Promoting Re-Epithelialization in Diabetic Foot Wounds Using Integrative Therapeutic Approaches
Abstract
1. Introduction
1.1. Epidemiology of Diabetes Mellitus
1.2. Diabetic Foot Complications
1.3. Pathophysiological Mechanisms of Impaired Healing
1.4. Current Therapies and Limitations
- Metabolic control: strict regulation of blood glucose level and associated metabolic risk factors.
- Wound care procedures: cleaning, antisepsis, debridement, and appropriate dressings.
- Surgical interventions: ranging from minor drainage to amputations in severe, non-salvageable cases.
- Patient education: focusing on hygiene, protective footwear, and early recognition and reporting of lesions.
- Adjunctive therapies: such as hyperbaric oxygen therapy (HBOT), growth factors, or bioengineered skin substitutes.
1.5. Rationale and Aim
2. Materials and Methods
2.1. Study Group
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- Grade 0: Skin intact, but the foot is “at risk” due to existing bony deformities;
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- Grade 1: Superficial ulcer, involving only the skin and subcutaneous tissue;
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- Grade 2: Deep ulcer with full-thickness extension;
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- Grade 3: Deep ulcer with abscess or osteomyelitis;
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- Grade 4: Partial gangrene of the foot;
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- Grade 5: Extensive gangrene.
2.2. Study Design
- Initial session: colon hydrotherapy, followed by rectal ozone insufflation (20 µg/mL, one session/week for 3 weeks, then every 2 weeks for 4 weeks), administration of oral probiotics, and adoption of an anti-inflammatory alkaline diet.
- Subsequent sessions (twice weekly):
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- Wound antisepsis and lavage with ozonized water;
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- Wound debridement (performed only at the first session);
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- Antibiotic therapy strictly guided by antibiogram results;
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- Local ozone therapy: limb bagging (70 µg/mL for 3–4 sessions, then gradually reduced to 40 µg/mL) and perilesional infiltrations (5–10 µg/mL);
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- Systemic ozone therapy: major autohemotherapy with 120–150 mL venous blood ozonated at 25–35 µg/mL, provided systolic BP ≤ 160 mmHg;
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- Wound dressing with sterile compresses and ozonated olive oil at the end of each procedure;
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- Pulsed electromagnetic field therapy (20–70 Hz, 10–15 Gauss, 30 min/session, 2 sessions/week), adapted to wound-healing phase.
- Phase I—Inflammatory phase: 70–100 Hz, providing anti-inflammatory and analgesic effects by decreasing pro-inflammatory cytokines (TNF-α, IL-1β) and improving microcirculation (~1 week) [56].
- Phase III—Tissue maturation and remodeling: 20–30 Hz to promote cellular metabolism and collagen synthesis; toward the final stage, 70 Hz was applied for its anti-inflammatory effect and to improve collagen quality, extracellular matrix remodeling, and re-epithelialization (>3–4 weeks) [59].
2.3. Statistical Analysis
3. Results
3.1. Participant Flow and Analysis Set
3.2. Baseline Characteristics
3.3. Primary Outcome: Ulcer Healing
3.4. Secondary Outcomes
3.4.1. Glycemic Control (Fasting Blood Glucose)
3.4.2. Glycated Hemoglobin (HbA1c)
3.4.3. Inflammatory and Coagulation Markers
- CRP: 6.16 ± 0.54 mg/L vs. 7.54 ± 0.69 mg/L (p < 0.001) at 4 weeks, and 5.59 ± 0.46 mg/L vs. 7.55 ± 0.62 mg/L (p < 0.001) at 8 weeks.
- Fibrinogen: 329.0 ± 26.5 mg/dL vs. 403.9 ± 46.0 mg/dL (p < 0.001) at 4 weeks, and 293.1 ± 23.3 mg/dL vs. 406.3 ± 43.6 mg/dL (p < 0.001) at 8 weeks.
3.4.4. Weight and BMI
3.5. Microbiology and Antibiotic Use
3.6. Safety and Tolerability
4. Discussion
4.1. Summary of Main Findings
4.2. Mechanistic Interpretation
4.3. Comparison with Existing Literature
4.4. Clinical Implications
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- Reduce healing time and accelerate re-epithelialization.
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- Lower systemic inflammation and improve metabolic control.
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- Reduce antibiotic use and potentially decrease amputation risk.
