This study explores the potential of tissue-engineered lungs for in vivo implantation. The researchers decellularized adult rat lungs, removing cellular components while preserving the extracellular matrix (ECM) that retains the hierarchical branching structures of airways and vasculature. They then seeded pulmonary epithelium and vascular endothelium onto the acellular lung matrix using a bioreactor that mimics fetal lung environment, including vascular perfusion and liquid ventilation. The engineered lungs displayed hierarchical organization and efficient repopulation of the vascular compartment. In vitro, the mechanical characteristics of the engineered lungs were similar to native lung tissue. When implanted into rats for short periods (45 to 120 minutes), the engineered lungs participated in gas exchange. These results suggest that repopulation of lung matrix is a viable strategy for lung regeneration, though further improvements are needed to enhance alveolar barrier function, surfactant production, and vascular endothelial coverage. The study also demonstrates the feasibility of applying these techniques to human lung tissues.This study explores the potential of tissue-engineered lungs for in vivo implantation. The researchers decellularized adult rat lungs, removing cellular components while preserving the extracellular matrix (ECM) that retains the hierarchical branching structures of airways and vasculature. They then seeded pulmonary epithelium and vascular endothelium onto the acellular lung matrix using a bioreactor that mimics fetal lung environment, including vascular perfusion and liquid ventilation. The engineered lungs displayed hierarchical organization and efficient repopulation of the vascular compartment. In vitro, the mechanical characteristics of the engineered lungs were similar to native lung tissue. When implanted into rats for short periods (45 to 120 minutes), the engineered lungs participated in gas exchange. These results suggest that repopulation of lung matrix is a viable strategy for lung regeneration, though further improvements are needed to enhance alveolar barrier function, surfactant production, and vascular endothelial coverage. The study also demonstrates the feasibility of applying these techniques to human lung tissues.