Management of diabetic foot: Brief synopsis for busy orthopedist

Abstract

According to available medical reports, over 10% of diabetic patients will develop foot ulcers during their lifetimes. This condition still remains great challenges to many clinicians. Various mechanisms may explain treatment-resistant entity. Treatment varies widely, relying on the severity of the ulceration as well as the presence of infection or ischemia. However, the most important things to keep in mind should consist of the following: 1) appropriate debridement; 2) off-loading of pressure; 3) effective control of infection; 4) local wound care strategy; 5) timely reconstructive surgery. The ideal flap for diabetic foot reconstruction should provide a well-vascularized tissue to control infection, adequate contour for footwear, durability, and solid anchorage to resist shearing forces. A thorough assessment of patient's general condition and voluntary motivation of the patient should be warranted to prevent any sort of postoperative recurrence.

1. Introduction

According to available medical reports, over 10% of diabetic patients will develop foot ulcers during their lifetimes.¹ Diabetic foot ulcers are well known to many clinicians that they respond poorly to conventional treatment, making them very difficult to care.² Various mechanisms including neuropathy, arterial insufficiency, decreased expression of various growth factors, sustained inflammation, and increased apoptosis may explain these treatment-resistant entity.³ Over the last decade, significant advances have been made regarding the treatment of diabetic foot ulceration.⁴

Treatment varies widely, relying on the severity of the ulceration as well as the presence of infection or ischemia. However, the cornerstones of treatment for diabetic foot ulcers regardless whether it is at past or in the present should consist of the following: 1) appropriate debridement; 2) off-loading of pressure; 3) effective control of infection; 4) local wound care strategy; 5) timely reconstructive surgery.

2. Diabetic foot management

2.1. Appropriate debridement

Debridement is necessary before application of other wound closure procedures and improves the overall outcome of the diabetic foot.⁵ Appropriate debridement causes activation of platelets (PLT) to control hemorrhagic responses and releases growth factors that initiate the cascade of wound healing process.⁶ After appropriate debridement, tissues should be kept moist to prevent formation of devitalized tissue and subsequent deepening of the wound.⁷ However, excessive moisture is a risk factor for pressure sores, and other dermatitis.

2.2. Effective control of infection

Diabetic foot ulcers act as portals of entry for systemic infection⁸. Diabetic Foot infections have a wide range of spectrum from paronychia, cellulitis, myositis, abscesses, necrotizing fasciitis, septic arthritis, tendinitis, and osteomyelitis. Risk factors for OM can be summarized as follows: Appearance of a swollen, deformed red toe, visible or palpable bone on probing, infected ulcer with an ESR > 70 mm per hour, nonhealing ulcer after a few weeks of appropriate care and off-loading of pressure, radio logically evident bone destruction beneath ulcer, ulcer area >2 cm² or >3 mm deep, ulceration over bony prominences > two weeks, ulceration with unexplained leukocytosis. The most common pathogens in acute, previously untreated, superficial diabetic foot infection are aerobic G (+) bacteria (particularly staphylococcus aureus and beta-hemolytic streptococci), while MRSA is a more frequently encountered pathogen in diabetic patients who have recently received antibiotic therapy in a hospital.

Diabetic foot infections are one of the major causes of amputation. Hence effective control and prevention are very important to decrease morbidity and mortality of the patients.

Topical antimicrobial therapies such as liquid silver nitrate, silver sulfadiazine, and silver-coated dressings have been shown to eliminate bacteria in diabetic foot ulcers.⁹

2.3. Relief of pressure

Various new off-loading modalities are being investigated, because of the drawbacks of total contact casting. At low risk group, prevention, education and basic footwear advice will do. At moderate risk group, intensive footwear advice and special footwear for feet are recommend. If patients with recurrence diabetic ulceration, total contact cases, air casts, scotch cast boots, hope cast boot, heel shoe, wheel chair ambulation, or best rest are recommended. Two examples are removable cast walkers and half-shoes.^{10, 11}

2.4. Local wound care strategy

2.4.1. Vacuum-drainage systems

Negative-pressure wound therapy has been shown to be beneficial in treating some soft tissue defects caused by diabetic foot wounds (Fig. 1).^{12, 13, 14, 15, 16, 17, 18, 19}

Fig. 1.

Showing wound vac in place.

