Leprosy is a neglected disease caused by Mycobacterium leprae and Mycobacterium lepromatosis, and is related to significant disabilities resulting from the neural damage generated by this mycobacteria. Neuropathic ulcers-lesions that can appear at the plantar and extra-plantar levels-are one such disability, and diagnosis requires an adequate dermatological, neurological and microbiological evaluation. The treatment of these lesions is based on a multidisciplinary approach that includes debridement of the necrotic tissue, controlling infections, reducing pressure areas, optimising blood flow, and nerve decompression. This review aims to describe the clinical features, diagnostic methods and treatment of neuropathic ulcers in leprosy. The diagnostic methods and medical management used in leprosy ulcers are based on those used for diabetic foot. This requires radical change as these diseases are immunologically and physiologically very different.

Diabetic foot ulcers are associated with significant morbidity and mortality while posing a challenge for healthcare professionals. Offloading is considered the mainstay of treatment. Total contact casting (TCC) is widely used but does not effectively offload the hindfoot. Some studies suggest that a metal stirrup is effective at offloading midfoot and hindfoot ulcers. The primary purpose of this study is to compare the offloading mechanism of TCC to a stirrup cast.

A pilot observational study assessing 12 healthy volunteers who underwent casting with a TCC or stirrup cast. A sensor (Pedar; Novel GmbH) that measures maximum force, peak pressure, and contact time and area of each foot region, was placed inside the cast to assess the offloading mechanisms of the 2 interventions.

We measured a reduction in all plantar foot loading parameters from the TCC to the stirrup cast. The highest reductions of 85% to 96% (±5%-13%) were noted in maximum force and peak pressure under the forefoot (P < .0001) and found reductions in maximum force, the contact area of all regions of the foot, peak pressure and contact time of the forefoot and midfoot, and contact area of the hindfoot (P < .05).

In this experimental trial of healthy adults, the stirrup cast was more effective than the TCC by offloading the foot mostly in the forefoot and midfoot.

Charcot neuroarthropathy is a devastating condition, most commonly affecting poorly controlled diabetic patients with peripheral neuropathy. Pharmacological options for the condition are currently limited. The purpose of this study was to investigate the potential of Prolia® (denosumab) as a safe and feasible option in the treatment of acute Charcot neuroarthropathy. A total of 7 consecutive subjects were enrolled and followed for 1 year. Subjects received a single one-time injection of denosumab 60 mg. Subjects also received standard of care treatment, which included total contact casting, restricted weightbearing status, and biweekly office visits until normalization of the skin temperature gradient. Overall, the pharmaceutical treatment was generally well-tolerated. One subject developed a diabetic foot infection with cellulitis of the contralateral lower extremity, which occurred following the 6-month follow-up visit and which resolved with oral antibiotics One subject identified transient muscle pain in the same upper extremity which received the injection. Subjects were found to exit the acute phase of the condition at an average of 52.00 ± 17.89 days after their injection, which was defined by normalization of skin temperature to within 2°C of the contralateral foot. Treatment of acute Charcot neuroarthropathy with denosumab was well-tolerated in this open-label, pilot study. The clinical outcomes suggest that the medication may be efficacious, though a larger sample size would be needed to confirm these preliminary results. An adequately-powered, randomized, controlled study may be an appropriate follow-up.

