At least half of all amputations occur in people with diabetes, most commonly because of an infected diabetic foot ulcer. A thorough understanding of the causes and management of diabetic foot ulceration is essential to reducing lower-extremity amputation risk. This compendium elucidates the pathways leading to foot ulcers and enumerates multiple contributory risk factors. The authors emphasize the importance of appropriate screening and wound classification and explain when patients should be referred for specialist care, targeted education, or therapeutic shoes or insoles. They provide a comprehensive review of treatment approaches, including devices for foot lesion off-loading and aggressive wound debridement through mechanical, enzymatic, autolytic, biologic, and surgical means. Because infection and peripheral artery disease are key contributors to amputation risk, the authors discuss the diagnosis and management of these conditions in detail. They also review the expanding armamentarium of evidence-based adjunctive treatments for foot ulcers, including growth factors, skin substitutes, stem cells, and other biologics. Because Charcot neuroarthropathy is a serious but frequently missed condition in people with diabetic neuropathy, the authors explain the differential diagnosis of the hot, swollen foot that is a hallmark of this condition. The article ends with an overview of four strategies for maintaining a foot in remission, followed by a brief look at the future of diabetic foot care.

Pathways to Diabetic Foot Complications

Although evidence is weak that foot care education reduces the risk of first ulceration (2), a thorough understanding of the etiopathogenesis of ulceration is essential if we are to succeed in reducing the incidence of foot lesions and ultimately amputations. The pathways to foot ulceration are summarized in Figure 1, with key contributory factors also listed below.

• ➤ Distal sensorimotor peripheral neuropathy. This condition is common in diabetes, affecting up to 50% of older people with type 2 diabetes. Small-fiber nerve dysfunction results in loss of pain and temperature perception; patients literally lose the “gift of pain” that normally protects us from tissue damage. Large-fiber dysfunction results in unsteadiness, increasing the risk of trips and falls; recurrent unnoticed minor injuries might increase the risk of Charcot neuroarthropathy. Motor neuropathy contributes to small-muscle wasting and a potential imbalance of flexor and extensor function in the foot.
• ➤ Autonomic neuropathy. Peripheral sympathetic dysfunction results in decreased sweating (i.e., dry foot skin, increasing the risk of callus formation) and, in the absence of PAD, warm feet due to the release of vasoconstriction. Plantar callus in the neuropathic foot is associated with a marked increase in ulcer risk.
• ➤ PAD. A major risk factor for foot lesions in diabetes, PAD is discussed in detail beginning on p. 11. Neuropathy and PAD often co-exist and may lead to neuroischemic ulceration.
• ➤ Deformity. Any deformity occurring in a foot with other risk factors increases ulcer risk. Clawing of the toes is common, leading to increased metatarsal head pressures that, in neuropathic patients, may result in breakdown due to repetitive moderate stress to an insensate area. Other examples include Charcot deformities and hallux valgus.
• ➤ Age, sex, and duration of diabetes. The risk of ulcers and amputations increases two- to fourfold with both age and duration of disease. In Western countries, male sex is associated with a 1.6-fold increase in foot ulcer risk (3).
• ➤ Ethnicity. In the United States, ulceration is more common among Hispanics, Native Americans, and individuals of African-Caribbean descent.
• ➤ Repetitive minor trauma. Such trauma can occur as a consequence of high pressures under a neuropathic foot or from an ill-fitting shoe or a foreign body inside a shoe.
• ➤ Past foot ulceration or amputation. Both are major risk factors. The annual incidence of ulceration may be as high as 30–50% in people with a history of foot ulcers (1).
• ➤ Other microvascular complications. Several other conditions are known to be associated with an increased risk of foot ulceration. Visual impairment as a result of retinopathy is an established risk factor for foot lesions. Perhaps the most high-risk group for ulceration is the dialysis population. It can be safely presumed that patients at all stages of nephropathy have increased risk of ulceration. Dialysis treatment is an independent risk factor for foot ulceration.
• ➤ Transplantation. People with diabetes remain at high risk of foot lesions even after successful kidney, pancreas, or combined pancreas-kidney transplantation.

FIGURE 1

Pathways to diabetic foot ulceration.

Screening for Foot Complications Risk

It is important to assess the neurological, vascular, dermatological, and musculoskeletal status of people with diabetes at least annually. The American Diabetes Association (ADA) developed a Comprehensive Foot Examination and Risk Assessment that can be performed rapidly with minimal equipment (5,6).

After assessment of the foot, Table 1 outlines suggested indications, priorities, and timelines for referral based on ADA guidelines (6). The table shows ADA patient risk categories (i.e., very low, low, moderate, and high risk) and follow-up recommendations.

TABLE 1

Modified ADA Diabetic Foot Risk Classification

Patients who present with tissue loss are assigned to a higher risk category. In such cases, the overall degree of limb threat should be assessed.

The three key factors associated with limb loss include degree of tissue loss (wound severity), severity of ischemia, and severity of foot infection. The acronym WIfI can be used as short-hand for these factors, which can assist the health care team in describing patients’ overall limb threat status (Figure 2) (7,8). Using the Society for Vascular Surgery (SVS) Threatened Limb Classification System (7), patients’ wounds, ischemia, and foot infections are graded on a numerical scale from 0 (none) to 3 (severe), and these grades are then translated into an overall “WIfI score” (discussed in more detail in the section on Recognizing and Treating PAD on p. 11).

FIGURE 2

SVS WIfI classification system. TcPO₂, transcutaneous oxygen pressure.

When and Where to Refer Diabetic Foot Problems

Appropriate patient referral is predicated on a complete history and foot examination. Patients with diabetic foot complications should be referred for preventive services and when acute pathology is identified.

The risk categories shown in Table 1 were adapted from the four-tiered diabetic foot risk classification system recommended by the International Working Group on the Diabetic Foot (9). Patients at the highest risk for ulceration are those who have a history of ulceration, amputation, peripheral vascular surgery, or Charcot neuroarthropathy. These patients are easy to identify from history alone and have a very high rate of developing ulceration (9). Of patients who have had an ulcer, 58–83% will develop another ulcer within 1 year if no preventive services are provided (10,11). When therapeutic shoes and insoles are provided, the incidence of ulcer recurrence decreases by 50% to 30–50% annually (1,9).

