Surgical Denervation of Specific Cutaneous Nerves Impedes Excisional Wound Healing of Small Animal Ear Pinnae

Damage to cutaneous nerves inhibits wound healing in patients. Results from animals on the nerve contributions to healing are various and sometimes contradictory. Here, we aim to clearly define the collective role of central, caudal, and rostral nerves in ear wound healing of mice, rats, and rabbits. These wounds heal with minimal contraction like wounds in humans. We resected central, caudal, and rostral nerves at the base of ear pinnae by microsurgery and created excisional full-thickness skin wounds in the pinnae neurologically downstream from the resections. Denervation in mice resulted in no closure for 14 days post-wounding (dpw) and led to only 17.2% closure at 21 dpw when the excisional wounds of non-denervated ear pinnae were completely closed. Compared to excisional wounds that were not denervated in sham surgery, wounds with denervation showed an increase of excisional wound areas for 5.0% by 7 dpw and a 43.7% reduction of wound closure at 12 dpw for rats. In rabbits, denervation attenuated wound closure for 14.2, 34.4, and 28.3% at 7, 14, and 18 dpw, respectively. Our histological analysis showed marked denervation impairment in pivotal healing processes, re-epithelialization and granulation tissue growth, suggesting denervation impairment in the regeneration of blood capillaries and/or connective tissue in wounds. These results reveal the critical contributions made by central, caudal, and rostral nerves in ear pinnae to minimal-contraction skin wound healing. Our study also provides small animal models of minimal-contraction wound healing of denervated ear skins that recapitulate human wound healing involving surgical or traumatic nerve damages.