Combating The Impact Of Oxygen Free Radicals On DFU Healing

For those with diabetes, careful management of blood sugar is imperative to prevent any number of complications, including those that contribute to poor wound healing, which is so common in diabetes.

   One such problem is the development of foot ulcers, which reportedly affects 15 percent of individuals with diabetes.1,2 Diabetic foot ulcers are significant problems as they can lead to amputation of a patient’s foot or even the entire leg.1 In fact, more than half of the people who undergo lower limb amputations in the United States each year suffer from diabetes.3

   Due to the serious issue of wound healing in patients with diabetes, it is important for those living with the disease to understand the nature of foot wounds and the current technology available in wound care. This technology includes new treatments that can promote fast healing and prevent wounds from becoming chronic.

   While foot ulcers can sometimes be shallow, they are often quite thick, extending through multiple skin layers. These wounds usually have low oxygen levels due to poor circulation (ischemia) or include injury to the nervous system (neuropathy). Uncontrolled blood sugar levels can lead to both. Once a foot ulcer occurs, ischemia can lead to slow healing and tissue death while the neuropathic loss of sensation can cause the wound to go unnoticed and untreated. In patients with diabetes, foot ulcers often become chronically non-healing wounds and 85 percent of amputations are preceded by ulceration.2

   Other diabetic conditions can exacerbate these ulcers. Approximately 60 to 70 percent of patients with diabetes develop diabetic neuropathy.4 This is a form of nerve damage caused by prolonged abnormal elevations in blood sugar. Diabetic neuropathy places a person at significant risk for the development of foot ulcers as the nerve damage decreases the sensation in the foot. Patients with diabetic neuropathy can no longer sufficiently detect trauma as their pain sensation is blunted. It is common for a patient with diabetic neuropathy to walk all day on a blister or not notice the pain from a needle or nail that has punctured his or her foot. Accordingly, the wound goes untreated and may become more serious as a result.

   Those with diabetes frequently experience poor blood flow to their legs, feet and toes due to another complication of diabetes, peripheral arterial disease (PAD), the narrowing of the blood vessels that carry blood to the legs. Such circulation issues can make skin injuries worse or prevent healing in patients with diabetic foot ulcers. Decreased blood flow results in ischemia (the limitation of oxygen delivery to the tissues) or hypoxia (abnormal oxygen levels in blood and tissue).4 Since oxygen is a necessary component of cell regeneration, ischemic and hypoxic tissue is less likely to heal, and is also at higher risk for infection.

   The combination of neuropathy and PAD often results in foot ulcers that deteriorate rather than heal. Complications related to chronic diabetic foot ulcers include cellulitis, osteomyelitis and gangrene. All of these issues place the patient with diabetes at a high risk for amputation, making aggressive and early treatment of such foot wounds essential.

Do Traditional Treatments Address The Underlying Causes Of DFUs?

Traditionally, several different methods have been used to treat diabetic foot wounds or ulcers. Physicians sometimes prescribe casts and bed rest to reduce pressure and repeated trauma. While preventing additional injury is important, this does not help circulation or actual healing.

   While topical antibiotics can help prevent infection, they do not necessarily speed healing. Furthermore, overuse of antibiotics can lead to antibiotic resistance, which can be a serious problem for those with diabetes.

   Moist dressings are helpful in creating a moist environment that can promote better healing than dry dressings.1 Whirlpool therapy is sometimes effective to clean wounds and stimulate circulation, particularly in necrotic wounds with high levels of exudate.5

   Even aggressive treatments with these procedures do not fully address or correct the underlying cause of diabetic foot ulcers. Neuropathy, tissue ischemia, tissue hypoxia and excess oxygen free radicals continue to place the patient with diabetes at risk for deterioration of the foot ulcers and ultimately at risk
for amputation.3

How Oxygen Free Radicals Impact Diabetic Wound Healing

Oxygen is an important part of good healing. By contrast, the healing process often generates oxygen free radicals, which can cause inflammation and slow healing, and can destroy surrounding healthy tissue.6,7 In healthy individuals, the cell damaging effects of oxygen-derived free radicals is mitigated by antioxidant defense and scavenging systems.6

   However, the presence of diabetes forces the oxidant/antioxidant balance into disequilibrium.6 Nonenzymatic protein glycosylation and glucose auto-oxidation are the two most cited factors that can disrupt the control of oxygen free radicals and antioxidants in patients who have diabetes. Diabetic wound healing can be so significantly compromised that mortality rates are very high with chronic foot wounds. In fact, up to 25 percent of all hospital admissions involving patients with diabetes are related to foot complications, including ulcers.8

   Combined with ischemic and neuropathic complications, the introduction of uncontrolled oxygen free radicals further serves to compromise patients with diabetes. Oxygen free radicals can cause damage at the cellular level, which can make treating diabetic foot wounds through traditional methods even less effective. However, there are some effective treatments to help re-oxygenate the wound and minimize the damage caused by radicals.

   Researchers have studied the effect of hypoxia in those with diabetes at length. Furthermore, diabetes results in many complications and cellular discrepancy, including the reduced ability to produce antioxidants, leading to an oxygen free radical imbalance. Numerous studies have shown a direct correlation between delayed wound healing and the presence of excess oxygen free radicals.9 Excessive amounts of reactive oxygen molecules can lead to exacerbation of diabetic foot disease, deterioration of foot ulcers and refractory healing of these wounds. Ultimately, the patient with diabetes is at high risk for amputation and extreme rates of morbidity.

