Search Results (13)

Chronic limb-threatening ischemia (CLTI), the most advanced form of peripheral arterial disease (PAD), is the comorbidity primarily responsible for major lower-limb amputations, particularly for diabetic patients. Autologous cell therapy has been the focus of efforts over the past 20 years to create non-interventional therapeutic options for no-option CLTI to improve limb perfusion and wound healing. Among the different available techniques, peripheral blood mononuclear cells (PBMNC) appear to be the most promising autologous cell therapy due to physio-pathological considerations and clinical evidence, which will be discussed in this review. A meta-analysis of six clinical studies, including 256 diabetic patients treated with naive, fresh PBMNC produced via a selective filtration point-of-care device, was conducted. PBMNC was associated with a mean yearly amputation rate of 15.7%, a mean healing rate of 62%, and a time to healing of 208.6 ± 136.5 days. Moreover, an increase in TcPO2 and a reduction in pain were observed. All-cause mortality, with a mean rate of 22.2% and a yearly mortality rate of 18.8%, was reported. No serious adverse events were reported. Finally, some practical and financial considerations are provided, which point to the therapy’s recommendation as the first line of treatment for this particular and crucial patient group. Full article

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. Full article

Background: Percutaneous deep vein arterialization (pDVA) is considered a treatment modality in patients with no-option critical limb ischemia. However, there is still a paucity of evidence regarding its safety and efficacy. Data sources: MEDLINE (via PubMed), Embase and Web of Science databases as well as the CENTRAL registry up to the end of June 2023. Methods: This review adhered to the PRISMA guidelines (PROSPERO registration no. CRD42023445171). The risk of bias was assessed using the methodological index for non-randomized studies (MINORS). Primary endpoints included technical success, overall survival and limb salvage during the follow-up. Amputation-free survival at 30 days, 6 months and 1 year as well as complete wound healing, major adverse limb events and reintervention were investigated as secondary outcomes. Results: Five observational studies, comprising 208 patients (142 Rutherford class 5/77 Rutherford class 6), were included. MINORS revealed a low risk of bias. The meta-analysis reached a pooled technical success rate of 96.2% (95% CI: 91.5–98.4), an overall survival of 82.8% (95% CI: 70.5–95.2) and a limb salvage rate of 77.2% (95% CI: 65.2–89.1) during the follow-up. The amputation-free survival at 30 days, 6 months and 1 year was 87.8%, 68.7% and 65.6%, respectively. Furthermore, pDVA resulted in a complete wound healing rate of 53.4% (95% CI: 30.3–76.5). The pooled reintervention rate was as high as 46.7% (37.1–56.3%). Conclusions: PDVA seems a feasible bail-out strategy for patients with no option for routine treatment of CLTI. However, due to the small number of studies, the strength of the evidence is low. Full article

Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation. Full article

Background: Patients presenting with critical limb-threatening ischemia (CLTI) have been increasing in number over the years. They represent a high-risk population, especially in terms of major amputation and mortality. Despite multiple guidelines concerning their management, it continues to be challenging. Decision-making between surgical and endovascular procedures should be well established, but there is still a lack of consensus concerning the best treatment strategy. The aim of this manuscript is to offer an overview of the contemporary management of CLTI patients, with a focus on the concept that evidence-based revascularization (EBR) could help surgeons to provide more appropriate treatment, avoiding improper procedures, as well as too-high-risk ones. Methods: We performed a search on MEDLINE, Embase, and Scopus from 1 January 1995 to 31 December 2022 and reviewed Global and ESVS Guidelines. A total of 150 articles were screened, but only those of high quality were considered and included in a narrative synthesis. Results: Global Vascular Guidelines have improved and standardized the way to classify and manage CLTI patients with evidence-based revascularization (EBR). Nevertheless, considering that not all patients are suitable for revascularization, a key strategy could be to stratify unfit patients by considering both clinical and non-clinical risk factors, in accordance with the concept of individual residual risk for every patient. The recent BEST-CLI trial established the superiority of autologous vein bypass graft over endovascular therapy for the revascularization of CLTI patients. However, no-option CLTI patients still represent a critical issue. Conclusions: The surgeon’s experience and skillfulness are the cornerstones of treatment and of a multidisciplinary approach. The recent BEST-CLI trial established that open surgical peripheral vascular surgery could guarantee better outcomes than the less invasive endovascular approach. Full article

