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Management of diabetic foot ulcers

Management of diabetic foot ulcers
Authors:
David G Armstrong, DPM, MD, PhD
Richard J de Asla, MD
Section Editors:
John F Eidt, MD
Joseph L Mills, Sr, MD
David M Nathan, MD
Deputy Editor:
Kathryn A Collins, MD, PhD, FACS
Literature review current through: Jan 2024.
This topic last updated: Apr 25, 2022.

INTRODUCTION — The lifetime risk of a foot ulcer in patients with diabetes (type 1 or 2) may be as high as 34 percent [1-3]. Diabetic foot ulcers are a major cause of morbidity [4], accounting for at least two-thirds of all nontraumatic amputations performed in the United States [5,6]. Infected or ischemic diabetic foot ulcers account for approximately 25 percent of all hospital stays for patients with diabetes [7]. Based on data from the World Health Organization, lower extremity complications of diabetes constitute a top ten condition in terms of years lived with disability [8,9]. Moreover, patients with diabetes with or without a diabetic foot ulcer have increased rates of depression, and expressing signs of depression is associated with an increased risk of diabetic foot ulcers [10,11]. These observations illustrate the importance of prompt and appropriate treatment of foot ulcers in patients with diabetes.

The management of diabetic foot ulcers, including local wound care, use of mechanical offloading, treatment of infection, and indications for revascularization, are reviewed here. The evaluation of the diabetic foot and specific management of the threatened limb are reviewed separately. (See "Evaluation of the diabetic foot" and "Management of chronic limb-threatening ischemia".)

ETIOLOGY — Risk factors that can lead to foot wounds in patients with diabetes include loss of protective sensation due to neuropathy, prior ulcers or amputations, foot deformity leading to excess pressure, external trauma, infection, and the effects of chronic ischemia, typically due to peripheral artery disease [1]. Patients with diabetes also have an increased risk for nonhealing related to mechanical and cytogenic factors, as well as a high prevalence of peripheral artery disease. (See "Evaluation of the diabetic foot", section on 'Risk factors'.)

ULCER CLASSIFICATION — The first step in managing diabetic foot ulcers is assessing, grading, and classifying the ulcer. Classification is based upon clinical evaluation of the extent and depth of the ulcer and the presence of infection or ischemia, which determine the nature and intensity of treatment. To assess for ischemia, all patients with diabetic foot ulcers should have ankle-brachial index and toe pressure measurements.

University of Texas system — The University of Texas (UT, San Antonio) in the United States introduced a clinical classification system for diabetic foot wounds that evaluates wound depth, the presence of infection, and peripheral arterial occlusive disease for every category of the wound assessment [12]. The UT system was the first diabetic foot ulcer classification to be validated [13]. This system updated the Wagner classification [14]. (See 'Wagner, PEDIS, and others' below.)

Grade:

●Grade 0: Pre- or postulcerative (Stages A to D) (picture 1)

●Grade 1: Full-thickness ulcer not involving tendon, capsule, or bone (Stages A to D) (picture 2)

●Grade 2: Tendon or capsular involvement without bone palpable (Stages A to D) (picture 3 and picture 4)

●Grade 3: Probes to bone (Stages A to D) (picture 5)

Stage:

●A: Noninfected

●B: Infected

●C: Ischemic

●D: Infected and ischemic (picture 6)

Threatened limb classification: WIfI — To provide a more quantitative assessment of peripheral artery disease (PAD) as a predictor and contributor to lower extremity pathology, the Society for Vascular Surgery has proposed the structure of the Wound/Ischemia/Foot Infection (WIfI) system. Scores are assigned on a "none/mild/moderate/severe basis (0/1/2/3)" using multiple specified criteria in the same fundamental categories as the University of Texas system [15]. This "threatened limb" system includes, in particular, more detailed measures and criteria for grading vascular status. It has been validated in four separate studies and shows promise as a pragmatic means to assess the likelihood of morbidity in at-risk limbs. The classification can be visualized as three intersecting rings of risk (figure 1) [16]. The quantitative scores for these individual categories can help identify the relative importance of the various factors underlying risk to a limb at a given point in time. In applying the WIfI system, it is recommended that diabetic and nondiabetic patients be considered in separate categories and the presence or absence of neuropathy be additionally noted in patients with diabetes [15]. While the specifics of what constitutes "none, mild, moderate, and severe" may change over time, the basic principles are likely to prove durable [16,17]. (See "Classification of acute and chronic lower extremity ischemia", section on 'WIfI (Wound, Ischemia, foot Infection)'.)

Wagner, PEDIS, and others — An early and often still used classification system at hyperbaric-based wound healing centers was originally proposed by Wagner [18]. This classification was based upon clinical evaluation (depth of ulcer and presence of necrosis) alone and did not account for variability in the vascular status of the foot. The ulcer classification is as follows:

●Grade 1: Superficial ulcer – Skin and subcutaneous tissue only

●Grade 2: Deep ulcer to tendon, muscle, joint capsule, or bone

●Grade 3: Deep ulcer with abscess, osteomyelitis, or tendinitis

●Grade 4: Partial foot gangrene

●Grade 5: Whole foot gangrene

The Wagner system is predictive of poor outcome, but only up to grade 3 [14]. It has fallen out of widespread use because of the lack of specificity to describe coexistent depth, infection, and ischemia.

The International Working Group on the Diabetic Foot proposed classifying all ulcers according to the following categories: perfusion, extent, depth, infection, and sensation (PEDIS) [19]. The PEDIS system is primarily used for research purposes. Other ulcer classification systems have also been described [20-22].

MANAGEMENT OVERVIEW — Our management approach is consistent with multidisciplinary guidelines for the management of the diabetic foot [23,24]. (See 'Society guideline links' below.)