A Closer Look At Modalities That May Address Oxygen Issues In Wound Healing

In order to mitigate the damaging effects of oxygen free radicals and to offset the complications of hypoxia and ischemia often present with diabetic foot ulcers, an increasingly popular treatment is hyperbaric oxygen therapy (HBOT).10 During hyperbaric treatment, the patient breathes 100 percent oxygen while being exposed to increased atmospheric pressure.3,10,11 An effective wound healing treatment for over 40 years, HBOT helps bring the healing effects of oxygen to a wound while decreasing inflammation, assisting white blood cells and helping to kill bacteria.3 While HBOT is often effective, it is time consuming and expensive as it often requires up to 30 treatments. Accordingly, the use of HBOT is typically limited to treating patients with infections or gangrene, who are at extreme risk for limb loss.12

   Wounds that heal quickly heal the most efficiently and with the fewest complications.13 It is clear that newer and alternative treatments are necessary for the proper, expeditious treatment of the diabetic foot. Novel therapies for the control of oxygen free radicals are under investigation. Topical gels with oxygen free radical scavenging properties have been developed and approved for patient use.

   One of these therapies is Wound-Be-Gone (Wake Pharma), which includes FDA approved ingredients that bind with oxygen free radicals and neutralize them while simultaneously facilitating a moist healing environment to help speed healing time. Authors have demonstrated clinically that this therapy stabilizes the inflammation associated with diabetic foot ulcers and other wounds, and contributes to improved wound healing.7 While this novel therapeutic option has promise, additional research regarding this technology is warranted.

Final Notes

Given the need to facilitate more rapid closure of diabetic foot wounds, the continued development of adjunctive modalities to help address the problematic impact of oxygen free radicals is key. Further research in this area is encouraged and may ultimately aid physicians and clinicians in thwarting complications such as hypoxia and ischemia, and facilitating improved outcomes in a high-risk population.

   Dr. Niezgoda is the Medical Director of the Centers for Comprehensive Wound Care and Hyperbaric Oxygen Therapy at Aurora Health Care in Milwaukee. He is the President and Chief Operating Officer of Hyperbaric and Wound Care Associates in Milwaukee.

   Dr. Eldridge practices at Rush Hospital Wound Care, Hyperbaric and Limb Salvage Center in Meridian, Miss.

   Dr. Mills is an Associate Professor in the Department of Physiology and Biophysics at the Howard University College of Medicine in Washington, D.C.

   Dr. Kondiles practices at Chicagoland Foot Care at the Center for Wellness and Neuropathy in Chicago. He is a Fellow of the American College of Foot and Ankle Surgeons.

   Dr. Snarski is a professor at Capella University in Minneapolis and teaches research skills to graduate level technology students.

   Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.

   Editor’s note: For related articles, see “Key Insights On Using Hyperbaric Oxygen For Wounds” in the January 2010 issue of Podiatry Today or “Is There A Role For HBOT In Limb Salvage?” in the August 2008 issue.

References:

1. Columbia University Medical Center (CUMC). (2007). Wound healing. Available online at https://www.columbiasurgery.org/cli/wound/foot_ulcer.html 2. Edmonds M, Foster A, Sanders L. A practical manual of diabetic foot care, 2004. Blackwell Publications, Malden, Mass. 3. National Hyperbaric Oxygen Therapy (NHOT). Wound management and hyperbaric oxygen, 2008. Available online at: https://www.diabeticinjury.com 4. Grieger L. Nutrition and wound care. Today’s Dietitian 2009; 11(8):12. 5. Sussman C, Bates-Jensen B. Wound care: Collaborative practice manual for physical therapists and nurses, 1998. Aspen Publishers, Gaithersburg, Md. 6. Carrascosa A, Domingues C, Gussinye M, Ruiz E. Oxidative stress at onset and in early stages of type 1 diabetes in children and adolescents. Diabetes Care 1998; 21(10):1736-1742. 7. Niezgoda JA, Yeager DA, Gumbiner BR. Novel hydrophilic gel (Wound-Be-Gone®) enhances healing via oxygen free radical binding technology. Poster presented at 23rd Annual Symposium on Advanced Wound Care And Wound Healing Society. Gaylord Palms Hotel and Convention Center, Orlando, Fla. Poster available at: www.woundbegone.com/clinical_posters.html 8. Sheppard M. Diabetic foot ulcers: Tip of the iceberg. Available online at: https://www.savannahvascular.com/home.cfm/page/Articles/article/17/Diabe…. 9. Senel O, Cetinkale O, Ozbay G, Ahcioglu F, Bulan R. Oxygen free radicals impair wound healing in ischemic rat skin. Ann Plast Surg 1997; 39(5):516-523. 10. Latham E, Hare M, Neumeister M. Hyperbaric oxygen therapy, 2008. Available online at: https://emedicine.medscape.com/article/1464149-overview 11. Heyneman C, Lawless-Liday C. Using hyperbaric oxygen to treat diabetic foot ulcers: Safety and effectiveness. Critical Care Nurse 2002; 22(6):52-60. 12. Hao L. Diabetic foot. Transcript available online at: https://www.authorstream.com/Presentation/aSGuest12035-145913-diabetic-f… 13. Garg H, Siebert JW. Chemistry of scarring. In Garg H, Longaker M (eds.): Scarless wound healing, 2000, Chapter 1. Marcel Dekker, New York.