This therapy should be considered in large foot ulcers and particularly post local amputation wounds. In addition, it is also indicated when satisfactory healing is not occurring after a 3-week implementation of the protocol.²⁰ Younan et al²¹ in their experimental study showed that vacuum-assisted closure therapy modulated nerve fiber and neuropeptide production in the wound. By optimizing the kinetics of vacuum-assisted closure application, clinicians can contribute to further improve wound healing in denervated wounds such as pressure sores and diabetic foot ulcerations.

Recently, Lerman et al introduced new ultraportable negative-pressure wound therapy devices reducing many disadvantages of previous products such as bulky and noisy characteristics, high cost and requiring an electrical power source.²²

2.4.2. Skin substitutes (e.g., Apligraf, Epifix)

Apligraf is a composite graft composed of a cultured living dermis and sequentially cultured epidermis and is derived from neonatal foreskin (Fig. 2).²³

Fig. 2.

Showing dermagraft in place.

Histologic comparison shows that Apligraf and human skin are very similar. Apligraf lacks Langerhans cells, melanocytes (epidermis level), any hair follicles, sweat glands, endothelial cells, or blood cells (dermis level). Instead of providing instant coverage, Apligraf instead serves as a vehicle for the delivery of growth factors and other cellular constituents essential to the normal wound healing process.^{23, 24} Epifix is a dehydrated human amnion/chorion membrane allograft, which includes amnion and chorion. These 2 layers are a rich source of collagen, connective tissue, cytokines and growth factors. Hence Epifix provides a biological active matrix and growth factors for cellular ingrowth. Results have shown that Epifix contains one or more soluble factors which can stimulate mesenchymal stem cell migration and recruitment.²⁵ There are no direct studies comparing the above modalities.

2.4.3. Blood bank platelet concentrate

According to Jeong et al,²⁶ the advantages of using a blood bank platelet concentrate as a source of growth factors in treating diabetic ulcers are as follows. First, many diabetic ulcer patients are hemodynamically unstable, and repeated blood sampling may harm patients. Second, the concentrated platelets can be obtained without the need for a platelet separation system. Third, this method obviates the time and effort required to locate a suitable donor for a homologous graft. Fourth, use of a blood bank platelet concentrate results in lower cost than other biotechnology products for nonhealing diabetic foot ulcers.

2.4.4. Hyperbaric oxygen therapy

Several anecdotal and retrospective reports suggest that hyperbaric oxygen therapy may be of value for the treatment of diabetic foot wounds, and a few recent prospective studies have shown promising results.^{27, 28, 29, 30, 31}

Cochrane review concluded that hyperbaric oxygen therapy significantly reduced.

The risk of major amputation related to a diabetic foot ulcer.³²

However, the limited availability and complexity in process of treatment may distract our interest as a major adjuvant treatment option.

2.4.5. Pulsed electromagnetic fields

In 2008, Matthew et al conducted an experiment about the efficacy of novel “pulsed electromagnetic fields” using Db/db and C57BL6 mice. According to his experiment, pulsed electromagnetic fields accelerated wound closure in diabetic and normal mice. Pulsed electromagnetic fields can be considered as an option to accelerate wound healing under diabetic and normal conditions by up-regulation of FGF-2–mediated angiogenesis.

Pulsed electromagnetic fields also prevented tissue necrosis in response to a standardized ischemic insult.

2.4.6. Gene therapy using synthetic growth factors

Gene therapy is emerging as a powerful tool for treating diabetic foot.^{33, 34, 35, 36, 37, 38, 39, 40} According to available literature, growth factors such as bFGF,⁴¹ PDFG-BB,^{40, 42, 43, 44, 45} EGF,^{36, 46} rhBMP-2,⁴² HGF,³⁹ REGEN-D 150,³⁷ and EPO³⁸ can accelerate healing by stimulating granulation tissue formation and enhancing epithelialization.⁴⁵ This led to a statistically significant increase in angiogenesis and thicker, more collagen formation.⁴⁷ One of the other areas of focus is p53 which is a master cell cycle regulator and is up regulated in diabetics. It also plays regulatory roles in vasculogenic and apoptotic pathways.^{48, 49, 50}

In their^{48, 49, 50} experimental study on mice showed that by silencing the p 53 resulted in improved vasculogenesis and decreased apoptosis which improved healing of diabetic wounds.

Lee et al³⁵ in their study on mice showed that lentiviral PDGF transfection of the diabetic wound enhanced PDGF production, improved vascularization and collagen organization, and has potential clinical applications in diabetic wound treatment.

However, due to the multitude of factors involved, the rapid degradation by wound proteases, and lack of a viable vehicle for sustained release, the development of a topically applied growth factor has been difficult.