Deep vein arterialization (DVA) is a therapeutic option in “no option” for revascularization chronic limb-threatening ischemia patients, creating an arteriovenous bypass between a proximal artery and a distal deep venous target at the ankle. Imaging plays a crucial role in peripheral arterial disease (PAD) patient management. We present the case of a 71-year-old PAD patient (Rutherford class 5) with focal gangrene of the first and second toes of the right foot, who was admitted to the vascular surgery department to undergo revascularization surgery by femoro-tibial artery bypass. During surgery a DVA was performed because of an unsatisfactory distal artery target. The post-operative computed tomography angiography showed the saphenous graft patency and opacification of distal foot veins. Subsequent angiography documented the presence of a large venous collateral, responsible for extensive early wash-out to leg venous vessels, which was then embolized. After two months, the patient underwent amputation of the right first and second necrotic toes at the level of the metatarsophalangeal joints. The post-operative course was excellent, with disappearance of pain at rest and good trophism of the surgical wound. Full article

Objective: To report early and mid-term outcomes of the arterialization of the deep venous system in no-option critical limb-threatening ischemia (CLTI) using duplex ultrasound and angiographic evaluation to improve limb perfusion. Methods: A single-center prospective study of patients with no-option CLTI treated with hybrid surgical arterialization of the deep venous circulation and staged endovascular embolization of the venous collateral. Embolization was performed using a controlled-release spiral, within two weeks after bypass surgery. Patients were assessed for clinical status, wound healing, median transcutaneous partial pressure of O₂ (TcPO₂), and post-operative duplex ultrasound evaluating peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI) to assess foot perfusion and bypass features. Primary endpoint analysis was primary technical success, limb salvage, patency rates, and clinical improvement. Secondary endpoints were 30-day and long-term mortality, major cardiovascular events (MACE), including myocardial infarction or stroke, and serious adverse events (SAE). Results: Five patients with no-option CLTI were treated at our center using the hybrid deep vein arterialization technique. Clinical stage was grade 3 in one patient and grade 4 in the remaining four. Mean age was 65.8 years (range 49–76 years), and two patients were affected by Buerger’s disease. Primary technical success was achieved in all patients, and all the bypasses were patent at the angiographic examination. At 30-day and at average follow-up of 9.8 months (range 2–24 months), mortality, major cardiovascular events (MACE), and serious adverse events (SAE) were not reported, with a primary patency and limb salvage rates of 100%. Three patients required minor amputation. Clinical improvement was demonstrated in all patients with granulation, resolution of rest pain, or both. Median TcPO₂ values rose from 10 mm Hg (range 4–25) before the procedure to 35 (range 31–57) after surgery, and to 59 mm Hg (range 50–76) after the staged endovascular procedure. Conclusions: In our initial experience, the arterialization of the deep venous circulation, with subsequent selective embolization of the venous escape routes from the foot, seems a feasible and effective solution for limb salvage in patients with no-option CLTI and those in the advanced wound, ischemia, and foot infection (WIfI) clinical stage. Full article

About 35% of patients affected by erectile dysfunction (ED) do not respond to oral phosphodiesterase-5 inhibitors (PDE5i) and more severe vasculogenic refractory ED affects diabetic patients. Innovative approaches, such as regenerative therapies, including stem cell therapy (SCT) and platelet-rich plasma (PRP), are currently under investigation. Recent data point out that the regenerative capacity of stem cells is strongly influenced by local immune responses, with macrophages playing a pivotal role in the injury response and as a coordinator of tissue regeneration, suggesting that control of the immune response could be an appealing approach in regenerative medicine. A new generation of autologous cell therapy based on immune cells instead of stem cells, which could change regenerative medicine for good, is discussed. Increasing safety and efficacy data are coming from clinical trials using peripheral blood mononuclear cells to treat no-option critical limb ischemia and diabetic foot. In this review, ongoing phase 1/phase 2 stem cell clinical trials are discussed. In addition, we examine the mechanism of action and rationale, as well as propose a new generation of regenerative therapies, evolving from typical stem cell or growth factor to immune cell-based medicine, based on autologous peripheral blood mononuclear cells (PBMNC) concentrates for the treatment of ED. Full article

