A Guide To Current And Emerging Topical Therapies For DFUs

Topical therapies for diabetic foot ulcers run the gamut from dressings and negative pressure wound therapy to hypochlorous acid and an anti-inflammatory resin derived from bees. These authors discuss the efficacy of various topical agents and the potential of newer therapies. 

Diabetic foot ulcers (DFUs) can lead to critical complications in the absence of proper care to the wounded area. Common causes of DFUs include poor circulation, hyperglycemia and nerve damage.¹ Diabetic foot ulcers often result in skin breakdown and exposure of the underlying tissue. If severe, DFUs may cause diabetic neuropathy, the two main types of which include nerve infarction and entrapment. Nerve infarctions such as polyneuropathy result from axonal degeneration and cause weakness, atrophy and the sudden onset of pain. Diabetic entrapment, such as mononeuropathy, creates a conduction block or decreases conductive activity from the onset of one nerve to the other.²

Chronic hyperglycemia stimulates several metabolic pathways that result in parasympathetic nerve fiber degeneration and ultimately cause neuropathy.³ One such mechanism by which hyperglycemia depletes nerve myoinositol is through a competitive uptake mechanism. This loss of myoinositol causes abnormal neuronal and axonal metabolism, and thus impairs axonal transport.³

According to the National Institutes of Health, 15 percent of patients with diabetes will have DFUs during their lifetime.⁴ Of these 15 percent, about 25 to 50 percent of patients reportedly have immediate amputations during their first hospital visits as a result of infection. Furthermore, 50 to 70 percent of all lower limb amputations result from diabetes.⁴ Given these statistics, it is important to evaluate current treatment options for this high-risk patient population as soon as possible.

Current topical treatments include skin/tissue grafts, donor cells such as treatment with keratinocytes or stem cells, acidic treatments such hypochlorous or hyaluronic acids, and antibiotics. However, most current methods are expensive and have various limitations.

A Closer Look At Current Debridement Options For DFUs

The current treatment regimen for chronic wounds includes assessment for infection, debridement (if required), cleaning and dressing. When it comes to diabetic ulcers specifically, this regimen also includes systemic glucose control and maintenance of adequate perfusion to the wound and lower extremities.⁵

Sharp/excisional debridement is a mainstay of topical treatment for DFUs and by all accounts is necessary for removing nonviable and infected tissue, senescent cells, nonproductive wound borders and bases, pseudoepithelium and biofilms. Additionally, sharp debridement promotes the wound healing cascade including neomicrovascular circulation. Physicians can perform debridement using a variety of tools including a surgical blade, scissor, curette, ultrasonic debridement, enzymatic debridement or hydrosurgery (Versajet, Smith and Nephew).

With many or most DFU ulcer bandage changes, physicians perform some form of mechanical debridement and wound lavage. This helps clear the wound of any bacterial contaminants and can assist in preventing colonization, biofilm or infection. It can also help stimulate neovascularization and healthy cell proliferation as we mentioned above. Sterile saline is the most commonly used fluid for cleansing a wound.

To clean wounds, one can use additional solutions and wound cleansers, such as CarraKlenz Dermal Wound Cleanser (Carrington Laboratories) along with various dilutions of Dakin’s solution and acetic acid solution. Physicians can apply some cleansers on gauze or other primary dressings depending on the suspected causative bacterial agent present. A gauze pad or other dressing can also help mechanically debride a wound. Some also consider the removal of a “wet to dry” dressing to be mechanical debridement.

What You Should Know About Autografts For DFUs

The use of split-thickness autografts in the treatment of DFUs entails the transfer of fascia from a donor to the wound. It often requires six weeks of healing post-procedure and is cosmetically pleasing, leaving only scarring and contracture around the wound. The most evident limitations are donor skin availability and the limited number of proliferating cells in donor skin.⁵

Other treatments that require donor tissue include topical use of keratinocytes and cultured epithelial autografts. Keratinocytes are epithelial cells that separate the organism from the environment.⁶ Unfortunately, in one study, keratinocytes failed to proliferate with placement in adult cell-conditioned media.⁵ This outcome did not differ when researchers obtained keratinocytes from newborns. Cultured epithelial autografts involve harvesting and raising epithelia to create grafting sheets that later serve as the patient’s permanent skin replacement.

