Current Status of Cell-Based Therapy in Patients with Critical Limb Ischemia

Abstract

(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.

Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia

“…Overall, the comparison of the results derived from different trials comprises an arduous task in which meta-analysis are becoming increasingly useful to support evidence-based medicine, allowing to summarize the accumulated evidence and also to drive future research [ 179 ]. A meta-analysis performed by Rigato et al includes robust statistical analysis of either randomized, controlled trials, and non-controlled studies.…”

“…Such study corroborates the effectiveness of using cell therapy with CLI patients, with a reduction in the number of major amputations and improved wound healing. Furthermore, for secondary outcomes such as ABI, TcPO 2 , and RPS, a general improvement is seen [ 179 ]. Despite this, larger studies are required to increase statistical significance, together with the design of placebo-controlled studies, as clinical outcome differences are not clear when compared to the placebo effect [ 181 , 182 ].…”

Dental Pulp Mesenchymal Stem Cells Attenuate Limb Ischemia via Promoting Capillary Proliferation and Collateral Development in a Preclinical Model

“…In past decades, MSC transplantation has emerged as a potential approach for treating CLI [8,25,26]. MSCs are ideal stem cells for mesodermal tissue remodeling and regeneration, due to their differentiation potential to mesodermderived cells, such as osteoblasts, chondrocytes, adipocytes, and vascular endothelial cells [27].…”

“…Mesenchymal stem cell (MSC) transplantation has emerged as a promising approach in treating ischemic diseases, such as peripheral artery diseases, myocardial infarction, and stroke [7][8][9][10]. MSCs could home to the ischemic sites and regenerate damaged tissues via various mechanisms, such as reducing inflammation, stimulating proliferation and angiogenesis, and inhibiting apoptosis, as well as differentiating into endothelial cells [11][12][13][14].…”

Strategies to Overcome the Barrier of Ischemic Microenvironment in Cell Therapy of Cardiovascular Disease

“…The development of encapsulation techniques for target orientated drug delivery to organs and delayed relief of drug agents have also influenced the field of cell and gene therapy during the last two decades [ 34 , 35 ]. However, cell products for the treatment of PAD or critical limb ischemia have demonstrated only modest results or failed in clinical studies due to poor cell retention within the ischemic microenvironment [ 36 , 37 , 38 ]. During the last decade, a research group from King’s College London has continually evolved a Good Manufacturing Practice (GMP)-compliant method for encapsulation of pro-angiogenic macrophages respectively monocytes introducing 300 µm alginate capsules ( Figure 1 E).…”