In this proposal, our primary goal is to explore the optimization of a biomaterial to prevent the recurrence of fibrosis and promote regeneration of mucosal epithelium following the surgical excession of fibrotic scars from the airway, specifically using a model of posterior glottic stenosis (PGS). PGS is a severe clinical problem typified by formation of an ulcer followed by a dense scarring of the airway that frequently results in respiratory distress and ventilatory collapse. PGS occurs in over 31% of patients undergoing prolonged intubation (>10 days) and typically presents in a delayed fashion due to slow wound contracture over 6 weeks. Mucosal epithelium contains large numbers of dedicated progenitor cells; however, the hostile environment of the upper airway impairs the effectiveness of cellular migration and healing. Our approach to this challenge is to optimize a biomaterial based on a platform technology we have developed, known as microparticle-based (MB) scaffold. MB scaffolds use an injectable hydrogel approach composed of highly concentrated microparticles that solidify in situ into a solid, porous scaffold (pore size ~10m) that has been published for treatment of injuries to skin and brain, and as an injectable filler for vocal tissue reconstruction. A critical aspect of our proposed optimization is designing a material that can be heterogeneously decorated with chondroitin sulfate (prevalent mucosal glycosaminoglycan) and a positively charged natural polymer (chitosan) to provide material cohesion and interfacial adhesion for increased material stability. To optimize the material for regeneration of mucosal epithelial tissue, we will measure the Young?s modulus and glycosaminoglycan levels in rabbit mucosal tissue to inform the creation of two microparticle populations, chondroitin sulfate or chitosan. Next, we will determine the ideal ratio of chondroitin sulfate to chitosan microparticles for creating a mechanically stable scaffold by using a standardized in vitro interfacial adhesion assay testing biomaterial adhesion to excised mucosal tissue. This biomaterial (including non-porous and porous homogeneous chondroitin sulfate or chitosan controls) will be tested in vitro for effects on biocompatibility (viability and proliferation) and migration. Finally, we will use a published in vivo leporine model of posterior glottic stenosis revision to test for wound closure and the emergence of markers of immunogenesis and fibrosis . If successful, this proposal will set the groundwork for significant progress in both translational treatment of mucosal injury and provide foundational knowledge for a mechanistic understanding tissue response to this new biomaterial platform.
Scars in the airway (from cancer removal or prolonged intubation) can partially to completely occlude breathing and require emergency surgical removal. This project aims to prevent these scars from recurring. This tissue area is difficult to treat due to movement (e.g coughing) and shear (e.g. swallowing). This proposal engineers a material designed for healing these injuries with a focus on mechanical stability.
