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Page 2 of 14 Nakamoto et al. Plast Aesthet Res 2024;11:54 https://dx.doi.org/10.20517/2347-9264.2024.82

pathways was measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR).

Results: The epithelialization rate on Day 14 was significantly higher in the treatment group. The days that the
epithelialization rate exceeded 85%, 90%, and 95% were significantly shorter in the treatment group. There was
no significant difference in wound blood flow or RNA abundance related to TGFβ, EMT, or MFA-related pathways
among the groups at any time point.

Conclusion: The results demonstrate that the beta-blocker timolol accelerates epithelialization of mesh skin
grafted full-thickness burn wounds through a mechanism other than improving wound blood flow.
Keywords: Beta-blocker, wound healing, burn, mesh skin graft

INTRODUCTION
Despite numerous studies and developments in burn treatment, limited donor skin and delayed wound
healing are still major problems. Surgical treatment for burns generally involves the removal of eschar and
[1,2]
skin graft for wound closure . In large burns, donor skin is frequently limited, and often the skin is
meshed to be grafted. The higher the mesh ratio, the greater the area that can be covered. However, this
[1,3]
increases the area of mesh gaps, so epithelialization of the mesh gap takes longer . Additionally, the
closure of meshes is delayed due to complications such as infection, hematoma, or other factors, even if the
wounds are covered with sufficient autologous skin. The longer epithelialization is delayed, the greater the
risk for skin and soft tissue infection, the reduced quality of life for patients, and the increased cost of
care . Therefore, safer, more effective, readily available, and more cost-effective interventions that
[2]
accelerate epithelialization of mesh gaps and raw surface areas due to graft loss are very valuable.

Wound healing includes hemostasis, inflammation, proliferation, and tissue remodeling phases . Among
[4]
these, keratinocyte migration during the proliferation phase is crucial for effective wound epithelialization.
Keratinocytes, located in the epidermis, play an important role in skin barrier function. Adrenergic
receptors expressed on keratinocytes are mainly beta-2 receptors , and several response systems triggered
[5-7]
by stimulation of the receptors have been shown to reduce the migration ability of keratinocytes .
[6-8]
Endogenous adrenaline, which decreases the migration ability of keratinocytes, has been reported to cause
[7]
delayed wound healing . Conversely, beta-adrenergic receptor blockers increase the migration ability of
keratinocytes.

Beta-adrenergic receptor blockers are drugs that act on beta receptors in the sympathetic nervous system
and inhibit their activation. Beta-blockers are used orally or intravenously for hypertension and tachycardia,
as eye drops for glaucoma, and recently for the treatment of infantile hemangiomas orally and topically. In
severe burns, beta-blockers have been used as an intravenous therapy to reduce inflammation, resting
energy expenditure, and hypermetabolism . Timolol is a beta-adrenergic receptor antagonist and is used as
[9]
[10]
an eye drop to treat glaucoma . Previous studies have demonstrated that timolol can be safely applied
topically to promote wound healing .
[8]
In recent years, some studies have demonstrated the efficacy of beta-blockers in wound healing. Previous
studies have reported that beta-blocker infusion promotes epithelialization of flame burns in murine
[11]
models , and that topical timolol improves wound healing of thermal burns in rat models . Additionally,
[7]
the topical application of timolol with dermal matrix, preconditioned human mesenchymal stem cells
promotes wound healing of the total skin defect wound in porcine models , and the topical application of
[12]
timolol promotes the epithelialization of donor wound of split-thickness skin graft in human . However,
[13]