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

Abstract

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.

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

“…Swine lungs were procured in standard fashion as previously described. 12,13 The mean duration of cold static lung preservation was 4.8 AE 0.6 hours.…”

“…A 20F cannula was secured within the pulmonary artery, and the trachea was intubated with a 7.5 mm cuffed endotracheal tube, as previously described. 12,13,17 The aortic arch, serving as an endothelialized biobridge between the lungs and the extracorporeal circuit, was secured to the left atrial cuff with a running 6-0 polypropylene suture. A 36F venous drainage Abbreviations and Acronyms BAL ¼ bronchoalveolar lavage EVLP ¼ ex vivo lung perfusion IFNg ¼ interferon gamma IL ¼ interleukin TNFa ¼ tumor necrosis factor alpha XC ¼ cross-circulation Scanning this QR code will take you to the article title page to access supplementary information.…”

“…Calcium gluconate (1 g) was administered intravenously to recipient swine, and cross-circulation of blood between recipient swine and extracorporeal lungs was initiated, as previously described. 12,13 The extracorporeal circuit contained a pump console (Jostra HL-20; Maquet Cardiopulmonary), disposable pump (Rotaflow Centrifugal Pump; Maquet Cardiopulmonary), and continuous monitoring software (VIPER; Spectrum Medical, Cheltenham, England). Circuit flow rate was maintained within a protective regime between 5% and 10% of the estimated cardiac output of recipient swine, with pulmonary artery pressures <20 mm Hg, and pulmonary vein pressures between 3 and 5 mm Hg ( Figure E1, A).…”

“…Circuit flow rate was maintained within a protective regime between 5% and 10% of the estimated cardiac output of recipient swine, with pulmonary artery pressures <20 mm Hg, and pulmonary vein pressures between 3 and 5 mm Hg ( Figure E1, A). 12,13 Extracorporeal lungs were ventilated (Oxylog 3000 plus; Dr€ ager, L€ ubeck, Germany) (Video 1) with the following settings: respiratory rate, 6 to 8 bpm; tidal volume, 6 to 8 mL/kg; positive endexpiratory pressure, 5 cm H 2 O; inspired oxygen fraction, 40%; and maintained on XC for a mean duration of 1.5 AE 0.1 hours before initiating recovery of recipient swine from general anesthesia.…”

“…To overcome these limitations, our group previously used a swine model of cross-circulation (XC) to establish a lung support system that extended normothermic extracorporeal support to 36 hours and enabled statistically significant ex vivo recovery of severely injured lungs. 12,13 The use of an XC system to achieve ex vivo lung recovery mimics the clinical setting where in situ recovery of marginal quality lungs is achieved in patients placed on extracorporeal membrane oxygenation support for several days after transplantation. [14][15][16] Motivated by this clinical practice, we hypothesize that extending the duration of extracorporeal support from hours to days could not only enable the recovery of damaged lungs not currently salvageable using EVLP systems but also enable investigation of bioengineering strategies to improve or personalize organs before transplantation.…”