The next risk tier includes patients with sensory neuropathy and foot deformity or PAD. Evaluation of these patients requires simple sensory testing with a 128-Hz tuning fork or a 10-g Semmes-Weinstein monofilament and clinical assessment of limited joint mobility, hammertoes, hallux valgus, and peripheral perfusion.

High-risk patients need referrals for diabetes education, therapeutic shoes and insoles, and regular foot evaluation and care. Unfortunately, only a small minority of patients receive preventive services (12,13).

For patients with a previous foot complication, diabetes care providers should find an educator who has a strong understanding of and education program specifically focused on diabetic foot complications. Patients need indepth education about sensory neuropathy, the etiology of ulcers and infections, warning signs, and preventive measures. Providing a “tear sheet” with a vague list of things to do and things to avoid without explaining the rationale behind such recommendations is probably not especially helpful to high-risk patients.

Therapeutic shoes and insoles are mainstays of preventing recurrent diabetic foot ulcers (DFUs). Providers should partner with a podiatrist in their community who is interested in diabetic foot complications. A podiatrist can help evaluate and monitor high-risk patients. They can evaluate patients’ biomechanics, structural foot deformities, joint range of motion, sensory neuropathy, and peripheral perfusion and provide a prescription for specific elements of custom insoles and shoes. The prescription will then be sent to a pedorthist or orthotist, who will fabricate the custom insoles and fit the shoes appropriately.

Shoes and insoles should be replaced on a regular basis, so evaluation of shoes, insoles, and the feet of high-risk patients should be a routine part of clinic examinations. Patients with foot ulcers, puncture wounds, ingrown toenails, or infections need prompt referral to a local podiatrist who is experienced in diabetic foot complications or a wound care center with expertise in DFUs.

These patients generally require imaging to evaluate bone infection and vascular testing to determine whether there is adequate perfusion to heal a foot wound. Patients with signs of ischemia or gangrene should be referred to a vascular surgeon, interventional cardiologist, or interventional radiologist for evaluation and treatment. These patients will need arterial Doppler studies and, if these are abnormal, angiography and possibly vascular intervention.

Off-Loading the Diabetic Foot Wound

Off-loading refers to the use of devices or surgeries that remove pressure or reduce the “load” at the site of ulceration to improve healing. DFUs often occur on the sole of the foot at sites of repetitive injury that are unrecognized by patients with diabetic sensory neuropathy. The ulcers are usually at a pressure point on the bottom of the foot where a callus has formed. If a neuropathic patient continues to walk on an ulcer, every step “crushes” new tissue that is attempting to organize and fill the soft-tissue void. People without sensory neuropathy find it painful to walk on an open wound and will instinctively avoid any weight-bearing forces on a wounded foot; they alter their gait or limp to protect the injured site. However, in people with sensory neuropathy, ulcers are painless and often unrecognized unless they leave a stain on socks or blood on the floor. Because neuropathy blocks the pain response, these patients continue to fully bear weight on the site of injury.

Off-loading devices facilitate healing in several ways. The most effective off-loading strategies reduce pressure and shear forces at the site of ulceration. They reduce motion of the joints of the foot, and they are usually associated with reduced activity. Reducing pressure and shear forces and decreasing the number of steps or loading cycles per day allows healing tissue to bridge the wound without continual dam-age. Off-loading is one of the most important interventions to facilitate the healing of foot ulcers.

There are a variety of approaches to protecting the site of ulceration from repetitive injury by off-loading the diabetic foot. These include the use of therapeutic shoes and custom insoles (often referred to as “diabetic shoes”), postoperative shoes or sandals, padded dressings, removable cast boots (RCBs), and casting to protect the foot and immobilize the joints of the foot, often referred to as “total contact casts” (TCCs). Randomized controlled trials (RCTs) of the various off-loading methods are summarized in Table 2, and readers are referred to a review by Health Quality Ontario (14) for details on the individual studies discussed here.

TABLE 2

Results of Selected RCTs Evaluating Different Off-Loading Approaches: Proportion of Ulcers That Heal and Time to Healing (2)

TCCs involve a casting technique that uses a minimal amount of cast padding. Plaster of paris or plaster cast material is molded to conform closely to the anatomic structures of the foot and ankle and to limit movement within the cast. Fiberglass cast material is then applied as an outer layer, so the patient can walk on the cast within 30 minutes.

The use of TCCs is one of the most frequently studied techniques for healing DFUs and is regarded by many as the “gold standard” for protecting and off-loading DFUs (15). Numerous RCTs have evaluated TCCs, other casting techniques, modifications of TCCs, and RCBs. Descriptive retrospective cohort studies and RCTs have reported that a high proportion of DFUs (70–100%) heal with an average healing time of approximately 6 weeks (14).

There are challenges involved in using TCCs, and thus the technique is not widely used. The casting technique requires training, and many clinics do not have the skill, staff, or facilities to use the technique effectively. In addition, wearing a TCC may not be well accepted by patients, especially if it impedes driving or in patients with postural instability. TCCs are hot, and they make daily activities such as bathing and walking difficult.

Alternative therapies include RCBs, which were initially designed to immobilize the foot and ankle to treat fractures. RCBs are safe, easy to use, and require little training or expertise. Patients like them because they can be removed to bathe, clean the foot, and apply new dressings. However, they can be expensive, and often insurance will not pay for RCBs to off-load diabetic foot ulcers. Moreover, because these are not custom-molded devices, they may not fit patients well, and they may need to be replaced every few months.

Several companies have designed modifications of RCBs to meet the needs of patients with foot ulcers. Although not all of these products are equally effective, several companies have designed boots that have been shown in RCTs to be as effective as a TCC in healing DFUs (16,17). However, other studies have shown much lower healing rates with RCBs than TCCs (22–52%) (14).

One of the reasons RCBs may not be as effective as TCCs is that patients can remove them and walk with their injured foot unprotected. Several studies have evaluated boots that can be “locked” on and thus have been deemed “instant TCCs” (iTCCs) (18). The rationale for this approach is that iTCCs, like RBCs, can provide the advantages of easy application without the need for special training or facilities while offering the same pressure reduction and “forced compliance” of TCCs. RCTs by Piaggesi et al. (16) and Katz et al. (19) reported similar healing rates with this approach compared to TCCs.

