Skin Care & The Wound Clinic: Increasing Skin Nutrition with Small Molecule Technology to Promote Healing of Diabetic Foot Ulcers

Diabetes mellitus has been described as “one of the main threats to human health of the 21st century.”¹ According to the most recent (2012) estimate from the American Diabetes Association, 29.1 million Americans live with diabetes.² The percentage of Americans with diagnosed (or undiagnosed) diabetes continues to rise, and the number of people living with type 2 diabetes is likely to reach epidemic proportions, due in part to poor lifestyle choices such as the consumption of processed foods and poor nutrition habits placing an increasing population at risk.³ In fact, one study projects as many as one in three Americans will live with diabetes by 2050.⁴ Diabetes is frequently undiagnosed due to many symptoms being ignored, including frequent urination, increased fatigue, and irritability.⁵ Other early warning signs include certain skin issues.^6,7 In fact, at least 30% of patients experience some skin complication, and patients living with diabetes frequently have wounds that are difficult to heal.^5,6,8 Hyperglycemia affects skin homeostasis by inhibiting fibroblast cell migration,^9,10 keratinocyte proliferation, differentiation, migration, and protein biosynthesis, as well as by inducing endothelial cell apoptosis. Hyperglycemia also decreases immune cell functions, including phagocytosis and chemotaxis, and the prevalence of skin infections is frequently increased among diabetes patients.^8,11 In addition, patients living with diabetes have up to a 25% lifetime risk of developing a diabetic foot ulcer (DFU),¹² and DFUs are a leading cause of morbidity that is often preceded by pain, suffering, and poor quality of life for these patients. Furthermore, DFUs are the cause of 84% of all diabetes-related lower leg amputations.¹³

Increasing Skin Nutrients, Decreasing Oxidative Stress 

Hyperglycemia can also lead to decreased nitric oxide synthesis¹¹ that is required for wound healing and can result in impaired blood flow through critical small vessels at the wound surface.⁵ Poor circulation decreases oxygen and other vital nutrient flow to the skin tissues, making patients living with diabetes more susceptible to skin damage, as well as contributing to impaired wound healing.¹⁴ 

Providing nutrients to skin to help strengthen skin and improve wound healing is critical. Impaired skin nutrition decreases skin integrity and functioning, as well as wound healing capability, by affecting the skin barrier and microvascular, as well as immune systems of skin.^15,16 Additionally, skin irritation and prolonged oxidative stress and inflammation frequently associated with diabetes can lead to impaired wound healing.¹⁷ Identifying skin care regimens that address the compromised nutritional status of the skin and that are transferable across various care settings will be an important component in assuring adherence to approved therapy, whether care is conducted in the clinic or at home.¹⁸ Topical small molecule technology (found in Viniferamine^® skin and wound care products, McCord Research, Coralville, IA) that provides penetrating nutrition to skin has been used to improve patient outcomes in the diabetic wound care setting.¹⁹ An option that may be considered among clinicians in the outpatient setting for patients who will require continued skin and wound care at home is the use of AtHome^™ Viniferamine Diabetic Skin Care specialty kits (incorporating small molecule technology) that provide hospital-grade skin care products and protocols and are easily acquired through retailers. AtHome Viniferamine products contain vital skin nutrients that decrease inflammation and oxidative stress. In fact, these products contain many ingredients that counteract oxidative stress, including the important small molecule polyphenols oleuropein, resveratrol, and epigallocatechin-3-gallate (EGCG) from olives, grapes, and green tea, respectively, as well as L-carnosine, melatonin, and L-glutathione.^20-25 Several of these ingredients also decrease inflammation, including oleuropein, resveratrol, EGCG, melatonin, carnosine and L-glutathione.^{20,22,23,26-28} Additionally, asiaticoside in titrated extracts of Centella asiatica (TECA); dipotassium glycyrrhizate from licorice; and avenanthramides in oats, aloe vera, panthenol, and shea butter possess anti-inflammatory activities.^29-34 

