ABSTRACT Tracheal deficiency of any cause represents a potentially fatal process. Presently there are no available substitutes for the trachea and it remains one of the few vital organs that can neither be reconstructed from other tissues nor effectively transplanted. Researchers have begun to explore the possibility of organ replacements from scaffolds (decellularized trachea) that can then be transplanted to a patient. However, these first cases have been troubled by a range of serious problems, including patient death, all ultimately linked to a lack of healing. We believe that the lack of healing could be related to the secreted protein thrombospondin-1 (TSP1) an identified anti-angiogenic agent that binds to matrix and to cell receptors and is induced by healing tracheal cells. We found that limiting TSP1 signaling through agents that prevent its binding to a specific cell membrane receptor, CD47, which is expressed on tracheal epithelial, vascular and non-vascular cells, increases cell restoration of decellularized tracheal scaffolds and tissue healing of transplanted decellularized tracheal scaffolds. We have developed several technologies that target the maladaptive TSP1-CD47 signal including CD47-specific antibody, peptide and morpholino. In tracheal cells we will test these technologies to increase cellular restoration of decellularized 2- and 3-D tracheal scaffolds, the later with a unique bioreactor. Bench top results will inform experiments to test these novel engineered tracheal transplants to heal tracheal loss in rodent and canine models of orthotopic tracheal transplantation. As humanized versions of CD47 targeting technologies are in development, and in the case of CD47 antibodies in clinical trials, results from this proposal will support accelerated translation into the clinic.