AIMS: Data about long-term clinical outcomes of revascularization procedures, especially for autologous cell therapy (ACT), in diabetic patients with chronic limb-threatening ischaemia (CLTI) are lacking. The aim of our study was to compare the mortality and amputation rates in patients with diabetic foot ulcers (DFU) and CLTI treated by ACT with patients treated by repeated percutaneous transluminal angioplasty (re-PTA) and those treated conservatively. MATERIALS AND METHODS: One-hundred and thirty patients with DFU and CLTI (defined as transcutaneous oxygen pressure-TcPO2 <30 mmHg after unsuccessful standard revascularization) treated in our foot clinic over 9 years were enrolled in the study. Forty-five patients were treated by ACT, 43 patients underwent re-PTA, and 42 patients were treated conservatively and formed the control group. Overall survival, amputation-free survival (AFS) and major amputation rate were assessed over a 7-year follow-up period. RESULTS: Baseline demographic characteristics and comorbidities were similar between groups. However, patients in ACT and control groups had significantly worse baseline angiograms in accordance with Graziani and GLASS (infrapopliteal region) classifications than the re-PTA group (both p < 0.001), but there were no differences in baseline values of TcPO2 between groups. AFS in the ACT and re-PTA groups were significantly longer compared to control (both p < 0.001). The rate of major amputation was significantly lower in both active groups (both p < 0.001). The re-PTA group showed significantly longer overall survival compared to the control group (p < 0.001), but there was no significant difference between ACT and control groups (p = 0.063) and ACT and re-PTA groups (p = 0.081) in this parameter. CONCLUSIONS: Our study showed significantly longer AFS and lower major amputation rates in patients treated by ACT and re-PTA in contrast to patients treated conservatively. Overall survival was significantly longer only in the re-PTA group. ACT was shown to be effective in long-term limb salvage in people with no-option CLTI.

• Keywords
• cellular research, clinical trial, diabetes complications, effectiveness,
• MeSH
• Amputation, Surgical statistics & numerical data   MeSH
• Angioplasty * MeSH
• Transplantation, Autologous MeSH
• Cell- and Tissue-Based Therapy * MeSH
• Chronic Limb-Threatening Ischemia * therapy   mortality   MeSH
• Diabetic Foot * therapy   mortality   complications   surgery   MeSH
• Ischemia * therapy   mortality   MeSH
• Conservative Treatment * MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Limb Salvage statistics & numerical data   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Autologous cell therapy (ACT) is primarily used in diabetic patients with chronic limb-threatening ischemia (CLTI) who are not candidates for standard revascularization. According to current research, this therapy has been shown in some studies to be effective in improving ischemia parameters, decreasing the major amputation rate, and in foot ulcer healing. This review critically evaluates the efficacy of ACT in patients with no-option CLTI, discusses the use of mononuclear and mesenchymal stem cells, and compares the route of delivery of ACT. In addition to ACT, we also describe the use of new revascularization strategies, e.g., nanodiscs, microbeads, and epigenetics, that could enhance the therapeutic effect. The main aim is to summarize new findings on subcellular and molecular levels with the clinical aspects of ACT.

• Keywords
• chronic limb-threatening ischemia, peripheral artery disease, stem cell therapy,
• MeSH
• Transplantation, Autologous * MeSH
• Cell- and Tissue-Based Therapy methods   MeSH
• Chronic Limb-Threatening Ischemia therapy   MeSH
• Diabetes Mellitus therapy   MeSH
• Ischemia therapy   MeSH
• Humans MeSH
• Mesenchymal Stem Cell Transplantation methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

This current opinion article critically evaluates the efficacy of autologous cell therapy (ACT) for chronic limb-threatening ischemia (CLTI), especially in people with diabetes who are not candidates for standard revascularization. This treatment approach has been used in 'no-option' CLTI in the last two decades and more than 1700 patients have received ACT worldwide. Here we analyze the level of published evidence of ACT as well as our experience with this treatment method. Many studies have shown that ACT is safe and an effective method for patients with the most severe lower limb ischemia. However, some trials did not show any benefit of ACT, and there is some heterogeneity in the types of injected cells, route of administration and assessed endpoints. Nevertheless, we believe that ACT plays an important role in a comprehensive treatment of patients with diabetic foot and severe ischemia.