General approach — The management of diabetic foot ulcers begins with a comprehensive assessment of the ulcer and the patient's overall medical condition (algorithm 1). Most patients with diabetes over age 40 should be offered measures to reduce their risk of developing cardiovascular complications. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Reducing the risk of macrovascular disease' and "Overview of peripheral artery disease in patients with diabetes mellitus", section on 'Risk factor modification'.)

Evidence of infection, underlying neuropathy, peripheral artery disease, edema, malnutrition, and any bony deformities should be actively sought and addressed systematically [25,26]. The incidence of neuropathic (Charcot) arthropathy may be as high as 13 percent in patients with diabetes [27]. (See "Diabetic neuroarthropathy" and "Surgical management of neuropathic arthropathy (Charcot foot)".)

For patients with evidence of arterial insufficiency, we suggest referral to a vascular specialist. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)

While it stands to reason that effective glucose control and adequate nutrition are important in healing diabetic foot wounds, there are few data to support either assumption. There are no randomized trials data to support that glucose control affects healing [28]. A trial evaluating the effectiveness of liquid oral protein supplementation failed to show a difference in healing between main groups but reported a significantly greater likelihood of healing in a subset of patients with low albumin or ischemia [29,30]. In addition, analysis of the Diabetes Control and Complications Trial (DCCT) suggested that intensive glucose control might reduce incidence of new ulceration by more than 23 percent [31].

Local ulcer care includes sharp debridement and proper wound coverage. When debridement is needed, we suggest surgical (sharp) debridement. Dressings are selected based upon ulcer appearance and other wound characteristics (table 1 and table 2). For extensive open wounds following debridement for infection and necrosis, or following partial foot amputation, we suggest negative pressure wound therapy, provided there is no residual necrotic tissue or infected bone (osteomyelitis) [32]. (See 'Local care' below and 'Dressings' below and 'Negative pressure wound therapy' below.)

Any ulcer that is subjected to sustained or frequent pressure and stress (ie, pressure-related heel ulcers or medial/lateral foot ulcers) or repetitive moderate pressure (plantar foot ulcers) will benefit from pressure reduction, which is accomplished with mechanical offloading. Several methods are available to achieve mechanical offloading, including total contact casts, cast walkers, wedge shoes, and bedrest. Following surgery, total contact casting and cast walkers are better alternatives to prolonged bed rest for the relief of pressure as they allow for the benefits and convenience of continued ambulation. (See 'Mechanical offloading' below.)

For some patients, successful offloading of a diabetic ulcer cannot be adequately achieved by mechanical devices alone. In such cases, surgical correction of the deformity may be required. Interventions include hammertoe corrections, bunion corrections, Achilles tendon or gastrocnemius lengthening, and Charcot foot reconstructions. (See "Diabetic neuroarthropathy" and "Surgical management of neuropathic arthropathy (Charcot foot)".)

After appropriately addressing debridement, pressure offloading, infection, and ischemia, there are a number of adjunctive therapies that may prove helpful in augmenting wound healing. (See 'Adjunctive local therapies' below.)

Whether such management can be accomplished in an outpatient setting and when admission to hospital is needed depends upon the skill set of the local wound care team, the resources available, and the personality and life circumstances of the patient.

Allowable time course for primary healing — In clinical practice, measurements of a patient's ulcer size should be taken at every visit so that comparisons can be made and progress documented. The surface area of a diabetic foot ulcer should decrease in size at a rate of approximately 1 to 2 percent a day. Thus, appropriate local wound care should achieve a greater than 40 to 50 percent surface area reduction or reduction of ulcer depth by four weeks [33]. If this rate of progress is not observed, in our system, the patient's care is transferred from the local team to a wound consultant who works with the patient's primary care physician to address issues such as glycemic control, edema, and other aspects of general health and nutrition. Ulcers that still do not improve should be reevaluated for ongoing soft tissue infection or osteomyelitis, impaired extremity vascular flow, and, most commonly, the need for more effective offloading or surgical debridement.

Coordination of care — Coordination among care providers is important. Meta-analyses have provided evidence that interdisciplinary teams have a profound impact in reducing the rate of amputation [34,35]. In a study of 10 Department of Veterans Affairs (VA) medical centers, decreased rates of amputation were seen in programs with the highest scores for availability of clinical protocols, educational seminars, discharge planning, and quality of care meetings [36]. Clinical teams may include podiatric, vascular, plastic and orthopedic surgeons. These surgeons, who focus on wound, ischemia, and foot infection-dominant conditions may be assisted by shoe specialists/prosthetists, physical therapy, nurse specialists, and nutritionists/dietitians. In addition, primary care physicians, infectious disease physicians, nephrologists, and diabetologists all play significant roles in limb preservation units [37].

Follow-up care and ulcer prevention — Once a patient has healed an ulcer, he or she remains at a very high risk for reulceration. Once healed, ulcer recurrence is 40 percent at one year, 66 percent at three years, and up to 75 percent at five years [4]. Therefore, people with healed ulcers should be considered "in remission," a term that better communicates the lifetime of visits (often bimonthly) needed to reduce the risk for severe recurrence, if not all ulcer recurrences [1,38,39]. The goals of long-term surveillance and care are to maximize ulcer-free, hospital-free, and activity-rich days.

Ongoing counseling regarding preventive foot care should be given to any patient whose feet are at risk for further ulcer development, particularly patients with existing neuropathy (table 3). Several measures can markedly diminish ulcer formation, such as avoiding poorly fitting shoes, not walking barefoot, and stopping smoking. (See "Evaluation of the diabetic foot", section on 'Risk factors' and "Evaluation of the diabetic foot", section on 'Preventive foot care' and 'Mechanical offloading' below.)

Certain oral diabetes agents (ie, SGLT2 inhibitors) may be associated with an increased risk of amputation compared with other oral treatments for type 2 diabetes [40]. If the patient is taking these agents, it should be discontinued. This issue is discussed in detail separately. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Amputations'.)

Approach by ulcer stage and depth — Treatment is based upon the ulcer classification. (See 'Ulcer classification' above.)

