Investigating Microfluidic-Based Strategies in Developing a Versatile High Throughput In Vitro Model of the Alveolus for Studying Ventilator-Induced Lung Injury

Mechanical Mechanical ventilation has been a critical part of basic life support for many years, with almost one-third of all patients in the Intensive Care Unit requiring the aid. However numerous studies over the past two decades have indicated that ventilators have the potential to cause or aggravate lung injury leading to increased morbidity and sometimes mortality.;Scaling-down to physiological length scales is critical in achieving similar interplay among the biomechanical forces and their magnitude. The preliminary prototypes focused on microfluidic devices to optimize cell culture conditions with respect to long-term cell sustainability in terms of media turnover rates, viable monolayer formation and phenotype maintenance. The utility of these devices were demonstrated by evaluating cell viability, alveolar surfactant production and transepithelial permeability.;The later prototype, the pressure chip model, incorporated the ability to test the response of alveolar cells exposed to sustained periods of supra-physiological pressure while cultured at an air-liquid interface with constant air-flow on apical and media replenishment on basolateral surfaces. The in vitro evaluations of the alveolar A549 cells indicated higher surfactant production and lower cell layer permeability in air-exposed cultures compared to conventional submerged cultures. Also, the cell types, A549 and H441, both indicated a drop in their transepithelial electrical resistance readings hinting a disruption of the cell monolayer integrity in response to pressure application. These results exhibit a magnitude- and duration-dependant response among both the cell types. Additionally, dexamethasone (0.1muM) treatment yielded an alleviated response to excess pressure.;These studies highlight the versatility of the pressure-chip model as a tool for isolating and analyzing the primary interaction of compressive mechanical forces on alveolar epithelial cells.;The lung with its anatomically complex architecture and unique amalgam of cell types and interfaces is very difficult to replicate in vitro . This study is focused on mimicking the distal unit of the alveolus in developing an analytical platform for evaluating primary cellular interactions. The alveoli encompassing the gas-exchange surface experiences various biomechanical forces in an in vivo environment. Each of these individual forces effect varied cellular interaction and response. Thus a series of cell culture platforms were designed to investigate the progressive introduction of these physiologically-relevant environmental parameters towards building the experimental in vitro model of the alveolus for studying ventilator-induced lung injury (VILI).