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. 2022 Jul 8;7(7):CD008347.
doi: 10.1002/14651858.CD008347.pub4.

Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia

Bobak Moazzami  1 , Zinat Mohammadpour  2 , Zohyra E Zabala  1 , Ermia Farokhi  3 , Aria Roohi  4 , Elena Dolmatova  5 , Kasra Moazzami  5
Affiliations

Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischaemia

Bobak Moazzami et al. Cochrane Database Syst Rev. .

Abstract

Background: Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients, the disease progresses to critical limb ischaemia (CLI), also known as critical limb-threatening ischaemia. In a substantial number of individuals with CLI, no effective treatment options other than amputation are available, with around a quarter of these patients requiring a major amputation during the following year. This is the second update of a review first published in 2011.

Objectives: To evaluate the benefits and harms of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for CLI.

Search methods: We used standard, extensive Cochrane search methods. The latest search date was 8 November 2021.

Selection criteria: We included all randomised controlled trials (RCTs) of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention, conventional conservative therapy, or placebo).

Data collection and analysis: We used standard Cochrane methods. Our primary outcomes of interest were all-cause mortality, pain, and amputation. Our secondary outcomes were angiographic analysis, ankle-brachial index (ABI), pain-free walking distance, side effects and complications. We assessed the certainty of the evidence using the GRADE approach.

Main results: We included four RCTs involving a total of 176 participants with a clinical diagnosis of CLI. Participants were randomised to receive either intramuscular cell implantation of BMMNCs or control. The control arms varied between studies, and included conventional therapy, diluted autologous peripheral blood, and saline. There was no clear evidence of an effect on mortality related to the administration of BMMNCs compared to control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.15 to 6.63; 3 studies, 123 participants; very low-certainty evidence). All trials assessed changes in pain severity, but the trials used different forms of pain assessment tools, so we were unable to pool data. Three studies individually reported that no differences in pain reduction were observed between the BMMNC and control groups. One study reported that reduction in rest pain was greater in the BMMNC group compared to the control group (very low-certainty evidence). All four trials reported the rate of amputation at the end of the study period. We are uncertain if amputations were reduced in the BMMNC group compared to the control group, as a possible small effect (RR 0.52, 95% CI 0.27 to 0.99; 4 studies, 176 participants; very low-certainty evidence) was lost after undertaking sensitivity analysis (RR 0.52, 95% CI 0.19 to 1.39; 2 studies, 89 participants). None of the included studies reported any angiographic analysis. Ankle-brachial index was reported differently by each study, so we were not able to pool the data. Three studies reported no changes between groups, and one study reported greater improvement in ABI (as haemodynamic improvement) in the BMMNC group compared to the control group (very low-certainty evidence). One study reported pain-free walking distance, finding no clear difference between BMMNC and control groups (low-certainty evidence). We pooled the data for side effects reported during the follow-up, and this did not show any clear difference between BMMNC and control groups (RR 2.13, 95% CI 0.50 to 8.97; 4 studies, 176 participants; very low-certainty evidence). We downgraded the certainty of the evidence due to the concerns about risk of bias, imprecision, and inconsistency.

Authors' conclusions: We identified a small number of studies that met our inclusion criteria, and these differed in the controls they used and how they measured important outcomes. Limited data from these trials provide very low- to low-certainty evidence, and we are unable to draw conclusions to support the use of local intramuscular transplantation of BMMNC for improving clinical outcomes in people with CLI. Evidence from larger RCTs is needed in order to provide adequate statistical power to assess the role of this procedure.

Trial registration: ClinicalTrials.gov NCT00371371 NCT00539266 NCT00616980 NCT00913900 NCT00468000.

PubMed Disclaimer

Conflict of interest statement

BM: none known ZM: none known ZZ: none known EF: none known AR: none known ED: none known KM: none known

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: BMMNC versus control, Outcome 1: All‐cause mortality
1.2
1.2. Analysis
Comparison 1: BMMNC versus control, Outcome 2: Amputation
1.3
1.3. Analysis
Comparison 1: BMMNC versus control, Outcome 3: Amputation ‐ sensitivity analysis
1.4
1.4. Analysis
Comparison 1: BMMNC versus control, Outcome 4: Side effects and complications
1.5
1.5. Analysis
Comparison 1: BMMNC versus control, Outcome 5: Side effects and complications ‐ sensitivity analysis
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Barc 2006 {published data only}
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References to studies excluded from this review