Noninfected — Superficial diabetic foot ulcers (University of Texas [UT] classification: grade 1; stage A) can typically be debrided in the clinic or at the bedside (algorithm 1). When a clinician with expertise in sharp debridement is not available, autolytic hydrogels can be used. For noninfected ulcers that extend to deeper tissues (grade/stage: 2A, 3A), we suggest initial surgical debridement in an operating room setting. For pressure-related ulcers, mechanical offloading should be implemented. (See 'Debridement' below and 'Mechanical offloading' below.)

Infected — The treatment of infected (UT classification: grades 1 to 3; stage B) diabetic foot ulcers includes antimicrobial therapy and surgical debridement (algorithm 1). The antibiotics chosen and duration of therapy depend upon the depth and severity of infection [23]. Consultation with a surgeon is important for any infection that extends beyond the dermis. (See 'Managing infection' below and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities".)

Ischemic — Approximately one-half of patients with diabetes who present with diabetic foot ulcers have some element of ischemia (UT classification: grades 1 to 3; stage C) [41]. In addition to proper local care (debridement, wound coverage, relief of pressure), patients with significant limb ischemia should be referred to a vascular specialist for possible revascularization (algorithm 1). Revascularization (open, endovascular) should be considered in patients with any degree of limb ischemia and foot ulcer that does not improve over an appropriate time course. (See 'Allowable time course for primary healing' above and "Management of chronic limb-threatening ischemia".)

Combined infection and ischemia — Infected and ischemic ulcers (UT classification: grades 1 to 3; stage D) constitute the highest risk for nonhealing and amputation [13,41]. These patients generally require team management by physicians and surgeons with expertise in medical and surgical control of infection and revascularization (algorithm 1). (See 'Infected' above and 'Ischemic' above.)

LOCAL CARE

Debridement — Debridement of necrotic tissue is important for ulcer healing [42]. The frequency of assessment and proper care may contribute more to wound healing than the type of debridement. In a review that examined chronic wound care among veterans, the chance of diabetic ulcer healing increased 2.5-fold when debridement was performed at 80 percent of visits and doubled when ischemia was assessed at the first visit [43].

There are few data to guide choice of debridement (sharp, enzymatic, autolytic, mechanical, and biological) for diabetic foot ulcer [44]. The types of debridement are reviewed separately. (See "Basic principles of wound management", section on 'Wound debridement'.)

When surgeons with expertise in sharp debridement are available, we prefer this method. Sharp debridement, the most widely used method, involves the use of a scalpel or scissors to remove necrotic tissue [45]. As an alternative, we suggest application of a hydrogel, but data are limited to support its efficacy in promoting ulcer healing. Enzymatic debridement (topical application of proteolytic enzymes such as collagenase) may be more appropriate in certain settings (eg, extensive vascular disease not under team management) [46,47]. Autolytic debridement may be a good option in patients with painful ulcers, using a semiocclusive or occlusive dressing to cover the ulcer so that necrotic tissue is digested by enzymes normally present in wound tissue.

Larval therapy has been used in some specialty clinics in high-risk patients as an adjunct to serial surgical debridement. There appears to be benefit from several days of targeted therapy [48]. As an example, in very frail patients for whom the goals are comfort care and lowering the risk for infection, "wound hospice" or "podiatric hospice" using larval therapy may increase the duration of antibiotic-free days [49]. (See "Basic principles of wound management", section on 'Biologic'.)

Dressings — After debridement, ulcers should be kept clean and moist but free of excess fluids (table 1). Dressings should be selected based upon ulcer characteristics, such as the extent of exudate, desiccation, or necrotic tissue (table 2). Some dressings simply provide protection, whereas others promote wound hydration or prevent excessive moisture. Wet-to-dry saline dressings are frequently used but can remove both nonviable and viable tissue and may result in a dry wound. Other dressings are impregnated with antimicrobial agents to prevent infection and enhance ulcer healing. For the management of foot ulcers in patients with diabetes, there is no high-quality evidence to suggest any significant differences in wound healing outcomes when comparing the various types of dressings [50,51]. (See "Basic principles of wound management", section on 'Wound dressings'.)

Adjunctive local therapies — Adjunctive therapies may help improve healing of diabetic foot ulcers [52-55].

Negative pressure wound therapy — Based on randomized trials showing improved wound healing [56-65], we suggest NPWT for extensive open wounds following debridement for infection and necrosis, or following partial foot amputation, provided there is no residual necrotic tissue or infected bone (osteomyelitis) [32].

NPWT, also called vacuum-assisted closure (VAC), involves the application of controlled subatmospheric pressure to the surface of the ulcer. NPWT enhances healing by increasing wound perfusion, reducing edema, reducing the local bacterial burden, and increasing the formation of granulation tissue. The indications, contraindications, and uses of negative pressure wound therapy systems are discussed in detail separately. (See "Negative pressure wound therapy".)

NPWT appears to improve healing of diabetic foot ulcers, as well as wounds following diabetic foot surgery [57-65]. NPWT also decreases the length of hospitalization, complication rates, and costs [66-68]. Among five trials in a systematic review, NPWT significantly increased the chance of foot ulcer healing compared with dressings (risk ratio [RR] 1.40, 95% CI 1.14-1.72) [65]. Among three trials, NPWT reduced the risk of amputation (RR 0.33, 95% CI 0.15-0.70). There was no effect on ulcer recurrence.

For managing postoperative wounds, a multicenter trial followed 162 diabetic patients for 16 weeks following partial foot amputation [59]. Compared with the control group, the NPWT group had a significantly higher percentage of patients with healed wounds (56 versus 39 percent), and shorter time to complete closure (42 versus 84 days).

Skin grafts and substitutes — Human skin grafts and bioengineered skin substitutes (eg, Dermagraft, Apligraf, TheraSkin, Graftskin, EpiFix, Zelen, Graftjacket, Hyalograft 3D, Kaloderm, OrCel) have been studied in individuals with noninfected, nonischemic chronic plantar diabetic foot ulcers [54,69-78]. The basic principles of skin grafting and skin substitutes are presented separately. (See "Skin autografting" and "Skin substitutes".)

