Microphysiological ("organ-on-a-chip") models of pulmonary infections for developing novel anti-infectives.

Infectious diseases are among the leading death causes globally, with the lung being particularly vulnerable due to its continuous exposure to inhaled pathogens. Yet, anti-infective research and drug development are hampered by the lack of models that accurately recapitulate the lung's complex immunological and pathophysiological responses to infections. Microphysiological ("organ-on-a-chip", OoC) models allow elegant incorporation of multiple cell types, biological barriers, mechanical stress and perfusion, not only in healthy, but also in diseased state. Besides enabling the evaluation of drug efficacy and safety, these models provide a platform to investigate host-pathogen interactions and their modulation by pharmaceutical interventions. This review examines microphysiological systems (MPS) designed to mimic pulmonary infections and highlights how these models capture key hallmarks of such diseases, including disruption of barrier integrity, changes of mucus, mucociliary clearance and surfactant, as well as the recruitment and stimulation of immune cells. Specific design considerations will be explained regarding the challenges of viral and bacterial pulmonary infections. Emphasis is further placed on how MPS may be implemented for repurposing established drugs, as well as for developing new small molecules, biologicals and delivery systems. Remaining challenges, such as incorporation of the microbiome, vaccine development and requirements for standardization and validation, are critically examined. These insights underscore the potential of MPS to bridge preclinical gaps in infection research, accelerate clinical translation, and guide the development of novel anti-infective drugs and delivery systems.