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Cross-circulation

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Cross-circulation
SpecialtyCardiac surgery, transplant medicine
UsesOpen-heart surgery, Organ preservation, Bioengineering

Cross-circulation is a medical technique in which the circulatory system of one individual is temporarily connected to and shared with that of another, typically to support or maintain physiological function in cases where one system alone would be insufficient. Initially pioneered in the 1950s by cardiac surgeon C. Walton Lillehei, cross-circulation allowed surgeons to perform open-heart surgery on infants and children before the development of reliable heart-lung machines. More recently, the concept has been adapted by researchers at Columbia University, Vanderbilt University, and the regenerative medicine company Xylyx Bio to rehabilitate injured donor organs and bioengineer transplantable grafts ex vivo.

History

Origins in cardiac surgery

In the early 1950s, open-heart surgery was limited by the lack of extracorporeal circulation technologies. In 1954, Dr. C. Walton Lillehei at the University of Minnesota introduced cross-circulation as a method to provide oxygenated blood to patients undergoing complex intracardiac repairs. In this procedure, the patient's circulation was temporarily connected to that of a healthy donor (often a parent), whose heart and lungs would maintain oxygenation and perfusion for both individuals during surgery.[1] This technique allowed for successful repair of congenital heart defects before the widespread availability of cardiopulmonary bypass machines.[2]

Although revolutionary, cross-circulation in its original form raised ethical and safety concerns due to the risks posed to healthy donors. It was largely replaced by mechanical heart-lung machines by the early 1960s.[3] Nevertheless, it marked a major milestone in the history of cardiac surgery and contributed to the evolution of extracorporeal support systems.

Modern applications in organ rehabilitation

Beginning in the 2010s, cross-circulation was re-envisioned as a platform to rehabilitate and regenerate donor organs outside the body. Drawing inspiration from the historic role of cross-circulation in cardiac surgery, researchers at Columbia University and Vanderbilt University pioneered a modern adaptation of the the technique to support and recover ex-vivo organs using a living swine host as physiologic support.[4][5] In this system, an extracorporeal circuit is established between an ex-vivo organ (e.g., lung, liver) and a swine host, allowing systemic regulation from the host to maintain organ homeostasis. This approach provides dynamic hormonal, immune, and metabolic regulation and support that cannot be replicated by conventional mechanical perfusion systems.[6]

Initial studies demonstrated normothermic support and preservation of ex-vivo lungs for 4 days[7] and the functional repair of ex-vivo lungs with ischemic, aspiration, or infectious injury that would otherwise be deemed unsuitable for transplant.[4][8] Innovations in cannulation strategies and circuit design were developed to optimize platform safety and scalability.[9] Through durable physiologic support and targeted therapeutic intervention, this platform facilitates active organ recovery, immune modulation, and functional regeneration.

In later work, researchers led by cardiothoracic surgeon Matthew Bacchetta and biomedical engineer Gordana Vunjak-Novakovic extended the technique to human donor organs using xenogeneic cross-circulation, where the swine host served as a systemic ‘xeno-support’ animal for an ex-vivo human donor organ.[10][11] These trailblazing studies garnered the attention of several mainstream media outlets.[12][13] Further studies examined immune interactions within this xenogeneic context, revealing an attenuated immune response and permissive environment for donor organ recovery.[14][15] Additional studies performed in collaboration with the regenerative medicine company Xylyx Bio confirmed that the platform enables rehabilitation of donor lungs using xeno-support without triggering hyperacute rejection in a human lung transplantation model, laying the groundwork for clinical translation.[16] The platform has since been refined with advanced ex-vivo organ assessment capabilities, integrating real-time monitoring, functional imaging, and molecular diagnostics to guide intervention and clinical decision-making.[17] This has broadened the platform’s potential to support a variety of donor organs – including kidneys, hearts, and vascularized composite allografts – under near-physiologic conditions for extended periods of time outside the body.

As of the mid-2020s, cross-circulation is emerging as a versatile tool in organ transplantation, bioengineering, and regenerative medicine.[18] It holds the potential to significantly expand the donor organ pool, enable therapeutic testing ex vivo, and support viable bioreactors for tissue engineering.

Applications

  • Cardiac surgery (historic): Temporary cardiopulmonary support for intracardiac procedures in infants and children.
  • Organ transplantation (modern): Rehabilitation and recovery of injured donor organs prior to transplantation.
  • Bioengineering: Maintenance of physiological conditions for the generation of bioengineered grafts and tissue constructs.

Advantages and limitations

Advantages

  • Enables physiological support of complex procedures without full reliance on mechanical systems.
  • Promotes tissue repair and immune regulation in organ rehabilitation.
  • Allows detailed study of organ physiology under near-normal conditions.