A systematic review identified 17 trials using skin grafts or substitutes for the treatment of diabetic foot ulcers [79]. The incidence of completed closure of diabetic foot ulcers was significantly improved for the skin grafts or substitutes compared with standard care (RR 1.55, 95% CI 1.30-1.85). In two trials, there were no significant differences for ulcer recurrence. Based upon four trials that directly compared two products, no specific type of skin graft or skin substitute was found to be superior over another. Among two trials that reported the incidence of lower limb amputations, skin grafts and substitutes were also associated with significantly lower risk for amputation, although the absolute risk reduction for amputation was small (RR 0.43, 95% CI 0.23-0.81; risk difference -0.06, 95% CI -0.10 to -0.01).

Growth factors — Tissue growth factors promote cellular proliferation and angiogenesis and thereby improve ulcer healing. A systematic review assessed outcomes of 28 trials using 11 different growth factors predominantly used as topical agents, including platelet-derived wound healing formula, autologous growth factor, allogeneic platelet-derived growth factor, transforming growth factor beta 2, arginine-glycine-aspartic acid peptide matrix, recombinant human platelet-derived growth factor (becaplermin), recombinant human epidermal growth factor, recombinant human basic fibroblast growth factor, recombinant human vascular endothelial growth factor, recombinant human lactoferrin, and recombinant human acidic fibroblast growth factor [80]. Overall, the quality of the trials was low with a high risk of bias. In a meta-analysis of 12 trials, the use of any growth factor compared with placebo or no growth factor significantly increased the number of participants with complete wound healing (53 versus 35 percent). The results were mainly based on platelet-derived wound healing formula (64 versus 26 percent, two trials), and recombinant human platelet-derived growth factor (becaplermin; 48 versus 33 percent, five trials). No clear differences were apparent with respect to amputation rates, but only two trials were included in this analysis.

Platelet-derived growth factor as a gel preparation (becaplermin) is approved by the US Food and Drug Administration as an adjuvant therapy for diabetic foot ulcers [81]. Although effective, its use has been limited by high cost and by postmarketing reports of an increased rate of mortality secondary to malignancy in patients treated with three or more tubes of becaplermin, compared with controls (3.9 versus 0.9 per 1000 person-years; adjusted rate ratio 5.2, 95% CI 1.6-17.6) [82,83].

Hyperbaric oxygen therapy — Hyperbaric oxygen therapy (HBOT) may be associated with improved healing as a component of diabetic ulcer management, but the indications for HBOT in the treatment of nonhealing diabetic foot ulcers remain uncertain. Most, but not all [84], meta-analyses of randomized trials suggest that hyperbaric oxygen therapy may offer a benefit in the treatment of diabetic foot ulcers; however, each meta-analysis noted variability in methodologic quality of the included studies [84-89]. The available trials are limited by small sample size and heterogeneity of the wounds being treated (eg, ulcer size, ulcer depth, microbial environment, presence of ischemia) [90-101]. No conclusions could be drawn regarding specific indications for or timing of therapy.

A pooled analysis found significantly improved wound healing (OR 9.99, 95% CI 3.97-25.1) and decreased risk of amputation (odds ratio [OR] 0.24, 95% CI 0.14-0.43) for HBOT [86]. A later meta-analysis found similar results [89]. As an example of these effects, in one of the larger trials that included 70 patients with severely ischemic foot ulcers, the amputation rate was 9 percent in the treatment group and 33 percent in the control [92]. In another trial that included 94 patients, significantly more wounds healed completely in the HBOT group compared with a placebo group (52 versus 29 percent) [99]. However, in a later longitudinal cohort of 6259 patients with diabetic foot ulcers, use of HBOT did not result in better wound healing, and amputation rates were similar to those not receiving the therapy [90].

Topical oxygen therapy — Topical oxygen therapy/continuous diffusion of oxygen appears to be associated with improved healing of diabetic foot ulcers [102,103]. This therapy involves local administration of oxygen and appears to improve epithelialization by upregulating vascular endothelial growth factor (VEGF) expression and collagen synthesis, improving overall matrix deposition, and altering microbiome ecology [104,105]. Several sham controlled, double-blind randomized trials support the use of this therapy, including a multinational study that included 220 subjects, which reported a 4.5-fold greater rate of healing in those receiving active topical oxygen therapy at home compared with placebo [106]. Other similarly designed studies have reported similar findings [107-110].

Shock wave therapy — Shock wave therapy, which consists of treatment using a handheld probe to deliver high-energy pulses locally to the wound, purportedly increases local perfusion and angiogenesis, disrupts biofilm, and may upregulate growth factors. Observational and small randomized trials suggest that shock wave therapy may improve healing of chronic diabetic foot ulcers [111-115]. In two proprietary trials, 336 patients were randomly assigned to shock wave therapy (DermaPACE) or usual care consisting of wet-to-dry dressings or debridement. At 24-week follow-up, significantly more patients in the shock wave group achieved complete wound closure compared with usual care (44 versus 30 percent) [116].

Others — Low-level light therapy uses low-power lasers or light-emitting diodes to alter cellular function and molecular pathways. A systematic review identified four randomized trials that included 131 patients comparing low-level light therapy with either nontherapeutic light therapy or sham treatment for the treatment of diabetic foot ulcers [117-121]. Each of the trials demonstrated beneficial outcomes for the light treatment with no adverse events; however, many limitations were noted with these generally small trials.

In a separate review, for other forms of energy, such as electrical stimulation, ultrasound, normothermic therapy, magnet therapy, and laser therapy, there was no convincing evidence of clear benefit [56]. (See "Basic principles of wound management", section on 'Adjunctive therapies'.)

Other therapies aimed at managing chronic wounds predominantly in patients with peripheral artery disease (PAD) have been tried, and some initial data appear promising, but further studies are required regarding dose/duration/delivery to provide recommendations on use [122,123]. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease", section on 'Stem cell therapy' and "Investigational therapies for treating symptoms of lower extremity peripheral artery disease", section on 'Therapeutic angiogenesis'.)

MECHANICAL OFFLOADING — All ulcers subjected to sustained or frequent pressure and stress (ie, pressure-related heel ulcers or medial/lateral foot ulcers) or repetitive moderate pressure (plantar foot ulcers) benefit from pressure reduction, which is accomplished with mechanical offloading. Offloading devices include total contact casts, cast walkers, shoe modifications, and other devices to assist in ambulation [124]. Although nonremovable pressure-relieving treatments improve healing, in clinical practice, the type of offloading that is used depends largely on local resources such as whether there is a surgeon who is skilled at contact casting, or a practitioner (eg, podiatrist) who can fit the patient with customized footwear. In the absence of such expertise, a removable cast walker may be the best option.

Evidence from randomized trials supports the use of total contact casts and nonremovable cast walkers for relief of pressure to improve healing of diabetic foot ulcers. A 2013 Cochrane review evaluated 14 trials comparing various forms of pressure-relieving treatments (nonremovable, removable) and dressings [125,126]. In five trials, the likelihood of wound healing was significantly better at 12 weeks for nonremovable, pressure-relieving casts compared with removable devices or dressings (relative risk [RR] 1.17, 95% CI 1.01-1.36). In one trial, no significant differences were found between different types of nonremovable pressure-relieving treatments.

Total contact cast — A total contact cast is a padded fiberglass or plaster shell designed to take pressure off the heel or elsewhere on the foot by averaging the pressure across the sole of the foot (ie, eliminates high- and low-pressure regions by providing contact at all points) or to generally unweight the entire foot through a total contact fit at the calf. Disadvantages of total contact casting include expertise needed in applying the cast, inability to inspect the foot frequently, inconvenience in activities of daily living (eg, bathing), and the risk of developing a secondary ulcer in an ill-fitting cast (particularly in patients with neuropathy) [25]. Frequent cast changes may be needed to avoid complications. Total contact casts should not be used in patients with infected ulcers or wounds, osteomyelitis, peripheral ischemia (ankle-brachial index <0.6), bilateral ulceration, lower extremity amputation, or heel ulceration [127].

Based upon randomized trials, total contact casting enhances diabetic ulcer healing and is the standard for relieving pressure from the forefoot [125,126,128-134]. As an example, in a trial of offloading modalities in 63 diabetic patients with superficial, noninfected, nonischemic plantar ulcers, the proportion of ulcers that were healed at 12 weeks was significantly higher in those randomly assigned to a total contact cast compared with a half-shoe or removable cast walker (90 versus 58 and 65 percent, respectively) [130]. Patients with a total contact cast also had faster healing. Another small trial found that, compared with the casting alone, casting combined with Achilles tendon lengthening resulted in significantly fewer ulcer recurrences at seven months (15 versus 59 percent) and at two years (38 versus 81 percent) [135].

Cast walkers — An alternative to total contact casting is a prefabricated brace called a cast walker that is designed to maintain a total contact fit (figure 2). Several cast walkers (nonremovable, removable) are commercially available and provide the capability to offload the foot similar to contact casts. A significant disadvantage of the cast walker is poor patient compliance if the cast walker is removed [136].

Prefabricated products are at least as good as total contact casting for offloading the foot and equalizing foot pressures when the foot anatomy is normal, as illustrated in the studies below, but data are not available demonstrating these effects for patients with diabetic foot deformities.

●One study compared plantar foot pressure metrics in a standard shoe, total contact cast, and cast walker (pneumatic) [137]. Five plantar foot sensors were placed at the first, third, and fifth metatarsal heads, fifth metatarsal base, and midplantar heel of 10 healthy male subjects who walked at a constant speed over a distance of 280 meters. Peak pressures were significantly reduced in the pneumatic walker compared with the standard shoe for all sensor locations to an equal or greater degree compared with the total contact cast in all sensor locations.

●Another study measured foot pressures using an in-shoe pressure measurement system (Novel Pedar) in 18 healthy subjects while wearing a cast walker or total contact cast [138]. Peak foot pressures using the cast walker were significantly reduced in the forefoot (12 versus 18 newtons [N]/cm2) and foot as a whole (14 versus 19 N/cm2) compared with a fiberglass total contact cast, but no differences were found for the heel or midfoot.

Cast walkers have been used for the treatment of neuropathic plantar ulcers, but these devices, thus far, have not been found to be superior to total contact casting in randomized trials. In one trial, the rate of ulcer healing was significantly higher in those randomly assigned to total contact casting compared with a half-shoe or removable cast walker [130]. Another trial that randomly assigned 48 patients to total contact casting or a removable cast walker (ie, Stabil-D) found no difference in the number of days to achieve healing (35 versus 39 days) [139].

Therapeutic shoes — After healing of the ulcer is achieved, prescriptive shoes with orthotic inserts are often prescribed to prevent recurrent ulceration [125]. In one trial, 400 diabetic patients with a history of foot ulcer were randomly assigned to wear therapeutic shoes or their usual footwear for two years [140]. The risk of reulceration was not found to be different between the groups. It should be noted, however, that this study consisted of, generally, relatively minor ulcers. Furthermore, over one-half of the patients did not have peripheral neuropathy. A subsequent study of prescriptive shoes with customized insoles based on pressure analysis showed a significant reduction in risk for reulceration [141,142].

Nonprescription rocker sole shoes (figure 3) may also offload the foot [143,144]. In a nonrandomized prospective study of 92 patients with healed diabetic foot ulcers, the first-year annual rate of foot ulcer relapse was significantly lower in patients who used stock diabetic shoes (rocker sole) compared with those who wore their usual footwear (15 versus 60 percent) [144]. In the United States, reimbursement from insurance carriers can be expected for one pair of shoes and three pairs of shoe inserts, provided the design of the shoe/insert meets qualifying guidelines.

