Abstract
Objective
To provide histological evidence to investigate a theory for post-tonsillectomy secondary hemorrhage (PTH) in a mouse model and to evaluate the potential for heparin-binding epidermal growth factor-like growth factor (HB-EGF) treatment on wound healing in this model.
Methods
A prospective randomized single-blinded cohort study. A uniform tongue wound was created in 84 mice (day 0). Mice were randomized to HB-EGF (treatment, n = 42) or saline (control, n = 42). In treatment mice, HB-EGF 5 µg/ml was administered intramuscularly into the wound daily (days 0–14). In control mice, normal saline was administered daily. Three mice from each group were sacrificed daily through day 14 and the wounds evaluated histologically by blinded reviewers.
Results
Key stages of wound healing, including keratinocyte proliferation and migration, wound contraction, epithelial separation, and neoangiogenesis, are defined with implications for post-tonsillectomy wound healing. Epithelial separation (59 vs. 100%, p = 0.003) and wound reopening (8 vs. 48%, p < 0.001) were reduced with HB-EGF. Epithelial thickness (220 vs. 30 µm, p = 0.04) was greater with HB-EGF. Wound closure (days 4–5 vs. day 6, p = 0.01) occurred earlier with HB-EGF.
Conclusions
In healing of oral keratinocytes on muscle epithelial separation secondary to muscle, contraction occurs concurrently with neoangiogenesis in the base of the wound, increasing the risk of hemorrhage. This potentially explains why post-tonsillectomy secondary hemorrhage occurs and its timing. HB-EGF-treated wounds showed greater epithelial thickness, less frequent epithelial separation and wound reopening, and earlier wound closure prior to neovascularization, suggesting that HB-EGF may be a potential preventative therapy for PTH.
Level of evidence
NA—animal studies or basic research.
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Funding
This project was funded by the Garnett Passe and Rodney Williams Memorial Foundation, Stanford’s SPARK, and the Stanford Child Health Research Institute.
Conflict of interest
Authors DMB, CSM, RC, and PSM are inventors on a patent, owned by Stanford University, which covers subject matter in this study. Author NFA has no conflict of interest.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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Beswick, D.M., Santa Maria, C., Ayoub, N.F. et al. Epithelial separation theory for post-tonsillectomy secondary hemorrhage: evidence in a mouse model and potential heparin-binding epidermal growth factor-like growth factor therapy. Eur Arch Otorhinolaryngol 275, 569–578 (2018). https://doi.org/10.1007/s00405-017-4810-6
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DOI: https://doi.org/10.1007/s00405-017-4810-6