Development Of Foot Ulcers Research Articles

Absent monofilament sensation in a type 2 diabetic feet.

Neuropathy is a common complication which can affect up to 90% of patients with diabetes mellitus. Asymptomatic neuropathy is a common presentation. We present a case that emphasises the importance of foot screening in people with diabetes. It also highlights that patient education is key to prevent development of foot ulceration which can lead to amputations. In addition, pharmacological therapy (as per NICE guidance) can be offered for pain relief. Patients with diabetic neuropathy are at high risk of falling and sustaining fractures.

Plantar pressures are elevated in people with longstanding diabetes-related foot ulcers during follow-up.

ObjectiveHigh plantar pressures are implicated in the development of diabetes-related foot ulcers. Whether plantar pressures remain high in patients with chronic diabetes-related foot ulcers over time is uncertain. The primary aim of this study was to compare plantar pressures at baseline and three and six months later in participants with chronic diabetes-related foot ulcers (cases) to participants without foot ulcers (controls).MethodsStandardised protocols were used to measure mean peak plantar pressure and pressure-time integral at 10 plantar foot sites (the hallux, toes, metatarsals 1 to 5, mid-foot, medial heel and lateral heel) during barefoot walking. Measurements were performed at three study visits: baseline, three and six months. Linear mixed effects random-intercept models were utilised to assess whether plantar pressures differed between cases and controls after adjusting for age, sex, body mass index, neuropathy status and follow-up time. Standardised mean differences (Cohen’s d) were used to measure effect size.ResultsTwenty-one cases and 69 controls started the study and 16 cases and 63 controls completed the study. Cases had a higher mean peak plantar pressure at several foot sites including the toes (p = 0.005, Cohen’s d = 0.36) and mid-foot (p = 0.01, d = 0.36) and a higher pressure-time integral at the hallux (p<0.001, d = 0.42), metatarsal 1 (p = 0.02, d = 0.33) and mid-foot (p = 0.04, d = 0.64) compared to controls throughout follow-up. A reduction in pressure-time integral at multiple plantar sites over time was detected in all participants (p<0.05, respectively).ConclusionsPlantar pressures assessed during gait are higher in diabetes patients with chronic foot ulcers than controls at several plantar sites throughout prolonged follow-up. Long term offloading is needed in diabetes patients with diabetes-related foot ulcers to facilitate ulcer healing.

Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition.

Impaired wound healing is a major complication of diabetes, and can lead to development of chronic foot ulcers in a significant number of patients. Despite the danger posed by poor healing, very few specific therapies exist, leaving patients at risk of hospitalization, amputation, and further decline in overall health. Recent Advances: Redox signaling is a key regulator of wound healing, especially through its influence on the extracellular matrix (ECM). Normal redox signaling is disrupted in diabetes leading to several pathological mechanisms that alter the balance between reactive oxygen species (ROS) generation and scavenging. Importantly, pathological oxidative stress can alter ECM structure and function. There is limited understanding of the specific role of altered redox signaling in the diabetic wound, although there is evidence that ROS are involved in the underlying pathology. Preclinical studies of antioxidant-based therapies for diabetic wound healing have yielded promising results. Redox-based therapeutics constitute a novel approach for the treatment of wounds in diabetes patients that deserve further investigation. Antioxid. Redox Signal. 27, 823-838.

Osteopontin and clusterin levels in type 2 diabetes mellitus: differential association with peripheral autonomic nerve function.

Osteopontin (OPN) and clusterin are secreted glycoproteins potentially associated with nerve function. Sudomotor dysfunction is associated with the development of foot ulcerations. The purpose of this study was to investigate the potential relationship of OPN and clusterin with sudomotor function (i.e., autonomic nerves that control sweating) in participants with type 2 diabetes mellitus (T2DM). Sudomotor function was assessed using SUDOSCAN® which measures electrochemical skin conductance (ESC) of the hands and feet. Demographics (e.g., age, gender, race, body mass index (BMI)), HbA1c, 25-hydroxyvitamin D, creatinine, OPN, and clusterin were also determined for the participants. Fifty individuals with T2DM (age=59±11years; 23/27 male/female; 13 African Americans) participated in this study. Lower ESC for the hands and feet were observed in African Americans versus Caucasians/Asians (p<0.05). No significant ESC differences were observed for good [HbA1c <7%] versus poor [HbA1c ≥7%] glycemic control. With regard to gender, ESC values were lower for the hands for females (p<0.05). In linear regression with ESC for the hands or feet as the dependent variable, increased OPN levels, but not clusterin, were independently associated with reduced sudomotor function while adjusting for age, gender, race, BMI, and glycemic control (ESC hands model R 2=0.504, p<0.001; ESC feet model R 2=0.534, p<0.001). The association between OPN and reduced sudomotor function found in our study warrants further investigation to delineate the underlying mechanisms and determine if OPN is neuroprotective, involved in the pathogenesis of sudomotor dysfunction, or simply a bystander.