The monitoring of some parameters, such as pressure loads, temperature, and glucose level in sweat on the plantar surface, is one of the most promising approaches for evaluating the health state of the diabetic foot and for preventing the onset of inflammatory events later degenerating in ulcerative lesions. This work presents the results of sensors microfabrication, experimental characterization and FEA-based thermal analysis of a 3D foot-insole model, aimed to advance in the development of a fully custom smart multisensory hardware-software monitoring platform for the diabetic foot. In this system, the simultaneous detection of temperature-, pressure- and sweat-based glucose level by means of full custom microfabricated sensors distributed on eight reading points of a smart insole will be possible, and the unit for data acquisition and wireless transmission will be fully integrated into the platform. Finite element analysis simulations, based on an accurate bioheat transfer model of the metabolic response of the foot tissue, demonstrated that subcutaneous inflamed lesions located up to the muscle layer, and ischemic damage located not below the reticular/fat layer, can be successfully detected. The microfabrication processes and preliminary results of functional characterization of flexible piezoelectric pressure sensors and glucose sensors are presented. Full custom pressure sensors generate an electric charge in the range 0-20 pC, proportional to the applied load in the range 0-4 N, with a figure of merit of 4.7 ± 1 GPa. The disposable glucose sensors exhibit a 0-6 mM (0-108 mg/dL) glucose concentration optimized linear response (for sweat-sensing), with a LOD of 3.27 µM (0.058 mg/dL) and a sensitivity of 21 µA/mM cm2 in the PBS solution. The technical prerequisites and experimental sensing performances were assessed, as preliminary step before future integration into a second prototype, based on a full custom smart insole with enhanced sensing functionalities.

Charcot foot is can result in bone deformities and soft tissue defects. We report a case of alcohol-induced Charcot (AIC) foot with soft tissue defect including the weight-bearing zone of the heel and osteomyelitis, which was successfully reconstructed with free tensor fascia lata true-perforator flap (TFLtp). A 56-year-old male suffered from AIC foot with an 18 × 6 cm defect. Based on the preoperative ultrasound, we identified the overlying upper thigh area offering one of the thickest dermis. A TFLtp flap was raised sparing the TFL muscle based on one perforator without including the main trunk of the transverse/ascending branch of the lateral femoral circumflex vessel. The TFLtp flap was transferred to the heel and anastomosed to the posterior tibial artery in an end-to-side fashion. The patient complained no postoperative discomfort of the donor site and was able to walk on his foot after 5 weeks. This case report highlights that the TFLtp flap may offer thick dermis, faster surgery due to perforator level dissection and a concealed donor site.

The Center for Disease Control and Prevention ranks diabetes mellitus (DM) as the seventh leading cause of death in the USA. The most prevalent forms of DM include Type 2 DM, Type 1 DM, and gestational diabetes mellitus (GDM). While the acute problem of diabetic hyperglycemia can be clinically managed through dietary control and lifestyle changes or pharmacological intervention with oral medications or insulin, long-term complications of the disease are associated with significant morbidity and mortality. These long-term complications involve nearly all organ systems of the body and share common pathologies associated with endothelial cell abnormalities. To better understand the molecular mechanisms underlying DM as related to future long-term complications following hyperglycemia, we have undertaken a study to determine the frequency that GDM did or did not occur in the second pregnancy of women who experienced GDM in their first pregnancy between 2013 and 2018 at Mayo Clinic, Rochester, MN. Within the five-year period of the study, the results indicate that 7,330 women received obstetrical care for pregnancy during the study period. Of these, 150 developed GDM in their first pregnancy and of these, 42 (28%) had a second pregnancy. Of these 42 women, 20 again developed GDM and 22 did not develop GDM in their second pregnancy within the study period. Following the occurrence of GDM in the first pregnancy, the study (1) established the number of women with and without GDM in the second pregnancy and (2) confirmed the feasibility to study diabetic metabolic memory using maternal placental tissue from GDM women. These studies represent Phase I of a larger research project whose goal is to analyze epigenetic mechanisms underlying true diabetic metabolic memory using endothelial cells isolated from the maternal placenta of women with and without GDM as described in this article.

The diabetic Charcot foot syndrome is a serious and potentially limbthreatening lower-extremity complication of diabetes.

The present review provides a concise account of the advances made over the last twentyfive years in understanding the pathogenesis and management of Charcot neuroarthropathy (CN).

