Matched-Comparative Modeling of Normal and Diseased Human Airway Responses Using a Microengineered Breathing Lung Chip

Abstract

Smoking represents a major risk factor for chronic obstructive pulmonary disease (COPD), but it is difficult to characterize smoke-induced injury responses under physiological breathing conditions in humans due to patient-to-patient variability. Here, we show that a small airway-on-a-chip device lined by living human bronchiolar epithelium from normal or COPD patients can be connected to an instrument that "breathes" whole cigarette smoke in and out of the chips to study smoke-induced pathophysiology in vitro. This technology enables true matched comparisons of biological responses by culturing cells from the same individual with or without smoke exposure. These studies led to identification of ciliary micropathologies, COPD-specific molecular signatures, and epithelial responses to smoke generated by electronic cigarettes. The smoking airway-on-a-chip represents a tool to study normal and disease-specific responses of the human lung to inhaled smoke across molecular, cellular and tissue-level responses in an organ-relevant context.

Biomimicry, Biofabrication, and Biohybrid Systems: The Emergence and Evolution of Biological Design

“…Ingber and co-workers have, for example, used their lung-on-a-chip model to investigate how cigarette smoke affects lung physiology at the molecular, cellular, and organ levels. [96] Similar studies studying disease onset in other engineered tissues and organoids, such as skeletal muscle, brain, gut, kidney, and liver, have likewise contributed significantly to the scientific community's understanding of biological design principles. [97][98][99] …”

Developmentally inspired human ‘organs on chips’

“…For example, fibroblasts have been integrated in a model of early stage human breast cancer (Choi et al, 2015). Most importantly, these more-complex organ chips with tissuetissue interfaces offer a much higher level of physiological mimicry for human organ function than most other multiphysiological systems, as they have been repeatedly shown to replicate results from healthy and diseased animal models Benam et al, 2016a;Jain et al, 2018), and even results from human studies (Benam et al, 2016b;Barrile et al, 2018). They should not be viewed as replacements for other culture models; instead, they should be viewed as alternatives to animal models and integrated into laboratories as a form of preclinical testing that more closely approximates human experimentation in vitro.…”

Best of Milan 2017—ERS Lung Science Conference session “Lung tissue repair and remodeling in chronic lung diseases: mechanisms and therapeutic approaches”

“…Additionally, complex biological processes such as neutrophil recruitment, rolling and adhesion can be investigated by introducing primary human neutrophils to the 'blood channel' (10). Furthermore, the system allows researchers to measure cytokine secretion and lately also trans-epithelial electrical resistance (TEER) (11) in real-time after application of stimuli such as IL-13 treatment to mimic asthma (10), cigarette smoke exposure (12) or viral and bacterial infections (10).…”