Post-occlusive reactive hyperaemia of skin microvasculature and foot complications in type 2 diabetes

AimsDiabetes-related microvascular disease has been implicated in the development of foot ulceration and amputation. Assessment of microvascular function may be effective in identifying those at risk of diabetic foot complications. We investigated the relationship between active or previous foot complication and post-occlusive reactive hyperaemia (PORH) measured by laser-Doppler fluxmetry (LDF) in people with type 2 diabetes. MethodsPORH measures were obtained from the hallux apex in 105 people with type 2 diabetes. Associations were investigated between active or previous foot complication and PORH measures: time to peak (TtPeak) and peak as a percentage of baseline (P%BL). Multinomial logistic regression was used to determine the association of PORH with the likelihood of active foot ulcer or previous foot complication. ResultsFor each second increase in TtPeak, the likelihood of a participant having a history of foot complication is increased by 2% (OR=1.019, p=0.01). This association was not reflected in people with an active foot ulcer (OR=1.003, p=0.832). P%BL was not found to be significantly different between those with a current or previous foot complication and those without (p=0.404). ConclusionsThis investigation in a cohort with type 2 diabetes has demonstrated that longer TtPeak is associated with history of diabetic foot complications.

Implementing Diabetic Foot Care in the Primary Care Setting

Patients with diabetes mellitus are at risk for foot ulcers and subsequent amputations. The outpatient diabetic population could benefit from services to prevent factors that lead to the development of foot ulcers and further complications. The purpose of this project was to evaluate the effectiveness and feasibility of implementing a foot care program in the primary care setting. An evaluation of the outcomes supported these foot care services. Future studies showing the effectiveness of foot care services in the primary care setting would further substantiate the benefits of providing diabetic foot care in primary care practice.

Prevalence of Foot Ulcers, Foot at Risk and Associated Risk Factors Among Jordanian Diabetics.

To examine the prevalence of foot ulcers, foot at risk, and the associated risk factors among Jordanian diabetics. A cross-sectional design was applied on 1000 diabetes patients (both type-1 and type-2) aged >20 years. The participants were selected systematically from among every second patient visiting the diabetes clinics at National Center for Diabetes, Endocrinology, and Genetics (NCDEG) in Amman, Jordan. The participants were interviewed, examined, and then their medical records were reviewed. The factors including sensory neuropathy, vibratory neuropathy, painful neuropathy, vascular insufficiency, retinopathy, and dermatological changes were recorded for all patients. Foot at risk was identified based on the risk category classification and foot ulcers were evaluated based on the Wagner's classification system. A total of 53 (5.3%) patients had foot ulcers, 17 (1.7%) had undergone amputations, and 172 (17.2%) had foot at risk. A total of 62 patients were identified in the risk category-1, 82 in the risk category-2, and 28 in the risk category-3. Loss of protective sensation was detected in 174 (17.4%) patients, loss of vibratory sensation in 162 (16.2%) patients, absence of posterior tibial pulse in 115 (11.5%) patients, absence of dorsalis pedis pulse in 97 (9.7%) patients, and claudication in 72 (7.2%) patients. Loss of protective sensation (p < 0.000), loss of vibratory sensation (p < 0.039), and vascular insufficiency (p = 0.02) were found to be significantly higher in diabetic patients with foot ulcers than in those without foot ulcers. The prevalence of foot ulcer in Jordan was 5.3%, while foot at risk was prevalent in 17.2% patients. Patients with loss of protective sensation, loss of vibratory sensation, and vascular insufficiency of the lower limbs were found to be at a higher risk for the development of foot ulceration.

