About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with end-stage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cell-seeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient's circulation and ventilated by means of the recipient's airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation.
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We thank Harvard Apparatus Inc. for providing bioreactor components and, in particular, J. Consiglio, R. Zink and T. Beha for technical support. We thank J. Titus for assistance with animal surgeries and video recording. We further thank E. Bassett and D. Hoganson for their help with bioreactor parts and materials, A. Pardo for her technical support with western blots and K. Kulig for assistance with confocal microscopy. Electron microscopy was performed in the Microscopy Core of the Center for Systems Biology/Program in Membrane Biology, which is partially supported by Inflammatory Bowel Disease Grant DK43351 and Boston Area Diabetes and Endocrinology Research Center Award DK57521.This study was supported by a Faculty Development Grant provided by the Department of Surgery, Massachusetts General Hospital and by a Young Clinician Researcher Award granted by the Center for Integration of Medicine and Innovative Technology (CIMIT).
The authors declare no competing financial interests.
Supplementary Figures 1–4, Supplementary Methods (PDF 703 kb)
Initiation of dry ventilation of a regenerated lung construct. (MOV 1075 kb)
Blood perfusion and ventilation of a regenerated lung construct. (MOV 1190 kb)
Orthotopic transplantation of a regenerated left lung construct. (MOV 3865 kb)
Fluoroscopy after orthotopic transplantation of a regenerated left lung construct. (MOV 1771 kb)
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Ott, H., Clippinger, B., Conrad, C. et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16, 927–933 (2010). https://doi.org/10.1038/nm.2193
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