Transcutaneous CO₂ Therapy in Recurrent Hard-to-Heal Diabetic Foot Ulcers

Recurrent and hard-to-heal diabetic foot ulcers (DFUs) represent a clinically challenging subgroup with delayed closure and frequent non-response to standard of care (SOC). Impaired local perfusion and superficial tissue hypoxia, commonly attributed to microcirculatory dysfunction, are proposed contributors to impaired wound-bed progression and prolonged healing trajectories in diabetes. Transcutaneous gaseous carbon dioxide (CO₂) therapy is a non-invasive adjunct intervention with a mechanistic rationale to modulate local microcirculation and tissue oxygenation; however, controlled clinical evidence in recurrent, hard-to-heal DFUs remains limited. This prospective, randomized, controlled, open-label, parallel-group clinical investigation compares transcutaneous CO₂ therapy plus SOC versus SOC alone over 4 weeks. The primary objective is to determine whether the proportion of completely healed DFUs at Week 4 differs between groups under a predefined healing confirmation procedure. Key secondary objectives include quantifying changes in superficial tissue oxygenation (StO₂) using hyperspectral imaging and assessing pain intensity (NPRS). Supportive outcomes include ulcer area reduction metrics and wound-bed appearance in unhealed.

Study Overview

• Status: Completed
• Conditions: Ulcer Foot
• Intervention / Treatment: Other: transcutaneous application of gaseous CO2 on lower part of the body

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Slovenia
  • Slovenia
    • Ljubljana, Slovenia, Slovenia, 1000
      • UMC Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• diabetes mellitus type 1 or 2
• recurrent hard to heal DFU

Exclusion Criteria:

• KOPD stage IV
• CKD stage IV
• malignant diseases
• pregnancy
• infected ulcer at baseline
• inability to comply with visits

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard of care + CO2 therapy; Standard of care (3 times weekly) + transcutaneous gaseous CO2 therapy 20 times (every weekday for 50 minutes)	Other: transcutaneous application of gaseous CO2 on lower part of the body; Participants in the intervention group received SOC alongside 20 sessions of CO₂ therapy. These 50-minute sessions were administered once daily on weekdays (Monday-Friday) over a 4-week period. CO₂ therapies were performed using the medical device. The participant's lower body was sealed in a single-use, biocompatible, medical-grade wrap. The wrap was filled with medical-grade CO₂ to a 99.9% concentration for a 50-minute session. After 50 minutes, CO₂ was pumped out and the wrap removed.
No Intervention: Standard of care; Standard of care (3 times weekly)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
complete ulcer healing	full epitelization without exudate confirmed at 2 consecutive exams	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in StO2	StO₂ (%) will be measured using Hyperspectral Imaging (by TIVITA HSI device) at baseline and weeks 1, 2, 3, and 4. The outcome is change from baseline in StO₂ (%). Higher values indicate better tissue oxygenation/perfusion.	4 weeks
change in pain intensity (NPRS)	Change from baseline in pain intensity assessed by the Numeric Pain Rating Scale (NPRS)Outcome Measure Description: Pain intensity will be self-reported using the Numeric Pain Rating Scale (NPRS), an 11-point scale from 0 = no pain to 10 = worst imaginable pain. The outcome is change from baseline in NPRS score at week 4.	4 weeks

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana

Publications and helpful links

General Publications

• Finzgar, M., Melik, Z., in Cankar, K. (2015). Effect of transcutaneous application of gaseous carbon dioxide on cutaneous microcirculation. Clinical Hemorheology and Microcirculation, 60(4), 423-435. https://doi.org/10.3233/CH-141898
• Macura, M., Ban Frangež, H., Cankar, K., Finžgar, M., in Frangež, I. (2020). The effect of transcutaneous application of gaseous CO2 on diabetic chronic wound healing-A double-blind randomized clinical trial. International Wound Journal, 17(5), 1182-1190. https://doi.org/10.1111/iwj.13436

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Actual): March 20, 2025
• Study Completion (Actual): August 30, 2025

Study Registration Dates

• First Submitted: February 10, 2026
• First Submitted That Met QC Criteria: February 10, 2026
• First Posted (Actual): February 18, 2026

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 22, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: microcirculation; Diabetic foot ulcer; CO2 therapy
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetic Angiopathies; Diabetes Complications; Skin Diseases; Skin Ulcer; Leg Ulcer; Diabetic Neuropathies; Foot Diseases; Skin and Connective Tissue Diseases; Diabetic Foot; Foot Ulcer
• Other Study ID Numbers: NM-DVS-CO2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No