Production and transplantation of bioengineered lung into a large-animal model

Abstract

The inability to produce perfusable microvasculature networks capable of supporting tissue survival and of withstanding physiological pressures without leakage is a fundamental problem facing the field of tissue engineering. Microvasculature is critically important for production of bioengineered lung (BEL), which requires systemic circulation to support tissue survival and coordination of circulatory and respiratory systems to ensure proper gas exchange. To advance our understanding of vascularization after bioengineered organ transplantation, we produced and transplanted BEL without creation of a pulmonary artery anastomosis in a porcine model. A single pneumonectomy, performed 1 month before BEL implantation, provided the source of autologous cells used to bioengineer the organ on an acellular lung scaffold. During 30 days of bioreactor culture, we facilitated systemic vessel development using growth factor-loaded microparticles. We evaluated recipient survival, autograft (BEL) vascular and parenchymal tissue development, graft rejection, and microbiome reestablishment in autografted animals 10 hours, 2 weeks, 1 month, and 2 months after transplant. BEL became well vascularized as early as 2 weeks after transplant, and formation of alveolar tissue was observed in all animals ( = 4). There was no indication of transplant rejection. BEL continued to develop after transplant and did not require addition of exogenous growth factors to drive cell proliferation or lung and vascular tissue development. The sterile BEL was seeded and colonized by the bacterial community of the native lung.

Bioengineering of Pulmonary Epithelium With Preservation of the Vascular Niche

“…In 2010, the studies conducted by Niklason's and Ott's groups on whole lung decellularization and recellularization ex vivo, demonstrated the capability of a decellularized lung graft to support engraftment of multiple cell types, despite the fact that alveolar edema and thrombosis caused lungs to fail after only a few hours following transplant (Ott et al, 2010;Petersen et al, 2010Petersen et al, , 2011Petersen et al, , 2012Song et al, 2011). These studies and other meritorious work (Gilpin et al, 2014;Nichols et al, 2014Nichols et al, , 2018Wagner et al, 2014;Zhou H. et al, 2018) emphasized three major developments in the field of lung bioengineering: (1) the capacity of a properly conditioned lung scaffold to facilitate cell engraftment; (2) the utilization of ex vivo devices, such as EVLP, to support, assess, and optimize lung grafts; (3) the possibility to intervene with cell therapy in lung grafts supported ex vivo. However, these advances also posed a major challenge to researchers: to create a graft with the functional capability of the lung, an extremely complex organ containing more than 40 different cell types (Colby et al, 2007;Franks et al, 2008;Beers and Morrisey, 2011;Wagner et al, 2013).…”

Rare Lung Disease Research

“…As one step toward this goal, an NIHfunded study recently demonstrated that adding autologous lung and mesenchymal stromal cells to an acellular scaffold led to successful implantation, growth, structure, and function of a bioengineered lung into a pig. 30…”

Advanced pulmonary MRI to quantify alveolar and acinar duct abnormalities: Current status and future clinical applications

“…The observation and assessment of lung regrowth in adults and in small animal models demonstrated this clinical potential for cases where MRI is a good alternative for noninvasive assessment of lung structure and function. In the new field of cell‐based replacement therapies and whole‐organ regeneration, MRI morphometry provides a noninvasive way to serially measure lung growth as well as the biomechanical and functional properties. For example, 3 He MRI morphometry was recently used to track lung growth over 30 days using MRI L m estimates and changes in the alveolar density …”