Other off-loading options include therapeutic shoes and insoles, padded dressings, and postoperative sandals. These have the advantage of being widely accepted by patients. They do not require expertise, special training, or special equipment. Insurance will often pay for therapeutic shoes and insoles, and postoperative sandals and padding are relatively inexpensive. These options do not interfere with normal walking, driving, or bathing. Unfortunately, they are the least effective off-loading strategies. Mueller and Caravaggi reported that only 21–32% of DFUs healed with these techniques during 12 week RCTs (14).

Off-loading is one of the most important treatments for healing DFUs. The evidence clearly indicates that there are significant differences in the proportion of ulcers that heal and the rate of healing based on the type of off-loading employed. Referral to a center that has experience with TCCs should be considered for patients with chronic non-healing ulcers if optimal off-loading is not otherwise available.

Wound Debridement: Surgical or Otherwise

TYPES OF DEBRIDEMENT

Mechanical

Mechanical debridement is perhaps the oldest form of debridement and involves the use of moist or wet flushes or dressings, which are subsequently removed. This removal and physical wound base disruption causes non-selective debridement of loose tissues and slough. Examples include direct wound irrigation with saline, wet-to-dry dressings, and hydrotherapy, including bath and whirlpool. Dressing changes are simple and can be performed independently by patients in many cases. However, mechanical debridement is considered non-selective in nature and thus may remove or damage healthy tissues if not performed meticulously.

Enzymatic

Enzymatic debridement involves using chemical agents to slough necrotic wound tissue. Collectively, these enzymes are derived from microorganisms such as Clostridium histolyticum or from plants, including collagenase, varidase, papain, and bromelain. This method is most useful for debridement of wounds with a large amount of necrotic tissue and poses little risk to healthy tissues.

Autolytic

Autolytic debridement uses the body’s own enzymatic processes to debride necrotic tissues and slough. This process interrupts dead and devitalized tissue over time by allowing wound fluids to maintain constant contact in the wound bed to hydrate, soften, and liquefy necrotic tissue and eschar. This method is achieved with the use of occlusive or semi-occlusive dressings with or without the supplementation of hydrocolloids, hydrogels, and transparent films and is suitable for cases in which the amount of dead tissue is not extensive and there is no infection.

Autolytic debridement is selective for necrotic tissues, easy to perform, and virtually painless to patients. However, it is by far the slowest type of debridement, and the wound must be rigorously monitored for signs of infection. For these reasons, this method is usually reserved for patients with poor access to resources or those requiring a break from other debridement methods.

Biologic

Biologic debridement employs medical maggots that have been grown in a sterile environment. Several young larvae of the green bottle fly (Lucilia sericata) are introduced into a wound bed and secured with a dressing. The maggots feed selectively on the necrotic tissue of the host without injuring living tissue and can quite effectively debride a wound in a matter of just a few days. The larvae derive nutrients by secreting a broad spectrum of enzymes that liquefy necrotic tissue for consumption. In an optimum environment, maggots molt twice, increasing in overall size and leaving a clean wound free of necrotic tissue when they are removed.

This method has gained popularity over time, but some patients find it painful, and some patients’ aversion to maggots being placed on their body may impede its use. That said, this method has the advantage of being non-surgical in nature and works faster than autolytic or enzymatic debridement with little risk to healthy tissues.

Surgical

Surgical debridement is arguably the most common and varied type of debridement (Figure 3). A myriad of instrumentation and adjuncts are used to physically excise non-viable tissue from the wound bed, either at the bedside, in the clinic, or in an operating room. The surgeon will debride tissue to viability, as determined by tissue character and the presence of vascularity in healthy tissues, using any combination of instruments, such as rongeur, curette, blade, scissors, and forceps. Adjuncts such as the micro water jet device have been developed for even more meticulous and selective debridement.

FIGURE 3

Progression of a diabetic foot ulcer from necrotic wound base (A), to surgical debridement (B), to complete healing (C).

A novel method used by the authors to ensure a more thorough debridement of wounds, especially those pending closure, is to completely paint the wound with methylene blue immediately before debridement. Sharp debridement sufficient to remove all of the blue-stained tissue provides a clear delineation between more superficial exposed tissues that may harbor bioburden and the healthy tissues below.

Surgical debridement is best suited for progressive or recalcitrant wounds; larger-sized wounds; those in abnormal or precarious locations; grossly infected wounds; and wounds considered to be of an unknown etiology, which necessitate surgical biopsy or resection. Surgical debridement is considered the fastest method of debridement because it is very selective and limited only by the skill and experience of the surgeon. Overall, surgical debridement affords superior control over which tissues and how much of them are removed, is the fastest way to achieve a clean wound bed, and can speed the healing process in most patients with diabetic foot wounds.

Management of Infection

Among patients with diabetes presenting with a foot wound, about half have clinical evidence of infection (23). The development of a diabetic foot infection (DFI), which typically begins in a break in the skin envelope and frequently spreads to deeper soft tissues (often including bone), is a sentinel event. For people with diabetes, DFIs are the most common diabetes-related reason for hospitalizations and for lower-extremity amputations. Recent studies have shown, however, that rapid recognition and appropriate management of DFIs can usually avert these adverse outcomes (23).

Recognizing and Treating Peripheral Artery Disease

Although it has been repeatedly demonstrated that creation of well-organized diabetic foot care teams is a highly effective means of reducing major limb amputations associated with DFUs and PAD, such teams are not the norm in many parts of the world, including the United States, where management of DFUs is often fragmented. For example, a recently published cross-sectional analysis of approximately 6.7 million patients with DFUs seen in ambulatory care settings from 2007 to 2013 across the United States reported that, compared to ambulatory visits of patients without DFUs, DFU visits were associated with a 3.4 times higher odds of direct emergency department or inpatient admission; double the number of previous visits during the past 12 months; double the odds of referral to another physician; and an outpatient visit length 1.4 times longer (29). In another study of more than 1 million patients presenting with DFUs to emergency departments in the United States from 2006 to 2010, more than 80% were admitted to the hospital. Among those admitted, annual estimated costs were $8.78 billion. Clinical outcomes included a sobering 2.0% mortality rate, 9.6% rate of sepsis, and 10.5% rate of minor or major amputations (30). Outcomes were significantly worse for patients residing in rural locations, Medicaid beneficiaries, and those residing in regions in the lowest quartile for income.

Failure to diagnose and adequately treat underlying PAD is a major cause of amputations in people with diabetes. The prevalence of PAD among people with diabetes has risen steadily throughout the past three decades, and PAD is estimated to be present in as many as 50–60% of patients with DFUs (1).

