Efficacy and Safety of 0.25% Timolol Gel in Healing Surgical Open Wounds: A Randomized Controlled Trial

Healing of a cutaneous defect by second intention is a complex process. Migration of fibroblasts, keratinocytes, and other cell types to the site of defect and their proliferation under stimulation by cytokines and growth factors occur during this process. The role of topical beta-blockers in promoting wound healing is currently emerging in the international literature (1-3). β2-Adrenergic receptors (B2AR) are the only subtype of beta-adrenoceptors expressed on skin (4-6). 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 (4-6). 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 (4-6). 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 (5-10).

Topical beta-blockers have been gaining increasing popularity and evidence over the last few years as enhancers of wound healing in acute and chronic open wounds. In particular, 0.25% timolol gel may represent a commercially available, safe and simple, painless-though perhaps moderately expensive-treatment for improving both acute and chronic open wounds, as well as for improving long-term cosmetic outcomes.

To assess the efficacy and safety of topically applied 0.25% timolol gel in promoting wound healing in surgical open wounds ≤1.5cm 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 reduction of open surgical wound;
2. Evaluating cosmetic outcomes of surgical wounds 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 patient discomfort during the healing process by means of a patient pain VAS;
4. Determining the side effects associated to 0.25% topical timolol versus SOC; and
5. Determining costs associated to the use of 0.25% topical timolol versus SOC.