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A Surgical Mouse Model for Advancing Laryngeal Nerve Regeneration Strategies

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Abstract

Iatrogenic recurrent laryngeal nerve (RLN) injury is a morbid complication of anterior neck surgical procedures. Existing treatments are predominantly symptomatic, ranging from behavioral therapy to a variety of surgical approaches. Though laryngeal reinnervation strategies often provide muscle tone to the paralyzed vocal fold (VF), which may improve outcomes, there is no clinical intervention that reliably restores true physiologic VF movement. Moreover, existing interventions neglect the full cascade of molecular events that affect the entire neuromuscular pathway after RLN injury, including the intrinsic laryngeal muscles, synaptic connections within the central nervous system, and laryngeal nerve anastomoses. Systematic investigations of this pathway are essential to develop better RLN regenerative strategies. Our aim was to develop a translational mouse model for this purpose, which will permit longitudinal investigations of the pathophysiology of iatrogenic RLN injury and potential therapeutic interventions. C57BL/6J mice were divided into four surgical transection groups (unilateral RLN, n = 10; bilateral RLN, n = 2; unilateral SLN, n = 10; bilateral SLN, n = 10) and a sham surgical group (n = 10). Miniaturized transoral laryngoscopy was used to assess VF mobility over time, and swallowing was assessed using serial videofluoroscopy. Histological assays were conducted 3 months post-surgery for anatomical investigation of the larynx and laryngeal nerves. Eight additional mice underwent unilateral RLN crush injury, half of which received intraoperative vagal nerve stimulation (iVNS). These 8 mice underwent weekly transoral laryngoscopy to investigate VF recovery patterns. Unilateral RLN injury resulted in chronic VF immobility but only acute dysphagia. Bilateral RLN injury caused intraoperative asphyxiation and death. VF mobility was unaffected by SLN transection (unilateral or bilateral), and dysphagia (transient) was evident only after bilateral SLN transection. The sham surgery group retained normal VF mobility and swallow function. Mice that underwent RLN crush injury and iVNS treatment demonstrated accelerated and improved VF recovery. We successfully developed a mouse model of iatrogenic RLN injury with impaired VF mobility and swallowing function that can serve as a clinically relevant platform to develop translational neuroregenerative strategies for RLN injury.

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Acknowledgements

We graciously thank Dr. Christina Goldstein for providing translational surgical insight from an orthopedic perspective. Alex Hackworth and Connor (Beau) Burkett assisted with post-mortem laryngeal nerve dissections in mice. Marc Trautmann performed microtome sectioning of paraffin-embedded murine laryngeal specimens. We also acknowledge Roderic Schlotzhauer (MU Physics Machine Shop) for contribution to design and construction of the custom surgical table and laryngoscope tips essential to this study.

Funding

This study was partially funded by an NIH-T32 Grant (#2T32OD011126-38), which provided a postdoctoral stipend and research support for Megan Haney, DVM (sponsor: Lever).

Author information

Author notes

  1. Alexis Mok and Jakob Allen equally contributed to this work.

Authors and Affiliations

  1. Department of Communication Science and Disorders, University of Missouri School of Health Professions, Columbia, MO, USA

    Alexis Mok

  2. Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA

    Jakob Allen, Bradford Zitsch, Marlena Szewczyk & Christopher I. Newberry

  3. Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA

    Megan M. Haney

  4. Department of Otolaryngology – Head & Neck Surgery, University of Missouri School of Medicine, Columbia, MO, USA

    Ian Deninger, Brayton Ballenger, Victoria Caywood, Kate L. Osman, Bridget L. Hopewell, Aaron Thiessen, Daniel Ohlhausen & Teresa E. Lever

  5. Department of Orthopedic Surgery, University of Missouri School of Medicine, Columbia, MO, USA

    Emily Leary

  6. One Hospital Dr. MA314, Columbia, MO, 65212, USA

    Teresa E. Lever

Authors
  1. Alexis Mok
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  2. Jakob Allen
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  3. Megan M. Haney
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  4. Ian Deninger
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  5. Brayton Ballenger
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  6. Victoria Caywood
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  7. Kate L. Osman
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  8. Bradford Zitsch
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  9. Bridget L. Hopewell
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  10. Aaron Thiessen
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  11. Marlena Szewczyk
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  12. Daniel Ohlhausen
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  13. Christopher I. Newberry
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  14. Emily Leary
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  15. Teresa E. Lever
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Corresponding author

Correspondence to Teresa E. Lever.

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Conflict of interest

The authors declare that they have no other potential conflicts of interest.

Research Involving Human Participants and/or Animals

No human participants were included in this study, only animals. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Mok, A., Allen, J., Haney, M.M. et al. A Surgical Mouse Model for Advancing Laryngeal Nerve Regeneration Strategies. Dysphagia 35, 419–437 (2020). https://doi.org/10.1007/s00455-019-10045-6

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  • DOI: https://doi.org/10.1007/s00455-019-10045-6

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