Investigating the effect of external trauma through a dynamic system modeling approach for clustering causality in diabetic foot ulcer development

Diabetes and its associated complications are realized as one of the most challenging medical conditions threatening more than 29 million people only in the USA. The forecasts suggest a suffering of more than half a billion worldwide by 2030. Amid all diabetic complications, diabetic foot ulcer (DFU) has attracted much scientific investigations to lead to a better management of this disease. In this paper, a system thinking methodology is adopted to investigate the dynamic nature of the ulceration. The causal loop diagram as a tool is utilized to illustrate the well-researched relations and interrelations between causes of the DFU. The result of clustering causality evaluation suggests a vicious loop that relates external trauma to callus. Consequently a hypothesis is presented which localizes development of foot ulceration considering distribution of normal and shear stress. It specifies that normal and tangential forces, as the main representatives of external trauma, play the most important role in foot ulceration. The evaluation of this hypothesis suggests the significance of the information related to both normal and shear stress for managing DFU. The results also discusses how these two react on different locations on foot such as metatarsal head, heel and hallux. The findings of this study can facilitate tackling the complexity of DFU problem and looking for constructive mitigation measures. Moreover they lead to developing a more promising methodology for managing DFU including better prognosis, designing prosthesis and insoles for DFU and patient caring recommendations.

The Role of Pressure Offloading on Diabetic Foot Ulcer Healing and Prevention of Recurrence.

An increased plantar pressure is a causative factor in the development of plantar foot ulcers in people with diabetes mellitus, and ulcers are a precursor of lower extremity amputation. In this article, the evidence is reviewed that relieving areas of increased plantar pressure (ie, offloading) can heal plantar foot ulcers and prevent their recurrence. Noninfected, nonischemic neuropathic plantar forefoot ulcers should heal in 6 to 8 weeks with adequate offloading. Recent meta-analyses and systematic reviews show that nonremovable knee-high devices are most effective. This is probably because they eliminate the problem of nonadherence with the use of a removable device. Studies show a large discrepancy between evidence-based recommendations on offloading and what is used in clinical practice. Many clinics continue to use methods that are less effective or have not been proven to be effective, while ignoring evidence-based methods. Strategies are proposed to address this issue, notably the adoption and implementation of recent international guidelines by professional societies and a stronger focus of clinicians on expedited healing. For the prevention of plantar foot ulcer recurrence in high-risk patients, 2 recent trials have shown that the incidence of recurrence can be significantly reduced with custom-made footwear that has a demonstrated pressure-relieving effect through guidance by plantar pressure measurements, under the condition that the footwear is worn. This review helps to inform clinicians about effective offloading treatment for healing plantar foot ulcers and preventing their recurrence.

High osteoprotegerin is associated with development of foot ulcer in type 1 diabetes

Background and aimThe bone-related peptide osteoprotegerin has been linked to vascular calcification and peripheral vascular disease. We investigated the association between osteoprotegerin and development of foot complications in persons with type 1 diabetes. Materials and methodsProspective observational study of 573 persons with type 1 diabetes, 225 women; age [mean±SD] 42.3±10.3years. Plasma osteoprotegerin was measured by ELISA. ResultsMedian (IQR) osteoprotegerin was 2.80(2.35–3.63)μg/L and follow-up time (median (range)) was 12.7(0.1–15.6)years. Endpoints included: new foot ulceration (n=153), Charcot foot (n=14), vascular surgery/amputation (n=53), loss of foot pulse (n=57), and peripheral neuropathy (n=99). In unadjusted analyses, higher osteoprotegerin was associated with development of all endpoints (p≤0.026). Higher osteoprotegerin remained associated with development of foot ulcer, and the combination of vascular surgery/amputation, loss of foot pulse and neuropathy (p≤0.001) in a sex and age adjusted model. After further adjustment (nephropathy status, smoking, HbA1c, systolic blood pressure, serum cholesterol, high sensitivity C-reactive protein, eGFR, and presence of neuropathy and/or claudication and/or foot ulcer at baseline), higher osteoprotegerin remained associated with development of foot ulcer (HR (95% CI) per doubling: 1.75 (1.04–2.97); p=0.037). ConclusionHigher osteoprotegerin levels were associated with development of foot ulcer, even after comprehensive adjustment.

