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Cross-circulation for extracorporeal support and recovery of the lung

Nature Biomedical Engineering volume 1, Article number: 0037 (2017) Cite this article

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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.

End-stage lung disease has a profound socioeconomic impact and remains the third leading cause of death worldwide1,2. Lung transplantation represents the only curative intervention. However, donor organ demand far exceeds supply3, and due to stringent listing criteria, the actual demand is probably underestimated. Currently, four out of five donor lungs are deemed unacceptable for transplantation at the time of donation4, making lung the least utilized solid organ and necessitating the increasing use of extracorporeal membrane oxygenation as a bridge-to-transplant for critically ill patients4–8.

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Figure 1: Experimental procedure and extracorporeal lung maintenance strategy.
Figure 2: Management of pulmonary venous drainage and utilization of donor vessel as a bio-bridge.
Figure 3: Recipient safety and stability throughout 36 h of cross-circulation support.
Figure 4: Extracorporeal lung stability and performance during prolonged maintenance and ischaemic recovery.
Figure 5: Analysis of extracorporeal lungs in prolonged maintenance group.
Figure 6: Extracorporeal recovery and maintenance of injured lungs.
Figure 7: Demonstration of multiscale interventions in extracorporeal lungs.

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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.

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Author notes

  1. John D. O’Neill and Brandon A. Guenthart: These authors contributed equally to this work.

Authors and 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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  1. John D. O’Neill
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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.

Corresponding authors

Correspondence to Matthew Bacchetta or Gordana Vunjak-Novakovic.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary text, figures and tables. (PDF 8336 kb)

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. (MOV 25221 kb)

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). (MP4 10158 kb)

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. (MOV 2302 kb)

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. (MOV 26628 kb)

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O’Neill, J., Guenthart, B., Kim, J. et al. Cross-circulation for extracorporeal support and recovery of the lung. Nat Biomed Eng 1, 0037 (2017). https://doi.org/10.1038/s41551-017-0037

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