Critical limb ischemia: Current and novel therapeutic strategies

Abstract

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease spectrum and is defined by limb pain or impending limb loss because of compromised blood flow to the affected extremity. Current conventional therapies for CLI include amputation, bypass surgery, endovascular therapy, and pharmacological approaches. Although these conventional therapeutic strategies still remain as the mainstay of treatments for CLI, novel and promising therapeutic approaches such as proangiogenic gene/protein therapies and stem cell‐based therapies have emerged to overcome, at least partially, the limitations and disadvantages of current conventional therapeutic approaches. Such novel CLI treatment options may become even more effective when other complementary approaches such as utilizing proper bioscaffolds are used to increase the survival and engraftment of delivered genes and stem cells. Therefore, herein, we address the benefits and disadvantages of current therapeutic strategies for CLI treatment and summarize the novel and promising therapeutic approaches for CLI treatment. Our analyses also suggest that these novel CLI therapeutic strategies show considerable advantages to be used when current conventional methods have failed for CLI treatment.

Three-year outcomes of peripheral blood mononuclear cells vs purified CD34+ cells in the treatment of angiitis-induced no-option critical limb ischemia and a cost-effectiveness assessment: A randomized single-blinded noninferiority trial

“…As the end stage of peripheral artery disease, critical limb ischemia (CLI) is characterized by rest pain and tissue loss with a 6‐month mortality rate of approximately 20% 1,2 . Owing to a high postoperative reocclusion rate and poor anatomical conditions, 20%‐50% of patients with CLI are not suitable for either surgical or endovascular treatment and are also called no‐option CLI (NO‐CLI) patients 3 .…”

“…Owing to a high postoperative reocclusion rate and poor anatomical conditions, 20%‐50% of patients with CLI are not suitable for either surgical or endovascular treatment and are also called no‐option CLI (NO‐CLI) patients 3 . For these patients, both the 6‐month major limb amputation rate and 1‐year mortality rate reached 10%‐40% 2,4,5 . Angiitis‐induced critical limb ischemia (AICLI), defined as ischemia caused by thromboangiitis obliterans (TAO) or other arteritis‐related autoimmunological diseases such as systemic lupus erythematosus (SLE), erythema nodosum, Crohn's disease, psoriasis, and scleroderma, constitutes a substantial proportion of NO‐CLI patients.…”

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

“…Unfortunately, not all the patients are amenable to surgical revascularization through coronary artery bypass surgery, percutaneous coronary intervention, or the deployment of intracoronary stents [ 5 ]. Pharmacological treatment with a wide array of drugs, including statins, prostanoids, and phosphodiesterase inhibitors, can be exploited as an adjuvant therapy to alleviate the symptoms and burden of PAD when surgical intervention is not feasible or fails to restore blood flow [ 6 ]. Therefore, novel and more efficient therapeutic approaches to promote neovascularization and rescue blood supply to ischemic tissues are urgently required.…”

“…Current strategies to induce vascular regrowth of ischemic tissues include the delivery of pro-angiogenic genes or peptides, e.g., vascular endothelial growth factor (VEGF)-A and fibroblast growth factor (FGF)-4 [ 5 ], or stem cell transplantation [ 7 ]. Cell-based therapy consists of the mobilization or transplantation of multiple types of pro-angiogenic stem cells, including bone marrow-derived mesenchymal stem cells (MSCs), hematopoietic cells, and endothelial progenitor cells (EPCs) [ 6 , 7 , 8 , 9 ]. As vascular endothelial cells possess limited regenerative capacity, there is growing interest in circulating EPCs due to their recognized role in the maintenance of endothelial integrity, function, and postnatal neovascularization [ 10 , 11 , 12 , 13 ].…”

“Elephant-trunk” negative pressure wound therapy for fixing artificial dermis with basic fibroblast growth factor for critical limb ischemia

“…Recently, in the field of clinical research for treating CLI and intractable foot-ulcer due to diabetes mellitus (DM), there are many reports describing the applications of regenerative medicine employing stem cells [ [5] , [6] , [7] ], scaffold [ 8 ], nanoparticle [ 9 ], and proangiogenic growth factor including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and insulin-like growth factor (IGF-1) [ 10 ]. Although conventional therapeutic strategies for CLI treatment attempt to increase the processes of neoangiogenesis, neovascularization at the ischemic tissues is known to be difficult.…”