To improve vascular care for such patients, the Society for Vascular Surgery (SVS) developed and published in 2014 a Threatened Limb Classification System based on grading the three major limb factors associated with amputation risk: Wound, Ischemia, and foot Infection (WIfI) (7). As briefly described in the section on Screening for Foot Complications Risk (p. 4), each of these three factors is graded on a scale from 0 to 3, and the resultant grades are used to classify a given limb into four clinical stages of amputation risk ranging from Stage 1 (very low) to Stage 4 (high) (Table 3). Readers are referred to the original publication for details regarding grading and classification (7).

TABLE 3

SVS Threatened Limb Classification System, With Clinical Stages 1–4 Based on Severity of Wound, Ischemia, and foot Infection (WIfI)

Although the presence of clearly palpable pedal pulses is reassuring, pulse palpation alone is unreliable to assess ischemia, and the application of WIfI grading mandates measurement of perfusion/hemodynamic status of the threatened limb. Because of the issue with falsely elevated ankle brachial index measurements due to underlying medial calcinosis of the arterial wall, toe waveforms and pressures are the preferred measurements in patients with DFUs. The WIfI classification is intended to stage the limb, much as the American Joint Committee on Cancer/Union for International Cancer Control TNM (Tumor, Nodes, and Metastases) classification is used to stage cancer. Data accumulated to date, as recently summarized in a detailed review of 19 studies that correlated WIfI clinical stage with clinically meaningful outcomes such as major-limb amputation, wound-healing time, hospital costs, and lengths of stay, have confirmed the utility of WIfI staging (31).

One of the principles of WIfI is that limb threat is a spectrum, and the use of an absolute critical level of perfusion or cut-off measure that mandates revascularization is not appropriate. The use of the term “chronic limb-threatening ischemia” (CLTI), has been suggested to avoid confusion and missed opportunities to identify ischemia associated with the anachronistic term “critical limb ischemia” (CLI).

The level of perfusion required to heal a foot ulcer is complicated and depends on a number of factors that include ulcer size, location, and depth; presence and extent of infection; and nutritional status. The amount of blood flow improvement required to heal a small, shallow, non-infected ulcer in a compliant patient with well-controlled diabetes and a toe pressure of 36 mmHg is likely to be less than that in a patient with diabetes in poor control who requires open amputation of multiple toes for wet gangrene and who has an identical toe pressure. In general, most patients with foot ulcers and an ischemia grade of 3 (severe) will require revascularization, but the decision regarding revascularization also depends on the wound stage, the presence or absence of infection, and a variety of patient factors such as functional status, advanced age (>80 years), and oxygen-dependent chronic obstructive lung disease. Importantly, patients with moderate ischemia who do not meet the traditional definition of CLI may also benefit from revascularization, particularly as wound and foot infection grades increase.

WIfI Stage 4 patients uniformly have a higher risk of amputation, even with aggressive revascularization, with a mean 1-year amputation rate of 23.8% (median 32.5%) based on a compilation of 2,939 patients treated at 10 centers (32). In contrast, the mean amputation rate in Stage 1 patients was 3.8% (median 0). Patients at Stages 2 and 3 exhibit intermediate amputation rates of 10–11% at 1 year, suggesting some overlap in these stages and opportunities to improve the classification in intermediate-risk patients.

Increasingly, revascularization may be carried out by an endovascular approach, including more complex techniques such as subintimal angioplasty or retrograde pedal access, as well as surgical bypass. Because patients with diabetes often have PAD below the level of the knee, interventions are frequently required to the tibial arteries and even the pedal level. To date, no prospective trials have been conducted randomizing patients to open versus endovascular revascularization based on WIfI clinical stage. However, in functional patients with available vein conduit presenting with Stage 4 limbs, open bypass may be more effective and durable than endovascular therapy (32), which has been associated with higher rates of failure of wound healing, the need for repeat revascularization, and limb amputation (33).

In summary, studies have shown that identification of PAD in patients with DFUs and aggressive, timely revascularization reduces amputation rates. WIfI is a systematic classification to aid in the identification of PAD and impaired perfusion. Patients with threatened limbs in whom significant ischemia is detected (ischemia grades 2 and 3) and any patient with failure to progress after 4 weeks of proper wound care and off-loading should be referred to a vascular limb salvage specialist for further evaluation and consideration for revascularization. Preferably, vascular specialists should serve as integral components of and routinely participate in diabetic foot and limb salvage teams.

Evidence-Based Adjunctive Therapies for Diabetic Foot Ulcers

DFUs are common and costly (34–36). One of six patients with a DFU undergoes an amputation, accounting for nearly 100,000 amputations each year in the United States and making diabetes the leading cause of non-traumatic amputation. Patients with a DFU or history of a DFU have an increased risk of 5- and 10-year mortality, but it is not yet proven that healing DFUs improves longevity. DFUs and their complications exact a financial cost as well; estimated costs of hospitalizations due to DFUs range from $9 to $13 billion, and $43.5 billion is spent on lower-extremity complications of diabetes each year (37,38).

Standard care includes ensuring good vascular supply, preventing and treating soft-tissue and bone infection, performing initial excisional debridement and maintenance debridement as indicted, and, of crucial importance, adhering to high-quality off-loading. Even in optimal situations, at least 25% of patients fail to heal. Instituting adjunctive therapy early improves outcomes. Typically, standard care is provided for a 4-week period because wounds that do not reduce in size by more than 50% after 4 weeks have a decreased likelihood of healing by 12 weeks. Referral to a wound center, where clinical expertise and access to advanced therapies are available, is often indicated.

Numerous therapies can be applied for these recalcitrant ulcers; however, few have been proven to improve complete ulcer healing in RCTs and fewer still in high- quality trials. Evidence-based ad-junctive therapies include cell and tissue-based products (CTPs) such as bioengineered cell-based therapies, acellular matrices, and placental-derived membranes; recombinant growth factors; platelet-rich plasma; negative pressure wound therapy; and possibly hyperbaric oxygen, all of which can improve complete healing and some of which may treat biofilm, prevent bone infection and limb loss, and improve patients’ quality of life (Table 4). The highest-quality evidence exists for products that have undergone the rigorous approval process of the U.S. Food and Drug Administration (FDA) (as opposed to those that have been “cleared” by the FDA) (39,40). Direct comparison of the clinical trial results (efficacy data) is not possible because of the varying rigor of trial design and analysis, inclusion and exclusion criteria, and sample sizes.

