Efficacy and Safety of 0.25% Timolol Gel in Enhancing Full Thickness Skin Grafts Healing and Cosmetic Outcomes

The role of topical beta-blockers in promoting wound healing is currently emerging in the
international literature. β2-Adrenergic receptors (B2AR) are the only subtype of
beta-adrenoceptors expressed on skin. They can be found in secretory coil of apocrine glands,
keratinocytes, fibroblasts and melanocytes. The distribution of these receptors provides
insight on dermatological disorders that may be affected by β-blockers. Keratinocyte
migration occurs by the facilitation of chemotaxis, the polarization of cells, and activation
of extracellular signal-related kinases essential in the signaling of promigratory pathways.
The B2AR activation inhibits keratinocyte migration by activating the serine/threonine
phosphatase-2a, which downregulates phosphorylation of extracellular signal-related kinases
necessary for migration. Therefore, B2AR antagonists prevent the phosphorylation of
phosphatase-2a and have the downstream effect of extracellular signal-related kinase
promotion, inducing a promigratory pathway in keratinocytes. Keratinocyte migration also
occurs by galvanotaxis, a phenomenon in which cells migrate in response to electric stimuli.
Keratinocytes can be stimulated to migrate with the formation of electrical poles and the
application of electrical fields. The B2AR antagonists improve the ability of keratinocytes
to respond to such migratory cues, whereas the B2AR agonists decrease keratinocytes' ability
to respond, further implicating the use of topical timolol for recalcitrant wounds.
Angiogenesis and dermal fibroblast proliferation are also regulated by B2ARs. The B2AR
antagonists have been found to promote angiogenesis in chick chorioallantoic membrane assays
and in vivo murine wound models. Dermal fibroblast migration is also increased (by 27%) when
exposed to B2AR antagonists, and epidermal differentiation is improved with B2AR antagonists
and β1- and β2-receptor antagonists.

Full-thickness skin grafts (FTSG) are one of the most commonly performed procedures in
dermatologic, plastic and burn surgery. Various experimental approaches to optimize the
healing of FTSG receiving sites have been described; however, no clearly superior and easily
applicable method has gained wide acceptance in daily practice.

As indicated by preliminary evidence in other wound healing endeavors, 0.25% timolol gel may
represent a commercially available, safe and simple, painless and relatively inexpensive
treatment for improving healing of FTSG receiving site, as well as for improving cosmetic
long term outcomes.

To assess the efficacy and safety of topically applied 0.25% timolol gel in promoting wound
healing in FTSG receiving site versus standard of care (SOC) by:

1. Evaluating healing in response to treatment with 0.25% topical timolol gel versus SOC in
terms of wound surface area and Graft Take Score at the receiving site of a FTSG at 7
and 14 days;

2. Evaluating cosmetic outcomes of the receiving site of a FTSG in terms of blinded
physician (Vancouver Scar Scale, VSS) and patient (Visual Analogue Scale, VAS)
assessment at 3 and 6 months' follow up;

3. Evaluating the need for further scar revision (dermabrasion or pulsed dye laser [PDL])
at the 6-month follow up;

4. Evaluating patient discomfort during the healing process by means of a patient pain VAS;
and

5. Determining the side effects associated with 0.25% timolol gel versus SOC

Inclusion Criteria:

1. Age ≥18 years of age

2. Undergoing a procedure which results in the need of a FTSG

3. Willing to provide written informed consent

Exclusion Criteria:

1. Age less than 18 years of age

2. Pregnant women

3. (Use of systemic drugs that can impede wound healing, such retinoids or
immune-suppressive drugs)

4. Severe coagulation disorders

5. Severe, uncontrolled systemic comorbidities, such as diabetes, arthritis, etc.

6. Hypersensitivity to 0.25% timolol gel

7. Not willing to provide written informed consent