Prospective study on microangiopathy in type 2 diabetic foot ulcer

We investigated the significance of microangiopathy in the development of foot ulcer, which is still disputed. We assessed microangiopathy by histological analysis of the capillary ultrastructure using transmission electron microscopy and capillary density and arteriolar morphology in paraffin-embedded sections from the skin of type 2 diabetic patients: 30 neuroischaemic patients (Isc) revascularised with peripheral angioplasty and 30 neuropathic patients (Neu) with foot ulcer, compared with ten non-diabetic volunteers. In the diabetic patients, capillaries in the dermal papillary layer were fewer (-22.2%, 159 ± 43 vs 205 ± 52mm(2) in non-diabetic volunteers, p < 0.01). They also showed detrimental remodelling, with a 2.2-fold increase in capillary basement membrane thickness (3.44 ± 1.19 vs 1.53 ± 0.34μm in non-diabetic volunteers, p < 0.001) and a 57.7% decrease in lumen area (14.6 ± 11.1 vs 34.7 ± 27.5μm(2), p < 0.001). No differences were observed between the diabetic Isc or Neu patients. Isc were more prone to develop arteriolar occlusion than Neu (16.8 ± 6.9% vs 6.7 ± 3.7%, respectively, p < 0.001). No patient had been amputated at 30days and healing time was significantly longer in Isc (180 ± 120 vs 64 ± 50days in Neu, p < 0.001). Capillary microangiopathy is present in equal measure in neuroischaemic and neuropathic diabetic foot skin. The predominance of arteriolar occlusions with neuroischaemia indicated the existence of an additional 'small vessel disease' that did not affect an effective revascularisation and did not worsen the prognosis of major amputations but slowed the healing process of the neuroischaemic foot ulcer. ClinicalTrials.gov NCT02610036.

Impaired T-cell differentiation in diabetic foot ulceration.

Foot ulceration is one of the most debilitating complications associated with diabetes, but its cause remains poorly understood. Several studies have been undertaken to understand healing kinetics or find possible therapies to enhance healing. However, few studies have been directed at understanding the immunological alterations that could influence wound healing in diabetes. In this study, we analysed the T-cell receptor (TCR) repertoire diversity in TCR-αβ+ T cells. We also analysed the distribution and phenotype of T cells obtained from the peripheral blood of healthy controls and diabetic individuals with or without foot ulcers. Our results showed that diabetic individuals, especially those with foot ulcers, have a significantly lower naive T-cell number and a poorer TCR-Vβ repertoire diversity. We also showed that the reduced TCR-Vβ repertoire diversity in diabetic individuals was mainly owing to the accumulation of effector T cells, the major source of tumour necrosis factor-α production, which was even more pronounced in patients with acute foot ulceration. Moreover, the expression of several inflammatory chemokine receptors was significantly reduced in diabetic patients. In conclusion, effector T-cell accumulation and TCR repertoire diversity reduction appear to precede the development of foot ulcers. This finding may open new immunological therapeutic possibilities and provide a new prognostic tool in diabetic wound care.

A study of risk factors and foot care behavior among diabetics.

Background:Diabetic foot results in considerable morbidity and mortality in developing countries and the prevalence of diabetes is expected to increase further in the next decades in these countries. Diabetic ulcers are the most common foot injuries leading to lower extremity amputation. Family physicians have a pivotal role in the prevention or early diagnosis of diabetic foot complications. Patient education regarding foot hygiene, nail care and proper footwear is crucial to reducing the risk of an injury that can lead to ulcer formation.Materials and Methods:This is a prospective study carried out from July 2013 to September 2015. Fifty patients of Diabetes with foot ulcer and two hundred without foot ulcers were examined. Risk factors and clinical profile of patients were studied which included age, gender, duration of diabetes, BMI, smoking, random BSLs history, hypertension, glycated haemoglobin levels, lipid profile, history of loss of sensation and history of amputation. MNSI questionnaire and MNSI practical assessment for neuropathy were administered to diabetic patients along with a pre-structured questionnaire regarding foot care practices.Results:In this study significant risk factors were peripheral neuropathy, peripheral vascular disease, gender, loss of sensation, duration of diabetes and smoking. MNSI questionnaire and practical assessment scores were higher in foot ulcer patients. Poor foot care practices were observed in patients with diabetic foot ulcer patients.Conclusion:Diabetic foot ulcers were more common in elderly males. Peripheral neuropathy, peripheral vascular disease, Smoking, trauma, duration of diabetes mellitus and high levels of glycated haemoglobin had significant association with occurrence of foot ulcers. MNSI scores had a high predictive value for development of foot ulcers amongst diabetics. Awareness regarding foot care was poor which underlines need to promote practice of foot care amongst diabetic population.