TABLE 4

Comparison of Evidence-Based Treatments for Refractory Ulcers

The Acute Hot, Swollen Foot: Charcot or Infection?

Primary care providers need to have a high index of suspicion that a red, hot, swollen foot is Charcot neuroarthropathy, especially in patients with sensory neuropathy. Charcot neuroarthropathy is a fracture dislocation process that affects the bones, joints, and ligaments of the foot and ankle in people with peripheral sensory neuropathy (54).

The disease process was originally described in patients with tertiary syphilis and usually presents as a unilateral red, hot, swollen foot and ankle (55). The diagnosis for the hot, swollen diabetic foot is often delayed by weeks or months or missed entirely, resulting in severe deformity, loss of function, ulceration, infection, and lower-extremity amputation.

Perhaps the easiest screening tool is to ask whether a patient has symptoms of neuropathy (i.e., numbness, tingling, formication, and burning) and then to test for sensory neuropathy.

The classic presentation is of a patient with painless unilateral swelling without a history of trauma. Sometimes, the patient will recall an incidental injury such as making a misstep when stepping down from a curb or a slight inversion of the ankle. The foot and ankle are usually swollen, red, and warm to the touch compared to the contralateral foot. The unilateral swelling could have lasted for days, weeks, or even months by the time of presentation. Patients sometimes comment that what brought them to see the doctor was that they could no longer fit their foot into a shoe or that the shape of their foot had changed, rather than that they were in pain.

Diagnosis of Charcot neuroarthropathy is based on medical history, physical examination, and plain radiographs (54,55). The differential diagnosis includes cellulitis, deep venous thrombosis, and trauma. Often, patients are treated with antibiotics, surgery, or amputation for infection, or they have multiple ultrasound examinations for deep vein thrombosis before the correct diagnosis is made.

The duration of the swelling and redness is important to ascertain in attempting to pinpoint the timing of the injury. Musculoskeletal deformity may be absent, or there can be severe deformity at initial presentation (56). Patients with an early presentation often have normal X-rays and a normal musculoskeletal clinical examination. Untreated injuries of longer duration have more severe bone and joint destruction and dislocation. Patients who seek medical care later in the disease process on inspection may have loss of the medial longitudinal arch of the foot compared to the contralateral foot, or their feet do not appear to be symmetrical. The classic “rocker-bottom” foot deformity is an example of endstage disease with severe fracture dislocation, collapse of the midfoot, dorsal dislocation of the metatarsals, and plantar dislocation of the tarsal bones.

Patients will have a history of neuropathy symptoms with a symmetrical distribution. Occasionally, patients will say that they feel as if they have a thick stocking on their feet when they are barefoot or that their feet feel cold when they are not. Simply put, if you ask these patients whether they have symptoms of neuropathy, they will often help to make the diagnosis before you do a physical examination (57).

Clinical examination often shows good peripheral pulses and severe sensory loss. Sensory testing can be quickly accomplished with a 128-Hz tuning fork or a 10-g monofilament or by testing light-touch perception. Examination of the joints of the foot and ankle can show abnormal alignment, joint effusion, and dislocations that are painless when examined. Plain X-rays maybe appear normal early in the Charcot process, or the radiographic signs can be subtle. Dislocation at the Lis Franc joint in the midfoot is a common presentation that can be missed even by experienced radiologists unless concerns regarding possible Charcot neuroarthropathy are voiced when imaging is ordered (54,55).

It is uncommon for adults to have infections without a wound. Inspect the skin for ulceration. Charcot patients sometimes also have ulcerations. If there is a wound, fractures and dislocations, and cellulitis, the patient may have both disease processes. Many people with diabetes who have cellulitis do not have leukocytosis, so using this in the decision process will be helpful to confirm infection when there are both leukocytosis and other systemic signs of infection. If there is no leukocytosis, you have not ruled infection out. If there is purulence from the wound or exposed bone when the wound is examined with a sterile probe, there is infection (54,56).

Treatment of Charcot neuroarthropathy requires prompt referral to a podiatric or orthopedic surgeon with experience in treating this complication. Early treatment requires immobilization and non-weight-bearing in a cast or wheelchair until the acute inflammatory process subsides, which may take weeks or months. Late treatment requires reconstructive surgery to repair the deformity and obtain a plantar-grade foot (54,57).

How to Maintain the Foot in Remission

The overall risk for developing a wound in people with diabetes is ∼2% per year. This risk increases to 7.5% for patients with neuropathy. However, the risk jumps to 40% in people with a history of ulceration (1). The risk further increases to nearly 60% at 3 years and up to 75% at 5 years (1). In fact, re-ulceration is not only common, it is likely. We therefore use the term “in remission” to refer to this population (58). Our goal is not necessarily to prevent every wound, but to maximize ulcer-free, hospital-free, and activity-rich days (59–61) by making each wound recurrence as uncomplicated as possible.

There are currently four key strategies associated with maximizing ulcer-free days: integrated foot care, self-management, therapeutic footwear, and, as necessary, reconstructive foot surgery. These are summarized in Table 5.

TABLE 5

Effect Sizes in Studies of Interventions to Reduce the Risk of Foot Ulcer Recurrence

Specifically, integrated foot care focuses on regular visits to podiatrists and other members of the diabetes foot care team as described earlier in this monograph. Self-management involves daily evaluation by patients, family members, or caregivers and the use of thermometry. Therapeutic footwear that off-loads the foot by at least 30% appears to be associated with lower risks of recurrence (62). If these non-surgical methods are problematic, foot surgery appears to provide benefit in reducing the severity of deformity and plantar pressure and therefore reduces the risk of recurrence (63–65).

Conclusions and Future Directions

Diabetic foot complications are, as has often been said, common, complex, and costly. Demographic trends suggest that these complications, including ulcers, infections, PAD, and amputations, will continue to be highly prevalent (29).

Future directions should focus not only on the promising therapeutic advances discussed in this monograph, but also on novel monitoring systems (59,66–71). For example, efforts designed to identify pre-ulcerative inflammation through the past generation have now culminated in home-based monitors that can alert patients up to several weeks in advance of a potential complication (69). Similarly, smart insoles paired with smart watches may be able to identify potentially damaging pressure, which over time can cause blistering or callusing and tissue loss (67).

