Vocal Fold Injury and Scar Modulation in an Ovine model

Abstract

Vocal fold injury that results in scarring, creates a permanent vocal deficit that currently has no reliable or efficacious treatment. Impaired voicing has significant occupational, social and personal impacts. More than 25% of adults identify themselves as vocal professionals, needing voice for work, and almost all social situations are based on spoken communication. Many recreational pursuits are also voice-dependent and loss of the ability to contribute is socially isolating. This corpus of work has examined the mechanisms involved in wound healing in the vocal fold (VF), in the context of general wound healing, but focusing on the unique microarchitecture that the VF exhibits. In gaining understanding of the molecular mechanisms, I have chosen to target a fibrotic pathway, the TGF-b cascade, and its transducer the Smad signalling proteins, to evaluate whether favourable modulation of VF wound healing is possible. This research aimed to validate an ovine laryngeal injury model, and determine the tolerability and efficacy of a specific Smad3 inhibitor – halofuginone – in modifying the fibrotic cascade, and ascertain whether any identified histological changes translated to meaningful rheological alterations. All sheep underwent controlled right VF injury and were then exposed to one of four experimental conditions. Sheep were assigned in a paired study design (left VF vs right VF) to receive no medications, halofuginone at varying dose levels, dexamethasone or triamcinolone. Comparison medications were selected based on current clinical practice. Ovine larynges were then harvested and examined for histological findings, immunohistochemical analysis and ex-vivo rheological evaluation. VF wounding demonstrated a predictable and consistent pattern from injury to restitution which was responsive to administered medication. Halofuginone and dexamethasone moderated collagen deposition (anti-fibrotic). However, halofuginone also protected against elastin depletion after injury. Ovine larynges produced consistent oscillation following treatment and healing, confirming that histological findings were reflected in functional phonation. VF injury in an ovine model results in a predictable wound response, mediated by the TGF-b pathway and able to be modified by Smad3 inhibitor, halofuginone, with benefit to vibratory function. This suggests this pathway is a suitable target for manipulation to prevent or reverse fibrosis in the glottis and restore voice quality.