E‐FLOAT: Extractable Floating Liquid Gel‐Based Organ‐on‐a‐Chip for Airway Tissue Modeling under Airflow

Abstract

Microfluidic lung‐on‐a‐chip systems are increasingly attractive tools for studying lung physiology and function because of their ability to accurately recapitulate spatiotemporal features of the airway tissue microenvironment including cellular organization, tissue architecture, and mechanical cues such as cyclic stretching and airflow. However, most lung‐on‐a‐chip devices to date rely on integrated design elements like membranes for airway cell culture, and focus mainly on enabling on‐chip monitoring and analysis while neglecting the need for off‐chip analysis. Here, an extractable floating liquid‐gel‐based organ‐on‐a‐chip for airway tissue modeling referred to as “E‐FLOAT” is described that is arrayable, scalable, and uniquely amenable to withstand physiologic airflow by microanchors. It is shown that E‐FLOAT can be combined with a custom airflow system that permits controlled injection of particulate matter for air pollution studies. Results show that airflow is critical to efficiently achieving physiologic mimicry of airway epithelium composition, tight junction expression, mucus production, and cilia formation on epithelial cells. It is also shown that E‐FLOAT allows standard on‐chip analysis while permitting complete sample extraction and off‐chip analysis via immunocytochemistry, microscopy, and histological sectioning and staining, thereby expanding the number and types of biological assays that can be used and questions that can be tackled.

Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases

“…OOC systems comprise a class of micro-engineered devices that combine biomaterials, three-dimensional (3D) cell culture, and microfluidics within the internal device architecture to recapitulate native tissue microenvironments in vitro and mimic physiological tissue-and organ-level functions 7 . OOCs have been developed to model lung alveoli 8 , lung airways 9,10 , gastrointestinal 11 , liver, kidney, pancreas, and heart tissues 12,13 in both normal and diseased states, with research developing rapidly for other organs as well as toward multi-organ systems.…”

Next‐generation preclinical models of lung development, physiology and disease

“…[50] Building on this platform, Park et al developed an extractable floating liquid-gel-based organ-on-a-chip, which enabled airflow through the airway channel, by using micropillars to stabilize the hydrogel (Figure 3H). [45] This study highlighted the importance of airflow-induced shear stress in driving epithelial differentiation for the first time and showed that a two-day culture at air-liquid interface followed by 2 days of airflow was sufficient for mature cilia formation and mucus production, exceeding the differentiation potential of long-term culture at the air-liquid interface. Additionally, this design has the advantage of sample extraction for downstream analysis and works toward higher throughput and mass manufacturing, a crucial milestone for drug discovery applications.…”

“…[43] (G) Schematic design and fabrication of a vascularized airway-on-a-chip, where a naturally driven vascular network is formed by 3D printing of endothelial cells and fibroblasts-embedded bioink and subsequently integrated with airway epithelium on a dECM-coated membrane. [44] (H) Schematic of an extractable floating liquid gelbased airway-on-a-chip grown under airflow [45] stimulation, the underlying vascular network was activated, as evidenced by the upregulation of intercellular adhesion molecules (ICAM-1), subsequently promoting the recruitment of circulating neutrophils, their migration across vascular channels to the epithelium, and, ultimately, phagocytosis of bacterial pathogens. This bioinspired microsystem was the first demonstration of mechanically active organ-on-a-chip devices and demonstrated the potential of organ-on-a-chip platforms for modelling lung physiology in vitro.…”

“…Additionally, this design has the advantage of sample extraction for downstream analysis and works toward higher throughput and mass manufacturing, a crucial milestone for drug discovery applications. [45,50]…”

Bidirectional airflow in lung airway-on-a-chip with matrix-derived membrane elicits epithelial glycocalyx formation

“…The airway-on-a-chip device used in this study was a modified version of the E-FLOAT device described previously, 51 with new geometric structures to enable thin membrane formation. In this paper, E-FLOAT refers in all instances to the previously published device using a thick extractable gel, whereas any mention of a new device pertains to UMM with a thin membrane.…”