Playing with Biophysics: How a Symphony of Different Electromagnetic Fields Acts to Reduce the Inflammation in Diabetic Derived Cells.

Several factors, such as ischemia, infection and skin injury impair the wound healing process. One common pathway in all these processes is related to the reactive oxygen species (ROS), whose production plays a vital role in wound healing. In this view, several strategies have been developed to stimulate the activation of the antioxidative system, thereby reducing the damage related to oxidative stress and improving wound healing. For this purpose, complex magnetic fields (CMFs) are used in this work on fibroblast and monocyte cultures derived from diabetic patients in order to evaluate their influence on the ROS production and related wound healing properties. Biocompatibility, cytotoxicity, mitochondrial ROS production and gene expression have been evaluated. The results confirm the complete biocompatibility of the treatment and the lack of side effects on cell physiology following the ISO standard indication. Moreover, the results confirm that the CMF treatment induced a reduction in the ROS production, an increase in the macrophage M2 anti-inflammatory phenotype through the activation of miRNA 5591, a reduction in inflammatory cytokines, such as interleukin-1 (IL-1) and IL-6, an increase in anti-inflammatory ones, such as IL-10 and IL-12 and an increase in the markers related to improved wound healing such as collagen type I and integrins. In conclusion, our findings encourage the use of CMFs for the treatment of diabetic foot.

Circulating Biomarkers of Endothelial Dysfunction and Inflammation in Predicting Clinical Outcomes in Diabetic Patients with Critical Limb Ischemia.

Critical limb ischemia (CLI) is a severe manifestation of peripheral artery disease characterized by ischemic pain, which is frequently associated with diabetes and non-healing lesions to inferior limbs. The clinical management of diabetic patients with CLI typically includes percutaneous transluminal angioplasty (PTA) to restore limb circulation and surgical treatment of diabetic foot ulcers (DFU). However, even after successful treatment, CLI patients are prone to post-procedure complications, which may lead to unplanned revascularization or foot surgery. Unfortunately, the factors predicting adverse events in treated CLI patients are only partially known. This study aimed to identify potential biomarkers that predict the disease course in diabetic patients with CLI. For this purpose, we measured the circulating levels of a panel of 23 molecules related to inflammation, endothelial dysfunction, platelet activation, and thrombophilia in 92 patients with CLI and DFU requiring PTA and foot surgery. We investigated whether these putative biomarkers were associated with the following clinical endpoints: (1) healing of the treated DFUs; (2) need for new revascularization of the limb; (3) appearance of new lesions or relapses after successful healing. We found that sICAM-1 and endothelin-1 are inversely associated with DFU healing and that PAI-1 and endothelin-1 are associated with the need for new revascularization. Moreover, we found that the levels of thrombomodulin and sCD40L are associated with new lesions or recurrence, and we show that the levels of these biomarkers could be used in a decision tree to assign patients to clusters with different risks of developing new lesions or recurrences.

Surgical OFF-LOADING of the diabetic foot.

Diabetic foot ulcer treatment is a challenge for the healthcare world. Widespread infection and the presence of critical ischemia (especially with end-stage renal disease) can lead to major amputation rather than amenable to conservative treatment. Surgical strategies of the diabetic foot have been changing over the past 10 years and are now focused on reconstructive treatment and limb salvage. These goals were achieved, thanks to an evolution of distal revascularization techniques and a distinct approach, which integrates various methods focused on limb salvage. Podoplastic techniques of the diabetic foot are focused on infection clearance, the surgical treatment of corrective deformities, soft tissue coverage and limb ischemia correction along with the management of diabetes and the comorbidities that compromise tissue repair processes. The reconstructive techniques used in diabetic foot treatment owe their effectiveness in part to the results of technological improvements such as the circular external fixator as a tool for stabilization and surgical site protection. In the last decade, many studies have shown that circular external fixation should be considered as the most useful method to protect the reconstructive surgical site in limb salvage of the diabetic foot. The objective of this review is to highlight the role of surgical offloading using circular external fixation as an adjunct to the podoplastic diabetic foot reconstruction procedures.

Use of Integra Dermal Regeneration Template for Limb Salvage in Diabetic Patients With No-Option Critical Limb Ischemia.

We have analyzed in a retrospective study of consecutive diabetic patients affected by no-option critical limb ischemia (CLI) the efficacy of the dermal substitute Integra Dermal Regeneration Template for treatment of complicated foot lesions. The primary end point was limb salvage and 1-year amputation-free survival. The secondary end point was healing time of surgical site. Between October 2014 and October 2017, 1024 patients with diabetic foot ulcer (DFU) and CLI were admitted. In 84 patients (8.2%), there was a failure in distal revascularization with a persistent CLI after the procedure. Despite the persistent CLI, a group of 26 patients of this cohort obtained complete wound healing. Among them, 13 patients were treated with surgical debridement or open amputations and application of dermal substitute Integra Dermal Regeneration Template and the other 13 patients were treated without any dermal substitute. The Integra group healed within a mean time of 83.5 days, and the control group healed within a mean of 139 days (P = .028). No major amputation was carried out at 1-year follow-up in the Integra group versus 15% in the control group. A conservative foot surgery or an approach with minor amputation in diabetic patients with no-option CLI may achieve limb salvage. The use of Integra Dermal Regeneration Template in patients with DFU and no-option CLI may be a useful option in a limb salvage program.

