Severely damaged lungs can be regenerated to transplant criteria

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Lung transplantation, the only life-saving therapy for an increasing population of patients with end-stage lung disease, is severely limited by the number of available donor organs. Currently, up to 80% of donor lungs are rejected for serious but potentially reversible injuries. Since the beginning of transplantation in 1960s, clinicians and scientists have been trying to address the critical shortage of donor organs.

Now, a multidisciplinary team from Columbia Engineering and Vanderbilt University has – for the first time – demonstrated in a clinically relevant model that severely damaged lungs can be regenerated to meet transplantation criteria. In a study, the researchers describe the cross-circulation platform that maintained the viability and function of the donor lung and the stability of the recipient for 36 to 56 hours.

As Brandon Guenthart, a lead author of the study, explains “to support lung recovery and to demonstrate cellular regeneration, we had to pursue a radically different approach and develop more minimally invasive diagnostics.” Current methodologies of lung support are limited to only 6 to 8 hours, a time that is too short for therapeutic interventions that could regenerate the injured lung and improve its function.

The team, co-led by Gordana Vunjak-Novakovic, professor and The Mikati Foundation professor of biomedical engineering and medical sciences Columbia Engineering, and Matthew Bacchetta, the H William Scott professor of surgery at Vanderbilt University and adjunct professor at Columbia University’s department of biomedical engineering, also developed new diagnostic tools for the non-invasive evaluation of the regenerating lung. They expect their advance will lead to an increase in the number of lungs for transplant, through the recovery of severely damaged lungs that are currently unsuitable for clinical use.

The researchers have long been focused on developing processes to recover lungs that are being turned down for transplant because of injury to enable people with end-stage lung disease to live longer and better lives. “We have been fortunate to assemble a highly talented, interdisciplinary team of bio-engineers, surgeons, pulmonologists, and pathologists, who have designed a durable physiologic support system for a donor lung outside the body, along with new technologies to achieve and monitor lung recovery,” Bacchetta says.

A previous study from the team demonstrated a cross-circulation platform that maintained the viability and function of a donor lung for 36 hours. The researchers were able to use their advanced support system to fully recover the functionality of lungs injured by ischaemia and make them suitable for transplant.

For this study, the team decided to test the effectiveness of their platform technology combined with conventional therapies and new diagnostics on lungs afflicted by the most frequent injury leading to donor lung rejection – gastric aspiration. This injury is caused by the entry of gastric material into the respiratory tract, resulting in severe injury to the pulmonary epithelium and thus making the lung unacceptable for transplantation. Currently, severely damaged donor lungs cannot be salvaged using existing devices or methods.

This study suggests that lungs injured by gastric aspiration can be maintained outside the body for several days, are amenable to repeated therapeutic interventions, and display evidence of cellular regeneration and improved function. Lungs regenerated on this platform met all criteria for transplantation.

“For seven years, we have diligently worked to develop new technologies for the maintenance and recovery of donor organs. This paper represents a culmination of fundamental and translational studies of lung bio-engineering that have converged into a system capable to recover severely damaged lungs. We now have the team and technology to bring this research to the patients, by making more donor lungs available for transplant,” says Vunjak-Novakovic.

The team plans to conduct further studies to evaluate the functional capacity of the lungs following transplantation and the safety of the method, using a clinically relevant large animal model with immuno-suppression.

“We envision that interventional cross-circulation may be used to investigate regeneration of other damaged organs, such as hearts, kidneys, and livers, expanding donor pools by salvaging severely damaged organs and leading to more organ transplants,” Bacchetta adds.

Abstract 1
The number of available donor organs limits lung transplantation, the only lifesaving therapy for the increasing population of patients with end-stage lung disease. A prevalent etiology of injury that renders lungs unacceptable for transplantation is gastric aspiration, a deleterious insult to the pulmonary epithelium. Currently, severely damaged donor lungs cannot be salvaged with existing devices or methods. Here we report the regeneration of severely damaged lungs repaired to meet transplantation criteria by utilizing an interventional cross-circulation platform in a clinically relevant swine model of gastric aspiration injury. Enabled by cross-circulation with a living swine, prolonged extracorporeal support of damaged lungs results in significant improvements in lung function, cellular regeneration, and the development of diagnostic tools for non-invasive organ evaluation and repair. We therefore propose that the use of an interventional cross-circulation platform could enable recovery of otherwise unsalvageable lungs and thus expand the donor organ pool.

Authors
Brandon A Guenthart, John D O’Neill, Jinho Kim, Dawn Queen, Scott Chicotka, Kenmond Fung, Michael Simpson, Rachel Donocoff, Michael Salna, Charles C. Marboe, Katherine Cunningham, Susan P Halligan, Holly M. Wobma, Ahmed E Hozain, Alexander Romanov, Gordana Vunjak-Novakovic, Matthew Bacchetta

Abstract 2
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.

Authors
John D O’Neill, Brandon A Guenthart, Jinho Kim, Scott Chicotka, Dawn Queen, Kenmond Fung, Charles Marboe, Alexander Romanov, Sarah XL Huang, Ya-Wen Chen, Hans-Willem Snoeck, Matthew Bacchetta, Gordana Vunjak-Novakovic

Columbia University material
Nature Communications abstract
Nature Biomedical Engineering abstract


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