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Pharmacokinetics and Pharmacodynamics of Drugs Delivered to the Lung
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Stefanie K. Drescher, Mong-Jen Chen, Jürgen B. Bulitta, Günther Hochhaus
Breathing lung-on-a-chip is a microfluidic three-dimensional device that reconstructs the microarchitecture and dynamic microenvironment of the alveolar-capillary unit of the living human lung. This micro-engineered lung model consists of a thin 10 µm microporous elastomeric membrane, which divides the air and blood chambers. In the upper chamber, the membrane is covered by human alveolar epithelial cells, whereas the membrane of the lower chamber is coated by pulmonary microvascular endothelial cells. To mimic the alveolar air space more realistically, the alveolar epithelial cells are exposed to air creating an air-liquid interface and breathing movements are introduced. During normal inspiration, the alveoli of the human lung will expand; this has been mimicked by a computer controlled cyclic stretching of the membrane with its adherent cell layer (Esch et al. 2015); however, this model lacks to incorporate changes in air flow and air pressure (Huh et al. 2010; Huh 2015). The lung-on-a-chip approach showed inflammatory responses to an induced alveolar bacterial infection. In addition, lung diseases such as pulmonary edema can be emulated (Huh et al. 2010; Esch et al. 2015). The suitability of this model to also probe for biopharmaceutical aspects of inhalation drug therapy still needs to be demonstrated.
3D models as tools for inhaled drug development
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Sally-Ann Cryan, Jennifer Lorigan, Cian O’Leary
In the past few years, research into the organ-on-a-chip microfluidic platform technology has significantly expanded. Novel microfluidic approaches have led to the creation of lung-on-a-chip technology to model the bronchoalveolar region. Chip platforms are microengineered biomimetic systems that represent key functional units of living human organs. They often consist of transparent 3D polymeric microchannels lined by living human cells and replicate three important aspects of intact organs: the 3D microarchitecture defined by the spatial distribution of multiple tissue types; functional tissue–tissue interfaces; and complex organ-specific mechanical and biochemical microenvironments, as reviewed in (109). As such, these systems are more integrated than the 2D models because they provide more detailed information about inflammatory responses and drug uptake (110,111).
Real-Time Physiological Data Collection and Analysis in Animal Inhalation Models: Predictive and Diagnostic Implications
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Benjamin Wong, Bryan. J. McCranor, Lewandowski Lewowski, Alfred. M. Sciuto
Alternatively, non-animal models for inhalation exposure exist, although the scope of their application is often inherently limited by their reduction of systemic physiology to isolated reference points. The function of any organ system is not solely reflective of its constituent organs but of the entire organism. While many advances have been made in the field of in vitro “organ/organoid-on-a-chip” technology, in which several cell types are seeded on a shared two- or three-dimensional surface, the lung-on-a-chip is a tool designed for “enhancing in vitro cell culture models for improving predictions about chemical toxicity and/or efficacy and [gaining] mechanistic insights into lung pathophysiology” (Salem and Katz, 2014). Clearly, these models do not accurately replicate real-time respiratory homeostasis. For example, the lung-on-a-chip is also currently incapable of modeling inhalation threats that compromise pulmonary and/or respiratory equilibrium through multi-organ system failure. One excellent example is the metabolic poison phosphine. Acute inhalation of phosphine does not induce histopathological damage to pulmonary tissue; however, it is capable of severely compromising mitochondrial, cardiac, and respiratory function (Wong et al., 2017). Thus, a lung-on-a-chip model that cannot account for alternate target organs or the complex interaction between target organs would severely underestimate the toxicity of phosphine and provide little useful toxicological information. Advances have also been made in computational and bioengineered lungs (Patel et al., 2012), but the general consensus is that substantial advances in tissue engineering and biocompatible materials must be made to overcome the challenges of building an integrated, multi-system model that is both accurate and precise. In silico and bioengineered systems are currently incapable of accurately replacing in vivo animal models, but advances in data collection and analysis techniques within existing animal inhalation models will be one step toward that goal.
Design of a microfluidic lung chip and its application in assessing the toxicity of formaldehyde
Published in Toxicology Mechanisms and Methods, 2023
Man Su, Xiang Li, Zezhi Li, Chenfeng Hua, Pingping Shang, Junwei Zhao, Kejian Liu, Fuwei Xie
Lung-on-a-chip models can simulate the lung’s microenvironment and functions in vivo, and have great application value for respiratory disease research, drug screening, toxicity assessment and other aspects (Nawroth et al. 2020; Francis et al. 2022; Li et al. 2022; Xia et al. 2023). The physiological microenvironment of the lung is very complex (Martinez et al. 2011). In order to simulate the physiological microenvironment realistically, Sakolish et al. (Sakolish et al. 2022) designed a microfluidic device. It could realize the co-culture of primary human small airway epithelial cells and lung microvascular endothelial cells, which recreates the parenchymal-vascular interface in the end of lung tissue. Varone et al. from Emulate Inc. (Varone et al. 2021) developed a novel organ-chip system that emulates three-dimensional architecture of the human epithelia, and the chip also has mechanical forces function including mechanical stretch and fluidic shear stress. Compared to the chip designed by Varone et al. our chip has no physical forces function. Indeed, the tissue-relevant mechanical forces acting on the chip is a critical element for biomimetic reconstruction of native tissue. Nevertheless, the advantage of the chip we designed is that multiple concentration gradients of gas and liquid can be achieved, as well as air-liquid interface exposure.
Discovery of CFTR modulators for the treatment of cystic fibrosis
Published in Expert Opinion on Drug Discovery, 2021
Miquéias Lopes-Pacheco, Nicoletta Pedemonte, Guido Veit
To more closely mimic the lung environment in vitro, lung-on-a-chip devices have been constructed. First systems, combining a differentiated, mucociliary bronchiolar epithelium and an underlying microvascular endothelium that experiences fluid flow, were used to study the drug-sensitive cytokine secretion in asthma and chronic obstructive pulmonary disease [189]. Recent iterations of such systems included human lung fibroblasts embedded in extracellular matrix in a 96-well plate that could support medium throughput compound screening approaches [190] (Figure 3C). Using this lung-on-a-chip system, Mejías and collaborators showed increased neutrophil recruitment into the microvascular compartment if CF HBE were used in the epithelial layer [190]. The prospect of lung-on-a-chip systems is to replace animal models [191], which bears particular relevance for CF, since rodent models do not recapitulate all aspects of the lung disease [192,193].