5. Limitations
6. Suggestions for Research
7. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
DM | diabetes mellitus |
WHO | World Health Organization |
IDF | International Diabetes Federation |
DFS | diabetic foot syndrome |
DFU | diabetic foot ulcers |
MMPs | matrix metalloproteinases |
AGEs | advanced glycation end-products |
NO | nitric oxide |
GM-CSF | granulocyte–macrophage colony-stimulating factor |
EGF | epidermal growth factor |
KGF-2/FGF-10 | keratinocyte growth factor-2/paracrine growth factor 10 |
bFGF/FGF-2 | basic fibroblast growth factor |
NPWT | negative pressure wound therapy |
HBOT | hyperbaric oxygen therapy |
PEMF | pulsed electromagnetic field |
VEGF | vascular endothelial growth factor |
FBG | fibrinogen |
ESR | erythrocyte sedimentation rate |
CRP | C-reactive protein |
BMI | body mass index |
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Group | Intervention | No. of Patients |
---|---|---|
G1-Control | Standard treatment (debridement, dressings, antibiotics when indicated by wound culture and antibiogram) + local and general ozone therapy | 14 |
G2-Protocol | Standard treatment + local and general ozone therapy + probiotic hydrocolonotherapy + alkaline diet + PEMF (20–70 Hz) | 14 |
Parameter | Control Group (n = 14) | Intervention Group (n = 14) | p-Value |
---|---|---|---|
Age (years) | 61.4 ± 8.2 | 60.7 ± 7.9 | 0.78 |
Male/Female | 8/6 | 9/5 | 0.68 |
Diabetes type I/II | 4/10 | 5/9 | 0.71 |
Duration of diabetes (years) | 12.3 ± 6.1 | 13.0 ± 5.8 | 0.65 |
Ulcer area (cm2) | 11.79 ± 5.41 | 13.00 ± 6.04 | 0.58 |
Fasting blood glucose (mg/dL) | 191.1 ± 25.4 | 183.8 ± 21.6 | 0.42 |
HbA1c (%) | 7.67 ± 2.09 | 8.02 ± 0.75 | 0.56 |
Weight (kg) | 84.4 ± 4.0 | 83.8 ± 4.0 | 0.67 |
BMI (kg/m2) | 25.9 ± 10.1 | 30.0 ± 1.6 | 0.15 |
CRP (mg/L) | 7.49 ± 0.64 | 7.05 ± 0.53 | 0.06 |
Fibrinogen (mg/dL) | 399.9 ± 48.1 | 369.5 ± 32.2 | 0.06 |
Timepoint | Control | Intervention | p-Value |
---|---|---|---|
Baseline | 11.79 ± 5.41 | 13.00 ± 6.04 | 0.58 |
4 weeks | 7.93 ± 4.14 | 5.79 ± 2.19 † | 0.009 |
8 weeks | 4.93 ± 3.41 | 1.79 ± 1.67 ‡ | 0.005 |
Parameter | Control 4w | Intervention 4w | p-Value | Control 8w | Intervention 8w | p-Value |
---|---|---|---|---|---|---|
Fasting glucose (mg/dL) | 216.6 ± 37.2 | 162.4 ± 16.8 § | <0.001 | 220.4 ± 36.5 | 136.6 ± 9.6 § | <0.001 |
HbA1c (%) | 9.17 ± 1.29 | 6.86 ± 1.86 ‡ | 0.001 | 8.58 ± 2.44 | 6.45 ± 0.45 ‡ | 0.004 |
CRP (mg/L) | 7.54 ± 0.69 | 6.16 ± 0.54 § | <0.001 | 7.55 ± 0.62 | 5.59 ± 0.46 § | <0.001 |
Fibrinogen (mg/dL) | 403.9 ± 46.0 | 329.0 ± 26.5 § | <0.001 | 406.3 ± 43.6 | 293.1 ± 23.3 § | <0.001 |
Weight (kg) | 85.3 ± 4.0 | 82.0 ± 3.8 ‡ | 0.004 | 85.3 ± 3.7 | 79.7 ± 3.7 § | 0.001 |
BMI (kg/m2) | 27.85 ± 7.69 | 29.38 ± 1.56 | 0.475 | 27.66 ± 7.6 | 26.69 ± 7.0 | 0.729 |
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Bubulac, L.; Gheorghe, I.-R.; Ungureanu, E.; Bogdan-Andreescu, C.F.; Albu, C.-C.; Gheorghe, C.-M.; Mușat, O.; Eremia, I.A.; Panea, C.A.; Burcea, A. Promoting Re-Epithelialization in Diabetic Foot Wounds Using Integrative Therapeutic Approaches. Bioengineering 2025, 12, 1053. https://doi.org/10.3390/bioengineering12101053
Bubulac L, Gheorghe I-R, Ungureanu E, Bogdan-Andreescu CF, Albu C-C, Gheorghe C-M, Mușat O, Eremia IA, Panea CA, Burcea A. Promoting Re-Epithelialization in Diabetic Foot Wounds Using Integrative Therapeutic Approaches. Bioengineering. 2025; 12(10):1053. https://doi.org/10.3390/bioengineering12101053
Chicago/Turabian StyleBubulac, Lucia, Iuliana-Raluca Gheorghe, Elisabeth Ungureanu, Claudia Florina Bogdan-Andreescu, Cristina-Crenguța Albu, Consuela-Mădălina Gheorghe, Ovidiu Mușat, Irina Anca Eremia, Cristina Aura Panea, and Alexandru Burcea. 2025. "Promoting Re-Epithelialization in Diabetic Foot Wounds Using Integrative Therapeutic Approaches" Bioengineering 12, no. 10: 1053. https://doi.org/10.3390/bioengineering12101053
APA StyleBubulac, L., Gheorghe, I.-R., Ungureanu, E., Bogdan-Andreescu, C. F., Albu, C.-C., Gheorghe, C.-M., Mușat, O., Eremia, I. A., Panea, C. A., & Burcea, A. (2025). Promoting Re-Epithelialization in Diabetic Foot Wounds Using Integrative Therapeutic Approaches. Bioengineering, 12(10), 1053. https://doi.org/10.3390/bioengineering12101053