Surgery for the diabetic foot: A key component of care.

Surgery for acute and chronic diabetic foot problems has long been an integral component of care. While partial foot amputations remain as important diabetic limb-salvaging operations, foot-sparing reconstructive procedures have become equally important strategies to preserve the functional anatomy of the foot while addressing infection, chronic deformities, and ulcerations. A classification of types of diabetic foot surgery is discussed in accordance with the soft tissue status and acuity of the presenting foot problem. This brief overview from the Association for Diabetic Foot Surgeons describes common conditions best treated by surgical interventions, as well as specific indications. While techniques and indications continue to evolve, effective surgical management of the diabetic foot remains an integral component of care as well as for the prevention of recurrent ulceration.

Limb salvage in diabetic patients with no-option critical limb ischemia: outcomes of a specialized center experience.

Objective: To describe the characteristics, the management and the outcome of a consecutive series of patients with diabetic foot lesions (DF) and no-option critical limb ischemia (CLI) treated with a multidimensional, interdisciplinary approach in a dedicated center. Research Design and Methods: The prospective database of the Diabetic Foot Unit of the Maria Cecilia Hospital (Cotignola, Italy) collects medical history, risk factors, chemistry values, angiographic data, characteristic of foot lesions, medical and surgical therapies of all patients admitted with a diagnosis of DF and CLI. All patients were followed-up for at least 1 year and/or total recovery. The primary endpoint was 1-year amputation-free survival (AFS), secondary endpoints were limb salvage and survival. Results: Between October 2014 and October 2017, 1024 patients with DF and CLI were admitted to the center. Eighty-four of them (8.2%) fulfilled the criteria for no-option CLI. At 1 year, AFS, limb salvage, and survival rates were 34%, 34%, and 83%, respectively. Lesions located proximal to the Lisfranc joint were associated with major amputation (HR 2.1 [1.2-3.6]). One-year survival of patients treated with minor procedures was significantly higher compared to patients treated with major amputation (96% vs 76%, log-rank p = 0.019). Major amputation was independently associated with mortality (HR 7.83 [1.02-59.89]). Conclusions: The application of dedicated and standardized strategies permitted limb salvage in one-third of patients with no-option CLI. Patients with stable lesions limited to the forefoot and without ischaemic pain had a greater probability to successfully receive conservative treatments. Limb salvage was associated with subsequent higher one-year survival.

Characterization of Dermal Stem Cells of Diabetic Patients.

Diabetic foot ulcers (DFUs) are lesions that involve loss of epithelium and dermis, sometimes involving deep structures, compartments, and bones. The aim of this work is to investigate the innate regenerative properties of dermal tissue around ulcers by the identification and analysis of resident dermal stem cells (DSCs). Dermal samples were taken at the edge of DFUs, and genes related to the wound healing process were analyzed by the real-time PCR array. The DSCs were isolated and analyzed by immunofluorescence, flow cytometry, and real-time PCR array to define their stemness properties. The gene expression profile of dermal tissue showed a dysregulation in growth factors, metalloproteinases, collagens, and integrins involved in the wound healing process. In the basal condition, diabetic DSCs adhered on the culture plate with spindle-shaped fibroblast-like morphology. They were positive to the mesenchymal stem cells markers CD44, CD73, CD90, and CD105, but negative for the hematopoietic markers CD14, CD34, CD45, and HLA-DR. In diabetic DSCs, the transcription of genes related to self-renewal and cell division were equivalent to that in normal DSCs. However, the expression of CCNA2, CCND2, CDK1, ALDH1A1, and ABCG2 was downregulated compared with that of normal DSCs. These genes are also related to cell cycle progression and stem cell maintenance. Further investigation will improve the understanding of the molecular mechanisms by which these genes together govern cell proliferation, revealing new strategies useful for future treatment of DFUs.

Combination of Open Subtotal Calcanectomy and Stabilization With External Fixation as Limb Salvage Procedure in Hindfoot-Infected Diabetic Foot Ulcers.