Benoit 2011 {published data only}
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Burt 2010 {published data only}
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Capiod 2009 {published data only}
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Chen 2009 {published data only}
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Debin 2008 {published data only}
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Dong 2013 {published data only}
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Gupta 2013 {published data only}
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Higashi 2010 {published data only}
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    1. Iafrati MD, O’Donnell TF Jr, Perler B, Illig KA, Hallett J, Woo K, et al. Bone marrow aspirate concentrate in critical limb ischemia: results of an abridged prospective randomized pivotal trial in no option CLI. Abstracts of the 2016 Vascular Annual Meeting, The Society for Vascular Surgery 2016;63(6 Suppl):47S.
JUVENTAS 2008 {published data only}
    1. Han ZC, Huang P, Li S. Autologous peripheral blood stem cell implantation as therapeutic angiogenesis for severe limb ischemia. Blood 2004;104:130b.
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    1. Sprengers RW, Moll FL, Teraa M, Verhaar MC, JUVENTAS Study Group. Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia. Journal of Vascular Surgery 2010;51(6):1564-8. - PubMed
Kirana 2007 {published data only}
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Kirana 2012 {published data only}
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Klepanec 2012 {published data only}
    1. Klepanec A, Mistrik M, Altaner C, Valachovicova M, Olejarova I, Slysko R, et al. No difference in intra-arterial and intramuscular delivery of autologous bone marrow cells in patients with advanced critical limb ischemia. Cell Transplantation 2012;21(9):1909-18. - PubMed
Korymasov 2009 {published data only}
    1. Korymasov EA, Tiumina OV, Aiupov AM, Kazantsev AV, Rossiev VA, Mikheev GV, et al. Use of autologous progenitor cells of the bone marrow in treatment of patients with lower-limb atherosclerosis obliterans. Angiologiia iSosudistaia Khirurgiia 2009;15(3):28-31. - PubMed
Lasala 2011 {published data only}
    1. Lasala GP, Silva JA, Minguell JJ. Therapeutic angiogenesis in patients with severe limb ischemia by transplantation of an autologous bone marrow-derived combination stem cell product. Journal of the American College of Cardiology 2011;57:E2020.
Lu 2011 {published data only}
    1. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Research and Clinical Practice 2011;92(1):26-36. - PubMed
Madaric 2011 {published data only}
    1. Madaric J, Klepanec A, Mistrik M, Altaner C, Valachovicova M, Necpal R. Autologous bone marrow cells transplantation in patients with advanced critical limb ischemia: no difference in intra-arterial and intramuscular application. Journal of the American College of Cardiology 2011;57(14 Suppl 1):E1473.
    1. Madaric JK. Higher CD34+ cells concentration and lower degree of inflammation are associated with better therapeutic response to autologous bone marrow cells application in patients with critical limb ischemia. Journal of the American College of Cardiology 2011;58:B150.
Majumdar 2015 {published data only}
    1. Majumdar AS, Balasubramanian S, Thej C, Rajkumar M, Krishna M, Dutta S, et al. A first of its kind phase II clinical trial in critical limb ischemia patients using bone marrow derived, pooled, allogeneic mesenchymal stromal cells (Stempeucel). Cytotherapy 2015;17:S84.
Mohamed 2020 {published data only}
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Molavi 2016 {published data only}
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Murphy 2017 {published data only}
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NCT00282646 {published data only}
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NCT00306085 {published data only}
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NCT00498069 {published data only}
    1. NCT00498069. Study of autologous bone marrow concentrate for the treatment of CLI. clinicaltrials.gov/ct2/show/NCT00498069 (first received 9 July 2007).
NCT00539266 {published data only}
    1. NCT00539266. Autologous bone marrow-derived mononuclear cells for therapeutic arteriogenesis in patients with limb ischemia (ABC). clinicaltrials.gov/ct2/show/NCT00539266 (first received 4 October 2007).
NCT00595257 {published data only}
    1. NCT00595257. Feasability study of autologous bone marrow aspirate concentrate for treatment of CLI. clinicaltrials.gov/ct2/show/NCT00595257 (first received 16 January 2008).
NCT00616980 {published data only}
    1. NCT00616980. Injection of autologous CD34-positive cells for critical limb ischemia (ACT34-CLI). clinicaltrials.gov/ct2/show/NCT00616980 (first received 15 February 2008).
NCT00913900 {published data only}
    1. NCT00913900. Safety study of adult stem cells to treat patients with severe leg artery disease (SCRIPT-CLI). clinicaltrials.gov/ct2/show/NCT00913900 (first received 4 June 2009).
NCT00922389 {published data only}
    1. NCT00922389. A clinical trial on diabetic foot using peripheral blood derived stem cells for treating critical limb ischemia. clinicaltrials.gov/ct2/show/NCT00922389 (first received 17 June 2009).
NCT00955669 {published data only}
    1. NCT00955669. Comparison of autologous mesenchymal stem cells and mononuclear cells on diabetic critical limb ischemia and foot ulcer. clinicaltrials.gov/ct2/show/NCT00955669 (first received 10 August 2009).