Wedge shoes (eg, Darco International), also called half shoes, are available as forefoot and heel wedge shoes to offload the forefoot and heel, respectively (figure 4). These shoes may be useful under certain circumstances. For example, plantar heel ulcers are particularly difficult to heal because of an inability to adequately offload this region; the heel wedge shoe can be useful to achieve this goal.

The disadvantage of wedge shoes is that most patients, especially older adult patients or those with proprioception abnormalities, may not be able to maintain their balance, and some patients find walking in them difficult, if not impossible.

Knee walkers — Knee walkers are ambulatory assist devices that may be indicated for anyone with a lower extremity issue where weight bearing needs to be avoided (figure 5). These devices are becoming more popular in the treatment of diabetic ulcer as a means to offload the foot. There are no trials evaluating the effectiveness of knee walkers in healing diabetic foot ulcers.

MANAGING INFECTION — The diagnosis of infection is clinical and is generally obvious when an ulcer contains purulent material or there is redness, swelling, or warmth around the ulcer. Treatment is based upon the clinical stages of infection [23]. Osteomyelitis is likely if bone can be seen at the floor of a deep ulcer, or if it can be easily detected by probing the ulcer with a sterile, blunt stainless-steel probe (wound grade/stage: 2B, 3B). Radiologic tests may be useful if the diagnosis of osteomyelitis remains uncertain. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities", section on 'Clinical manifestations' and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities", section on 'Diagnosis'.)

Tissue samples for culture and sensitivity should be obtained by wound curettage, rather than wound swab or irrigation, because they provide more accurate results [145]. Ideally, tissue for culture should be obtained after debridement but prior to initiation of empiric antibiotic therapy. However, at times this may not be practical.

The most common infecting organisms in Western nations include aerobic gram-positive cocci. Other frequent pathogens are aerobic gram-negative bacilli and anaerobes, usually as a second organism [23,146]. Empiric antimicrobial therapy should be selected based upon the severity of infection and the likelihood of resistant organisms. Subsequent antibiotic therapy should be tailored to the results of wound culture and susceptibility. It is not always necessary to cover all microorganisms isolated from cultures. The duration of treatment depends on the severity of infection and the presence of underlying or residual osteomyelitis. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities", section on 'Empiric therapy' and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities", section on 'Duration of therapy'.)

ISCHEMIA AND REVASCULARIZATION — Assessment of the adequacy of the circulation is an important component of the evaluation of all ulcers or postsurgical wounds, particularly those in patients with diabetes. Symptoms of claudication or extremity pain at rest, and physical findings of diminished or absent pulses, cool temperature, pallor on elevation, or dependent rubor should raise suspicion about the presence of peripheral artery disease. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Overview of peripheral artery disease in patients with diabetes mellitus".)

Noninvasive vascular studies (ie, ankle-brachial index, toe waveforms and pressures, pulse volume recordings) should be obtained to confirm the diagnosis. The ankle-brachial index is a measurement of the ratio of blood pressure at the ankle to that in the brachial artery that correlates with the presence and severity of arterial occlusive disease [147]. In patients with diabetes, the blood vessels may be incompressible and ankle-brachial index values misleading. Segmental volume plethysmography and toe-brachial index values are more reliable for determining the severity of disease. The noninvasive diagnosis of lower extremity peripheral artery disease is reviewed in detail elsewhere. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Toe-brachial index'.)

Revascularization plays an important role in the management of diabetic foot ulcers in patients with documented peripheral artery disease (to avoid the need for amputation) [25]. When achievable, revascularization is associated with a lower incidence of amputation in patients with a diabetic foot ulcer and severe limb ischemia. As an example, in a longitudinal study of 564 patients, angioplasty or bypass grafting was performed in 75 and 21 percent, respectively [148]. Neither procedure was possible in the remaining 5 percent. The amputation rates were 8.2, 21.2, and 59.2 percent among patients who underwent angioplasty, bypass, or no revascularization. (See "Overview of peripheral artery disease in patients with diabetes mellitus".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Chronic wound management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Foot care for people with diabetes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patient assessment – The treatment of diabetic foot ulcers begins with a comprehensive assessment of the ulcer and the patient's overall medical condition. Evidence of underlying neuropathy, bony deformity, and peripheral artery disease should be actively sought. The ulcer is classified upon initial presentation and with each follow-up visit using a standardized system to document the examination and treatment plan, and to follow the progress of healing. (See 'Introduction' above and 'Ulcer classification' above.)

●Ulcer management – Adequate debridement, proper local wound care (debridement and dressings), redistribution of pressure on the ulcer by mechanical offloading, and control of infection and ischemia (when present) are important components of treatment for all ulcers, regardless of stage and depth. (See 'Management overview' above.)

•Debridement – For most patients with diabetic foot ulcers, we suggest surgical (sharp) debridement rather than another method (Grade 2C). If a surgeon with clinical expertise in sharp debridement is not available, we suggest autolytic debridement with hydrogels (Grade 2C). Alternatively, the patient can be referred to a facility with appropriate surgical expertise in the management of diabetic foot problems.

•Dressings – Dressings are selected based upon ulcer or postsurgical wound characteristics. For managing extensive open wounds following debridement for infection or necrosis, or partial foot amputation, we suggest negative pressure wound therapy (NPWT) (Grade 2A). All necrotic tissue or infected bone (osteomyelitis) first must be removed from the wound prior to using NPWT. (See 'Negative pressure wound therapy' above and "Negative pressure wound therapy", section on 'Contraindications'.)

•Offloading – Several methods are available to achieve mechanical offloading and include total contact casts, cast walkers, wedge shoes, and bedrest. The type of offloading that is used depends largely on local expertise. (See 'Mechanical offloading' above.)