In this study, the widely known pathogenetic mechanisms underpinning CN are brought into focus, particularly the role of RANKL/RANK/OPG system and advanced glycation end production in the pathogenesis of CN. Furthermore, other potential triggering factors, namely nitric oxide, endothelial dysfunction, macro calcifications and body weight that influence CN have also been discussed.

The wide range of diagnostic tools available to clinicians for accurate staging of this pathology has been examined, particularly radiological and nuclear medicine imaging. Additionally, the difficult differential diagnosis between osteomyelitis and CN is also elucidated.

The review concludes with the comprehensive summary of the major promising therapeutic strategies, including conservative treatment involving orthopedic devices, pharmacological approach, and the most common surgical techniques currently employed in the diagnosis and treatment of this acute disease.

There is a critical need for strategies that effectively enhance cell viability and post-implantation performance in order to advance cell-based therapies. Spheroids, which are dense cellular aggregates, overcome many current limitations with transplanting individual cells. Compared to individual cells, the aggregation of cells into spheroids results in increased cell viability, together with enhanced proangiogenic, anti-inflammatory, and tissue-forming potential. Furthermore, the transplantation of cells using engineered materials enables localized delivery to the target site while providing an opportunity to guide cell fate in situ, resulting in improved therapeutic outcomes compared to systemic or localized injection. Despite promising early results achieved by freely injecting spheroids into damaged tissues, growing evidence demonstrates the advantages of entrapping spheroids within a biomaterial prior to implantation. This review will highlight the basic characteristics and qualities of spheroids, describe the underlying principles for how biomaterials influence spheroid behavior, with an emphasis on hydrogels, and provide examples of synergistic approaches using spheroids and biomaterials for tissue engineering applications.

Diabetes mellitus places a substantial burden on society worldwide. Diabetic foot ulcers are a challenging problem for clinicians. Seven generally accepted detriments to healing of diabetic foot ulcers were identified: infection, glycaemic control, vascular supply, smoking, nutrition, deformity and offloading. The aim of this paper is to present a comprehensive evidence based review of the literature available on detriments to healing of diabetic foot ulcers.

A research question was generated for each of the detriments to healing and a comprehensive review of the literature was performed using the Pubmed database in July 2014. All articles were assessed for relevancy and a level of evidence was assigned. An analysis of the total body of literature was used to assign a grade of recommendation to each detriment.

Grade A recommendation was assigned to offloading as there was good evidence supporting this intervention. Grade B recommendation was assigned to deformity as there was fair evidence consistent with the hypothesis. Infection and vascular supply had poor quality evidence supporting the research question and grade C recommendation was assigned. Grade I recommendation was assigned to glycaemic control, smoking and nutrition as there was insufficient and conflicting evidence available.

Our literature review revealed good evidence for some factors and insufficient literature on others. Further studies are needed to provide quality evidence regarding detriments to healing of diabetic ulcers.

Mesenchymal stem cell therapies promote wound healing by manipulating the local environment to enhance the function of host cells. Aggregation of mesenchymal stem cells (MSCs) into three-dimensional spheroids increases cell survival and augments their anti-inflammatory and proangiogenic potential, yet there is no consensus on the preferred conditions for maximizing spheroid function in this application. The objective of this study was to optimize conditions for forming MSC spheroids that simultaneously enhance their anti-inflammatory and proangiogenic nature. We applied a design of experiments (DOE) approach to determine the interaction between three input variables (number of cells per spheroid, oxygen tension, and inflammatory stimulus) on MSC spheroids by quantifying secretion of prostaglandin E₂ (PGE₂ ) and vascular endothelial growth factor (VEGF), two potent molecules in the MSC secretome. DOE results revealed that MSC spheroids formed with 40,000 cells per spheroid in 1% oxygen with an inflammatory stimulus (Spheroid 1) would exhibit enhanced PGE₂ and VEGF production versus those formed with 10,000 cells per spheroid in 21% oxygen with no inflammatory stimulus (Spheroid 2). Compared to Spheroid 2, Spheroid 1 produced fivefold more PGE₂ and fourfold more VEGF, providing the opportunity to simultaneously upregulate the secretion of these factors from the same spheroid. The spheroids induced macrophage polarization, sprout formation with endothelial cells, and keratinocyte migration in a human skin equivalent model-demonstrating efficacy on three key cell types that are dysfunctional in chronic non-healing wounds. We conclude that DOE-based analysis effectively identifies optimal culture conditions to enhance the anti-inflammatory and proangiogenic potential of MSC spheroids. Stem Cells 2017;35:1493-1504.

