Transitioning To Advanced Therapies For DFUs: Are Four Weeks And 50 Percent The Magic Numbers?

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What One Study Reveals About A Bioengineered Skin Substitute And The Rate Of Healing Of Diabetic Foot Ulcers

In a prospective, randomized, multicenter study, Veves and colleagues analyzed 208 patients with diabetes who had full-thickness neuropathic ulcers, and observed the healing rates of diabetic neuropathic ulcers that were treated with Apligraf (Organogenesis) versus diabetic neuropathic ulcers treated with saline-moistened gauze.10 At baseline, the two groups were similar in regard to demographics, the type and duration of diabetes, and ulcer size and duration. The Apligraf group was comprised of 112 patients and there were 96 patients in the control group, which utilized saline-moistened gauze as treatment. Both groups received periodic debridement and offloading in addition to the respective treatment for their group.

The researchers analyzed 162 patients at the end of the study. The rate of healing was higher among those who had Apligraf applied every week than those who received saline moistened gauze. At the 12-week follow-up visit, 63 (56 percent) Apligraf-treated patients were completely healed in comparison to 36 patients (38 percent) treated with saline-moistened gauze. The average time to complete closure was 65 days for Apligraf, significantly lower than the 90 days researchers observed in the saline-moistened gauze group.

The rate of adverse reactions was similar between the two groups with the exception of osteomyelitis (3 percent in the Apligraf group versus 10 percent in the control group) and lower-limb amputations (6 percent versus 16 percent), both of which were less frequent in the Apligraf group. The study also noted the improvement in maceration, exudates and eschar in the Apligraf group from week 0 to week 12. Physicians should consider Apligraf for the management of diabetic foot ulcers that are resistant to the currently available standard of care.

Chanel Houston, DPM, Samirah Mohammed, DPM, and Peter A. Blume, DPM, FACFAS

When do you make the transition to advanced modalities for diabetic foot ulcers? With this question in mind, these authors discuss key diagnostic pointers and offer salient insights from the literature on when physicians should consider advanced modalities to facilitate improved healing and outcomes.

The treatment of diabetic foot ulcers can be a long, multifaceted task. Not only does one need to address the actual ulcer, clinicians need to consider other contributing factors such as foot deformities, biomechanics, glycemic control, ischemia, and peripheral and autonomic neuropathy.1,2 For these reasons, the diabetic foot ulcer often proves recalcitrant to certain treatment modalities and can be a challenging feat for many patients and practitioners alike.

   Advanced therapies may be beneficial to patients with chronic diabetic foot ulcers. However, in order to consider the use of these modalities, one must examine the ulcer etiology, review the clinical findings, ensure a proper workup, determine if there is adequate vascularity and assess the length of time to adequate healing.

   In regard to the aforementioned etiological factors, the most significant predictor of diabetic foot ulcer formation is neuropathy. Peripheral neuropathy is basically altered sensation, which creates a basis for skin breakdown in the presence of pressure areas. Autonomic neuropathy impairs capillary vasodilatation in response to injury. While understanding that one of the main etiologies of ulcer formation is neuropathy, it is also very important to understand what leads to neuropathy in the patient with diabetes.

   Abnormalities in the polyol pathway and inadequate nerve regeneration are direct results of neuropathic changes in the patient with diabetes.2 The effects of diabetes impair wound healing by altering protein and lipid metabolism, and affect granulation tissue formation. Due to these alterations, there is a significant lack of normal enzymatic glycosylation. Excess glucose binds to lipids and proteins without any proper glycosylation, and become products that accumulate over surface cell membranes and proteins. These products become known as advanced glycation end products (AGEs), which are seen on extracelluar matrix proteins such as laminin, vitronectin and collagen. These matrix proteins become altered by advanced glycation end products through cross-linking, which produces tissue stiffness, granulation tissue and basement membrane thickening in arterioles and capillaries.

   Microangiopathy and atherosclerotic disease also impede adequate wound healing, and are highly prevalent in patients with diabetes. Diminished blood flow plays a crucial role in the development of ulceration and is a strong barrier to cellular proliferation and wound healing.3

   Chronic wounds, in particular, are extremely complex and slow to heal due to constant inflammation affecting the healing process. Chronic wounds are unable to enter the proliferative phase of healing and develop over time due to edema, inadequate perfusion, poor nutrition, infection, trauma and certain rheumatologic factors. Another huge contributor to chronic wounds is matrix metalloproteinase, which modifies the extracellular matrix by metabolizing collagen, elastins and proteoglycans. This in turn affects tissue reabsorption, remodeling, platelet aggregation, macrophage and neutrophil function, cell migration, and angiogenesis.2

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