•Revascularization – For patients who present with a diabetic foot ulcer and severe limb ischemia, we recommend early revascularization (Grade 1B). Revascularization should also be performed in patients with a nonhealing ulcer and any degree of limb ischemia. (See 'Allowable time course for primary healing' above and 'Ischemia and revascularization' above.)

●Preventing recurrence – Once a patient has healed an ulcer, he or she remains at a very high risk for reulceration. Therefore, people with healed ulcers should be considered "in remission," a term that better communicates the lifetime of visits (often bimonthly) needed to reduce the risk of recurrence. The goals of long-term surveillance and care are to maximize ulcer-free, hospital-free, and activity-rich days. (See 'Follow-up care and ulcer prevention' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David K McCulloch, MD, who contributed to an earlier version of this topic review.

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  130. Armstrong DG, Nguyen HC, Lavery LA, et al. Off-loading the diabetic foot wound: a randomized clinical trial. Diabetes Care 2001; 24:1019.
  131. Nabuurs-Franssen MH, Huijberts MS, Sleegers R, Schaper NC. Casting of recurrent diabetic foot ulcers: effective and safe? Diabetes Care 2005; 28:1493.
  132. Piaggesi A, Macchiarini S, Rizzo L, et al. An off-the-shelf instant contact casting device for the management of diabetic foot ulcers: a randomized prospective trial versus traditional fiberglass cast. Diabetes Care 2007; 30:586.
  133. 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.
  134. Piaggesi A, Viacava P, Rizzo L, et al. Semiquantitative analysis of the histopathological features of the neuropathic foot ulcer: effects of pressure relief. Diabetes Care 2003; 26:3123.
  135. Mueller MJ, Sinacore DR, Hastings MK, et al. Effect of Achilles tendon lengthening on neuropathic plantar ulcers. A randomized clinical trial. J Bone Joint Surg Am 2003; 85-A:1436.
  136. Armstrong DG, Lavery LA, Kimbriel HR, et al. Activity patterns of patients with diabetic foot ulceration: patients with active ulceration may not adhere to a standard pressure off-loading regimen. Diabetes Care 2003; 26:2595.
  137. Baumhauer JF, Wervey R, McWilliams J, et al. A comparison study of plantar foot pressure in a standardized shoe, total contact cast, and prefabricated pneumatic walking brace. Foot Ankle Int 1997; 18:26.
  138. Pollo FE, Brodsky JW, Crenshaw SJ, Kirksey C. Plantar pressures in fiberglass total contact casts vs. a new diabetic walking boot. Foot Ankle Int 2003; 24:45.
  139. 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.
  140. Reiber GE, Smith DG, Wallace C, et al. Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA 2002; 287:2552.
  141. Ulbrecht JS, Hurley T, Mauger DT, Cavanagh PR. Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial. Diabetes Care 2014; 37:1982.
  142. IWGDF Guidance on footwear and offloading interventions to prevent and heal foot ulcers in patients with diabetes. http://iwgdf.org/guidelines/guidance-on-footwear-and-offloading-2015/ (Accessed on July 14, 2015).
  143. Brown D, Wertsch JJ, Harris GF, et al. Effect of rocker soles on plantar pressures. Arch Phys Med Rehabil 2004; 85:81.
  144. Busch K, Chantelau E. Effectiveness of a new brand of stock 'diabetic' shoes to protect against diabetic foot ulcer relapse. A prospective cohort study. Diabet Med 2003; 20:665.
  145. Lipsky BA. Medical treatment of diabetic foot infections. Clin Infect Dis 2004; 39 Suppl 2:S104.
  146. Lipsky BA, Pecoraro RE, Larson SA, et al. Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med 1990; 150:790.
  147. Fowkes FG. The measurement of atherosclerotic peripheral arterial disease in epidemiological surveys. Int J Epidemiol 1988; 17:248.
  148. Faglia E, Clerici G, Clerissi J, et al. Long-term prognosis of diabetic patients with critical limb ischemia: a population-based cohort study. Diabetes Care 2009; 32:822.
Topic 8175 Version 48.0

References

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36 : The relationship between provider coordination and diabetes-related foot outcomes.

37 : The impact and outcomes of establishing an integrated interdisciplinary surgical team to care for the diabetic foot.

38 : How can I maintain my patient with diabetes and history of foot ulcer in remission?

39 : Toward a change in syntax in diabetic foot care: prevention equals remission.

40 : Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes.

41 : Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study.

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43 : Evidence-based chronic ulcer care and lower limb outcomes among Pacific Northwest veterans.

44 : A systematic review and meta-analysis of débridement methods for chronic diabetic foot ulcers.

45 : Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group.

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47 : Hydrogel dressings for healing diabetic foot ulcers.

48 : Maggot therapy for wound debridement: a randomized multicenter trial.

49 : Maggot therapy in "lower-extremity hospice" wound care: fewer amputations and more antibiotic-free days.

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51 : Silver based wound dressings and topical agents for treating diabetic foot ulcers.

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55 : Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers.

56 : A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes.

57 : Vacuum assisted closure improves the quality of life in patients with diabetic foot.

58 : A blinded, prospective, randomized controlled trial of topical negative pressure wound closure in India.

59 : Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial.

60 : 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.

61 : Vacuum-assisted closure versus saline-moistened gauze in the healing of postoperative diabetic foot wounds.

62 : A prospective randomized evaluation of negative-pressure wound dressings for diabetic foot wounds.

63 : Interim analysis of a prospective, randomized trial of vacuum-assisted closure versus the healthpoint system in the management of pressure ulcers.

64 : The use of negative pressure wound therapy on diabetic foot ulcers

65 : Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus.

66 : Vacuum-assisted closure therapy for diabetic foot ulcers: clinical and cost analysis

67 : Outcomes of subatmospheric pressure dressing therapy on wounds of the diabetic foot.

68 : Consensus statement on negative pressure wound therapy (V.A.C. Therapy) for the management of diabetic foot wounds.

69 : Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial.