• MeSH
• Amputation, Surgical MeSH
• Cell- and Tissue-Based Therapy MeSH
• Diabetes Mellitus * MeSH
• Diabetic Foot * therapy   MeSH
• Ischemia etiology   therapy   MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Autologous cell therapy (ACT) is a new treatment method for patients with diabetes and no-option chronic limb-threatening ischemia (NO-CLTI). We aimed to assess the impact of ACT on NO-CLTI in comparison with standard treatment (ST) in a randomized controlled trial. METHODS: Diabetic patients with NO-CLTI were randomized to receive either ACT (n=21) or ST (n=19). After 12 weeks, those in the ST group, who did not improve were treated with ACT. The effect of ACT on ischemia and wound healing was assessed by changes in transcutaneous oxygen pressure (TcPO2) and the number of healed patients at 12 weeks. Pain was evaluated by Visual Analogue Scale (VAS). Amputation rates and amputation-free survival (AFS) were assessed in both groups. RESULTS: During the first 12 weeks, TcPO2 increased in the ACT group from 20.8 ± 9.6 to 41.9 ± 18.3 mm Hg (p=0.005) whereas there was no change in the ST group (from 21.2 ± 11.4 to 23.9 ± 13.5 mm Hg). Difference in TcPO2 in the ACT group compared to ST group was 21.1 mm Hg (p=0.034) after 12 weeks. In the period from week 12 to week 24, when ST group received ACT, the TcPO2 in this group increased from 20.1 ± 13.9 to 41.9 ± 14.8 (p=0.005) while it did not change significantly in the ACT in this period. At 24 weeks, there was no significant difference in mean TcPO2 between the two groups. Wound healing was greater at 12 weeks in the ACT group compared to the ST group (5/16 vs. 0/13, p=0.048). Pain measured using VAS was reduced in the ACT group after 12 weeks compared to the baseline, and the difference in scores was again significant (p<0.001), but not in the ST group. There was no difference in rates of major amputation and AFS between ACT and ST groups at 12 weeks. CONCLUSIONS: This study has showed that ACT treatment in patients with no-option CLTI and diabetic foot significantly improved limb ischemia and wound healing after 12 weeks compared to conservative standard therapy. Larger randomized controlled trials are needed to study the benefits of ACT in patients with NO-CLTI and diabetic foot disease. TRIAL REGISTRATION: The trial was registered in the National Board of Health (EudraCT 2016-001397-15).

• Keywords
• autologous cell therapy, chronic limb-threatening ischemia, diabetic foot, major amputation of lower extremity, revascularization,
• MeSH
• Pain MeSH
• Cell- and Tissue-Based Therapy MeSH
• Chronic Limb-Threatening Ischemia MeSH
• Diabetes Mellitus * MeSH
• Diabetic Foot * therapy   MeSH
• Ischemia therapy   MeSH
• Oxygen MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Oxygen MeSH

Endothelial progenitors are a population of cells with the inherent capacity to differentiate into mature endothelial cells and proangiogenic paracrine action. These characteristics have led to extensive studies being performed and tested in the treatment of tissue ischemia. The natural course of diabetes mellitus (DM) results in multiple areas of vascular damage. Thus endothelial progenitor cells'(EPCs) beneficial potential is particularly desirable in diabetic patients. In this review, we summarize contemporary knowledge of EPC biology in DM. It has been shown that EPC functions are considerably impaired by DM. The presence of peripheral arterial disease (PAD) seems to further exacerbate the deficiencies of EPCs. However, studies examining EPC counts in PAD and DM observed disparate results, which can be due to a lack of consensus on precise EPC immunotype used in the different studies. Nevertheless, the results of EPC-based autologous cell therapy (ACT) are promising. In addition, EPCs have been shown to bean independent predictor of cardiovascular risk and diabetic foot ulcer healing.

• Keywords
• Autologous cell therapy, Diabetes mellitus, Endothelial progenitor cells, Peripheral arterial disease, Vascular repair,
• MeSH
• Cell- and Tissue-Based Therapy methods   MeSH
• Cell Differentiation * MeSH
• Diabetes Mellitus therapy   MeSH
• Endothelial Progenitor Cells cytology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Peripheral Arterial Disease therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH