A multidisciplinary team from Columbia Engineering and Vanderbilt University have successfully demonstrated that severely injured donor lungs that were rejected for transplantation can be recovered outside of the body by a system using cross circulation of whole blood between the lung and an animal host: parabiosis/plasmapheresis dialysis. The accomplishment of this major milestone was attributed to the physiologic milieu and systemic regulation that their unique platform provides to explanted human lungs.
“It is the provision of intrinsic biological repair mechanisms over long-enough periods of time that enabled us to recover severely damaged lungs that cannot otherwise be saved,” said the study’s lead authors, Ahmed Hozain (surgical research fellow at Columbia Engineering) and John O’Neill (adjunct associate research scientist at Columbia Engineering).
Worldwide respiratory disease is the third leading cause of death, and for those with end stage lung disease lung transplantation is still the only cure. Lung transplantation remains limited by the availability of healthy donor organs, and despite the advances in the field most donor lungs are rejected due to severe but potentially reversible injuries. Ex vivo lung perfusion procedures are used currently to provide lung support outside of the body and to recover marginal quality donor lungs before transplantation, but EVLP only provides a duration of 6-8 hours of support which is not enough time to recover the majority of severely damaged donor lungs.
Over the past decade the researchers have been developing their platform to provide more lungs for patients in dire need of organ transplantation, and in 2017 the feasibility of cross circulation support of whole lungs was demonstrated outside of the body. Then in 2019 the efficacy of cross circulation by regenerating severely damaged swine lungs was demonstrated; and in 2020 the duration of cross circulation support was successfully extended to an unprecedented 4 days.
In this paper the team describes how explanted human lungs that were already declined for transplantation were successfully recovered using their cross circulation platform to maintain lung integrity and result in functional lung recovery; during the 24 hours of cross circulation substantial improvements of cell viability, tissue quality, inflammatory responses and respiratory function were observed.
“We were able to recover a donor lung that failed to recover on the clinical ex vivo lung perfusion system, which is the current standard of care. This was the most rigorous validation of our cross-circulation platform to date, showing great promise for its clinical utility,” Vunjak-Novakovic said.
This donor lung demonstrated persistent swelling and fluid buildup that could not be resolved, thus it was rejected for transplantation by multiple transplant centers and was eventually offered up to research. By the time the lung reached the team it had experienced two periods of cold ischemia totaling 22.5 hours, plus it had received 5 hours of clinical EVLP treatment. After being on 24 hours of the cross circulation platform the same lung showed functional recovery.
“As a lung transplant surgeon, I have seen many patients not receive lung transplants they desperately needed. I find this work intriguing and hope this technology will make more donor lungs available,” commented Zachary Kon, Director of Lung Transplantation Program, NYU Langone Health, who was not involved in the study.
Although it was emphasized that more work is required before the platform can become a clinical reality, two clinical scenarios are envisioned for the application of the cross circulation platform which the team plans to pursue. One is to directly translate their method from this study with a human donor lung recovered by xenogeneic cross circulation with a medical grade and pathogen free animal host, to which the safety, feasibility, risk profiles, and outcomes of xenogeneic cross circulation will need to be evaluated in large numbers.
The second approach is to help critically ill patients awaiting transplant on artificial lung support serve as the cross circulation host to recover an injured donor lung to which that patient would then receive the lung for transplantation as soon as the organ recovers sufficiently. Their paper described how the xenogeneic cross circulation platform may also serve as a research tool to investigate organ regeneration, transplant immunology, and for the development of therapeutics.
Looking further ahead the team hopes that they are able to extend the benefits of their platform to the recovery of other human organs such as livers, hearts, kidneys, and even limbs.
