A Comparison of Wound Healing Therapies

A Comparison of Wound Healing Therapies:
Transdermal Carbon Dioxide, 
Vacuum Assisted Bandages, Hyperbaric Oxygen,
ESWT, Ozone, and Low Level Laser For Wound Healing

Richard Rivers, M.D., Ph.D
Microvascular Physiologist
Johns Hopkins University
Associate Professor
Baltimore, Maryland

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This paper describes some of the pathophysiology of wound healing. It then presents six published methods for treating the healing wound and defines what each method offers in the treatment of the wound and how it might fit in with a busy veterinarian practice.

Wound healing is a fundamental property of living tissue (5). There are three stages to the healing process. First is the vascular inflammatory stage. During this phase bleeding vessels contract and blood coagulates. This sets off the coagulation cascade and the generation of a fibrin network. This network makes the foundation of a temporary matrix for cell migration while forming a barrier to infection and restoration of skin barrier function. At the same time the inflammatory cascade is triggered with influx of leukocytes and other immune cells. This creates tissue edema and tissue destruction through the release of lysosomal enzymes and reactive oxygen species. The inflammatory cascade also induces the release and attraction of many cytokines. The subsequent influx of neutrophils clean up debris and participate in the death of invading organisms. 

During this stage there is also the release of potent vasodilators such as prostaglandins. Endothelial cells are activated and release PDGF, VEGF, and TGF beta which appear to be critical in the initiation of granulation tissue.

The second stage of wound healing is the proliferative stage. This stage starts within 48 hours and lasts for several weeks. During this stage the lesion is closed through angiogenesis, fibroplasia, and reepithelialization. New blood vessels form that carry fluid, oxygen, nutrients, and immune cells to the healing tissue. More granulation tissues is formed during the second stage. This three-dimensional structure made from fibroblasts, collagen, and elastin, is attracted by integrins on endothelial cells to replace the coagulation found in the lesion. Variation in the healing process is dictated by the inflammatory response of the cells that border the lesion and the unpredictable blend of cytokines that influence migration, proliferation, and cell differentiation. 

Any new tissue will require a blood supply. Thus, angiogenesis must also occur. It is critical for wound healing. The flow of fresh blood through new vessels brings in necessary nutrients, oxygen, and immune-competent cells while carrying away accumulated waste. 

Wound contraction begins during this stage as well. Fibroblasts accumulate at the border of the wound and contract the border towards the center of the lesion. While the edges contract, epithelial cells proliferate and keratinocytes migrate to cover the stroma. Once the surface if covered, the stratified epidermis reforms along with the subjacent basal lamina. Collagens III degrades and is replace by collagen type I. Thus begins remodeling, the third stage of wound healing. 

During the third stage there is an attempt to recover normal tissue structure. Granulation tissue loses its cells and blood vessels to form scar tissue. 

Good and poor healing is influenced by exogenous and endogenous factors. Systemic disorders, such as diabetes, immunosuppression, venous stasis, as well as those resulting from external agents, such as the use of corticosteroid therapy and smoking, can slow the closure of the wound. 

Therapies for wound healing (1)

In most cases, appropriate debridement proper bandaging is adequate for wound healing. On occasion speed of healing and return to function have a high priority. Then, other modalities need to be considered. Wounds on the limbs of horses are especially prone to non-healing and the development of excessive granulation tissue. This dysfunctional healing process has been attributed to occluded micro-vessels and the imbalance of cell apoptosis that prevents to efficient removal of excess fibroblasts. (3) 

Thus, treatment with modalities that improve tissue flow and oxygenation should be predicted to have a positive effect on wound healing. Various adjuncts have been proposed for improving the healing of “difficult to treat” wounds. This may be due to pressure points, diabetes, chronic non-healing conditions (rubbing or movement).

Transdermal carbon dioxide gas therapy

  • Wound is debrided and may or may not be covered with a dressing

  • Plastic cover placed over the wound and nearby skin

  • Air is evacuated from the cover

  • Moist carbon dioxide gas is instilled and allowed to diffuse into the tissue and wound

  • Increases in tissue blood flow and tissue oxygenation

  • Generates new blood vessels

  • Well oxygenated tissues are more effective for antibiotic therapy and PMNs. This is balanced by the anti-oxidant effect of carbon dioxide itself

  • Improves wound healing (2, 11)

Vacuum dressings

  • Wound is debrided, edges are dried, occlusive dressing is applied, suction is applied and negative pressure is maintained over the wound.

  • Pain during initial vacuum – need sedation.

