Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Regeneration and orthotopic transplantation of a bioartificial lung


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Perfusion decellularization of whole rat lungs.
Figure 2: Histology of regenerated lung constructs.
Figure 3: Protein analysis, morphometry and stereology of regenerated lung constructs.
Figure 4: In vitro functional testing of regenerated lung constructs.
Figure 5: Orthotopic transplantation and in vivo function.


  1. Anonymous. National Health Interview Survey 1982–1996 (National Center for Health Statistics, 2004).

  2. Anonymous. Deaths: Final Data for 2002 (National Vital Statistics System, 2004).

  3. Ng, C.Y., Madsen, J.C., Rosengard, B.R. & Allan, J.S. Immunosuppression for lung transplantation. Front. Biosci. 14, 1627–1641 (2009).

    Article  CAS  Google Scholar 

  4. Nichols, J.E., Niles, J.A. & Cortiella, J. Design and development of tissue engineered lung: Progress and challenges. Organogenesis 5, 57–61 (2009).

    Article  Google Scholar 

  5. Nichols, J.E. & Cortiella, J. Engineering of a complex organ: progress toward development of a tissue-engineered lung. Proc. Am. Thorac. Soc. 5, 723–730 (2008).

    Article  Google Scholar 

  6. Sugihara, H., Toda, S., Miyabara, S., Fujiyama, C. & Yonemitsu, N. Reconstruction of alveolus-like structure from alveolar type II epithelial cells in three-dimensional collagen gel matrix culture. Am. J. Pathol. 142, 783–792 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Olsen, C.O., Isakson, B.E., Seedorf, G.J., Lubman, R.L. & Boitano, S. Extracellular matrix-driven alveolar epithelial cell differentiation in vitro. Exp. Lung Res. 31, 461–482 (2005).

    Article  CAS  Google Scholar 

  8. Mondrinos, M.J., Koutzaki, S., Lelkes, P.I. & Finck, C.M. A tissue-engineered model of fetal distal lung tissue. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L639–L650 (2007).

    Article  CAS  Google Scholar 

  9. Chen, P., Marsilio, E., Goldstein, R.H., Yannas, I.V. & Spector, M. Formation of lung alveolar-like structures in collagen-glycosaminoglycan scaffolds in vitro. Tissue Eng. 11, 1436–1448 (2005).

    Article  CAS  Google Scholar 

  10. Mondrinos, M.J. et al. Engineering three-dimensional pulmonary tissue constructs. Tissue Eng. 12, 717–728 (2006).

    Article  CAS  Google Scholar 

  11. Mondrinos, M.J. et al. In vivo pulmonary tissue engineering: contribution of donor-derived endothelial cells to construct vascularization. Tissue Eng. Part A 14, 361–368 (2008).

    Article  CAS  Google Scholar 

  12. Andrade, C.F., Wong, A.P., Waddell, T.K., Keshavjee, S. & Liu, M. Cell-based tissue engineering for lung regeneration. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L510–L518 (2007).

    Article  CAS  Google Scholar 

  13. Suki, B., Ito, S., Stamenovic, D., Lutchen, K.R. & Ingenito, E.P. Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces. J. Appl. Physiol. 98, 1892–1899 (2005).

    Article  Google Scholar 

  14. Coraux, C. et al. Embryonic stem cells generate airway epithelial tissue. Am. J. Respir. Cell Mol. Biol. 32, 87–92 (2005).

    Article  CAS  Google Scholar 

  15. Reynolds, S.D. et al. Conditional stabilization of beta-catenin expands the pool of lung stem cells. Stem Cells 26, 1337–1346 (2008).

    Article  CAS  Google Scholar 

  16. Cortiella, J. et al. Tissue-engineered lung: an in vivo and in vitro comparison of polyglycolic acid and pluronic F-127 hydrogel/somatic lung progenitor cell constructs to support tissue growth. Tissue Eng. 12, 1213–1225 (2006).

    Article  CAS  Google Scholar 

  17. Loi, R., Beckett, T., Goncz, K.K., Suratt, B.T. & Weiss, D.J. Limited restoration of cystic fibrosis lung epithelium in vivo with adult bone marrow-derived cells. Am. J. Respir. Crit. Care Med. 173, 171–179 (2006).

