When was epidermal growth factor (EGF) first used in humans for corneal wound healing?

First Use of Epidermal Growth Factor (EGF) in Humans for Corneal Wound Healing

Epidermal growth factor (EGF) was first used in humans for corneal wound healing in the early 1990s, following promising experimental studies in animal models.

Historical Development of EGF for Corneal Applications

Preclinical Research

• The groundwork for human applications began with animal studies, particularly in rabbits, where human recombinant EGF (hEGF) was shown to accelerate epithelial wound healing in various corneal wound models 1
• These early experimental studies demonstrated that hEGF at concentrations of 10-500 μg/ml administered four times daily could accelerate corneal epithelial healing by up to 45% compared to controls 1
• The research established that EGF plays a crucial role in corneal epithelial migration and proliferation during wound healing 2

Mechanism of Action

• EGF functions by binding to the EGF receptor (EGFR), a tyrosine kinase receptor that becomes activated during corneal epithelial wound repair 3
• EGFR activation is a necessary component of the wound healing process, as inhibition of the EGFR signaling cascade significantly slows migration rates 3
• EGF promotes endothelial wound healing predominantly through cell migration, with some limited acceleration of DNA synthesis 4

Transition to Human Applications

• Following successful animal studies in the early 1990s, EGF began to be investigated in human corneal applications
• Early human studies focused on evaluating the effects of human EGF on endothelial wound healing of human corneas in organ culture models 4
• These studies demonstrated that hEGF significantly increased wound closure rates and resulted in higher endothelial cell densities compared to controls 4

Clinical Applications and Evidence

Clinical Trials

• By the early 1990s, EGF had transitioned from experimental models to human clinical applications for corneal wound healing
• Several clinical trials were conducted throughout the 1990s and early 2000s with varying results
• Early clinical studies included dose-ranging trials of topical EGF cream, which showed significant improvement in healing at 12 weeks with higher doses compared to placebo 5

Formulations and Administration

• Various formulations have been developed, including:
  • Topical EGF cream at different concentrations
  • Recombinant human EGF (rhEGF) gel
  • Intralesional injections of rhEGF
  • Topical spray treatment with 0.005% rhEGF 5

Current Status and Considerations

Efficacy Evidence

• Despite widespread use in some countries, the evidence for EGF in corneal wound healing remains mixed
• Only three moderate to high-scoring RCTs have been identified, with conflicting results 5
• No clear outcomes in terms of healing or area reduction have been consistently demonstrated across studies 5

Clinical Applications

• EGF continues to be studied as part of the growth factor family that influences corneal epithelial wound healing, alongside KGF, HGF, IGF, insulin, and TGF-beta 6
• The concept of "alarmins" and inter-receptor cross-talk in response to wounding has advanced our understanding of how EGF and related factors contribute to the healing process 6

While EGF showed promising results in early experimental and clinical studies beginning in the early 1990s, the current evidence does not strongly support its routine use for corneal wound healing without further research to establish optimal dosing regimens and consistent efficacy outcomes.