The interrelationship between diabetes mellitus and cardiovascular disease is well-documented, and, secondary to the latter, is the use of antiplatelet therapy. Although diabetes and the associated vascular manifestations are driving forces behind lower extremity amputations, few data are available on the risks of perioperative antiplatelet therapy with foot and ankle amputations. The goal of the present study was to address the surgical effect of continuing or discontinuing antiplatelet therapy before foot and/or ankle amputation. The following data were retrospectively collected: blood loss, pre- and postoperative hematocrit and hemoglobin, operative time, amputation type, age, diabetic status, antiplatelet treatment, and number of transfusions during the perioperative period. Perioperative antiplatelet therapy was defined as exposure to aspirin or clopidogrel within 3 days before surgery. To compare the outcomes between groups, the following factors were analyzed using bivariate analyses and then multivariate regression models: (1) the need for transfusions, (2) high blood loss (>20 mL), (3) volume of blood loss, and (4) operative time. The noninferiority of continued antiplatelet use was assessed in terms of operative time and blood loss, using a noninferiority margin of 10 minutes or 10 mL, respectively. Antiplatelet therapy was not a statistically significant risk factor for any of the studied outcomes on multivariate analysis. Equivalence testing revealed that continuing antiplatelet therapy is not inferior to discontinuing perioperative therapy in terms of blood loss and operative time. Multivariate analysis of the data suggested that antiplatelet therapy has no statistically significant impact on blood loss, transfusion rate, or operative time.

It has been reported that ozone therapy might be helpful in treating foot ulcers in people with diabetes mellitus (DM).

To assess the effects of ozone therapy on the healing of foot ulcers in people with DM.

In March 2015 we searched: The Cochrane Wounds Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE (In-Process & Other Non-Indexed Citations), Ovid EMBASE, EBSCO CINAHL, Science Citation Index, Chinese Biomedical Literature Database and The Chinese Clinical Registry. There were no restrictions based on language, date or study setting.

We included randomised controlled trials (RCTs) that compared ozone therapy with sham ozone therapy or any other interventions for foot ulcers in people with DM, irrespective of publication date or language.

Two reviewers independently screened all retrieved citations, selected relevant citations and extracted data. Disagreements were resolved by discussion with a third reviewer. The methodological quality of included studies and the evidence level of outcomes were assessed using the Cochrane risk of bias tool and the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach respectively. Data were expressed using risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with their 95% confidence interval (95% CI). Review Manager (RevMan) software was used to analyse the data.

Three studies (212 participants) were included in this review. The overall risk of bias was high for two trials and unclear for one.One trial (101 participants) compared ozone treatment with antibiotics for foot ulcers in people with DM. The study had a follow-up period of 20 days. This study showed that ozone treatment was associated with a greater reduction in ulcer area from baseline to the end of the study than treatment with antibiotics (MD -20.54 cm(2), 95% CI -20.61 to -20.47), and a shorter duration of hospitalisation (MD -8.00 days, 95% CI -14.17 to -1.83), but did not appear to affect the number of ulcers healed over 20 days (RR 1.10, 95% CI 0.87 to 1.40). No side effects were observed in either group.The other two trials (111 participants) compared ozone treatment plus usual care with usual care for foot ulcers in people with DM. The meta-analysis results did not show evidence of a difference between groups for the outcomes of reduction of ulcer area (MD -2.11 cm(2), 95% CI -5.29 to 1.07), the number of ulcers healed (RR 1.69, 95% CI 0.90 to 3.17), adverse events (RR 2.27, 95% CI 0.48 to 10.79), or amputation rate (RR 2.73, 95%CI 0.12, 64.42).