While there is no risk of graft rejection using this method, leg and DFU ulcers only demonstrate a 30 percent success rate with autografts.⁵ Furthermore, these layers are four to six cell layers thick, rendering the wound susceptible to infection and digestion by enzymes present in the wound.⁵ As with other grafts, this method is expensive and requires a month to prepare. Due to the aforementioned limitations, split-thickness autografts, keratinocytes, cultured epithelial autografts and other donor-tissue based treatments may be replaced by future technologies that have higher success rates and lower costs.

Key Insights On Acidic And Antibacterial Treatments

In a recent study published in 2017, researchers compared the efficacy of hypochlorous acid treatment to hydrogen peroxide treatment with the subsequent use of povidone iodine.⁶ The authors found hypochlorous acid to be effective against harmful bacteria strains including Candida, Proteus, Klebsiella and various others. In comparison to hydrogen peroxide (H₂O₂), washing therapy using hypochlorous acid was better able to reduce bacteria count.⁶ Unlike other topical treatments, hypochlorous acid is a low-cost, efficient method for preparing DFUs for tissue grafts.

As we mentioned, if the efficiency of donor tissue treatment increases and it continues to be a leading therapy, research involving hypochlorous acid and other useful agents should expand in order to create effective and consistent treatment plans. Neomycin, gentamycin, mupirocin, polymyxin, metronidazole and povidone iodine are some of the commonly used topical antimicrobials. Obtaining an appropriate culture, preferably from a tissue sample or from a swab culture, can be helpful in determining which of these agents is most appropriate. Follow-up cultures help clinicians determine any changes necessary to the prescribed antimicrobials.

Iodine-containing products, such as Iodosorb and Iodoflex (Smith and Nephew), are antimicrobial, and also absorb exudate. One can use these as gels or in patches. There are many silver-containing antimicrobial products such as silver sulfadiazine (cream) although some silver products fall into foam, alginate and other categories.

Fungus, yeast or mold contamination, infection or co-infection should be considerations in the differential diagnosis. Obtain fungal cultures, especially in chronic or other non-healing wounds. In these cases, it may be effective to use appropriate antifungal agents and dyes that may also be antibacterial, such as gentian violet and Hydrofera Blue Foam (Hollister Wound Care). Also consider culturing for mycobacteria.

Similar to hypochlorous acid, propolis is also a low-cost antibacterial agent that could potentially provide therapy for DFUs. Propolis is a bee-derived natural anti-inflammatory resin. When researchers administered propolis to an experimental group, the ulcer area reduced by an average of 41 percent in comparison to the 16 percent decrease in the control group.⁷ Though propolis seems to be a low-cost, efficient means of treating DFUs, there have been relatively few controlled trials analyzing topical propolis therapy. As Sheehan and colleagues noted, if 50 percent of the wound does not heal by week four of treatment, there is only a 9 percent chance that the wound will heal within the next three months.⁸ Patients using propolis achieved, in a mean of 63 percent, healing by week three, indicating that further research on topical treatment with propolis may be highly beneficial for finding effective, low-cost cures for DFUs.⁷

Hyaluronic acid, like hypochlorous acid, also demonstrates a role in supporting tissue recovery in DFUs. Physicians sometimes use hyaluronic acid wound dressings as templates for keratinocytes to aid epithelial proliferation. However, studies have demonstrated that epidermis thickness was unaffected by the use of hyaluronic acid.⁵ As hyaluronic acid is often a preparation for or co-treatment with keratinocyte/other skin grafts with notable limitations, it seems likely that further research should focus on alternative topical treatments.

What Dressings Can Have An Impact For DFUs?