  • Benefits – wound coverage, controlled exudate drainage, improved second intention, skin graft adherence, vacuum has less bulky bandage, deceased bacteria in wound bed.

  • Diminution of peri-wound edema removes edema and allows for better blood flow and capillary formation.

Hyperbaric oxygen therapy

  • Whole body enters a chamber where it is exposed to 1.5 – 3 atmospheric pressures of oxygen.

  • Mechanical force of pressure affects response.

  • Increased oxygen in the tissue. Oxygen dissolved in plasma is more than that in red cells.

  • Causes vasoconstriction and decreased blood flow – esp. brain, retina, skeletal muscle.

  • Bacteriostatic and bactericidal.

  • HBOT reverses hypoxia in tissue to decrease inflammation and make leukocytes more effective.

  • Increased tissue oxygen increases superoxides. Well oxygenated tissues are more effective for antibiotic therapy and PMNs.

  • Angiogenesis – mixed results for detecting VEGF. Some studies show improved healing in five days. Angiogenesis is part of normal healing process.

Extracorporeal shock-wave therapy

  • Metal hammer taps on the tissue with variable focusing tips and pressure on the tissue.

  • Treatment is variable and unpredictable (7)

  • Treats a few square centimeters with each application; treating entire wound is slow

  • Studies are difficult to interpret due to lack of details and difficult to reproduce treatments

  • Preliminary studies show positive findings for treating chronic wounds (12)

Ozone

  • Ozone is very highly reactive compound that will generate free radicals and oxidize tissue components and can be toxic if it is inhaled. It readily kills bacteria. 

  • Oxidizes molecules in the first layer of skin, then byproducts diffuse deeper to cause other biological effects. The superficial effects are reported to be sufficient for treating diabetic ulcers and chronic wounds although additional studies are needed to be conclusive.4,6,8

  • Multifarious mechanisms will treat some skin diseases, yet can cause skin damage with if concentration is not well controlled, or applied for too long. (10)

Photobiomodulation - Low level laser therapy

  • Mechanisms of action is the red or infrared light activates the electron transport chain embedded in the inner membrane of the mitochondria to generate non-specific biological responses. For example, there can be an increase in the production of adenosine triphosphate (ATP), a release of nitric oxide (NO) and reactive oxygen species (ROS), and the advent of numerous biochemical events that can affect cellular functions. Reported reduction of pain and inflammation and healing of tissue.(9) 

  • Superficial response – laser depth is variable and depends on skin pigments and scattering of the beam. Deep therapy requires long exposures that risk damage from heat and have a less predictable response.

  • Requires training to learn how to treat. Variables of beam intensity, beam size, wavelength, treatment duration and frequency, need to be considered.

  • Large wounds require a prolonged treatment times.

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References

  1. Alford CG, Caldwell FJ and Hanson R. Equine distal limb wounds: new and emerging treatments. Compendium (Yardley, PA) 34: E5, 2012.

  2. Brandi C, Grimaldi L, Nisi G, Brafa A, Campa A, Calabrò M, Campana M and D'Aniello C. The role of carbon dioxide therapy in the treatment of chronic wounds. In vivo (Athens, Greece) 24: 223, 2010.

  3. Dubuc V, Lepault E and Theoret CL. Endothelial cell hypertrophy is associated with microvascular occlusion in horse wounds. Canadian journal of veterinary research  Revue canadienne de recherche vétérinaire 70: 206-210, 2006.

  4. Gonzalez, ACO, Costa TF, Andrade ZA and Medrado, ARAP. Wound healing - A literature review. Anais Brasileiros de Dermatologia 91: 614-620, 2016.

  5. Kristin Dietz-Laursonn, Rainer Beckmann, Siegfried Ginter, Klaus Radermacher and Matias de la Fuente. In-vitro cell treatment with focused shockwaves-influence of the experimental setup on the sound field and biological reaction. Journal of Therapeutic Ultrasound 4: 10, 2016.

  6. Riegel RJ. Laser Therapy for the Treatment of Equine Wounds. In: Laser Therapy in Veterinary Medicine, editied by Riegel R. Hoboken, NJ, USA: John Wiley & Sons, Inc, 2017, p. 375-389.

  7. Wollina U, Heinig B and Uhlemann C. Transdermal CO2 Application in Chronic Wounds. The International Journal of Lower Extremity Wounds 3: 103-106, 2004.

  8. Zhang L, Weng C, Zhao Z and Fu X. Extracorporeal shock wave therapy for chronic wounds: A systematic review and meta‐analysis of randomized controlled trials. Wound Repair and Regeneration 25: 697-706, 2017.