A Biomimetic Human Lung‐on‐a‐Chip with Colorful Display of Microphysiological Breath

Abstract

Lung‐on‐a‐chip models hold great promise for disease modeling and drug screening. Herein, inspired by the iridescence phenomenon of soap bubbles, a novel biomimetic 3D microphysiological lung‐on‐a‐chip system with breathing visualization is presented. The system, with an array of pulmonary alveoli at the physiological scale, is constructed and coated with structural color materials. Cyclic deformation is induced by regular airflow, resembling the expansion and contraction of the alveoli during rhythmic breathing. As the deformation is accompanied with corresponding synchronous shifts in the structural color, the constructed system offers self‐reporting of the cell mechanics and enables real‐time monitoring of the cultivation process. Using this system, the dynamic relationships between the color atlas and disease symptoms, showing the essential role of mechanical stretching in the phenotypes of idiopathic pulmonary fibrosis, are investigated. These features make this human lung system ideal in biological study, disease monitoring, and drug discovery.

Real‐Time Measurement of Cell Mechanics as a Clinically Relevant Readout of an In Vitro Lung Fibrosis Model Established on a Bioinspired Basement Membrane

“…Albeit the reported stiffness is only an apparent elastic modulus, the fact that we can detect changes in membrane stiffness due to the presence of cells (Figure 3h) or profibrotic stimulation of primary fibroblasts (Figure 3k) is indirect evidence that the elastic modulus of the BETA membrane is of similar magnitude as that of in vitro cell culture models of the lung, which has been reported to be 0.74-1.02 and 2.44-3.31 kPa for fibroblasts from healthy patients with and without TGF-β1 stimulation, respectively. [50] Our novel method to measure the cell stiffness via the differential pressure across a mechanoactivated membrane-not just pressure change on one side of the membrane as implemented in the other lung model [11] -combined with our highly elastic membrane allows for real-time monitoring of the formation of ECM proteins and tissue compliance. It is important to note that currently available literature data on the measurement of cell stiffness mostly rely on the atomic-force-microscope-based method, which represents a highly localized measurement rather than an entire cell layer as described in this study.…”

“…[27] Over the last decades, numerous preclinical in vitro models of the lung have been developed, trying to resemble the morphological and functional features of the human lung. [4,5,9,11,12,[28][29][30] However, more than ≈95% of the previously reported in vitro studies of IPF rely on a monoculture of epithelial or fibroblast cells cultured on rigid substrates without considering the significance of substrate elasticity and mechanical strain on the fibrotic phenotype of cell culture models. [8,9,31,32] Among the remaining ≈5% of the IPF models, some incorporated elastic substrates and cyclic stretch in a monoculture model.…”

“…systems leveraging new techniques such as hydrogel/organoid to mimic substrate stiffness and cell microenvironments, [7,10] integration of mechanical forces due to cyclic stretch using organ-chip platforms on poly(dimethylsiloxane) (PDMS) membranes, [5,[11][12][13] and establishing multiple coculture models. [14] Nevertheless, the lack of sufficiently complex in vitro models and the high propensity of failure of successfully preclinically tested agents in animal and human studies due to unreliable in vitro-in vivo translation, emphasizes an urgent need for the development of realistic, and human-based alternative preclinical in vitro cell models with clinically relevant functional readouts for lung fibrosis.…”

Integrated biosensors for monitoring microphysiological systems

“…136 For cardiac and neural tissue, another important parameter is their electrical activity, which indicates myocardial and neural functions. 137 In this context, researchers have developed microfluidic heart-on-a-chip models for real-time recording of electrophysiological signals from cardiac tissues. In most cases, the electrode signals were measured with micro-electrode arrays (MEAs), on which cells were cultured.…”

Highway to heal: Influence of altered extracellular matrix on infiltrating immune cells during acute and chronic lung diseases

“…Inclusion of respiratory mechanics associated with breathing and blood flow also poses a challenge while modeling these systems. One such event is cyclic deformations which have been mimicked in lung-on-chip models recently ( Kumar et al, 2022 ; Zhu et al, 2022 ). Including cyclic deformations in the state-of-the-art ECM-based migration models would increase the translational capacity of the models and bring them one step closer to in vivo .…”