Physicians commonly use hyaluronic products, such as Aquacel Ag Extra Hydrofiber Dressing (Convatec), on DFUs after debridement or surgery. These hyaluronic products consist of hydrofibers that prevent infection while maintaining moisture in the wounded area.⁹ The main concern is daily dressing changes. This may be problematic because removal often results in damage to tissue in the wounded area, which may then lead to inflammation and slower healing.

Silvercel Non-Adherent Dressing (Acelity) uses silver and alginate to reduce ulcer exudation. It addresses the pain and tissue damage associated with dressing removal. Silvercel Non-Adherent uses EasyLIFT™ Precision Film technology to allow for clean removal of the wrapping.¹⁰ Furthermore, clinical evaluations of Silvercel Non-Adherent Dressing as a treatment option demonstrated statistically significant decreases in malodor, exudate or bleeding when changing dressings as well as self-reported pain scores.¹¹ However, popular criticisms of Silvercel are often aimed at cost efficiency as many studies state the treatment is expensive.¹¹

Silver nitrate dressings are anti-inflammatory and may aid in neovascularization. However, there is a recent shift away from silver nitrates because research has shown nanocrystalline silver dressings such as Acticoat have greater efficiency in healing and lower susceptibility to wound infection than silver nitrate treatment.¹⁰

Finally, technological advancements have produced combined therapies such as a bioelectric dressing in conjunction with negative pressure. Researchers used a wireless electroceutical dressing (Procellera, Vomaris Innovations) with negative pressure wound therapy (NPWT) to decrease susceptibility to infection and thus decrease the required frequency of wrapping changes.¹² This reduced treatment expense by almost $600. Furthermore, the decreased frequency showed no evidence of complications as the experimental group and control group both experienced comparable levels of healing rates and infection.

Unlike previously mentioned dressings, Promogran Prisma (Acelity) does not rely on reduced infection or inflammation to treat DFUs. Instead, Promogran Prisma is a wound dressing treatment that consists of collagen and oxidized regenerated cellulose. Based on previously collected data from studies, Promogran Prisma is the most effective standard of care for treating chronic DFUs.¹³ This dressing can serve as a primary modality for chronic wounds in physically modifying the wound microenvironment, thereby promoting granulation tissue formation. Previous studies have consequently shown that if proteases become uncontrolled, devastating tissue damage can result and can lead to chronic wound pathophysiology.¹⁴

In addition, studies have also shown that elevated protease levels lead to detrimental effects on degrading de novo granulation tissue and endogenous biologically active proteins such as cytokines and growth factors.¹⁴

A Quick Overview On NPWT And DFUs

Physicians can use NPWT with foam dressings supplied by the manufacturer and with many of the additional aforementioned wound products. Negative pressure can remove fluid from the wound and stimulates wound healing and wound granulation. The NPWT system consists of a suction pipe, a reservoir, a vacuum pump and a porous polyurethane sponge. Under sterile conditions, one would cut the porous sponge to cover the entirety of the wound and apply the sponge directly while sealing it with a transparent adhesive and vapor-permeable film. As a result, the wound with the applied porous polyurethane sponge is connected to the reservoir through a suction tube, allowing control of the volume of secretion suction and a negative local pressure in continuity.

Due to the flexibility of treatment for DFUs, NPWT has become a useful option in the management of DFUs. One can apply NPWT effectively to treat acute, chronic and complex wounds, and several studies have shown NPWT to be more effective than traditional moist therapy in terms of healing and rate of wound closure.^15–17

In a variety of surgical procedures, surgeons have implemented flap rotation and skin grafting to help sustain final coverage. Based on previous research, no severe consequences have been recorded as a result from using Vacuum Assisted Closure (VAC) Therapy (KCI/Acelity) treatments aside from minimal cases of deep bleeding or worsening local infection.¹⁸ Patients generally experienced improved wound sites with infection eradication. Another potential complication might include mild local itching but the use of non-invasive therapies can allow the maintenance of the patient’s treatment.

