Advanced tissue engineering strategies for generating replacement tracheal tissues

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Malignancy, subglottic stenosis, and traumatic injury to the trachea require surgical resection. When short segments are involved, primary re-anastomosis affords excellent results. Longer lesions, however, have no currently acceptable solution. Some patients need permanent tracheostomies or receive only palliative treatment. Recent progress in airway transplantation has provided renewed optimism for potential solutions to these problems, however much remains to be done. Tissue engineered solutions, using constructed substrates, offer the best hope for a far simpler approach with much reduced risk of immunogenicity. Substantial work to date has provided exciting progress but has largely focused on chondrocyte regeneration and structural integrity. The epithelial layer of the airway has several functions: a barrier function, secretion of mucous, and mucociliary clearance of inhaled pathogens yet it has received much less attention. This latter role requires the synchronized, aligned beating of the cilia of the many millions of epithelial cells comprising the entire airway tree. The factors controlling optimal epithelial maturation and organization have barely been explored let alone defined. The present collaborative proposal will bring together a team of engineers and clinicians to enhance our understanding of physical factors that can be engineered to control epithelial organization and tissue functionality. Specifically, we will expose developing epithelium to controlled physical forces and examine the resulting effects on epithelial organization in two and three-dimensional epithelial layers. We hypothesize that physical forces will influence the growth, organization and functional maturation of the epithelial cells, grown from local progenitors on engineered basement membrane, and that engineering specific physical forces during tissue development will provide a novel strategy for improving the quality and clinical utility of