Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine

Abstract

Objectives: Lung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to<24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using crosscirculation with conscious swine.Methods: A swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed.

Bioengineering of Pulmonary Epithelium With Preservation of the Vascular Niche

“…Recognizing that more advanced bioengineering therapies would necessitate even longer perfusion times, we next sought to further extend the XC timeline. In our most recent studies, we demonstrated that the duration of XC for normothermic extracorporeal lung support in a swine model can be extended to 100 h (Hozain et al, 2019). This model provided the maintenance of the lung ex vivo that was connected to an awake swine host, with full hemodynamic stability.…”

“…Methods for optimization of lung scaffolds have radically improved over time to promote cell engraftment Gilpin and Yang, 2017). Additionally, advances in the field of ex vivo whole organ bioreactors allowed for extended support of lung grafts outside the body using either EVLP (Steen et al, 2001;Wierup et al, 2006;Cypel et al, 2008Cypel et al, , 2011Divithotawela et al, 2019) or the XC platform pioneered by our group Guenthart et al, 2019b;Hozain et al, 2019). Recognizing the challenge of repopulating a fully denuded scaffold with the many cell types critical to lung function, researchers have shifted from whole recellularization to a more targeted approach.…”

“…In diseases affecting predominantly conductive airways, such as cystic fibrosis, targeted de-epithelialization of the conductive airways could allow removal of the mutant transmembrane conductance regulator (CFTR) epithelial cells and replacement with normal human bronchial epithelial cells or iPSCs where CFTR mutation is corrected (Cutting, 2015;Berical et al, 2019). Furthermore, extended lung support on XC up to four days that has been recently shown by our group (Hozain et al, 2019), could allow sufficient time for engraftment and differentiation of delivered cells prior to transplantation into a recipient patient.…”

Commentary: Development of a new concept is achieved only step-by-step

“…They successfully developed a prolonged ex vivo lung support technique by using cross circulation with a conscious preclinical swine model recipient; 4 days of extended normothermic extracorporeal lung support maintained the physiologic function and histology of the lung outside the recipient's body. Although Hozain and colleagues 4 have mentioned that the physiologic lung function and histology were stable during the extended perfusion period, the peak airway pressure and lung weight gradually increased with pulmonary edema. The current cross circulation system and protocol should be fine-tuned to preserve the donor lungs ex vivo for a few days.…”

“…Hozain and his colleagues 4 have reported that the current cross circulation system between the donor lung and the recipient body imitated a clinical situation in which posttransplant injuries are ameliorated in the implanted lungs by extracorporeal membrane oxygenation support. In a clinical setting, posttransplant extracorporeal membrane oxygenation support is basically applied to impede the further progression of lung injuries that are acquired after a lung transplant, such as ischemiareperfusion-induced lung injury.…”