    Article  CAS  Google Scholar 

  18. Kim, C.F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    Article  CAS  Google Scholar 

  19. Giangreco, A., Reynolds, S.D. & Stripp, B.R. Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am. J. Pathol. 161, 173–182 (2002).

    Article  Google Scholar 

  20. Kotton, D.N. et al. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 128, 5181–5188 (2001).

    CAS  PubMed  Google Scholar 

  21. Pereira, R.F. et al. Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc. Natl. Acad. Sci. USA 92, 4857–4861 (1995).

    Article  CAS  Google Scholar 

  22. Ott, H.C. et al. Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008).

    Article  CAS  Google Scholar 

  23. Uygun, B.E. et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat. Med. 16, 814–820 (2010).

    Article  CAS  Google Scholar 

  24. Macchiarini, P. et al. Clinical transplantation of a tissue-engineered airway. Lancet 372, 2023–2030 (2008).

    Article  Google Scholar 

  25. Ochs, M. et al. The number of alveoli in the human lung. Am. J. Respir. Crit. Care Med. 169, 120–124 (2004).

    Article  Google Scholar 

  26. Park, K.S. et al. Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 34, 151–157 (2006).

    Article  CAS  Google Scholar 

  27. Xu, J., Liu, M., Tanswell, A.K. & Post, M. Mesenchymal determination of mechanical strain-induced fetal lung cell proliferation. Am. J. Physiol. 275, L545–L550 (1998).

    CAS  PubMed  Google Scholar 

  28. Samadikuchaksaraei, A. et al. Derivation of distal airway epithelium from human embryonic stem cells. Tissue Eng. 12, 867–875 (2006).

    Article  CAS  Google Scholar 

  29. Kim, D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4, 472–476 (2009).

    Article  CAS  Google Scholar 

  30. Cortiella, J. et al. Influence of acellular natural lung matrix on murine embryonic stem cell differentiation and tissue formation. Tissue Eng. Part A published online, doi:10.1089/ten.tea.2009.0730 (23 April 2010).

  31. Kitterman, J.A. The effects of mechanical forces on fetal lung growth. Clin. Perinatol. 23, 727–740 (1996).

    Article  CAS  Google Scholar 

  32. Weibel, E.R. & Knight, B.W. A morphometric study on the thickness of the pulmonary air-blood barrier. J. Cell Biol. 21, 367–396 (1964).

    Article  CAS  Google Scholar 

  33. Cowan, G.M. Jr., Staub, N.C. & Edmunds, L.H., Jr. Changes in the fluid compartments and dry weights of reimplanted dog lungs. J. Appl. Physiol. 40, 962–970 (1976).

    Article  Google Scholar 

  34. Soccal, P.M. et al. Matrix metalloproteinases correlate with alveolar-capillary permeability alteration in lung ischemia-reperfusion injury. Transplantation 70, 998–1005 (2000).

    Article  CAS  Google Scholar 

Download references


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).

Author information

Authors and Affiliations



H.C.O. conceived, designed and oversaw all of the studies, collection of results, interpretation of the data and writing of the manuscript. He was responsible for the primary undertaking, completion and supervision of all experiments. B.C. was responsible for cell culture and preparation of cell suspensions. C.S. characterized fetal lung cells. C.C. assisted in animal surgeries. I.P. provided advice on animal protocols and histology techniques. L.I. performed immunohistochemistry. D.K. provided input on developmental aspects and reviewed and edited the manuscript. J.P.V. provided input on tissue engineering aspects and reviewed and edited the manuscript.

Corresponding author

Correspondence to Harald C Ott.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Methods (PDF 703 kb)

Supplementary Video 1

Initiation of dry ventilation of a regenerated lung construct. (MOV 1075 kb)

Supplementary Video 2

Blood perfusion and ventilation of a regenerated lung construct. (MOV 1190 kb)

Supplementary Video 3

Orthotopic transplantation of a regenerated left lung construct. (MOV 3865 kb)

Supplementary Video 4

Fluoroscopy after orthotopic transplantation of a regenerated left lung construct. (MOV 1771 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ott, H., Clippinger, B., Conrad, C. et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 16, 927–933 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research