Article

Cross-circulation for extracorporeal support and recovery of the lung

  • Nature Biomedical Engineering 1, Article number: 0037 (2017)
  • doi:10.1038/s41551-017-0037
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Abstract

The shortage of transplantable donor organs has profound consequences, especially for patients with end-stage lung disease, for which transplantation remains the only definitive treatment. Although advances in ex vivo lung perfusion have enabled the evaluation and reconditioning of marginally unacceptable donor lungs, clinical use of the technique is limited to ~6 h. Extending the duration of extracorporeal organ support from hours to days would enable longer recovery and recipient-specific manipulations of the donor lung, with the goal of expanding the donor organ pool and improving long-term outcomes. By using a clinically relevant swine model, here we report the development of a cross-circulation platform wherein recipient support enabled 36 h of normothermic perfusion that maintained healthy lungs and allowed for the recovery of injured lungs. Extended support enabled multiscale therapeutic interventions in all extracorporeal lungs. Lungs exceeded transplantation criteria, and recipients tolerated cross-circulation with no significant changes in physiologic parameters throughout 36 h of support. Our findings suggest that cross-circulation should enable extended support and interventions in extracorporeal organs.

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Acknowledgements

The authors thank J. Sonett and A. Griesemer for discussions of the experimental design; D. Sachs for providing research swine; S. Halligan for administrative and logistical support; the Institute of Comparative Medicine veterinary staff, including K. Fragoso and A. Rivas, for their support with the animal studies; S. Ma for live cell imaging; B. Lee and H. Wobma for manuscript review; K. Brown and L. Cohen-Gould for TEM imaging; the Herbert Irving Comprehensive Cancer Center Molecular Pathology Shared Resources, including T. Wu, D. Sun and R. Chen for help with the analytics; M. Cheerharan, M. P. Salna and A. Taubman for experimental assistance; V. Dorrello for valuable discussions; J. Bernhard and J. Ng for providing mesenchymal cells; J. Bhattacharya for providing experimental reagents. The authors gratefully acknowledge funding support from the National Institutes of Health (grants HL134760, EB002520 and HL007854), the Richard Bartlett Foundation and the Mikati Foundation.

Author information

Author notes

    • John D. O’Neill
    •  & Brandon A. Guenthart

    These authors contributed equally to this work.

Affiliations

  1. Department of Biomedical Engineering, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • John D. O’Neill
    • , Brandon A. Guenthart
    • , Jinho Kim
    • , Dawn Queen
    •  & Gordana Vunjak-Novakovic
  2. Department of Surgery, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Brandon A. Guenthart
    • , Scott Chicotka
    •  & Matthew Bacchetta
  3. Department of Clinical Perfusion, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Kenmond Fung
  4. Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Charles Marboe
  5. Institute of Comparative Medicine, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Alexander Romanov
  6. Center for Human Development, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Sarah X. L. Huang
    • , Ya-Wen Chen
    •  & Hans-Willem Snoeck
  7. Department of Medicine, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Sarah X. L. Huang
    • , Ya-Wen Chen
    • , Hans-Willem Snoeck
    •  & Gordana Vunjak-Novakovic
  8. Center for Translational Immunology, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Hans-Willem Snoeck
  9. Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, New York 10032, USA

    • Hans-Willem Snoeck

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Contributions

J.D.O., B.A.G., J.K., S.C., D.Q., K.F., A.R. and M.B. performed the experiments. S.X.L.H. provided the human lung stem cells and experimental reagents. Y.-W.C. performed the live imaging. C.M. performed the blinded pathologic assessment. J.D.O., B.A.G., H.-W.S., M.B. and G.V.-N. co-analysed the data. J.D.O., B.A.G., H-W.S., M.B. and G.V.-N co-wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Matthew Bacchetta or Gordana Vunjak-Novakovic.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary text, figures and tables.

Videos

  1. 1.

    Supplementary Video 1

    Time-lapse footage (1 frame per minute) of the extracorporeal lung, recipient vitals (top right panel), and perfusion data showing the trans-pulmonary pressure gradient (bottom right panel), from cannulation through 36 hours of cross-circulation.

  2. 2.

    Supplementary Video 2

    Bronchoscopic video obtained on an ischemic recovered lung. Video obtained at the start of cross-circulation (left panel; demonstrating pulmonary edema), and video obtained at the conclusion of 36 hours of extracorporeal support (right panel; demonstrating intact bronchial microvasculature and the absence of airway edema and secretions).

  3. 3.

    Supplementary Video 3

    Real-time transpleural video surveillance of near-infrared (NIR)-labelled cells delivered into the extracorporeal lung. The transpleural imaging system allows the lung to be ventilated while imaging.

  4. 4.

    Supplementary Video 4

    Live cilia imaging demonstrating coordinated ciliary beating via the movement of fluorescent microbeads (diameter, 0.2 µm). Airway specimen obtained after 36 hours of cross-circulation support.