Relevant Pearls On The Use Of A Dermal Substitute

Dermagraft (Organogenesis) is a sterilized human fibroblast-derived dermal substitute generated by the culture of neonatal dermal fibroblasts onto a bioabsorbable polyglactin mesh scaffold. These human fibroblasts proliferate to fill the spaces of the scaffolds and secrete collagen fibers, growth factors, cytokines, et cetera, in order to form a three-dimensional human tissue that performs metabolic functioning of active living cells. Not only can Dermagraft treat DFUs but clinicians can also use the therapy for other off-label conditions such as chronic surgical wounds, wound dehiscence after amputations and epidermolysis bullosa.

Based on previous clinical studies, Dermagraft is an excellent choice for regenerative medicine for its ability to create normal functioning wound tissue and retain regulatory and structural proteins.¹⁹ Currently, there have not been any reports of potential complications due to Dermagraft treatment.

A Guide To Other Topical DFU Treatments

Creams and patches. Some common topical treatments include capsaicin cream and lidocaine 5% patches. Capsaicin stimulates C-fiber release and the depletion of substance P.²⁰ Many patients using capsaicin experience a stinging sensation during the first week of treatment but this decreases with continuous usage. One may use topical creams with capsaicin to help treat painful diabetic neuropathy. When patients use capsaicin cream (0.075%) three or four times daily for eight weeks, the medication reportedly reduces the severity of the painful diabetic neuropathy.²¹ Lidocaine 5% patches block neuronal sodium channels. Although this medication has a low rate of effectiveness, a randomized controlled trial in 2003 revealed a number needed to treat of 4.4 for 50 percent pain reduction.19 Adverse effects are primarily dermatologic if patients remove the patch.⁸

Complementary and alternative medicine. Complementary and alternative medicine options may also assist with diabetic peripheral neuropathic pain. Such therapies include L-acetylcarnitine and alpha lipoic acid that are available over the counter. Benefits of alpha lipoic acid include stimulation of nerve growth factor and promoting fiber regeneration.²³ In one study, consumption of 600 mg IV of alpha lipoic acid daily for three weeks reduced pain, paresthesias and numbness in patients with polyneuropathy.²⁴ In addition, acute infusion of alpha-lipoic acid improved nitric oxide-mediated and endothelium-dependent vasodilation while also improving microcirculation in patients with polyneuropathy.

L-acetylcarnitine, on the other hand, can significantly improve sensory nerve conduction velocity and pain sensation.²⁵ Researchers have observed a significant improvement of vibration perception threshold and pain scores after one year of L-acetylcarnitine usage.⁸

Honey. Honey-containing products including MediHoney (Integra Life Sciences) facilitate removal of necrotic tissue and aid in wound healing. One can apply honey, in gel or paste form, directly to a wound. Honey is also present in several treatments including alginates and hydrocolloids.  

In Conclusion

As diabetes mellitus is one of the most prevalent health conditions in the United States with 15 percent of patients developing diabetic foot ulcers, it is essential that we seek more efficient and accessible methods of treatment. In 2012, approximately $245 billion was spent on diabetes care in the U.S., an estimate which calls for improved treatment and better cost-efficiency.²⁶

Dr. Faroqi is the Director of Clinical Research for DISCOVeR Lab at the Stanford University School of Medicine.

Dr. Guberman is the Director of Podiatric Medical Education and the Co-Chief of the Podiatry Division in the Department of Surgery at Wyckoff Heights Medical Center in Brooklyn, NY.

J.H. Velasco is the Assistant Clinical Research Coordinator for DISCOVeR Lab at Stanford University School of Medicine.

G.S. Schreiner is a Clinical Research Intern for DISCOVeR Lab at Stanford University School of Medicine.

Ms. Bonde is an Assistant Clinical Research Coordinator for DISCOVeR Lab at Stanford University School of Medicine.

Dr. Armstrong is a Professor of Surgery in the Department of Surgery at the Keck School of Medicine of the University of Southern California (USC). He is the Co-Director of the Southwestern Academic Limb Salvage Alliance (SALSA).

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