Mechanisms of regeneration in tissue engineered tracheal grafts

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PROJECT SUMMARY / ABSTRACT Long-segment airway defects can arise at birth or later in life as a result of trauma, infection, or malignancy. Although rare, these defects are often fatal. There is currently no established surgical technique to reconstruct defects of this nature, so in the rare case in which patients survive, they frequently need to rely on a long-term tracheostomy tube for breathing. Without reconstructive strategies, the pursuits of tracheal substitutes have explored the use of foreign materials, non-viable tissues, and transplantation. These approaches have been fraught with complications. Regenerative medicine and tissue engineering have the capacity to replaced failed tissue with a normal, living organ instead of treating a compromised organ. Given the significant impact of long segment tracheal compromise, tissue engineered tracheal grafts (TETG) have had limited use in the clinical setting for heroic measures. Although this has been a life saving treatment for some, problems will graft narrowing and regrowth of airway tissue have limited the clinical translation of TETG. To explore the efficacy of a bioartificial TETG, we developed a large animal model of TETG and demonstrated that like the clinical experience, graft narrowing is the most common complication observed. This objective of this proposal is to support the career development of a surgeon scientist devoted to the development of tissue-engineered constructs to treat complex aerodigestive disorders. To advance the field of tissue engineered tracheal replacement, it will be important to define the mechanisms of regeneration as well as graft narrowing. It is our hypothesis that these two processes are related: stenosis can result from delayed regeneration; acceleration of regeneration can attenuate graft stenosis. To explore how we can affect graft regeneration and minimize stenosis, we will be modulating the constituents critical to the construction of a tissue-engineered trachea: the seeded cells, the scaffold, and the host response. We developed a mouse model of TETG to address our three aims. Our first aim will examine the dose dependent impact and fate of seeded cells. Our second aim will explore the impact of changing scaffold porosity and composition on regeneration. Our third aim will identify the impact of the host immune response on regeneration. Defining the relative impact of each of these elements not only address questions central to many different approaches to airway tissue engineering, but will allow us to strategize our approach for the rational design the next generation of TETG and explore targeted therapies to optimize regeneration. Completion of the career development plan and the research proposed in this application will generate preliminary data which will serve as a foundation for R01 funding to develop tissue engineered airways.