population of stem cells (adult or pluripotent), and are capable of maintaining stem cells during in vitro culture. During formation, organoids develop into 3D tissues that recreate in vivo-observed microanatomy through self-organization (Fang and Eglen, 2017;Ainslie et al, 2019). Compared to spheroids, organoids exhibit long-term viability and rely on internal developmental processes (rather than cell-cell adhesions) to drive tissue/organ-like microarchitecture formation.…”

“…To address the disconnection that often exists in spheroids and organoids in including both cellular and organ-level complexities in vitro, some groups have turned to an ex vivo system called precision cut lung slices (PCLS), which maintain the cellular structure and the biological processes of the lung (Ainslie et al, 2019). Importantly, PCLS generation from healthy explants and diseased tissue can reveal differences in the cellular and molecular interactions within the microenvironment of the lung.…”

“…Among the simplest of the 3D lung models are spheroids. Spheroids are multicellular sphere-like culture systems that enable recapitulation of cell–cell interactions; they are either utilized as freely floating cell aggregates or get seeded onto 3D bio-scaffolds ( Ainslie et al, 2019 ). Spheroids utilize tumor-derived cells, patient-derived xenograft cells, and immortalized cell lines, and have been applied to study intercellular interactions and response to therapies in the context of cancer ( Ekert et al, 2014 ; Meenach et al, 2016 ; Klameth et al, 2017 ; Lewis et al, 2018 ), lung progenitor cells differentiation ( Chimenti et al, 2017 ), and pulmonary fibrosis ( Surolia et al, 2017 ).…”

“…However, despite their use of primary human lung airway epithelial cells (hAECs) and recapitulation of mucociliated histology, they have several limitations in recreating organ-level functionalities of the human lung. For example, they do not enable (1) real-time analysis of dynamic intercellular (e.g., leukocyte-endothelial cell) interactions under physiological flow, (2) study of inhalation exposure to whole cigarette smoke, as a representative inhaled material, under physiological breathing airflow without disturbing ALI, (3) recreation of blood-like vascular perfusion to continually supply nutrients and growth factors, (4) introduction and perturbation of vascular and airflow shear stress to simulate different pathophysiological conditions, and (5) high-resolution kinetic analysis of biological responses (e.g., the time-course release of secreted factors, like cytokines/chemokines, in response to pathogenic challenge) (Fang and Eglen, 2017;Ainslie et al, 2019). In addition, these platforms are commonly used in the absence of sub-epithelial extracellular matrix (ECM; Yamaya et al, 1992;Gray et al, 1996).…”