70 : A metabolically active human dermal replacement for the treatment of diabetic foot ulcers.

71 : Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers.

72 : HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial.

73 : Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis.

74 : Meshed skin graft versus split thickness skin graft in diabetic ulcer coverage.

75 : Split-thickness skin grafting the high-risk diabetic foot.

76 : New treatments in ulcer healing and wound infection.

77 : Influence of bioengineered skin substitutes on diabetic foot ulcer and venous leg ulcer outcomes.

78 : Advanced biological therapies for diabetic foot ulcers.

79 : Skin grafting and tissue replacement for treating foot ulcers in people with diabetes.

80 : Growth factors for treating diabetic foot ulcers.

81 : 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.

82 : 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.

83 : 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.

84 : Hyperbaric oxygen therapy for chronic wounds.

85 : Hyperbaric oxygen for the treatment of diabetic foot ulcers: a systematic review.

86 : Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review.

87 : Systematic review of hyperbaric oxygen in the management of chronic wounds.

88 : Hyperbaric oxygen for treating wounds: a systematic review of the literature.

89 : Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers.

90 : Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation: a cohort study.

91 : Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial.

92 : Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.

93 : Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers.

94 : Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.

95 : The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.

96 : Hyperbaric oxygen therapy in diabetic foot.

97 : The vascular effects of hyperbaric oxygen therapy in treatment of early diabetic foot

98 : Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study.

99 : Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes.

100 : Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study.

101 : Hyperbaric oxygen in diabetic gangrene treatment.

102 : Topical oxygen therapy for diabetes-related foot ulcers: A systematic review and meta-analysis.

103 : Impact of topical oxygen therapy on diabetic foot ulcer healing rates: a systematic review.

104 : Topical Oxygen Therapy Shifts Microbiome Dynamics in Chronic Diabetic Foot Ulcers.

105 : Revisiting the essential role of oxygen in wound healing.

106 : A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study.

107 : Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study.

108 : Interim results for a prospective, randomized, double-blind multicenter study comparing continuous diffusion of oxygen therapy to standard moist wound therapy in the treatment of diabetic foot ulcers.

109 : Application of Topical Oxygen Therapy in Healing Dynamics of Diabetic Foot Ulcers - A Systematic Review.

110 : Topical oxygen therapy results in complete wound healing in diabetic foot ulcers.

111 : Extracorporeal shockwave therapy in the treatment of chronic diabetic foot ulcers: a prospective randomised trial.

112 : Extracorporeal shockwave therapy in diabetic foot ulcers.

113 : Efficacy of shock wave therapy on chronic diabetic foot ulcer: a single-blinded randomized controlled clinical trial.

114 : The management of neuropathic ulcers of the foot in diabetes by shock wave therapy.

115 : Extracorporeal shock wave therapy for management of chronic ulcers in the lower extremities.

116 : Extracorporeal shock wave therapy for management of chronic ulcers in the lower extremities.

117 : A systematic review of low-level light therapy for treatment of diabetic foot ulcer.

118 : Efficacy of low level laser therapy on wound healing in patients with chronic diabetic foot ulcers-a randomised control trial.

119 : A randomized clinical trial on the effect of low-level laser therapy on chronic diabetic foot wound healing: a preliminary report.

120 : Visible light-induced healing of diabetic or venous foot ulcers: a placebo-controlled double-blind study.

121 : Phototherapy promotes healing of chronic diabetic leg ulcers that failed to respond to other therapies.

122 : Potential of Allogeneic Adipose-Derived Stem Cell-Hydrogel Complex for Treating Diabetic Foot Ulcers.

123 : Meta-analysis on the treatment of diabetic foot ulcers with autologous stem cells.

124 : A systematic review and meta-analysis of off-loading methods for diabetic foot ulcers.

125 : Pressure relieving interventions for preventing and treating diabetic foot ulcers.

126 : Pressure-relieving interventions for treating diabetic foot ulcers.

127 : Total contact casts: pressure reduction at ulcer sites and the effect on the contralateral foot.

128 : Total contact casting in treatment of diabetic plantar ulcers. Controlled clinical trial.

129 : Effectiveness and safety of a nonremovable fiberglass off-bearing cast versus a therapeutic shoe in the treatment of neuropathic foot ulcers: a randomized study.

130 : Off-loading the diabetic foot wound: a randomized clinical trial.

131 : Casting of recurrent diabetic foot ulcers: effective and safe?

132 : An off-the-shelf instant contact casting device for the management of diabetic foot ulcers: a randomized prospective trial versus traditional fiberglass cast.

133 : A randomized trial of two irremovable off-loading devices in the management of plantar neuropathic diabetic foot ulcers.

134 : Semiquantitative analysis of the histopathological features of the neuropathic foot ulcer: effects of pressure relief.

135 : Effect of Achilles tendon lengthening on neuropathic plantar ulcers. A randomized clinical trial.

136 : Activity patterns of patients with diabetic foot ulceration: patients with active ulceration may not adhere to a standard pressure off-loading regimen.

137 : A comparison study of plantar foot pressure in a standardized shoe, total contact cast, and prefabricated pneumatic walking brace.

138 : Plantar pressures in fiberglass total contact casts vs. a new diabetic walking boot.

139 : Effectiveness of removable walker cast versus nonremovable fiberglass off-bearing cast in the healing of diabetic plantar foot ulcer: a randomized controlled trial.

140 : Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial.

141 : Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial.

142 : Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial.

143 : Effect of rocker soles on plantar pressures.

144 : Effectiveness of a new brand of stock 'diabetic' shoes to protect against diabetic foot ulcer relapse. A prospective cohort study.

145 : Medical treatment of diabetic foot infections.

146 : Outpatient management of uncomplicated lower-extremity infections in diabetic patients.

147 : The measurement of atherosclerotic peripheral arterial disease in epidemiological surveys.

148 : Long-term prognosis of diabetic patients with critical limb ischemia: a population-based cohort study.

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