Review of Foot Plantar Pressure—Focus on the Development of Foot Ulcerations

There are many causes of plantar ulceration, which is a painful sore that occurs in the plantar tissue, common in cases of diabetes, peripheral arterial disease, obesity, and even high cholesterol. By way of perspective, approximately 15% of over 29.1 million diabetics in the U.S. will develop foot ulceration [1] and [2]. These causes could be diagnosed using multiple methods with reasonable accuracy; however, ulcers will still occur due to trauma to the plantar tissue. Measurement of the pressures within the plantar tissue has been suggested to be a suitable surrogate to the measurement of trauma; thus, many methods have been developed to measure the pressures and stresses in the plantar tissue. These methods – which include pressure mats, force platforms combined with fluoroscopy or footprint analysis as well as finite element modeling – describe the pressures and stresses that occur within the foot; however, they are limited in their analysis. The limitations include analysis of only the stance phase of gait, measurement of compression stress, and analysis of only healthy individuals. Further studies will be needed to meet the goal of measuring stress within plantar tissues from compression and shear forces during all phases of gait, and using the results to diagnose plantar ulcerations.

Human Achilles tendon glycation and function in diabetes

Diabetic patients have an increased risk of foot ulcers, and glycation of collagen may increase tissue stiffness. We hypothesized that the level of glycemic control (glycation) may affect Achilles tendon stiffness, which can influence gait pattern. We therefore investigated the relationship between collagen glycation, Achilles tendon stiffness parameters, and plantar pressure in poorly (n = 22) and well (n = 22) controlled diabetic patients, including healthy age-matched (45-70 yr) controls (n = 11). There were no differences in any of the outcome parameters (collagen cross-linking or tendon stiffness) between patients with well-controlled and poorly controlled diabetes. The overall effect of diabetes was explored by collapsing the diabetes groups (DB) compared with the controls. Skin collagen cross-linking lysylpyridinoline, hydroxylysylpyridinoline (136%, 80%, P < 0.01) and pentosidine concentrations (55%, P < 0.05) were markedly greater in DB. Furthermore, Achilles tendon material stiffness was higher in DB (54%, P < 0.01). Notably, DB also demonstrated higher forefoot/rearfoot peak-plantar-pressure ratio (33%, P < 0.01). Overall, Achilles tendon material stiffness and skin connective tissue cross-linking were greater in diabetic patients compared with controls. The higher foot pressure indicates that material stiffness of tendon and other tissue (e.g., skin and joint capsule) may influence foot gait. The difference in foot pressure distribution may contribute to the development of foot ulcers in diabetic patients.

Preventing and treating foot complications associated with diabetes mellitus

Diabetes mellitus is associated with a series of macrovascular and microvascular changes that can manifest as a wide range of complications. Foot ulcerations affect ∼2-4% of patients with diabetes mellitus. Risk factors for foot lesions include peripheral and autonomic neuropathy, vascular disease and previous foot ulceration, as well as other microvascular complications, such as retinopathy and end-stage renal disease. Ulceration is the result of a combination of components that together lead to tissue breakdown. The most frequently occurring causal pathways to the development of foot ulcers include peripheral neuropathy and vascular disease, foot deformity or trauma. Peripheral vascular disease is often not diagnosed in patients with diabetes mellitus until tissue loss is evident, usually in the form of a nonhealing ulcer. Identification of patients with diabetes mellitus who are at high risk of ulceration is important and can be achieved via annual foot screening with subsequent multidisciplinary foot-care interventions. Understanding the factors that place patients with diabetes mellitus at high risk of ulceration, together with an appreciation of the links between different aspects of the disease process, is essential to the prevention and management of diabetic foot complications.

Foot deformities within the diabetic foot and their influence on biomechanics: A review of the literature.