Combining the evidence-based and common-sense therapies described here with emerging technologies has the potential to help us maximize ulcer-free, hospital-free, and activity-rich days for our patients.

ACKNOWLEDGMENTS

The authors acknowledge Jayson N. Atves, DPM, CO, for contributions to the section on debridement.

Editorial and project management services were provided by Debbie Kendall of Kendall Editorial in Richmond, VA.

AUTHOR CONTRIBUTIONS

A.J.M.B. and D.G.A. served as co-editors and, as such, co-wrote the introduction and conclusion and reviewed and edited the entire manuscript. A.J.M.B. also wrote “Pathways to Diabetic Foot Complications,” and D.G.A. wrote “Screening for Foot Complications Risk” and “How to Maintain the Foot in Remission” and co-wrote “The Acute Hot, Swollen Foot: Charcot or Infection?”

C.E.A. co-wrote “Wound Debridement: Surgical or Otherwise.” R.S.K. wrote “Evidence-Based Adjunctive Therapies for Diabetic Foot Ulcers.”

L.A.L. wrote “When and Where to Refer Diabetic Foot Problems” and “Off-Loading the Diabetic Foot Wound” and co-wrote “The Acute Hot, Swollen Foot: Charcot or Infection?” B.A.L. wrote “Management of Infection.” J.L.M. wrote “Recognizing and Treating Peripheral Artery Disease.” J.S.S. co-wrote “Wound Debridement: Surgical or Otherwise.” A.J.M.B. and D.G.A. are the guarantors of this work.

DUALITIES OF INTEREST

A.J.M.B., D.G.A., and J.L.M. have no relevant dualities of interest to disclose. C.E.A. is a consultant for Acelity and Integra. R.S.K. has received honoraria for participation in educational programs for Healogics. L.A.L. has received research grants from Cardinal Health; serves on speakers bureaus for Integra, Osiris, and Smith & Nephew; and is a consultant or advisor to Apilon Medical Users, Boehringer Ingelheim, Harbor MedTech, and Medline Industries.

B.A.L. is a consultant for Medimmune, Microbion, and Debiopharm. J.S.S. is a consultant for Integra and Syntactx.

REFERENCES

1.

Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367–2375 [PubMed: 28614678]

2.

Jeffcoate WJ, Vileikyte L, Boyko EJ, Armstrong DG, Boulton AJM. Current challenges and opportunities in the prevention and management of diabetic foot ulcers. Diabetes Care 2018;41:645–652 [PubMed: 29559450]

3.

Abbott CA, Carrington AL, Ashe H, et al; North-West Diabetes Foot Care Study. The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 2002;19:377–384 [PubMed: 12027925]

4.

Boulton AJM. The pathway to ulceration. In The Foot in Diabetes, 5th ed. Boulton AJM, Rayman G, Wukich DK, Eds. Chichester, U.K., John Wiley & Sons, 2019. In press

5.

Miller JD, Carter E, Shih J, et al. How to do a 3-minute diabetic foot exam. J Fam Pract 2014;63:646–656 [PubMed: 25362495]

6.

Boulton AJ, Armstrong DG, Albert SF, et al.; American Diabetes Association; American Association of Clinical Endocrinologists. Comprehensive foot examination and risk assessment: a report of the Task Force of the Foot Care Interest Group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008;88:1679–1685 [PMC free article: PMC2494620] [PubMed: 18663232]

7.

Mills JL Sr, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg 2014;59:220–234.e1–e2 [PubMed: 24126108]

8.

Armstrong DG, Mills JL. Juggling risk to reduce amputations: the three-ring circus of infection, ischemia and tissue loss-dominant conditions. Wound Medicine 2013;1:13–14

9.

Lavery LA, Peters EJ, Williams JR, Murdoch DP, Hudson A, Lavery DC; International Working Group on the Diabetic Foot. Reevaluating the way we classify the diabetic foot: restructuring the diabetic foot risk classification system of the International Working Group on the Diabetic Foot. Diabetes Care 2008;31:154–156 [PubMed: 17934155]

10.

Uccioli L, Faglia E, Monticone G, et al. Manufactured shoes in the prevention of diabetic foot ulcers. Diabetes Care 1995;18:1376–1378 [PubMed: 8721941]

11.

Edmonds ME, Blundell MP, Morris ME, Thomas EM, Cotton LT, Watkins PJ. Improved survival of the diabetic foot: the role of a specialized foot clinic. Q J Med 1986;60:763–771 [PubMed: 3774959]

12.

van Houtum WH. Barriers to implementing foot care. Diabetes Metab Res Rev 2012;28(Suppl. 1):112–115 [PubMed: 22271735]

13.

Skrepnek GH, Mills JL, Armstrong DG. Foot-in-wallet disease: tripped up by “cost-saving” reductions? Diabetes Care 2014;37:e196–e197 [PubMed: 25147261]

14.

Health Quality Ontario. Fibreglass total contact casting, removable cast walkers, and irremovable cast walkers to treat diabetic neuropathic foot ulcers: a health technology assessment. Ont Health Technol Assess Ser 2017;17:1–124 [PMC free article: PMC5628703] [PubMed: 28989556]

15.

Coleman WC, Brand PW, Birke JA. The total contact cast: a therapy for plantar ulceration on insensitive feet. J Am Podiatry Assoc 1984;74:548–552 [PubMed: 6389655]

16.

Piaggesi A, Goretti C, Iacopi E, et al. Comparison of removable and irremovable walking boot to total contact casting in offloading the neuropathic diabetic foot ulceration. Foot Ankle Int 2016;37:855–861 [PubMed: 27083507]

17.

Faglia E, Caravaggi C, Clerici G, et al. Effectiveness of removable walker cast versus nonremovable fiberglass off-bearing cast in the healing of diabetic plantar foot ulcer: a randomized controlled trial. Diabetes Care 2010;33:1419–1423 [PMC free article: PMC2890332] [PubMed: 20357377]

18.

Armstrong DG, Short B, Espensen EH, Abu-Rumman PL, Nixon BP, Boulton AJ. Technique for fabrication of an “instant total-contact cast” for treatment of neuropathic diabetic foot ulcers. J Am Podiatr Med Assoc 2002;92:405–408 [PubMed: 12122129]

19.

