Progress towards the construction of entire organs is gated by the lack of a reliable way to produce sufficient vascular networks. Natural tissue comes equipped with hundreds of tiny capillaries passing through every cubic millimeter, and lacking this network means that engineered tissue can only be a few millimeters in thickness. One way to work around this problem in the near term is to use a donor organ, stripping it of all its cells in the process known as decellularization, leaving the extracellular matrix and its chemical cues to guide replacement cells. Even this isn't enough in cases where a suitable recipe for rebuilding the necessary structures with patient-matched cells has yet to be established. So here, researchers suggest an approach of partial decellularization: only remove the cells and structures that can presently be replaced, and go forward on that basis. Intriguingly, this might even be made to work in a living patient, replacing some types of tissue section by section in damaged or diseased lungs.
Lung transplantation - the only definitive treatment for patients with end-stage lung disease - remains limited by a severe shortage of donor organs such that only 20% of patients waiting for a donor lung undergo transplantation. Strategies aimed at increasing the number of transplantable lungs would have an immediate and profound impact. Tissue engineering strategies are currently under development to regenerate or replace injured lungs. Because of the extreme complexity of the lung, with its hierarchical three-dimensional architecture, diverse cellular composition, highly specialized extracellular matrix (ECM), and region-specific structure and function, bioengineering a functional lung is still an elusive goal. The lungs bioengineered by full decellularization and recellularization have shown a limited and temporary function, largely due to blood clotting and pulmonary edema, which have led to lung failure within a few hours following transplantation. To date, whole-organ engineering methods using lung grafts with denuded vascular networks have failed to produce functional grafts.
Given the essential need for intact and functional pulmonary vasculature, we developed an airway-specific approach to removing the pulmonary epithelium while preserving the surrounding cells, matrix, basement membrane, and vasculature. Previously established methods for decellularization of the entire organ were designed to remove both the epithelium and endothelium and could only be applied ex vivo. This study developed the first procedure for the removal of epithelium from the lung airway with the full preservation of vascular epithelium, which could be applied in vivo to treat diseases of lung epithelium. Whole lung scaffolds with an intact vascular network may also allow for recellularization using patient-specific cells and bioengineering of chimeric lungs for transplantation. In addition to the clinical potential, lung scaffolds lacking an intact epithelial layer but with functional vascular and interstitial compartments may also serve as a valuable physiological model for investigating (i) lung development, (ii) the etiology and pathogenesis of lung diseases involving pulmonary epithelium, (iii) acute lung injury and repair, and (iv) stem cell therapies.
Lung decellularization has resulted in substantial advances in lung bioengineering and the ability to create scaffolds for tissue engineering applications. We believe that our methodology can address some of the challenges that have slowed the progress in lung bioengineering by (i) preserving the vascular endothelium throughout the lung (from large vessels to capillaries) and (ii) targeting the removal of airway epithelium while maintaining structural and cellular components essential for lung repair. In summary, the creation of de-epithelialized whole lungs with functional vasculature may open new frontiers in lung bioengineering and regenerative medicine. Additionally, de-epithelialization could be applied to other organs with dual flow, such as the liver or kidney.