Diabetes mellitus causes a multitude of complications. Foot ulceration is one complication with serious consequences, amputation. Foot deformities contribute to ulcer development. It would be advantageous to ascertain whether foot deformities are preventable as their presence increases amputation risk. The objectives were to understand the development of foot deformities in diabetes and explore their biomechanical effects. Literature review. In February 2014 CINAHL, Embase, Ovid and Medline were searched. Studies in English of adults with Diabetes that reported neuropathy, foot deformities or associated gait abnormalities were included for review. All study designs were considered. The articles' quality was considered high overall, assessed using SIGN and CARS. In total, 17 studies were reviewed. The main themes identified in relation to foot deformities were nerve function, intrinsic foot muscles, muscle weakness and limited joint mobility. Nerve function and intrinsic foot muscle atrophy did not display definitive associations with foot deformities. However, muscle weakness and limited joint mobility were associated with foot deformities, although the relationship is still unclear. The development of common foot deformities in diabetes is not well understood. The literature did not support the common belief that motor neuropathy, atrophy and muscle imbalance cause foot deformities. An understanding of the aetiology of foot deformities in diabetes mellitus may allow for pro-active management of the foot in anticipation of the development of foot deformities and ulceration. If the aetiology of deformity was established preventative treatment may reduce the incidence of foot deformities and resultant ulcerations and amputations.

Preventing amputation in adults with diabetes: identifying the risks.

Good management of diabetes can reduce the risk of complications of the disease. When not well managed, diabetes is associated with the complications of heart disease, stroke, blindness, kidney disease and amputations. Diabetes can reduce the blood supply to the feet and cause a loss of feeling. As a result, foot injuries do not heal well and the person may not realise that their foot is sore or injured. Damage to the foot may lead to the development of foot ulcers, which if left untreated may result in amputation of the limb. Preventive care is a priority, but when complications occur the next step is to halt progression. Therefore, effective foot care and timely treatment of foot ulcers are important in preserving foot function and mobility, and preventing amputation in adults with diabetes.

Risk factors for foot ulceration and lower extremity amputation in adults with end-stage renal disease on dialysis: a systematic review and meta-analysis.

Adults with end-stage renal disease are at increased risk of foot ulceration and lower extremity amputation. However, the central determinants of lower limb injury and loss are incompletely understood. We conducted a systematic review of non-randomized studies that quantified the major risk factors for foot ulceration and amputation in adults treated with dialysis and analysed patient populations in which risks were greatest. Random-effects meta-analysis was used to generate summary estimates. Thirty studies (48 566 participants) were identified. Risk factors for foot ulceration and amputation included previous foot ulceration (odds ratios, OR, 17.56 and 70.13), peripheral arterial disease (OR, 7.52 and 9.12), diabetes (OR, 3.76 and 7.48), peripheral neuropathy (OR, 3.24 and 3.36) and coronary artery disease (OR, 3.92 and 2.49). Participants with foot ulceration or amputation had experienced a longer duration of diabetes (mean difference, MD, 4.04 and 6.07 years) and had lower serum albumin levels (MD, -0.23 and -0.13 g/dL). Risk factors for foot ulceration also included retinopathy (OR, 3.03), previous amputation (OR, 15.50) and higher serum phosphorus levels (MD, 0.40 mg/dL), while risk factors for amputation also included male sex (OR, 1.50), current smoking (OR, 2.26) and higher glycated haemoglobin levels (MD, 0.75%). Dialysis patients who have markedly higher risks of ulceration or amputation include those with previous foot ulceration or amputation, peripheral neuropathy, diabetes or macrovascular disease. The temporal relationship between these risk factors and the development of foot ulceration and/or limb loss is uncertain and requires further study. Stable estimates of the key risk factors for ulceration and amputation can inform the design of future trials investigating clinical interventions to reduce the burden of lower limb disease in the dialysis population.

Peripheral arterial disease and revascularization of the diabetic foot.

Diabetes is a complex disease with many serious potential sequelae, including large vessel arterial disease and microvascular dysfunction. Peripheral arterial disease is a common large vessel complication of diabetes, implicated in the development of tissue loss in up to half of patients with diabetic foot ulceration. In addition to peripheral arterial disease, functional changes in the microcirculation also contribute to the development of a diabetic foot ulcer, along with other factors such as infection, oedema and abnormal biomechanical loading. Peripheral arterial disease typically affects the distal vessels, resulting in multi-level occlusions and diffuse disease, which often necessitates challenging distal revascularisation surgery or angioplasty in order to improve blood flow. However, technically successful revascularisation does not always result in wound healing. The confounding effects of microvascular dysfunction must be recognised--treatment of a patient with a diabetic foot ulcer and peripheral arterial disease should address this complex interplay of pathophysiological changes. In the case of non-revascularisable peripheral arterial disease or poor response to conventional treatment, alternative approaches such as cell-based treatment, hyperbaric oxygen therapy and the use of vasodilators may appear attractive, however more robust evidence is required to justify these novel approaches.