The available evidence was three small RCTs with unclear methodology, so we are unable to draw any firm conclusions regarding the effectiveness of ozone therapy for foot ulcers in people with DM.

Adults with end-stage renal disease treated with dialysis experience a high burden of foot ulceration and lower extremity amputation. However, the risk factors for foot ulceration in the dialysis population are incompletely understood due to the lack of high-quality prospective evidence. This article outlines the design of a prospective observational cohort study, which aims to investigate the risk factors for foot ulceration in adults on dialysis.

This study will recruit 430 participants with end-stage renal disease on dialysis from satellite and home-therapy dialysis units across multiple health organisations in Melbourne, Victoria, Australia. Data collection at baseline will include a participant interview, medical record review, completion of a health-status questionnaire and a non-invasive foot assessment. Twenty participants will also be recruited to a reliability study to evaluate the reproducibility of testing procedures. Primary outcome data includes: new foot ulcer(s). Secondary outcome data includes: number of new foot ulcers, time to onset of new foot ulcer(s), new lower extremity amputation(s), episodes of infection of the foot or lower extremity, episodes of osteomyelitis, foot-related hospitalisations, revascularisation procedure(s) of the lower extremity, new podiatry interventions, kidney transplantation, and mortality. Participants will be assessed at baseline, and at 12 months they will be evaluated for the primary and secondary outcomes. Multivariate Cox proportional hazards models will be used to assess predictors of new foot ulceration and time to event secondary outcomes. Logistic regression will be used for binary outcomes including prevalence of foot ulcerations.

This is the first multi-centre prospective observational cohort study to investigate risk factors for foot ulceration in adults with end-stage renal disease on dialysis. This study will improve on prior studies by using prospective methods, multi-centre recruitment, statistical methods to control for confounding variables, and a pre-specified sample size estimation. The findings can inform the design of future trials evaluating the effectiveness of clinical interventions, which may lead to improved patient outcomes in the dialysis setting.

Charcot foot is a serious complication of diabetes, characterized by deformity and overlying ulceration. The condition most commonly affects the midfoot. However, little information is available on the use of a medial plantar artery flap to treat diabetic midfoot ulceration. The purpose of the present study was to evaluate the versatility of ostectomy and medial plantar flap reconstruction for midfoot plantar ulceration associated with rocker-bottom deformity secondary to Charcot foot. Four patients underwent ostectomy and medial plantar flap reconstruction. Before flap reconstruction, the devitalized soft tissues and bone were radically resected. After the infection had been controlled, the ulcerated portion was minimally excised, and the bony prominence underlying the ulcer was removed. A medial plantar artery flap was applied to the ulcer. The donor site was covered with a split-thickness skin graft or artificial dermis. In all patients, the ulcers healed and independent ambulation was achieved. However, 1 patient experienced ulcer recurrence, and subsequent infection necessitated a major amputation. Limb salvage is challenging in the setting of deformity and intractable plantar ulceration. The advantages of medial plantar artery flap reconstruction are that tissues with a rich blood supply are used to cover the exposed bone, and the flap can withstand the pressure and shear stress of the patient's body weight. However, a dominant artery in the foot is sacrificed. Therefore, the patency of the dorsalis pedis artery must be confirmed in every patient. The results of the present study have demonstrated that a medial plantar artery can be an effective alternative for diabetic patients with a plantar ulcer secondary to Charcot foot.