Currently, the only commercially available product for diabetic foot ulcers is recombinant platelet derived growth factor-BB (becaplermin).^{42, 43, 44} Becaplermin is well tolerated and represents an innovative, pharmacologically active treatment for chronic lower extremity diabetic ulcers.⁵¹ This aqueous gel provides a moist wound healing environment with negligible systemic absorption.⁴³ Becaplermin gel is easy for patients or their caregivers to apply in a nonformal clinical setting, and published studies have shown that it has an excellent safety profile.^{40, 51}

2.4.7. Stem cells therapy

The crux behind healing is to encourage blood supply. Following injury revascularization occurs and one third of this revascularization is harnessed by endothelial progenitor cells. Normally, ischemic insult induces the release of endothelial progenitor cells and other progenitor cells from the bone marrow.⁵² These cells are exported via blood circulation to the site of insult, where they participate in revascularization and tissue repair.⁵² In Diabetics not enough progenitor cells are seen at site of repair, the cause of which is a dysfunctional release mechanism in diabetes.⁵³ Also whatever progenitor cells are released into circulation have impaired migration/homing to peripheral sites of injury and decreased proliferation and differentiation once present in the wound.^{54, 55, 56, 57} Warren et al⁵⁸ reported on their observations in mice when they showed that by using Single-dose topical application of lineage-negative progenitor cells to diabetic wounds was effective in significantly accelerating diabetic wound closure. By supplying the cells which were not recruited they by passed one of the mechanisms which was responsible for impaired healing. Recently, both bone marrow–derived stem cells, peripheral blood–derived endothelial progenitor cells, and human adipose-derived stem cells have been shown to accelerate healing in diabetic mice.^{59, 60, 61} According to Chan et al,⁶² a population of bone marrow–derived hematopoietic stem cells has the capacity to improve regeneration of diabetic wounds. Although understanding of exact mechanism of action of these cells is still under work, there have been increasing evidences that different stem cell populations play crucial roles in wound healing process. However, further future studies are warranted to investigate the mechanism of action of these hematopoietic stem cells.

2.5. Reconstructive surgery

Reconstructive therapies may be useful treatment options when the area of the diabetic foot ulcer has not decreased by more than 10% after the above mentioned.

Approaches have been applied for 2 months.⁶³

Despite the recent significant advances in microsurgery, its application to reconstruction of wounds in diabetic patients has been low.⁶⁴ The concerns regarding flap efficacy and viability, occlusion of flow to the distal limb, systemic condition, patient compliance, and economical burden remain problematic.⁶⁵ When performing a microsurgical reconstruction of the diabetic foot, surgeons should follow some guidelines and preparation despite its controversies.

Angiogram is generally required to analyze the vascular patency of ATA (anterior tibial artery), PTA (posterior tibial artery), and PA (peroneal artery) for the reconstruction of diabetic foot.⁶⁶ A thorough assessment of patient's general condition and voluntary motivation of the patient should be warranted to prevent any sort of postoperative recurrence.

The ideal flap for diabetic foot reconstruction should provide a well-vascularized tissue to control infection, adequate contour for footwear, durability, and solid anchorage to resist shearing forces.

The use of fasciocutaneous flaps, muscle flaps with skin grafts, and diverse perforator flaps for reconstruction of the diabetic foot has been conducted successfully.^{64, 65, 67, 68} Considering its pros and cons, controversy still remains regarding which flap is the most reliable one. This endless question should be continued with the development of microvascular surgery techniques. In 2006, Hong et al favored the anterolateral thigh (ALT) perforator flaps for the management of the diabetic foot.⁶⁵ He also published a review article regarding the usefulness of a multidisciplinary approach along with an algorithm to manage and salvage diabetic foot ulcers from amputation and also found an interesting findings that diabetic foot reconstruction using free flaps increases overall 5-year-survival rate^{69, 70}.

3. Conclusion

Numerous treatment methods including vacuum-drainage systems, skin substitutes especially Apligraf, blood bank platelet concentrate, hyperbaric oxygen therapy, pulsed electromagnetic fields, gene therapy using synthetic growth factors, and stem cells therapies have been proposed for local wound care of diabetic foots, suggesting that no single effective method has surfaced as the accepted standard. Proper selection among diverse local care modalities along with reconstructive microvascular treatment options including fasciocutaneous flaps, muscle flaps with skin grafts, and versatile perforator flaps would yield optimal wound management of diabetic foot. We propose the following algorithm (Fig. 3).

Fig. 3.

Treatment algorithm for diabetic foot ulcer.

Conflicts of interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.