Background: The healing of foot wounds in patients with diabetes mellitus is frequently complicated by critical limb threatening ischemia (neuro-ischemic diabetic foot syndrome, DFS). In this situation, imminent arterial revascularization is imperative in order to avoid amputation. However, in many patients this is no longer possible (“too late”, “too sick”, “no technical option”). Besides conservative treatment or major amputation, many alternative methods supposed to decrease pain, promote wound healing, and avoid amputations are employed. We performed a narrative review in order to stress their efficiency and evidence. Methods: The literature research for the 2014 revision of the German evidenced-based S3-PAD-guidelines was extended to 2020. Results: If revascularization is impossible, there is not enough evidence for gene- and stem-cell therapy, hyperbaric oxygen, sympathectomy, spinal cord stimulation, prostanoids etc. to be able to recommend them. Risk factor management is recommended for all CLTI patients. With appropriate wound care and strict offloading, conservative treatment may be an effective alternative. Timely amputation can accelerate mobilization and improve the quality of life. Conclusions: Alternative treatments said to decrease the amputation rate by improving arterial perfusion and wound healing in case revascularization is impossible and lack both efficiency and evidence. Conservative therapy can yield acceptable results, but early amputation may be a beneficial alternative. Patients unfit for revascularization or major amputation should receive palliative wound care and pain therapy. New treatment strategies for no-option CLTI are urgently needed. Full article

Peripheral blood mononuclear cells (PBMNCs) are reported to prevent major amputation and healing in no-option critical limb ischemia (NO-CLI). The aim of this study is to evaluate PBMNC treatment in comparison to standard treatment in NO-CLI patients with diabetic foot ulcers (DFUs). The study included 76 NO-CLI patients admitted to our centers because of CLI with DFUs. All patients were treated with the same standard care (control group), but 38 patients were also treated with autologous PBMNC implants. Major amputations, overall mortality, and number of healed patients were evaluated as the primary endpoint. Only 4 out 38 amputations (10.5%) were observed in the PBMNC group, while 15 out of 38 amputations (39.5%) were recorded in the control group (p = 0.0037). The Kaplan–Meier curves and the log-rank test results showed a significantly lower amputation rate in the PBMNCs group vs. the control group (p = 0.000). At two years follow-up, nearly 80% of the PBMNCs group was still alive vs. only 20% of the control group (p = 0.000). In the PBMNC group, 33 patients healed (86.6%) while only one patient healed in the control group (p = 0.000). PBMNCs showed a positive clinical outcome at two years follow-up in patients with DFUs and NO-CLI, significantly reducing the amputation rate and improving survival and wound healing. According to our study results, intramuscular and peri-lesional injection of autologous PBMNCs could prevent amputations in NO-CLI diabetic patients. Full article

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these “no-option” patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described. Full article

(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords “critical limb ischemia and cell therapy”. In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6–3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective. Full article

The study aimed to evaluate clinical and vascular characteristics, as well as outcomes, for diabetic persons with foot ulceration and no-option critical limb ischemia (CLI). The study group included a sample of patients admitted to our diabetic foot unit because of a new diabetic foot ulcer and CLI. All subjects were managed using a limb salvage protocol which includes lower-limb revascularization. According to whether or not the revascularization procedure was a success, patients were respectively divided into two groups: successfully treated CLI patients (ST-CLI) and no-option CLI patients (NO-CLI). Failed revascularization was considered in the case of technical recanalization failure of occluded vessels (inability to overcome the obstruction) and/or absence of arterial flow to the foot. Limb salvage, major amputation, and death after 1 year of follow-up were evaluated and compared between the two groups. Overall, 239 patients were included, 74.9% belonging to ST-CLI and 25.1% to NO-CLI. NO-CLI patients reported more cases of ischemic heart disease (80 vs. 62.1, p = 0.008), heart failure (63.3 vs. 32.4%, p < 0.0001), and end-stage renal disease (ESRD) (60 vs. 25.7%) than ST-CLI patients. In addition, more vessels were affected in the NO-CLI group (5.2 ± 1.6 vs. 4 ± 1.5, p < 0.0001), and there was more involvement of tibio-peroneal trunk (50 vs. 30.2%, p = 0.006), anterior tibial (93.3 vs. 82.7, p = 0.03), posterior tibial (93.3 vs. 73.7%, p = 0.0005), peroneal (70 vs. 48%, p = 0.002), and below-the-ankle arteries (73.3 vs. 39.1%, p < 0.0001) than ST-CLI. The 1 year outcomes for the whole population were 69.9% limb salvage, 10.9% major amputation, and 19.2% death. The outcomes for NO-CLI and ST-CLI were, respectively, as follows: limb salvage (13.8 vs. 73.4%, p < 0.0001), amputation (30 vs. 4.5%, p = 0.0001), and mortality (50 vs. 8.9%, p < 0.0001). NO-CLI patients showed a more severe pattern of peripheral arterial disease (PAD) with distal arterial lesions and worse outcomes than ST-CLI. Full article