Katz IA, Harlan A, Miranda-Palma B, et al. A randomized trial of two irremovable off-loading devices in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care 2005;28:555–559 [PubMed: 15735187]

20.

Guthrie HC, Clasper JC. Historical origins and current concepts of wound debridement. J R Army Med Corps 2011;157:130–132 [PubMed: 21805760]

21.

Attinger CE, Clemens MW, Ducic I, Levin MM, Zelen C. The use of local muscle flaps in foot and ankle reconstruction. In Lower Extremity Soft Tissue & Cutaneous Plastic Surgery, 2nd ed. Dockery GD, Ed. Kidlington, England, U.K., Elsevier Science, 2011, p. 269-288

22.

Attinger CE, Janis JE, Steinberg JS, Schwartz J, Al-Attar A, Couch K. Clinical approach to wounds: debridement and wound bed preparation including the use of dressings and wound-healing adjuvants. Plast Reconstr Surg 2006;111(Suppl. 7):72S–109S [PubMed: 16799376]

23.

Lipsky BA, Aragón-Sánchez J, Diggle M, et al.; International Working Group on the Diabetic Foot. IWGDF guidance on the diagnosis and management of foot infections in persons with diabetes. Diabetes Metab Res Rev 2016;32(Suppl. 1):45–74 [PubMed: 26386266]

24.

Lauri C, Tamminga M, Glaudemans WJM, et al. Detection of osteomyelitis in the diabetic foot by imaging techniques: a systematic review and meta-analysis comparing MRI, white blood cell scintigraphy, and FDG-PET. Diabetes Care 2017;40:1111–1120 [PubMed: 28733376]

25.

Pereira SG, Moura J, Carvalho E, Empadinhas N. Microbiota of chronic diabetic wounds: ecology, impact, and potential for innovative treatment strategies. Front Microbiol 2017;8:1791 [PMC free article: PMC5613173] [PubMed: 28983285]

26.

Selva Olid A, Solà I, Barajas-Nava LA, Gianneo OD, Bonfill Cosp X, Lipsky BA. Systemic antibiotics for treating diabetic foot infections.Cochrane Database Syst Rev 2015;CD009061. [PMC free article: PMC8504988] [PubMed: 26337865]

27.

Dumville JC, Lipsky BA, Hoey C, Cruciani M, Fiscon M, Xia J. Topical antimicrobial agents for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev 2017;CD011038 [PMC free article: PMC6481886] [PubMed: 28613416]

28.

Lipsky BA, Dryden M, Gottrup F, Nathwani D, Seaton RA, Stryja J. Antimicrobial stewardship in wound care: a position paper from the British Society of Antimicrobial Chemotherapy and European Wound Management Association. J Antimicrob Chemother 2016;71:3026–3035 [PubMed: 27494918]

29.

Skrepnek GH, Mills JL, Lavery LA, Armstrong DG. Health care service and outcomes among an estimated 6.7 million ambulatory care diabetic foot cases in the U.S. Diabetes Care 2017:40:936–942 [PubMed: 28495903]

30.

Skrepnek GH, Mills JL Sr, Armstrong DG. A diabetic emergency one million feet long: disparities and burdens of illness among diabetic foot ulcer cases within emergency departments in the United States, 2006–2010. PLoS One 2015;10:e0134914 [PMC free article: PMC4527828] [PubMed: 26248037]

31.

Mayor JM, Mills JL. The correlation of the Society for Vascular Surgery Wound, Ischemia, and foot Infection Threatened Limb Classification with amputation risk and major clinical outcomes. Indian J Vasc Endovasc Surg 2018;5:83–86

32.

Causey MW, Ahmed A, Wu B, et al. Society for Vascular Surgery limb stage and patient risk correlate with outcomes in an amputation prevention program. J Vasc Surg 2016;63:1563–1573 [PubMed: 27036309]

33.

Kobayashi N, Hirano K, Yamawaki M, et al. Characteristics and clinical outcomes of repeat endovascular therapy after infrapopliteal balloon angioplasty in patients with critical limb ischemia. Catheter Cardiovasc Interv 2018;91:505–514 [PubMed: 28799724]

34.

Singer AJ, Tassiopoulos A, Kirsner RS. Evaluation and management of lower-extremity ulcers. N Engl J Med 2017;377:1559–1567 [PubMed: 29045216]

35.

Alavi A, Sibbald RG, Mayer D, et al Diabetic foot ulcers: Part I. Pathophysiology and prevention. J Am Acad Dermatol 2014;70:21.e1–e18 [PubMed: 24355276]

36.

Alavi A, Sibbald RG, Mayer D, et al Diabetic foot ulcers: Part II. Management. J Am Acad Dermatol 2014;70:21.e1–e24 [PubMed: 24355276]

37.

Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers. Diabetes Care 2014;37:651–658 [PubMed: 24186882]

38.

Lavery LA, Fulmer J, Shebetka KA, et al.; Grafix Diabetic Foot Ulcer Study Group. The efficacy and safety of Grafix® for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised,blinded, clinical trial. Int Wound J 2014; 11:554–560 [PMC free article: PMC7951030] [PubMed: 25048468]

39.

Hughes OB, Rakosi A, Macquhae F, Herskovitz I, Fox JD, Kirsner RS. A review of cellular and acellular matrix products: indications, techniques, and outcomes. Plast Reconstr Surg 2016;138(Suppl. 3):138S–147S [PubMed: 27556754]

40.

Braun LR, Fisk WA, Lev-Tov H, Kirsner RS, Isseroff RR. Diabetic foot ulcer: an evidence-based treatment update. Am J Clin Dermatol 2014;15:267–281 [PubMed: 24902659]

41.

Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers: a phase III randomized placebo-controlled double-blind study. Diabetes Care 1998;21:822–827 [PubMed: 9589248]

42.

Driver V, Hanft J, Fylling CP, Beriou JM; Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2006;52:68–70,72,74 passim [PubMed: 16799184]

43.

Veves A, Falanga V, Armstrong DG, Sabolinski ML; Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care 2001;24:290–295 [PubMed: 11213881]

44.

Edmonds M; European and Australian Apilgraf Diabetic Foot Ulcer Study Group. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds 2009;8:11–18 [PubMed: 19189997]

45.

Marston W, Hanft J, Norwood P, Pollak R; Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 2003;26:1701–1705 [PubMed: 12766097]

46.

