The gold standard for diabetic foot ulcer treatment includes debridement of the wound, management of any infection, revascularization procedures when indicated, and off-loading of the ulcer.

Other methods have also been suggested to be beneficial as add-on therapies, such as hyperbaric oxygen therapy (HBOT), use of advanced wound care products, and negative-pressure wound therapy (NPWT) . However, data so far have not provided adequate evidence of the efficacy and cost-effectiveness of these add-on treatment methods.

1. Debridement

Debridement should be carried out in all chronic wounds to remove surface debris and necrotic tissues. It improves healing by promoting the production of granulation tissue and can be achieved surgically, enzymatically, biologically, and through autolysis.

Surgical debridement, known also as the “sharp method,” is performed by scalpels, and is rapid and effective in removing hyperkeratosis and dead tissue. Particular care should be taken to protect healthy tissue, which has a red or deep pink (granulation tissue) appearance. Using a scalpel blade with the tip pointed at a 45° angle, all nonviable tissue must be removed until a healthy bleeding ulcer bed is produced with saucerization of the wound edges. If severe ischemia is suspected, aggressive debridement should be postponed until a vascular examination has been carried out and, if necessary, a revascularization procedure performed.

Enzymatic debridement can be achieved using a variety of enzymatic agents, including crab-derived collagenase, collagen from krill, papain, a combination of streptokinase and streptodornase, and dextrans. These are able to remove necrotic tissue without damaging the healthy tissue. Although expensive, enzymatic debridement is indicated for ischemic ulcers because surgical debridement is extremely painful in these cases 

Biological debridement has been applied recently using sterile maggots. Maggots have the ability to digest surface debris, bacteria, and necrotic tissues only, leaving healthy tissue intact. Recent reports suggest that this method is also effective in the elimination of drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus, from wound surfaces 

Autolytic debridement involves the use of dressings that create a moist wound environment so that host defense mechanisms (neutrophils, macrophages) can clear devitalized tissue using the body’s enzymes. Autolysis is enhanced by the use of proper dressings, such as hydrocolloids, hydrogels, and films. Autolysis is highly selective, avoiding damage to the surrounding skin.

In conclusion, debridement, especially the “sharp method,” is one of the gold standards in wound healing management, significantly contributing to the healing process of the wound, including the diabetic ulcer.

2. Off-loading

Off-loading of the ulcer area is extremely important for the healing of plantar ulcers. Retrospective and prospective studies have shown that elevated plantar pressures significantly contribute to the development of plantar ulcers in diabetic patients.

In addition, any existing foot deformities may increase the possibility of ulceration, especially in the presence of diabetic peripheral neuropathy and inadequate off-loading. Furthermore, inadequate off-loading of the ulcer has been proven to be a significant reason for the delay of ulcer healing even in an adequately perfused limb. The value of ulcer off-loading is increasing, as it has been reported that the risk of recurrence of a healed foot ulcer is high if the foot is not properly off-loaded (in the high-pressure areas), even after closure of the ulcer.

The most effective method of off-loading, which is also considered to be the gold standard, is the nonremovable total-contact cast (TCC). It is made of plaster or fast-setting fiberglass cast materials, has relatively low costs, and permits restricted activity . Nonremovable TCCs are indicated for the effective off-loading of ulcers located at the forefoot or midfoot. Severe foot ischemia, a deep abscess, osteomyelitis, and poor skin quality are absolute contraindications to the use of a nonremovable TCC. Nonremovable TCCs work by distributing the plantar pressures from the forefoot and midfoot to the heel. They allow complete rest of the foot whilst also permitting restricted activity. Nonremovable TCCs also reduce edema, and compliance with treatment is necessarily high .There are a number of other devices like removable cast walkers (RCW), instant total-contact cast (ITCC), &  Half shoes 

3. Dressings

Ulcers heal more quickly and are often less complicated by infection when in a moist environment. The only exception is dry gangrene, where the necrotic area should be kept dry in order to avoid infection and conversion to wet gangrene. A wound’s exudate is rich in cytokines, platelets, white blood cells, growth factors, matrix metalloproteinases (MMPs), and other enzymes. Most of these factors promote healing via fibroblast and keratinocyte proliferation and angiogenesis, while others, such as leukocytes and toxins produced by bacteria, inhibit the healing process. 

