Table 1 Evidence of clinical use of stem cells in CLI
Author (year) | Design study and sample size (n) | Type of transplant and stem cell source | CLI model | Delivery method | Follow-up time (months) | Therapeutic effect and /or action mechanism |
|---|---|---|---|---|---|---|
Gupta et al. (2021)[78] | Phase IV, open-label, and multicenter clinical trial (n = 50) | Allogeneic BM-MSCs | CLI due to Buerger's disease | Intramuscular and around the ulcer | 12 | Improvement in rest pain, ankle systolic pressure, and ankle–brachial pressure index with accelerated ulcer healing Anti-inflammatory, immunomodulatory, and angiogenic properties |
Norgren et al (2019)[83] | Phase III, randomized, double-blind, multicenter, multinational placebo-controlled, and parallel group clinical trial (n = 246) | Allogeneic placental-derived MSCs | CLI Rutherford 5, ineligibility for revascularization or failed revascularization | Intramuscular | 12—36 | Improvement of amputation-free survival and trends in reduction of pain scores and increase of tissue perfusion Pro-angiogenic, anti-inflammatory, immunomodulating and regenerative properties |
Wang et al 2018[9] | Phase I/II, single-center, and open-label clinical trial (n = 32) | Allogeneic BM-MSCs and autologous concentrated bone marrow aspirate | CLI with required amputation within next 30 days | Intramuscular | 6 | Changes in peripheral cytokine signaling, microRNA expression, and pro-angiogenic and inflammatory mononuclear phenotypes Angiogenesis, to decrease muscle fiber apoptosis, and to stimulate re-epithelialization of wound beds |
Wijnand et al 2018 [7] | Phase I/II, randomized, double-blind, placebo and controlled clinical trial (n = 66) | Allogeneic BM-MSCs | Patients with CLI who are not eligible for conventional revascularization | Intramuscular | 6 | Improvement mortality, limb status, clinical evolution and changes in pain score |
Gupta et al 2017[84] | Phase II, prospective, nonrandomized, open-label, multicenter, and dose-ranging clinical trial | Allogeneic BM-MSCs | CLI due to Buerger’s who had not responded to, or were not eligible for, revascularization | Preclinical: intramuscular (adductor) Clinical: intramuscular (gastrocnemius) and locally [22] | 24 | Reduction in rest pain, healing of ulcers, improvement in ankle–brachial pressure index and total walking distance No significant difference was observed in the number of collateral vessels and amputation-free survival. Angiogenesis |
Tournois et al 2017[85] | No randomization (n = 40) | Autologous BM aspirate or peripheral blood | Patients with CLI not suitable for revascularization | Intramuscular | 6 | Paracrine effect |
Bura et al 2014[80] | Phase I consecutively enrolled clinical trial (n = 7) | Autologous adipose-derived stroma cell | Diabetic or non-diabetic not suitable candidates for surgery | Intramuscular | 6 | Increase in the transcutaneous oxygen pressure Improvement ulcers evolution and wound healing Decreased rest pain and number of lesions Differentiation toward endothelial-like cells Paracrine activities |
Gupta et al 2013 [78] | Phase I/II, randomized, double-blind, placebo-controlled, multicenter clinical trial (n = 20) | Allogeneic BM-MSCs | Controlled diabetic or non-diabetic, failed revascularization or not suitable candidates for surgery | Intramuscular | 6 (24) | Increase in the transcutaneous oxygen pressure Improvement in rest pain and ankle–brachial pressure index and ulcer healing |
Li et al 2013[86] | Phase II, single-blinded, placebo-controlled clinical trial (n = 58) | Autologous bone marrow mononuclear cells | Patients with chronic critical limb ischemia unresponsive to standard revascularization treatment | Intramuscular | 6 | Improvement in rest pain, ankle–brachial pressure index and ulcer healing No significant differences in the incidence of adverse events among the groups No significant differences in major amputation rates Differentiation into vascular endothelial cells and smooth secretion of vascular growth factors and cytokines Vascular remodeling Neovascularization and collateral vascularization |
Das et al 2013 [87] | Phase I, single-center open-label prospective clinical trial (n = 10) | Allogeneic BM-MSCs | CLI Rutherford III or more (4 or more) | Intra-arterial | 6 | Improvement in rest pain and ulcer healing Vasculogenesis that occurs mainly in smaller vessels |
Mohammadzadeh et al. 2013 [88] | Randomized, controlled, and parallel clinical trial (n = 21) | Autologous peripheral blood MSCs mobilized by G-CSF | Diabetic, angioplasty failure (or else could not benefit from angioplasty) | Intramuscular | 3 | Improvement in amputation rate, pain-free walking distance and wound healing. Differentiation and incorporation into the endothelial cells lining the blood vessels and neovascularization blood flow |
Powell et al 2012 [82] | Phase II, double-blind, placebo-controlled, randomized clinical trial (n = 72) | Ixmyelocel T: (Autologous MNC, MSC, activated macrophages) | Diabetic and non-diabetic, not revascularizable | Intramuscular | 12 | Significant reduction in the risk of treatment failure in the Ixmyelocel T-treatment group The occurrence of adverse events and serious adverse events was similar between the two treatment groups No reported amputation-free survival |
Lu et al. 2011[79] | Phase I /II double-blind, randomized, placebo-controlled clinical trial (n = 41) | Autologous BM-MSCs or bone marrow mononuclear cells | Type 2 diabetic patients with bilateral critical limb ischemia | Intramuscular | 6 | Improvement in ulcer healing rate, painless walking time and ankle–brachial pressure index. No significant difference in amputation Increase in the transcutaneous oxygen pressure. Significantly increased collateral vessels (increased scores > 2) greater in MSCs group. Release of angiogenic factors Increased blood flow |
Lasala et al 2010 [81] | Phase I, single-center, nonrandomized, single-group assignment clinical trial (n = 10) | Autologous BM-derived mononuclear and BM-MSCs | Severe limb ischemia (Fontaine stages 2B to 4), non-revascularizable | Intramuscular | 6 (10) | Improvement, painless walking time, ankle–brachial pressure index and physical functioning Significant formation of new blood vessels. Paracrine effect therapeutic. Vasculogenesis. Enhancement of blood flow Collateral vessel formation |
Kim et al. 2006 [89] | Clinical trial (n = 27) | Allogeneic MSCs derived from umbilical cord blood or mobilize endothelial progenitor cells (EPCs) from bone marrow | CLI Buerger’s disease | Intramuscular and subcutaneous (adjacent lesions) | 4 | Increased capillary formation on the affected lesions and decreased vascular resistance and arteriogenesis Paracrine factors(cytokines and growth factors) No side effects |