Limitations

  • Original human-to-human cross-circulation raised ethical concerns and donor risk.
  • Modern approaches rely on an animal host, raising translational and regulatory challenges.
  • Requires specialized facilities and interdisciplinary coordination.

See also

References

  1. ^ Gott, Vincent L.; Shumway, Norman E. (2004-03). "Cross-circulation: a milestone in cardiac surgery". The Journal of Thoracic and Cardiovascular Surgery. 127 (3): 617. doi:10.1016/j.jtcvs.2003.12.028. {{cite journal}}: Check date values in: |date= (help)
  2. ^ Lillehei, C. Walton (1955-05). "Controlled Cross Circulation for Direct-Vision Intracardiac Surgery: Correction of Ventricular Septal Defects, Atrioventricularis Communis, and Tetralogy of Fallot". Postgraduate Medicine. 17 (5): 388–396. doi:10.1080/00325481.1955.11708211. ISSN 0032-5481. {{cite journal}}: Check date values in: |date= (help)
  3. ^ Stoney, William S. (2009-06-02). "Evolution of Cardiopulmonary Bypass". Circulation. 119 (21): 2844–2853. doi:10.1161/CIRCULATIONAHA.108.830174. ISSN 0009-7322.
  4. ^ a b O’Neill, John D.; Guenthart, Brandon A.; Kim, Jinho; Chicotka, Scott; Queen, Dawn; Fung, Kenmond; Marboe, Charles; Romanov, Alexander; Huang, Sarah X. L.; Chen, Ya-Wen; Snoeck, Hans-Willem; Bacchetta, Matthew; Vunjak-Novakovic, Gordana (2017-03-06). "Cross-circulation for extracorporeal support and recovery of the lung". Nature Biomedical Engineering. 1 (3). doi:10.1038/s41551-017-0037. ISSN 2157-846X.
  5. ^ Wu, Wei Kelly; Tumen, Andrew; Stokes, John W.; Ukita, Rei; Hozain, Ahmed; Pinezich, Meghan; O’Neill, John D.; Lee, Michael J.; Reimer, Jonathan A.; Flynn, Charles R.; Talackine, Jennifer R.; Cardwell, Nancy L.; Benson, Clayne; Vunjak-Novakovic, Gordana; Alexopoulos, Sophoclis P. (2022-04). "Cross-Circulation for Extracorporeal Liver Support in a Swine Model". ASAIO Journal. 68 (4): 561–570. doi:10.1097/MAT.0000000000001543. ISSN 1058-2916. PMC 9984766. PMID 34352819. {{cite journal}}: Check date values in: |date= (help)
  6. ^ O'Neill, John D.; Guenthart, Brandon A.; Hozain, Ahmed E.; Bacchetta, Matthew (2022-04). "Xenogeneic support for the recovery of human donor organs". The Journal of Thoracic and Cardiovascular Surgery. 163 (4): 1563–1570. doi:10.1016/j.jtcvs.2021.07.055. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Hozain, Ahmed E.; Tipograf, Yuliya; Pinezich, Meghan R.; Cunningham, Katherine M.; Donocoff, Rachel; Queen, Dawn; Fung, Kenmond; Marboe, Charles C.; Guenthart, Brandon A.; O'Neill, John D.; Vunjak-Novakovic, Gordana; Bacchetta, Matthew (2020-04). "Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine". The Journal of Thoracic and Cardiovascular Surgery. 159 (4): 1640–1653.e18. doi:10.1016/j.jtcvs.2019.09.121. PMC 7094131. PMID 31761338. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Guenthart, Brandon A.; O’Neill, John D.; Kim, Jinho; Queen, Dawn; Chicotka, Scott; Fung, Kenmond; Simpson, Michael; Donocoff, Rachel; Salna, Michael; Marboe, Charles C.; Cunningham, Katherine; Halligan, Susan P.; Wobma, Holly M.; Hozain, Ahmed E.; Romanov, Alexander (2019-05-07). "Regeneration of severely damaged lungs using an interventional cross-circulation platform". Nature Communications. 10 (1). doi:10.1038/s41467-019-09908-1. ISSN 2041-1723. PMC 6504972. PMID 31064987.