Diabetic hindfoot ulcers, complicated by osteomyelitis, are associated with a high risk of major amputation. Partial calcanectomy, preceded by an effective management of the infection and of the eventual peripheral artery disease, can be considered as valid therapeutic option. We have evaluated a therapeutic protocol for diabetic hindfoot ulcers complicated by osteomyelitis, which, besides an adequate surgical debridement, considers a reconstructive pathway assisted by the positioning of a circular external fixator. We made a prospective study of a cohort of diabetic patients affected by heel ulcer complicated by osteomyelitis. All patients underwent open partial calcanectomy associated with the positioning of a circular external frame specifically designed for hindfoot stabilization and offloading. A reconstructive procedure was implemented starting with the application of negative pressure wound therapy and coverage with dermal substitute and split thickness skin grafting. From November 2014 to November 2015, 18 consecutive patients were enrolled. Mean follow-up period was 212.3 ± 64.0 days. Healing was achieved in 18 (100%) patients. The mean healing time was 69.0 ± 64.0 days. No major amputation had to be performed during the follow-up. Open partial calcanectomy associated with external fixation and skin reconstruction was as efficient as limb salvage in patients with infected lesions of the hindfoot complicated by calcaneal osteomyelitis.

Extension and grading of osteomyelitis are not related to limb salvage in Charcot neuropathic osteoarthropathy: A cohort prospective study.

AIMS: Charcot neuropathic osteoarthropathy (CN) represents a complication for diabetic patients which involves a progressive alteration of the osteoarticular apparatus with high risk of amputation. The aim of the study was to assess whether the localization of CN and the extent or grading of the osteomyelitis have an influence on the rate of limb salvage and the time to recovery. METHODS: We treated a diabetic population affected by CN complicated by ulceration and widespread osteomyelitic involvement. All patients were treated surgically to eliminate infected tissues, stabilize and correct the bone deformities. Histopathological and microbiological analyses were carried out on the bone specimens. RESULTS: Thirty-three patients affected by CN complicated by large osteomyelitic involvement of midfoot and/or ankle were treated between January 2010 and May 2014. The mean follow-up was 409,35 ± 154,06 days. Thirty patients had complete recovery (90.91%) at the end of follow-up. No difference in limb salvage rate and time to recovery was observed when stratifying the population according to CN localization, extent and grading of osteomyelitis. CONCLUSIONS: In this cohort prospective study we observed a high percentage of limb salvage in patients affected by CN complicated by diffuse midfoot/hindfoot osteomyelitis. The localization of Charcot deformity and the extent/stage of osteomyelitis did not change the rate of limb salvage.

Conservative Surgical Treatment of Infected Ulceration of the First Metatarsophalangeal Joint With Osteomyelitis in Diabetic Patients.

Ulceration of the plantar aspect of the first metatarsophalangeal joint is a common localization in the diabetic foot. Conservative treatment of this lesion is a challenging problem, performed through the soft tissues and osseous debridement. The present study included a cohort of 28 patients affected by diabetes mellitus and a first ray lesion penetrating the bone. After surgical debridement with removal of the infected bone, we positioned antibiotic-loaded bone cement and stabilized the treated area with an external fixator. All patients with critical limb ischemia had their vascular disease treated before the procedure. The mean follow-up was 12.2 ± 6.9 months. Four patients developed a relapse of the ulceration after the procedure. In the postoperative period, 1 patient (3.57%) developed dehiscence of the surgical site and underwent a second procedure. In the follow-up period, 2 patients (7.14%) experienced bone cement dislocation. In 1 of these patients, a new ulceration was observed dorsally to the surgical site. The approach was surgical revision with bone cement replacement and stabilization with a new external fixator. In the other patient, given the absence of ulcerations, the cement was removed, and arthrodesis with internal stabilization using 2 cannulated screws was performed. One patient (3.57%), who had developed a relapse of ulceration after recurrent critical ischemia, underwent a percutaneous revascularization procedure and transmetatarsal amputation. During the follow-up period, no ulceration recurrences, transfer ulcerations, shoe fit problems, or gait abnormalities were detected in the other 24 patients. Our study presents the results of a technique requiring a 1-stage surgical approach to a relatively common problem, which is often difficult to solve.

Confronting a dramatic situation: the charcot foot complicated by osteomyelitis.

Charcot osteoarthropathy is a serious complication of diabetic neuropathy. Its prevalence in the diabetic population varies in the literature in relation to certain variables, such as the method of assessment, clinical or instrumental; the population studied; and the scope of the selection. This article is intended as a review of the recent literature concerning Charcot osteoarthropathy in its evolution and complications characterized by the development of ulceration and subsequent bone infection. Diagnosis and treatment strategies--either medical or surgical--are discussed both for Charcot arthropathy and osteomyelitis.

Limb salvage in Charcot foot and ankle osteomyelitis: combined use single stage/double stage of arthrodesis and external fixation.

