Regeneration of severely damaged lungs using an interventional cross-circulation platform

Organ transplantation has overcome significant technical, immunological, and ethical hurdles to become a lifesaving treatment¹. The full potential of organ transplantation remains constrained by the global shortage of organs—a problem that has been described as “the greatest crisis facing biomedicine today”². Notably, up to 80% of donated lungs are not utilized³, often as a result of injury at the time of death (e.g., trauma, pulmonary contusion, aspiration, ventilator-associated lung injury). Major efforts to expand the donor pool are underway^4,5,6, including ex vivo lung perfusion (EVLP), which is under clinical investigation as a means to evaluate and improve marginal quality donor lungs⁷. With the use of hyperosmotic and blood-based perfusates, EVLP has been shown to decrease pulmonary edema and enable ~6 h of normothermic perfusion prior to transplantation^8,9. EVLP is also used as an investigational platform for the delivery of therapeutic agents including antibiotics¹⁰, pulmonary surfactant^11,12, immunomodulatory viral vectors^13,14, and mesenchymal stem cells^15,16.

Despite the clinical use of EVLP since its introduction in 2012 and expansion of criteria for donor lungs, the annual number of lung transplants in the United States has not dramatically increased¹⁷. Consequently, there is a compelling need to extend organ recovery capabilities beyond the limited category of marginal lungs to severely damaged lungs, such as those injured by aspiration of gastric contents (hydrochloric acid, bile acids, gastric enzymes, and food particulates^18,19). Gastric aspiration results in damage to the pulmonary epithelium, leading to pneumonitis and respiratory insufficiency¹⁸. Previous attempts to recover lungs injured by gastric aspiration using EVLP have been unsuccessful²⁰, having resulted in increased edema²¹and failure to reduce levels of inflammatory cytokines²² or improve tissue morphology²³ (Supplementary Table 1–3).

We previously reported the development of an extracorporeal organ support platform that utilized cross-circulation to radically extend the duration of time that lungs can be maintained outside the body (normothermic perfusion time 37.7 ± 1.8 h; total extracorporeal preservation time 56.2 ± 0.1 h)²⁴. Following these prolonged extracorporeal preservation times, lungs met all transplantation criteria and showed maintenance of pulmonary vasoregulation, microvascular and bronchial epithelial tight junctions, alveolar type II pneumocyte surfactant recycling, airway submucosal gland secretory activity, and a coordinated mucociliary escalator. Based on these results, we hypothesized that normothermic perfusion via cross-circulation could enable therapeutic interventions leading to functional recovery and regeneration of severely damaged lungs.

In this study, we use an established clinically relevant large animal model of gastric aspiration to recapitulate severe injury that currently renders a large number of donated lungs unsalvageable for clinical transplantation. We investigate the ability of the cross-circulation platform to: (i) provide prolonged normothermic extracorporeal support of severely damaged lungs outside the body, and (ii) enable continuous assessment of lung regeneration at the molecular, cellular, and tissue levels. Severely damaged lungs are subjected to multiple therapeutic interventions—bronchoalveolar lavage, surfactant replacement, and alveolar recruitment—on an interventional cross-circulation platform that provided physiologic systemic regulation. We also apply non-invasive diagnostics (exosomes, surface thermography) in extracorporeal lungs on cross-circulation support, and establish benchmarks of lung repair and regeneration and corresponding scope of analyses (Supplementary Table 4).