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 ~10µm) 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.