Diabetics are prone to foot ulceration as a result of local tissue ischemia, immune impairment, and biomechanical derangement in the setting of neuropathy. Healing ulcers in the setting of Charcot neuroarthropathy is challenging, as the skeletal changes usually signify advanced disease.

Records were reviewed for all patients with the diagnosis of Charcot neuroarthropathy and ulceration treated over a 7-year period. Demographic data, anatomical wound location, therapeutic interventions, and wound healing rates were recorded.

Three hundred fourteen wounds in 259 patients were examined. One hundred ninety-three wounds with documented follow-up data were analyzed. Fifty wounds (25.9 percent) were on the forefoot, 73 (37.8 percent) were on the midfoot, 28 (14.5 percent) were on the hindfoot, and 42 (21.8 percent) were about the ankle. Wounds were débrided surgically an average of four times. Primary closure was attempted in 29 wounds (15.0 percent). Delayed primary closure was attempted in 35 wounds (18.1 percent). Bioengineered alternative tissues were used in 61 wounds (31.6 percent). Autologous skin grafting was performed on 41 wounds (21.2 percent). Fifteen local flaps (7.8 percent) and five free flaps (2.6 percent) were performed. Forty-eight patients (31.6 percent) required a major amputation. Excluding patients who underwent major amputation, 95 wounds (65.1 percent) were healed at the time of final follow-up.

The majority of ulcers on Charcot feet required multiple débridements to achieve a clean wound. Multiple therapeutic modalities were used to achieve a 65 percent rate of healing. Despite those efforts, many patients required partial foot or major amputations, with more proximal wounds being at highest risk of the latter.

Charcot neuroarthropathy (CN) is a rare, progressive, deforming disease of bone and joints, especially affecting the foot and ankle and leading to considerable morbidity. It can also affect other joints such as the wrist, knee, spine and shoulder. This disease, described originally in reference to syphilis, is now one of the most common associates of diabetes mellitus. As the number of diabetics increase, the incidence of CN is bound to rise. Faster initial diagnosis and prompt institution of treatment may help to reduce its sequelae. There should be a low threshold for ordering investigations to assist coming to this diagnosis. No single investigation is the gold standard. Recent studies on pathogenesis and development of newer investigation modalities have helped to clarify the mystery of its pathogenesis and of its diagnosis in the acute phase. Various complementary investigations together allow the correct diagnosis to be made. Osteomyelitis continues to be confused with acute CN. Hybrid positron emission tomography has shown some promise in differentiating these conditions. A multispecialty approach involving diabetologists, orthopaedists and podiatrists should be used to tackle this difficult problem. The aim of this article is to describe current knowledge about CN with particular reference to the status of diagnostic indicators and management options.

Charcot neuroarthropathy (CN) is a serious complication of diabetes mellitus that can cause major morbidity including limb amputation. Since it was first described in 1883, and attributed to diabetes mellitus in 1936, the diagnosis of CN has been very challenging even for the experienced practitioners. Imaging plays a central role in the early and accurate diagnosis of CN, and in distinction of CN from osteomyelitis. Conventional radiography, computed tomography, nuclear medicine scintigraphy, magnetic resonance imaging, and positron emission tomography are the imaging techniques currently in use for the evaluation of CN but modalities other than magnetic resonance imaging appeared to be complementary. This study focuses on imaging findings of acute and chronic neuropathic osteoarthropathy in diabetes and discrimination of infected vs. non-infected neuropathic osteoarthropathy.

In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats. Intramuscular transplantation demonstrated the best efficacy. This effect is associated with granulation tissue formation, angiogenesis, cellular proliferation, and high vascular endothelial growth factor expression in wound tissues. In addition, bone marrow-derived mesenchymal stem cells have been shown to mobilize and find home for ischemic and wounded tissues to participate in the process of wound healing. Intramuscular transplantation of exogenous isogeneic stem cells may be suitable for clinical application in the treatment of diabetic foot ulcers although the safety of this therapy should be considered.