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Review
. 2021 Sep:176:113901.
doi: 10.1016/j.addr.2021.113901. Epub 2021 Jul 29.

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Arbel Artzy-Schnirman  1 , Sivan Arber Raviv  2 , Ofri Doppelt Flikshtain  2 , Jeny Shklover  2 , Netanel Korin  1 , Adi Gross  3 , Boaz Mizrahi  3 , Avi Schroeder  2 , Josué Sznitman  4
Affiliations
Review

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Arbel Artzy-Schnirman et al. Adv Drug Deliv Rev. 2021 Sep.

Abstract

Over the past years, advanced in vitro pulmonary platforms have witnessed exciting developments that are pushing beyond traditional preclinical cell culture methods. Here, we discuss ongoing efforts in bridging the gap between in vivo and in vitro interfaces and identify some of the bioengineering challenges that lie ahead in delivering new generations of human-relevant in vitro pulmonary platforms. Notably, in vitro strategies using foremost lung-on-chips and biocompatible "soft" membranes have focused on platforms that emphasize phenotypical endpoints recapitulating key physiological and cellular functions. We review some of the most recent in vitro studies underlining seminal therapeutic screens and translational applications and open our discussion to promising avenues of pulmonary therapeutic exploration focusing on liposomes. Undeniably, there still remains a recognized trade-off between the physiological and biological complexity of these in vitro lung models and their ability to deliver assays with throughput capabilities. The upcoming years are thus anticipated to see further developments in broadening the applicability of such in vitro systems and accelerating therapeutic exploration for drug discovery and translational medicine in treating respiratory disorders.

Keywords: Aerosols; In vitro; Inhalation therapy; Lung diseases; Lung-on-chips; Preclinical models.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Bridging the gap between in vivo and in vitro interfaces in the lungs: Left: schematic of the respiratory region (i.e. pulmonary acinus) exemplifying the alveolar-capillary barrier and its cellular make-up. Right: Overview of preclinical in vitro models for pulmonary research spanning traditional assays including culture plates under immersed conditions and air-liquid interface (ALI) based assays to advanced in vitro models, featuring “soft” membrane-based assays and microfluidic lung-on-chips.
Figure 2
Figure 2
Examples of in vitro phenotypical endpoints using advanced in vitro lung models. (a) Monitoring secretion of cytokines in a biochip of pulmonary sarcoidosis model [230]. (b) Measurement of metabolic activity following deposition of PM-like particles in airway-on-chip platforms [148]. (c) Assessment of therapeutics in an alveolus-on-a-chip model of intravascular thrombosis [173]. (d) Permeability assay in a breathing alveolus-on-chip model [77]. (e) Single cell distortion as a function of applied force in a stretching alveolar-capillary chip [83]. (f) Imaging tight junction (TJ) and adherent junction markers in a lung-on-a-chip with an array of stretchable alveoli-like membranes [125].
Figure 3
Figure 3
In vitro approaches currently exhibit a trade-off between throughput capacity and physiological and biological complexity. The feasibility for high-throughput data collection decreases as the in vitro model design mimics physiological and biological characteristics of the lungs in the effort to recapitulate more closely in vivo models, and humans in particular.
Figure 4
Figure 4
Liposome-based therapies for treatment of respiratory diseases including method of administration.
See this image and copyright information in PMC

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