 The ideal dressing should be free from contaminants, be able to remove excess exudates and toxic components, maintain a moist environment at the wound-dressing interface, be impermeable to microorganisms, allow gaseous exchange, and, finally, should be easily removed and cost-effective. 

Growth Factors

PDGF-beta has been developed as a topical therapy for the treatment of non infected diabetic foot ulcers. It is applied in the form of a once-daily gel along with debridement on a weekly basis. Initial studies have indicated a significant positive effect of becaplermin on ulcer healing; however, more recent studies have reported an increased incidence of cancer in patients treated with becaplermin, especially at high doses. Consequently, the US Food and Drug Administration has published a warning of an increased risk of cancer if more than three tubes of becaplermin are used. Further studies are necessary in order to explore the benefit-to-risk ratio, as well as the cost effectiveness of this therapy.

Platelet-rich plasma (PRP) is an autologous product, extracted from the patient’s plasma, which includes a high platelet concentration in a fibrin clot that can be easily applied to the ulcer area. The fibrin clot is absorbed during wound healing within days to weeks following its application. There are a few studies reporting a shorter closure time and higher healing percentage in patients using PRP and platelet-derived products. However, further studies are required to support the possible beneficial effect of this method in ulcer healing.

The results of the subcutaneous administration of granulocyte colony-stimulating factor (GCFS) in patients with infected foot ulcers vary, with some studies indicating faster resolution of the infection and faster healing, while others did not report any significant difference. 

Basic fibroblast growth factor (bFGF) is known to be beneficial in the formation of granulation tissue and normal healing; however, one small study failed to prove any significant difference between the intervention and the control group.

 Epidermal growth factor (EGF) acts on epithelial cells, fibroblasts, and smooth muscle cells to promote healing . Evidence for the use of EGF in diabetic ulcers is limited, with only a small amount of data reporting a significantly higher rate of ulcer healing with EGF use compared with placebo [62].

Bioengineered Skin Substitutes

Tissue-engineered skin substitutes are classified into 

1. Allogenic cell-containing

2. Autologous cell-containing 

3. Acellular matrices

The first two types of matrix contain living cells, such as keratinocytes or fibroblasts, in a matrix, while acellular matrices are free of cells and act by releasing growth factors to stimulate neovascularization and wound healing.Accumulating evidence shows that bioengineered skin substitutes may be a promising therapeutic adjunct therapy to the standard wound care for the management of non infected diabetic foot ulcers. 

Extracellular Matrix Proteins are semisynthetic ester of hyaluronic acid which facilitates the growth and movement of fibroblasts, and controls hydration.

MMP Modulators Matrix metalloproteinases regulate the extracellular matrix components. During normal wound healing, there is a balance between the construction and the destruction of the extracellular matrix. In chronic wounds, a high expression of MMP-2 in fibroblasts and the endothelium is detected and is believed to favor destruction. Thus, downregulation of MMP-2 expression may enhance the healing process. 

Negative-Pressure Wound Therapy Negative-pressure wound therapy (NPWT) has emerged as a new treatment for diabetic foot ulcers. It involves the use of intermittent or continuous subatmospheric pressure through a special pump (vacuum-assisted closure) connected to a resilient open-celled foam surface dressing covered with an adhesive drape to maintain a closed environment. 

 Hyperbaric oxygen (HBOT) There is strong evidence that fibroblasts, endothelial cells, and keratinocytes are replicated at higher rates in an oxygen-rich environment. Moreover, leukocytes kill bacteria more effectively when supplied by oxygen.