Synergistic CO2 Cryotherapy and EGF Delivery for Accelerated Wound Healing Through Anti-Inflammatory and Regenerative Pathways

Int J Mol Sci. 2025 Sep 10;26(18):8796. doi: 10.3390/ijms26188796.

Abstract

Wound healing remains a significant clinical challenge worldwide, and effective management strategies are essential for improving outcomes. This study investigates the therapeutic potential of the AcuCool™ system, a novel multifunctional device that combines high-velocity CO2 cryotherapy with intradermal delivery of epidermal growth factor (EGF), in promoting wound healing. Using a full-thickness skin wound model in Sprague Dawley rats, we compared the effects of Device+EGF treatment to those of conventional microneedling-based EGF delivery and untreated controls. Macroscopic assessments revealed significantly accelerated wound closure in the Device+EGF group. Histological analysis showed enhanced re-epithelialization, reduced inflammatory cell infiltration, and increased collagen deposition. Molecular evaluations further demonstrated downregulation of pro-inflammatory markers (TNF-α, IL-1β, MCP-1) and upregulation of remodeling-related genes including TGF-β1, Collagen I, and Vimentin. In addition, nitrite assays confirmed reduced local nitric oxide levels, indicating suppression of oxidative stress. The AcuCool™ platform offers precise, non-invasive drug delivery with dual physical and biochemical therapeutic mechanisms, enabling superior control of inflammation and tissue regeneration. These findings suggest that AcuCool™ represents a promising therapeutic strategy for accelerating wound healing in acute models. While further studies are warranted in chronic wound settings, this approach may hold translational potential for future clinical applications.

Keywords: CO2 cryotherapy; anti-inflammatory therapy; epidermal growth factor; transdermal drug delivery; wound healing.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents* / pharmacology
  • Carbon Dioxide* / pharmacology
  • Cryotherapy* / methods
  • Epidermal Growth Factor* / administration & dosage
  • Epidermal Growth Factor* / pharmacology
  • Inflammation
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Regeneration* / drug effects
  • Skin / drug effects
  • Skin / injuries
  • Skin / metabolism
  • Wound Healing* / drug effects

Substances

  • Epidermal Growth Factor
  • Carbon Dioxide
  • Anti-Inflammatory Agents