Noninvasive management of the diabetic foot with critical limb ischemia: Current options and future perspectives

Therapeutic advances in endocrinology and metabolism 12/2011; 2(6):247-55. DOI: 10.1177/2042018811427721
Source: PubMed


Foot ulcers are a major complication in patients with diabetes mellitus and involve dramatic restrictions to quality of life and also lead to enormous socio-economical loss due to the high amputation rate. The poor and slow wound healing is often aggravated by the frequent comorbidity of foot ulcers with peripheral arterial disease, making the treatment of this condition even more complicated. While the local treatment of foot ulcers is mainly based on mechanical relief and prevention or treatment of infection, improving perfusion of the impaired tissue remains the major challenge in peripheral arterial disease. While focal arterial stenosis is the domain of interventional angioplasty or vascular surgery, patients with critical limb ischemia and lacking options for revascularization have a much worse prognosis, because current treatment options avoiding amputation are scarce. However, based on recent research efforts, there is rising hope for promising and more-effective therapeutic approaches for these patients. Here, we discuss the current improvements of established therapies aimed at an improvement of limb perfusion, as well as the development of novel cutting-edge therapies based on stem-cell technology. The experiences of a 'high-volume center' for treatment of diabetic foot syndrome with a current major amputation rate of 4% are discussed.

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    • "Patients with signs of ischemia (decompensated ischemia) were seen by the interventional angiologist and the vascular surgeon. If vascular reconstruction or interventional radiologic procedures were not possible, prostaglandins, low-dose urokinase or autologous bone marrow derived mononuclear cells (“stem cells”, intramuscular application) were applied in order to improve perfusion [8]. "
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    ABSTRACT: We tested the effects of structured health care for the diabetic foot in one region in Germany aiming to reduce the number of major amputations. Research design and methods In a prospective study we investigated patients with diabetic foot in a structured system of outpatient, in-patient and rehabilitative treatment. Subjects were recruited between January 1st, 2000 and December 31, 2007. All participants underwent a two-year follow-up. The modified University of Texas Wound Classification System (UT) was the basis for documentation and data analysis. We evaluated numbers of major amputations, rates of ulcer healing and mortality. In order to compare the effect of the structured health care program with usual care in patients with diabetic foot we evaluated the same parameters at another regional hospital without interdisciplinary care of diabetic foot (controls). 684 patients with diabetic foot and 508 controls were investigated. At discharge from hospital 28.3% (structured health care program, SHC) vs. 23.0% (controls) of all ulcers had healed completely. 51.5% (SHC) vs. 49.8% (controls) were in UT grade 1. Major amputations were performed in 32 subjects of the structured health care program group (4.7%) vs. 110 (21.7%) in controls (p<0.0001). Mortality during hospitalization was 2.5% (SHC) vs. 9.4% in controls (p<0.001). With the structured health care program we achieved a significant reduction of major amputation rates by more than 75% as compared to standard care.
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    ABSTRACT: This study was designed to evaluate the distribution of Tregs/Th17/Th1 cells in type 2 diabetic patients with foot disease before and after human umbilical cord blood mesenchymal stem cell (hUCB-MSCs) transplantation. Fifteen diabetic patients with foot disease under insulin therapy received hUCB-MSC transplantation. The hUCB-MSCs were directly injected into the quadriceps thigh muscles in patients with foot disease (cell quantity at 2×106 per point). Physical attributes, blood cytokines, blood glucose and insulin dosage were evaluated before treatment and 1, 2, 4, 8, and 12 weeks thereafter. The ratios of Treg/Th17, Treg/Th1, and Th17/Th1 cells were measured using flow cytometry and their correlation with various cytokines (FoxP3, IL-17, INF-γ, C-RP, TNF-α, and VEGF) was scrutinized. Levels of blood glucose and insulin dosage were significantly reduced in all 15 patients following hUCB-MSC transplantation. The ratios of CD4+CD25hiFoxP3+ Treg/Th17 and CD4+CD25hiFoxP3+ Treg/Th1 cells were significantly increased 4 weeks after transplantation (p < 0.01), while the ratio of Th17/Th1 cells remained unchanged. Serum levels of VEGF peaked at 4 weeks following transplantation. Levels of C-RP and TNF-α were significantly reduced 4 weeks after transplantation. Intriguingly, the ratios of Treg/Th17 were positively correlated with VEGF levels, and were inversely correlated with plasma IL-6 levels. Our data indicated that immune disorders are associated with the development of type 2 diabetes and its complications. Levels of blood glucose and required insulin dosage were reduced after hUCB-MSC transplantation accompanied with improved clinical profiles in diabetic patients. These data favor a role for Treg cells in the onset and progression of T2D.
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    ABSTRACT: Introduction: The aim of this study was to assess the safety and efficacy of combined autologous bone marrow mononuclear cell and VEGF165 gene therapy in patients with diabetes mellitus suffering from critical limb ischaemia (CLI). Material and methods: The administration of mononuclear cells (MNCs) and naked VEGF165 plasmid was performed in 16 limbs of 16 patients with rest pain and ischaemic ulcers due to diabetes. MNCs and plasmid were injected into the muscles of the ischaemic limbs. The levels of VEGF in serum and the ankle-brachial index (ABI) were measured before and after treatment. The Visual Analogue Scale (VAS) was used to evaluate pain sensation. CT angiography was performed before and after three months of therapy. Results: Mean (± SD) plasma levels of VEGF increased non-significantly from 257 ± 80 pg/L to 391 ± 82 pg/L (p 〉 0.05) two weeks after therapy. The ABI improved significantly from 0.26 ± 0.22 to 0.49 ± 0.30 (p 〈 0.001) three months after therapy. A decrease in rest pain was observed in all patients; mean VAS decreased from 6.3 ± 1.4 to 1.2 ± 1.1 after three months (p 〈 0.002). Angiograms showed the development of collateral vessels in 12 limbs. Ischaemic ulcers healed in 12 limbs. Amputation was performed in four patients only, because of advanced wound infection. However, the level of amputations was lowered below knee level in these cases. Complications were limited to transient leg oedema in two patients and fever in two patients. Conclusions: Intramuscular bone marrow MNCs autotransplantation combined with the administration of phVEGF165 gene is safe, feasible and effective for patients with diabetes and CLI.
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