Peripheral arterial disease (PAD) is a common atherosclerotic syndrome associated with significant morbidity and mortality. It is characterized by progressive narrowing and occlusion of arterial vessels, ultimately reducing distal perfusion. Critical limb ischemia (CLI) represents the end stage of lower-extremity PAD, in which severe arterial obstruction leads to ischemic rest pain, non-healing ulcers, and a high risk of limb loss. The standard therapy for severe, limb-threatening ischemia is revascularization to restore blood flow to the affected extremity. When revascularization is not feasible or is unsuccessful, amputation may be required.

Stem cell therapy has been proposed as an alternative treatment for CLI secondary to PAD. The rationale of hematopoietic or bone marrow-derived cell therapy in PAD is to induce arteriogenesis by boosting the physiological repair processes. This approach requires large numbers of functionally active autologous precursor cells and, subsequently, a large quantity of bone marrow or other sources of stem cells. The concentration of bone marrow aspirate contains a mix of cell types, including lymphocytoid cells, erythroblasts, monocytoid cells and granulocytes. Following isolation and concentration, the hematopoietic cell/bone marrow concentrate is administered either intra-arterially or through multiple injections into the muscle.

POLICY

Treatment of peripheral arterial disease, including critical limb ischemia, with injection or infusion of stem cells concentrated from bone marrow, expanded in vitro, stimulated from peripheral blood, or from an allogeneic source, is considered investigational.

IMPORTANT REMINDERS

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ADDITIONAL INFORMATION

Due to insufficient evidence and lack of high-quality data, the impact of this therapy on net health outcomes cannot be determined. Larger, well-designed randomized controlled trials with long-term follow-up are required to establish safety and effectiveness.

SOURCES

American Heart Association, American College of Cardiology. (2024). 2024 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease. Retrieved April 25, 2025 from https://www.acc.org/guidelines.

BlueCross BlueShield Association. Evidence Positioning System. (2:2026). Stem cell therapy for peripheral arterial disease (8.01.55). Retrieved April 20, 2026 from www.bcbsaoca.com/eps/. (31 articles and/or guidelines reviewed)

Conte, M. S., Bradbury, A. W., Kolh, P., White, J. V., Dick, F., Fitridge, R., et al. (2019). Global vascular guidelines on the management of chronic limb-threatening ischemia. Journal of Vascular Surgery, 69 (6S), 3S-125S.e40, doi: 10.1016/j.jvs.2019.02.016. (Level 2 evidence)

Dubsky, M., Husakova, J., Bem, R., Jirkovska, A., Nemcova, A., Fejfarova, V., et al. (2022). Comparison of the impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in patients with chronic limb-threatening ischemia: A randomized controlled trial. Frontiers in Endocrinology, 29:13:888809. doi: 10.3389/fendo.2022.888809. (Level 3 evidence)

Gao, W., Chen, D., Liu, G., & Ran, X. (2019). Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Research and Therapy, 10 (1), 140. (Level 1 evidence)

Horie, T., Yamazaki, S., Hanada, S., Kobayashi, S., Tsukamoto, T., Haruna, T., et al. (2018). Outcome from a randomized controlled clinical trial - improvement of peripheral arterial disease by granulocyte colony-stimulating factor-mobilized autologous peripheral-blood-mononuclear cell transplantation (IMPACT). Circulation Journal, 82 (8), 2165-2174. (Level 2 evidence)

Moazzami, B., Mohammadpour, Z., Zabala, ZE., Farokhi, E., Roohi, A., Domatova, E., et al. (2022). Local intramuscular transplantation of autologous bone marrow mononuclear cells for critical lower limb ischemia (review). Cochrane Database of Systematic Reviews, 7 (7), CD008347. doi: 10.1002/14651858. (Level 3 evidence)

Peeters Weem, S., Teraa, M., de Borst, G., Verhaar, M., & Moll, F. (2015). Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. European Journal of Vascular and Endovascular Surgery, 50 (6), 775-783. (Level 2 evidence)

Pu, H., Huang, Q., Zhang, X., Wu, Z., Qiu, P., Jiang, Y., et al. (2022). A meta-analysis of randomized controlled trials on therapeutic efficacy and safety of autologous cell therapy for atherosclerosis obliterans. Journal of Vascular Surgery, 75 (4), 1440-1449. (Level 1 evidence)

Qadura, M., Terenzi, D.C., Verma, S., Al-Omran, M., & Hess, D.A. (2017). Cell therapy for critical limb ischemia: an integrated review of pre-clinical and clinical studies. Stem Cells, 36 (2), 161-171. (Level 1 evidence)

Rigato, M., Monami, M., & Fadini, G.P. (2017). Autologous cell therapy for peripheral arterial disease: systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circulation Research, 120 (8), 1326-1340. (Level 2 evidence)

Xie, B., Luo, H., Zhang, Y., Wang, Q., Zhou, C., & Xu, D. (2018). Autologous stem cell therapy in critical limb ischemia: a meta-analysis of randomized controlled trials. Stem Cells International, 2018, 7528464. (Level 2 evidence)

ORIGINAL EFFECTIVE DATE: 12/10/2011

MOST RECENT REVIEW DATE: 6/18/2026

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