Engineering extracellular environments to study and treat lung pathologies

Lung disease is the third leading cause of death worldwide. The only curative intervention for end-stage lung disease is lung transplantation, which remains limited by the shortage of viable donor organs. Strategies to improve outcomes for patients with end-stage lung disease include: (i) ex vivo recovery of initially unusable donor lungs to a level suitable for transplantation, and (ii) repair of damaged lungs in situ to avoid the need for transplantation. Recovery of damaged lungs both ex vivo and in situ necessitates precise regulation of the lung extracellular environment, which includes biochemical, physical, and mechanical stimuli across scales. This thesis describes the development of bioengineering tools, including bioreactors and biomaterials, that leverage the lung extracellular environment across cellular, tissue, and organ scales to: (i) recover whole injured donor lungs ex vivo, (ii) assess and repair regional lung tissue injury in situ, and (iii) study the pathological cellular microenvironment in cystic fibrosis. In Chapter 1, regulation of the organ macroenvironment (ventilation, perfusion, systemic metabolism) with a homeostatic cross-circulation bioreactor enabled up to 100 hours of ex vivo lung support and recovery of injured human donor lungs. In Chapter 2, quantitative analysis of localized lung tissue properties, including lung sounds, enabled detection and assessment of pulmonary air leak, and recapitulation of lung microenvironmental features (structure, mechanics, composition) in a therapeutic biomaterial sealant enabled rapid treatment of air leaks. In Chapter 3, the first quantitative characterization of the cystic fibrosis matrisome (matrix proteome) identified pathological alterations to the microenvironment, and investigated implications for inflammation and immunity in cystic fibrosis. Collectively, these studies demonstrate that macro- and microenvironmental signals, including ventilation and perfusion mechanics, homeostatic metabolic regulation, and extracellular matrix structure and composition, can be leveraged to reveal previously unknown drivers of disease and promote recovery and repair of damaged lungs.