  9. ^ Guenthart, Brandon A.; O’Neill, John D.; Bacchetta, Matthew (2022-11). "Cannulation Strategies in Ex Vivo Lung Perfusion". ASAIO Journal. 68 (11): e222 – e222. doi:10.1097/MAT.0000000000001621. ISSN 1058-2916. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Hozain, Ahmed E.; O’Neill, John D.; Pinezich, Meghan R.; Tipograf, Yuliya; Donocoff, Rachel; Cunningham, Katherine M.; Tumen, Andrew; Fung, Kenmond; Ukita, Rei; Simpson, Michael T.; Reimer, Jonathan A.; Ruiz, Edward C.; Queen, Dawn; Stokes, John W.; Cardwell, Nancy L. (2020-07). "Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs". Nature Medicine. 26 (7): 1102–1113. doi:10.1038/s41591-020-0971-8. ISSN 1078-8956. PMC 9990469. PMID 32661401. {{cite journal}}: Check date values in: |date= (help)
  11. ^ Wu, Wei Kelly; Ukita, Rei; Patel, Yatrik J.; Cortelli, Michael; Trinh, Vincent Q.; Ziogas, Ioannis A.; Francois, Sean A.; Mentz, Meredith; Cardwell, Nancy L.; Talackine, Jennifer R.; Grogan, William M.; Stokes, John W.; Lee, Youngmin A.; Kim, Jinho; Alexopoulos, Sophoclis P. (2023-09). "Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers". Hepatology. 78 (3): 820–834. doi:10.1097/HEP.0000000000000357. ISSN 0270-9139. PMC 10440302. PMID 36988383. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Kolata, Gina (2020-07-13). "In Astounding Test, Scientists Revive Damaged Lungs for Transplant". The New York Times. ISSN 0362-4331. Retrieved 2025-04-09.
  13. ^ Cooney, Elizabeth (2020-07-13). "Connecting donated human lungs to pigs repaired damage to the organs, scientists report". STAT. Retrieved 2025-04-09.
  14. ^ Wu, Wei K.; Stier, Matthew T.; Stokes, John W.; Ukita, Rei; Patel, Yatrik J.; Cortelli, Michael; Landstreet, Stuart R.; Talackine, Jennifer R.; Cardwell, Nancy L.; Simonds, Elizabeth M.; Mentz, Meredith; Lowe, Cindy; Benson, Clayne; Demarest, Caitlin T.; Alexopoulos, Sophoclis P. (2023-03-31). "Immune characterization of a xenogeneic human lung cross-circulation support system". Science Advances. 9 (13). doi:10.1126/sciadv.ade7647. ISSN 2375-2548. PMC 10065447. PMID 37000867.
  15. ^ Shishido, Yutaka; Tracy, Kaitlyn M.; Wu, W. Kelly; Cortelli, Michael; Petrovic, Mark; Harris, Timothy R.; Simon, Victoria; Francois, Sean; Tucker, William D.; Petree, Brandon S.; Cardwell, Nancy L.; Ukita, Rei; Demarest, Caitlin T.; Alexopoulos, Sophoclis P.; Shaver, Ciara M. (2024-09-18). "Characterization of Porcine Immunoglobulin Deposition in Human Livers Recovered Using a Xenogeneic Cross-Circulation". ASAIO Journal. doi:10.1097/MAT.0000000000002311. ISSN 1058-2916. PMC 11913748. PMID 39288356.
  16. ^ Tracy, Kaitlyn M.; Harris, Timothy R.; Petrovic, Mark; Cortelli, Michael; Tucker, William; François, Sean; Shishido, Yutaka; Simon, Victoria; Petree, Brandon; Johnson, Carl A.; Wu, Wei K.; Cardwell, Nancy L.; Simonds, Elizabeth; Adesanya, TiOluwanimi T.; Fortier, Avery K. (2025-03). "Lung rehabilitation using xenogeneic cross-circulation does not lead to hyperacute rejection in a human lung transplantation model". The Journal of Heart and Lung Transplantation. doi:10.1016/j.healun.2025.02.1696. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Pinezich, Meghan R.; O’Neill, John D.; Guenthart, Brandon A.; Kim, Jinho; Vila, Olaia F.; Ma, Stephen P.; Chen, Ya-Wen; Hozain, Ahmed E.; Krishnan, Aravind; Fawad, Moeed; Cunningham, Katherine M.; Wobma, Holly M.; Van Hassel, Julie; Snoeck, Hans-Willem; Bacchetta, Matthew (2025-03). "Theranostic methodology for ex vivo donor lung rehabilitation". Med: 100644. doi:10.1016/j.medj.2025.100644. {{cite journal}}: Check date values in: |date= (help)
  18. ^ Andrijevic, David; Spajic, Ana; Hameed, Irbaz; Sheth, Kevin N.; Parnia, Sam; Griesemer, Adam D.; Montgomery, Robert A.; Sestan, Nenad (2025-03-20). "Mechanisms and strategies for organ recovery". Nature Reviews Bioengineering. doi:10.1038/s44222-025-00293-7. ISSN 2731-6092.
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