Driver VR, Lavery LA, Reyzelmam AM, et al. A clinical trial of Integra Template for diabetic foot ulcer treatment. Wound Repair Regen 2015;23:891–900 [PubMed: 26297933]

47.

Cazzell SM, Lange DL, Dickerson JE Jr, Slade HB. The management of diabetic foot ulcers with porcine small intestine submucosa tri-layer matrix: a randomized controlled trial. Adv Wound Care (New Rochelle) 2015;4:711–718 [PMC free article: PMC4651054] [PubMed: 26634183]

48.

Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J 2009;6:196–208 [PMC free article: PMC7951349] [PubMed: 19368581]

49.

Zelen CM, Gould L, Serena TE, Carter MJ, Keller J, Li WW. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J 2015;12:724–732 [PMC free article: PMC7950807] [PubMed: 25424146]

50.

Armstrong DG, Lavery LA; Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet. 2005;366:1704–1710. [PubMed: 16291063]

51.

Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31:631–636 [PubMed: 18162494]

52.

Löndahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010;33:998–1003 [PMC free article: PMC2858204] [PubMed: 20427683]

53.

Santema KTB, Stoekenbroek RM, Koelemay MJW, et al.; DAMO2CLES Study Group. Hyperbaric oxygen therapy in the treatment of ischemic lower-extremity ulcers in patients with diabetes: results of the DAMO2CLES multicenter randomized clinical trial. Diabetes Care 2018;41:112–119 [PubMed: 29074815]

54.

Rogers LC, Frykberg RG, Armstrong DG, et al. The Charcot foot in diabetes. Diabetes Care 2011;34:2123–2129 [PMC free article: PMC3161273] [PubMed: 21868781]

55.

Konarzewska A, Korzon-Burakowska A, Rzepecka-Wejs L, Sudoł-Szopińska I, Szurowska E, Studniarek M. Diabetic foot syndrome: Charcot arthropathy or osteomyelitis? Part I: Clinical picture and radiography. J Ultrason 2018;18:42–49 [PMC free article: PMC5911718] [PubMed: 29844940]

56.

Jeffcoate WJ. Charcot foot syndrome. Diabet Med 2015;32:760–770 [PubMed: 25818542]

57.

Armstrong DG, Todd WF, Lavery LA, Harkless LB, Bushman TR. The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic. Diabet Med 1997;14:357–363 [PubMed: 9171250]

58.

Armstrong DG, Mills JL. Toward a change in syntax in diabetic foot care: prevention equals remission. J Am Podiatr Med Assoc 2013;103:161–162 [PubMed: 23536510]

59.

Khan T, Armstrong DG. Ulcer-free, hospital-free and activity-rich days: three key metrics for the diabetic foot in remission. J Wound Care 2018;27(Suppl. 4):S3–S4 [PubMed: 29641340]

60.

Miller JD, Salloum M, Button A, Giovinco NA, Armstrong DG. How can I maintain my patient with diabetes and history of foot ulcer in remission? Int J Low Extrem Wounds 2014;13:371–377 [PubMed: 25143315]

61.

Boghossian J, Miller J, Armstrong D. Offloading the diabetic foot: toward healing wounds and extending ulcer-free days in remission. Chronic Wound Care Management and Research 2017;4:83–88

62.

van Netten JJ, Lazzarini PA, Armstrong DG, et al. Diabetic Foot Australia guideline on footwear for people with diabetes. J Foot Ankle Res 2018;11:2 [PMC free article: PMC5769299] [PubMed: 29371890]

63.

Finestone AS, Tamir E, Ron G, Wiser I, Agar G. Surgical offloading procedures for diabetic foot ulcers compared to best non-surgical treatment: a study protocol for a randomized controlled trial. J Foot Ankle Res 2018;11:6 [PMC free article: PMC5819289] [PubMed: 29467829]

64.

Armstrong DG, Lavery LA, Stern S, Harkless LB. Is prophylactic diabetic foot surgery dangerous? J Foot Ankle Surg 1996;35:585–589 [PubMed: 8986899]

65.

Bus SA, Armstrong DG, van Deursen RW, Lewis JE, Caravaggi CF, Cavanagh PR; International Working Group on the Diabetic Foot. IWGDF guidance on footwear and offloading interventions to prevent and heal foot ulcers in patients with diabetes. Diabetes Metab Res Rev 2016;32(Suppl. 1):25–36 [PubMed: 26813614]

66.

Basatneh R, Najafi B, Armstrong DG. Health sensors, smart home devices, and the Internet of Medical Things: an opportunity for dramatic improvement in care for the lower extremity complications of diabetes. J Diabetes Sci Technol 2018;12:577–586 [PMC free article: PMC6154231] [PubMed: 29635931]

67.

Najafi B, Ron E, Enriquez A, Marin I, Razjouyan J, Armstrong DG. Smarter sole survival: will neuropathic patients at high risk for ulceration use a smart insole-based foot protection system? J Diabetes Sci Technol 2017;11:702–713 [PMC free article: PMC5588829] [PubMed: 28627227]

68.

Roser MC, Canavan PK, Najafi B, Cooper Watchman M, Vaishnav K, Armstrong DG. Novel in-shoe exoskeleton for offloading of forefoot pressure for individuals with diabetic foot pathology. J Diabetes Sci Technol 2017;11:874–882 [PMC free article: PMC5951007] [PubMed: 28859516]

69.

Frykberg RG, Gordon IL, Reyzelman AM, et al. Feasibility and efficacy of a smart mat technology to predict development of diabetic plantar ulcers. Diabetes Care 2017;40:973–980 [PubMed: 28465454]

70.

Armstrong DG, Holtz-Neiderer K, Wendel C, Mohler MJ, Kimbriel HR, Lavery LA. Skin temperature monitoring reduces the risk for diabetic foot ulceration in high-risk patients. Am J Med 2007;120:1042–1046 [PubMed: 18060924]

71.

Yap MH, Chatwin KE, Ng CC, et al. A new mobile application for standardizing diabetic foot images. J Diabetes Sci Technol 2018;12:169–173 [PMC free article: PMC5761973] [PubMed: 28637356]

The opinions expressed are those of the authors and do not necessarily reflect those of Healogics, Inc., Organogenesis, Inc., or the American Diabetes Association. The content was developed by the authors and does not represent the policy or position of the American Diabetes Association, any of its boards or committees, or any of its journals or their editors or editorial boards.