Vocal fold scarring is one of the most challenging, recalcitrant, and functionally debilitating conditions affecting the human voice. Treatment progress for vocal fold scarring is hindered by our limited understanding of the immunological architecture of the larynx, specifically the role of macrophages and their response to inflammation. Injuries to the vocal fold (i.e. surgical) trigger a highly complex wound healing response, involving resident and infiltrating macrophages that resolve inflammation and initiate tissue repair by expressing a cascade of inflammatory mediators that breakdown extracellular matrix components, eliminate necrotic cells and debris, and promote angiogenesis and stromal cell proliferation. Considering the complex cellular and molecular components involved in wound healing, it is necessary to confront and understand the immunological activity that controls inflammation and the healing cascade, which is central to many fibrotic disorders. The goal of this project is to identify macrophage behavior regulating scar formation and assess the interaction of these cells with cell based therapeutic approaches for tissue regeneration. In this application we will 1) Characterize macrophage function in the vocal fold lamina propria using pig surgical injury model 2) Measure the effects of MSC-hydrogel constructs on macrophage function and resolution of inflammation using a pig surgical injury model. We will demonstrate that macrophages play a dual role in the resolution of inflammation through regulation of both pro- and anti- inflammatory responses throughout the wound healing process, which can affect the pathogeneses of vocal fold scar. We hypothesis that macrophages residing in the lamina propria will express distinct classical and alternative activated phenotypes, depending on the phase of wound healing (i.e. inflammation, proliferation, remodeling). Findings from this proposal will characterize macrophage function in the vocal fold lamina propria, providing vital insight into the pathogeneses and treatment of vocal fold scar. An understanding of macrophage behavior may allow us to manipulate future tissue engineering strategies for vocal fold scar, with direct, anti-inflammatory benefits.

Public Health Relevance

The proposed research specifically addresses a clinical problem associated with the pathogenesis of vocal fold scar and approaches for treatment. This project will analyze the immunologic characterization of macrophages function in the vocal fold lamina propria. We expect that scientific knowledge obtained from these studies will be highly influential in directing the creation of the next generation of biomaterials for the vocal fold tha truly heals.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDC1-SRB-L (45))
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Sklare, Dan
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University of Wisconsin Madison
Schools of Medicine
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King, Suzanne N; Guille, Jeremy; Thibeault, Susan L (2015) Characterization of the Leukocyte Response in Acute Vocal Fold Injury. PLoS One 10:e0139260