NCT01049919 {published data only}
    1. NCT01049919. Safety and efficacy study of autologous concentrated bone marrow aspirate (cBMA) for critical limb ischemia (CLI). clinicaltrials.gov/ct2/show/NCT01049919 (first received 15 January 2010).
NCT01245335 {published data only}
    1. NCT01245335. Bone marrow aspirate concentrate (BMAC) for treatment of critical limb ischemia (CLI). clinicaltrials.gov/ct2/show/NCT01245335 (first received 22 November 2010).
NCT01584986 {published data only}
    1. NCT01584986. Autologous angiogenic cell precursors (ACPs) for the treatment of peripheral artery disease. clinicaltrials.gov/ct2/show/NCT01584986 (first received 25 April 2012).
NCT02336646 {published data only}
    1. NCT02336646. Cell therapy with mesenchymal stem cell in ischemic limb disease. clinicaltrials.gov/ct2/show/NCT02336646 (first received 13 January 2015).
NCT03174522 {published data only}
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NCT03214887 {published data only}
    1. NCT03214887. Autologous BMMNC combined with HA therapy for PAOD. clinicaltrials.gov/ct2/show/NCT03214887 (first received 12 July 2017).
NCT03304821 {published data only}
    1. NCT03304821. Granulocyte-macrophage stimulating factor (GM-CSF) in peripheral arterial disease. clinicaltrials.gov/ct2/show/NCT03304821 (first received 9 October 2017).
NCT03339973 {published data only}
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Niven 2017 {published data only}
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Ohtake 2017 {published data only}
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Pawan 2012 {published data only}
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Perin 2011 {published data only}
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Perin 2017 {published data only}
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Prochazka 2010 {published data only}
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PROVASA 2011 {published data only}
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RESTORE‐CLI 2012 {published data only}
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Skóra 2015 {published data only}
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Subramaniyam 2009 {published data only}
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Szabo 2013 {published data only}
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Teraa 2015 {published data only}
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    1. Teraa M, Sprengers RW, Schutgens RE, Slaper-Cortenbach IC, Graaf Y, Algra A, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled rejuvenating endothelial progenitor cells via transcutaneous intra-arterial supplementation (JUVENTAS) trial. Circulation 2015;131(10):851-60. - PubMed
Tournois 2015 {published data only}
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Walter 2011 {published data only}
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Wang 2014 {published data only}
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    1. Wang SK, Green LA, Motaganahalli RL, Wilson MG, Fajardo A, Murphy MP. Rationale and design of the MarrowStim PAD Kit for the treatment of critical limb ischemia in subjects with severe peripheral arterial disease (MOBILE) trial investigating autologous bone marrow cell therapy for critical limb ischemia. Journal of Vascular Surgery 2017;65(6):1850–7.e2. - PubMed
Wang 2018 {published data only}
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Wijnand 2018 {published data only}
    1. NCT03042572. Allogeneic mesenchymal stromal cells for angiogenesis and neovascularization in no-option ischemic limbs (SAIL). clinicaltrials.gov/ct2/show/NCT03042572 (first received 3 February 2017).
    1. Wijnand JGJ, Teraa M, Gremmels H, Rhijn-Brouwer FCC, Borst GJ, Verhaar MC. Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia. Journal of Vascular Surgery 2018;67(2):656-61. - PubMed
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Zhang 2010 {published data only}
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Zhao 2008 {published data only}
    1. Zhao ZG, Yuan HJ, Zhang HF, Zhang CL, Wang YF, Ma SP, et al. Combined transplantation of autologous peripheral blood and bone narrow stem cells for the treatment of diabetic lower limb ischaemia: randomized controlled trial. Journal of Clinical Rehabilitative Tissue Engineering Research 2008;12(8):1464-6.
Zhou 2017a {published data only}
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Zhou 2017b {published data only}
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References to ongoing studies

NCT00753025 {published data only}
    1. NCT00753025. Autologous bone marrow for lower extremity ischemia treating. clinicaltrials.gov/ct2/show/study/NCT00753025 (first received 16 September 2008).
NCT01446055 {published data only}
    1. NCT01446055. Safety and efficacy study of autologous BM-MNC processed by two methods for treating patients with chronic limb ischemia. clinicaltrials.gov/ct2/show/study/NCT01446055 (first received 4 October 2011).
NCT02454231 {published data only}
    1. NCT02454231. Monocentric trial: stem cell emergency life threatening limbs arteriopathy (SCELTA). clinicaltrials.gov/ct2/show/NCT02454231 (first received 27 May 2015).

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References to other published versions of this review

Moazzami 2011
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Publication types

Associated data