Capturing the Onset of Bacterial Pulmonary Infection in Acini-On-Chips

Bacterial invasion of the respiratory system leads to complex immune responses. In the deep alveolar regions, the first line of defense includes foremost the alveolar epithelium, consisting of alveolar type I and type II cells, the surfactant-rich liquid lining and alveolar macrophages. Typical in vitro models come short of mimicking the complexity of the airway environment in the onset of airway infection; amongst other, they neither capture the relevant anatomical features nor the physiological flows innate of the acinar milieu. Here, we present novel microfluidic-based acini-on-chips that mimic more closely the native acinar airways at true scale with an anatomically-inspired, multi-generation alveolated tree and deliver an inhalation-like maneuver. Composed of human Alveolar Epithelial Lentivirus immortalized (hAELVi) cells and differentiated macrophages-like human THP-1 cells at an air-liquid interface (ALI), our models maintain critically an epithelial barrier with immune function. To demonstrate, the usability and versatility of our in vitro platforms, we recapitulate a realistic inhalation exposure assay mimicking bacterial infection, whereby the alveolar epithelium is exposed to lipopolysaccharides (LPS)-laden droplets directly aerosolized and the innate immune response is assessed by monitoring the secretion of IL8 cytokines. The present platforms offer robust benchmarking assays for future efforts with more complex human primary cells. These efforts underscore the potential to deliver advanced in vitro biosystems that can provide new insights into drug screening as well as acute and sub-acute toxicity assays.