New approach to bioengineering lungs selectively treats epithelium that lines the lung airway, while preserving lung vasculature; this transformative technique could lead to improved care of patients with lung disease.

Researchers exploring new ways to both promote lung repair and increase the number of available donor lungs have been challenged by the organ’s extreme complexity - the lung has more than 40 different cell types residing in its matrix and the total surface area between the airway and the vasculature is the size of a tennis court. Efforts to bioengineer functional lungs from fully decellularized or synthetic scaffolds that lack functional vasculature have been largely unsuccessful until now.

A Columbia Engineering team led by Gordana Vunjak-Novakovic, University Professor and the Mikati Foundation Professor at Columbia Engineering and professor of medical sciences (in Medicine) at Columbia University, and N. Valerio Dorrello, assistant professor of pediatrics at Columbia University Medical Center, is the first to successfully bioengineer a functional lung with perfusable and healthy vasculature in an ex vivo rodent lung. Their new approach (DOI 10.1126/sciadv.1700521), which allows the removal of the pulmonary epithelium while maintaining the viability and function of the vascular network and the lung matrix, was published in the journal Science Advances.

In the past seven years, several research groups have been able to fully decellularize lungs to build scaffolds for lung bioengineering with the proper architecture and stiffness that can be repopulated by newly introduced cells. To rebuild a functional lung from this cell-free scaffold, researchers need to regenerate both the epithelial surfaces in the airway and the endothelial lining of the vasculature. An intact vascular network - missing in these scaffolds - is critical not only for maintaining the blood-gas barrier and allowing for proper graft function, but also for supporting the cells introduced to regenerate the lung. This has proved to be a daunting challenge.

“We developed a radically new approach to bioengineering of the lung,” said Vunjak-Novakovic, a pioneer in tissue engineering who directs the Laboratory for Stem Cells and Tissue Engineering. “We reasoned that an ideal lung scaffold would need to have perfusable and healthy vasculature, and so we developed a method that maintains fully functional lung vasculature while we remove defective epithelial lining of the airways and replace it with healthy therapeutic cells. This ability to selectively treat the pulmonary epithelium is important, as most lung conditions are diseases of the epithelium.”

Earlier techniques for decellularization of the entire lung were designed to remove all cells from the lung, generating a cell-free lung scaffold. The Columbia team has now demonstrated a transformative approach to obtaining functional vascularized lung grafts. They developed an airway-specific method to remove the pulmonary epithelium while preserving the lung vasculature, matrix and other supporting cell types such as fibroblasts, myocytes, chondrocytes, and pericytes. Following lung cannulation in a rodent lung, they ventilated the lungs and perfused them on an ex vivo lung perfusion system (EVLP), similar to the extracorporeal membrane oxygenation (ECMO) system utilized to support patients with cardiovascular and respiratory failure. They then delivered intratracheally a mild detergent solution to an isolated single lung to remove epithelial cells and protected the vasculature by circulating a perfusate containing electrolytes and energy substrates. The lung scaffold maintained the bronchial and vascular architecture, and supported the attachment and growth of human adult and stem cell–derived pulmonary cells in this ex vivo bioreactor.