During normal healing, microvascular endothelial cells migrate to form new blood vessels (angiogenesis) in response to wounds. Oxidative stress induced by hyperglycemia can result in endothelial dysfunction and wound healing impairment.³⁵ Oleuropein has been shown to restore function in endothelial progenitor cells.³⁶ In addition, resveratrol and EGCG have been shown to inhibit endothelial dysfunction and enhance wound healing.^37-39 Hyperglycemia associated with diabetes can also result in the production of advanced glycation end products (AGEs), which are highly stable, cross-linked complexes of proteins and glucose. AGEs have been shown to induce collagen crosslinking that leads to decreased elasticity in skin and blood vessels.^40,41 AGEs are also involved in diabetes-related immunosuppression that affects wound healing via impaired leukocyte functioning and the imbalance or dysfunction of growth factors.¹¹ Moreover, interactions between AGEs and their receptors are thought to produce oxidative stress.⁴¹ Interestingly, several nutrients have been found to inhibit AGEs and protein glycation, including vitamins C, E, B3, B6, and carnosine.^23,42 AtHome products contain beneficial vitamins, including vitamins C and E from aloe vera and oat extracts, as well as vitamin B3 (nicotinamide or niacinamide) and vitamin B6 (pyridoxine), both of which have been shown to have antioxidant activities.^43,44 Beneficial vitamins included in the products also have anti-inflammatory and/or wound healing activities, including vitamins C, B3, and D.^15,45 Moreover, vitamin D has been shown to improve skin immunity by stimulating the important antimicrobial peptide cathelicidin.¹⁵ 

DFUs, Optimal Nutrition, & Improved Wound Healing

DFUs do not follow the orderly process of normal wound healing that requires a well-orchestrated integration of complex biological events (including cell migration, cell proliferation, and extracellular matrix [ECM] deposition).¹⁴ Collagen, the most abundant protein found in tissues such as skin, cartilage, and ligaments, plays an important role in wound healing due to its ability to provide tensile strength to wounds. In addition, collagen modulates critical inflammatory and wound healing processes by binding to receptors that activate other molecules involved in tissue remodeling and repair, including matrix metalloproteases, cytokines, and growth factors.^46,47 

Optimal nutrition is vital for human health and every cellular function is nutrition-dependent, including those involved in wound healing.⁴⁸ Suboptimal nutrition can affect immune function and collagen synthesis. When optimal skin nutrition cannot be provided by blood circulation due to diabetes-related microvascular compromise or malnutrition related to aging or obesity (frequently associated with diabetes), nutrition should be provided topically. Nutrient-rich extracts of TECA and aloe vera stimulate collagen synthesis and enhance wound healing. Other ingredients found in the products discussed in this article that have also been shown to promote wound healing include oleuropein, L-carnosine, nicotinamide (niacinamide), L-glutathione, asiaticoside and aloe vera.^{25,36,45,49,50-52} Hyaluronic acid (HA) plays a vital role in wound healing and is important for maintaining tissue homeostasis and angiogenesis.⁵³ HA is a structural component of the ECM, a complex interlocking meshwork found outside of skin cells that includes fibrous proteins such as collagen, elastin, and fibronectin.⁵⁴ HA has been found to be effective for treating DFUs and has been shown to accelerate DFU healing.⁵⁵ AtHome skin products contain ingredients (including dipotassium glycyrrhizate and aloe vera) that help maintain natural levels of HA. Many of the ingredients contained in the products have been found to specifically promote diabetic wound healing, including oleuropein, resveratrol, EGCG, asiaticoside, and L-carnosine.^56-60

Summary

DFUs frequently result in a decreased quality of life. Understanding how increased skin nutrition provided by small molecule technology can help prevent DFUs and promote DFU healing can aid clinicians in adapting their care plans to benefit their patients. Utilizing specialized skin care kits such as AtHome Viniferamine Diabetic Skin Care can be a determining factor in preventing DFUs and potential amputations, and can be an effective method to continue clinical care plans across different care settings, including in the clinic and at home. 

D. Elizabeth McCord, senior researcher at McCord Research, Coralville, IA, is a renowned biochemist in the field of skin and wound care. She has been awarded six patents and two medical devices, and has more than 60 health products marketed globally. She previously commercialized wound and skin care products under the Remedy^® Olivamine^® brand. 

Kyle D. Hilsabeck is vice president of pharmaceutical affairs at McCord Holdings and licensed by the Iowa Board of Pharmacy. He completed bachelor’s degrees in biology and biochemistry at Wartburg College, and his doctorate at the University of Iowa College of Pharmacy. He completed a community pharmacy residency through the University of Iowa and taught for the University of Iowa College of Pharmacy. 

Nancy B. Ray is science officer at McCord Research. She currently writes and presents on diabetes, skin care, and other topics to advance skin care and wound healing awareness. She received her PhD in biochemistry and biophysics at Oregon State University and was a postdoctoral fellow at the National Institutes of Health, Harvard University, Dana-Farber Cancer Institute, and the University of Iowa. She also earned bachelor’s degrees in chemistry and microbiology from the University of Montana.

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