Exposure on a chip to better design aerosolised drug delivery deep into the lungs

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It is not known how the structure and function of the fragile alveolar epithelial-capillary endothelial barrier and its crosstalk between the juxtaposed tissue layers confers the essential integrity and selective permeability to protect us. We hypothesise that respiratory barrier integrity and function critically depends on effective communication between the juxtaposed alveolar epithelium and alveolar endothelium. If this communication is compromised due to external (e.g., inhaled toxins) or endogenous (e.g., changes in blood flow/pressure-shear) factors, there will be loss of barrier integrity and increased permeability. Our understanding at the molecular level could be enhanced using mechanistic in vitro studies; but this is hampered by the lack of relevant in vitro models in combination with advanced quantitative imaging techniques to measure real-time molecular interactions. The main aim of our proposal is to develop a unique and flexible dynamic microfluidic 3D tissue model of the human alveolar gas-blood interface coupled into an advanced imaging platform, capable of resolving live-cell events in real-time (4D) at the nanoscale and, simultaneously, to monitor the functional integrity and permeability of the transepithelial/transendothelial barrier under proinflammatory conditions and physiological stress (these will be carried out by generating an injury to the 3D complex cellular model in the AOC). For this purpose, we will integrate a microfluidic AOC into a high-resolution live-cell imaging platform (AOC-HRIP) to study respiratory pathophysiological scenarios. Our AOC-HRIP model will i) handle physiologically 3D stratified and interconnected human respiratory barrier models; ii) monitor functional barrier integrity and permeability; and iii) will follow the molecular mechanisms involved in real-time at the correct length and time scales at different exposure and breathing regimes.