BACKGROUND: Charcot neuroarthropathy of the foot/ankle is a devastating complication of diabetes. Along with neuroarthropathy, osteomyelitis can occur which can result in amputation. This prospective study evaluated a limb salvage procedure as an alternative to amputation through surgical treatment of osteomyelitis of the midfoot or the ankle and stabilization with external fixation. MATERIALS AND METHODS: Forty-five patients with Charcot arthropathy and osteomyelitis underwent debridement and attempted fusion with an external fixator. Chart and radiograph review was performed to assess the success of the fusion and eradication of infection. RESULTS: Out of 45 patients, 39 patients healed using emergent surgery to drain an acute manifestation of the infection while maintaining the fixation for an average of 25.7 weeks. Two patients were treated with intramedullary nail in a subsequent surgical procedure. In four patients, the infection could not be controlled, therefore a major amputation was carried out. CONCLUSION: For select patients, external fixation proved to be a reasonable alternative to below-knee amputation.

Mastering the antegrade femoral artery access in patients with symptomatic lower limb ischemia: learning curve, complications, and technical tips and tricks.

BACKGROUND: Antegrade femoral access is fraught by technical challenges and steeper learning curve, in comparison with retrograde contralateral femoral access. We appraised learning curve, complications, and technical aspects inherent in the adoption of antegrade approach. METHODS: Consecutive cases in which antegrade access was attempted by a cardiologist experienced in retrograde access, but inexperienced in antegrade, under supervision of an operator with anterograde expertise, were collected. The primary end-point was the occurrence of antegrade access failure or local complications. Major complications were defined as those life-threatening, requiring transfusion, percutaneous, or surgical repair. RESULTS: Anterograde access was attempted in 120 patients. The primary end-point occurred in 14 (11.6%) cases, but according to the learning curve, in 12 (20%) for first 60 cases vs 2 (3.3%) for the last 60 cases (P = 0.008). Access failure in the hands of the in-training operator was similarly found in all cases but one during the first 60 cases. No major complications occurred, while minor complications were found in 9 (7.5%) patients, again with all but two of them occurring in the first 60 cases. These included peri-adventitial extravasation in 8 patients (6.7%), and perforation of a small branch in one (0.8%); all these complications were conservatively and successfully managed. Obesity was the only significant predictor of access failure/complication (P = 0.004). CONCLUSIONS: This work, the first to report on the learning curve of the antegrade approach, supports the feasibility and safety of this access site even for an in-training operator, if supervised. A minimum caseload of 60 procedures is likely needed to master this technique.

Treatment of diabetic foot ulcer: an overview strategies for clinical approach.

Diabetic foot disease is a major health problem, which concerns 15% of the 200 million patients with diabetes worldwide. Major amputation, above or below the knee, is a feared complication of diabetes. More than 60% of non-traumatic amputations in the western world are performed in the diabetic population. Many patients who undergo an amputation, have a history of ulceration. Major amputations increase morbility and mortality and reduce the patient's quality of life. Treatment of foot complications is one of the main items in the absorption of economic and health resources addressed to the diabetic population. It is clear that effective treatment can bring about a reduction in the number of major amputations. Over recent years, we have seen a significant increase in knowledge about the physiopathological pathways of this complication, together with improvements in diagnostic techniques, but above all a standardized conservative therapeutic approach, which allows limb salvage in a high percentage of cases. This target has been achieved in specialized centers. An important prelude to diabetic foot treatment is the differing diagnosis of neuropathic and neuroischemic foot. This differentiation is essential for effective treatment. Ulceration in neuropathic foot is due to biomechanical stress and high pressure, which involves the plantar surface of toes and metatarsal heads. Treatment of a neuropathic plantar ulcer must correct pathological plantar pressures through weight bearing relief. Surgical treatment of deformities, with or without ulcerations, is effective therapy. A neuropathic ulcer that is not adequately treated can become a chronic ulcer that does not heal. An ulcer that does not heal for many months has a high probability of leading to osteomyelitis, for which treatment with antibiotics is not useful and which usually requires a surgical procedure. Charcot neuroarthropathy is a particular complication of neuropathy which may lead to fragmentation or destruction of joints and bones. A well-timed diagnosis of Charcot neuroartropathy is essential to avoid deformities of chronic evolution. In the diabetic population peripheral vascular disease (PVD) is the main risk factor for amputation. If peripheral vascular disease is ignored, surgical treatment of the lesion cannot be successful. In diabetic patients, PVD is especially distal, but often fully involves the femoral, popliteal and tibial vessels. It can be successfully treated with either open surgical or endovascular procedures. Infection is a serious complication of diabetic foot, especially when neuroischemic: phlegmon or necrotizing fascitis are not only limb-threatening problems, but also life-threatening ones. In this case, emergency surgery is needed. Primary and secondary prevention of foot ulceration is the main target. Prevention programs must be carried out to highlight risk factors, lowering amputation incidence.