The application of cell products for the treatment of critical limb ischemia in patients with diabetes mellitus: a review of the literature

The number of patients with diabetes mellitus (DM) has been progressively increasing worldwide over the past decades, and many international organizations consider DM as a public health emergency of the 21st century.

Critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease (PAD) in DM and is characterized by a high risk of limb loss without revascularization. Traditional treatment tactics include open and endovascular revascularization surgical techniques. However, in patients not eligible for revascularization and in cases where performed surgical treatment performed has been ineffective, there are almost no therapeutic alternatives, often leading to amputations and death. As of today, one of the newest non-surgical treatment options is cell therapy. Among different cells, mesenchymal stromal cells (MSCs) are potentially one of the most prospective for use in this patient population.

This article provides an overview of clinical trials using cell therapy in patients with CLI.

To analyze publications, electronic databases PubMed, SCOPUS, ClinicalTrials, and ScienceDirect were searched to identify published data from clinical trials, research studies, and review articles on cell therapy for critical lower extremity ischemia. After the search, 489 results were received.

As a result of systematic selection, 22 clinical trials were analyzed.

According to the analyzed literature data, the use of cell products in this category of patients is effective and safe. Cell therapy can stimulate the formation of new vessels and enhances collateral circulation; it is also reported improved distal perfusion, increased pain-free walking distance, decreased amputation rates, and increased survival rates.

Nevertheless, further study of the potential use of this category of drugs is needed.

1. Dedov II, Shestakova MV, Vikulova OK, et al. Diabetes mellitus in the Russian Federation: dynamics of epidemiological indicators according to the Federal Register of Diabetes Mellitus for the period 2010–2022. Diabetes mellitus. 2023;26(2):104-123. (in Russ.) doi: https://doi.org/10.14341/DM13035

2. Galstyan GR, Tokmakova AYu, Bondarenko ON, et al. Arterial diseases of lower extremities in diabetic patients: current state and prospects of therapy. Diabetes mellitus. 2011;14(1):74-80. (In Russ.) doi: https://doi.org/10.14341/2072-0351-6253

3. Dedov I, Shestakova M, Mayorov A, et al. Standards of Specialized Diabetes Care / Edited by Dedov II, Shestakova MV, Mayorov AYu. 11th Edition. Diabetes mellitus. 2023;26(2S):1-157. (In Russ.) doi: https://doi.org/10.14341/DM12042

4. Spiliopoulos S, Festas G, Paraskevopoulos I, et al. Overcoming ischemia in the diabetic foot: Minimally invasive treatment options. World J Diabetes. 2021;12(12):2011-2026. doi: https://doi.org/10.4239/wjd.v12.i12.2011

5. Bondarenko ON, Galstyan GR, Dedov II. The clinical course of critical limb ischaemia and the role of endovascular revascularisation in patients with diabetes. Diabetes mellitus. 2015;18(3):57-69. (In Russ.) doi: https://doi.org/10.14341/DM2015357-69

6. Gorbacheva AM, Abdulvapova ZN, Galstyan GR, et al. Long-term prognosis of diabetic patients with critical limb ischemia after endovascular therapy. Problems of Endocrinology. 2016;62(5):28-29. (In Russ.) doi: https://doi.org/10.14341/probl201662528-29

7. Ayubova NL, Bondarenko ON, Galstyan GR, et al. Clinical outcomes of lower limb peripheral vascular disease after endovascular intervention in patients with diabetes mellitus, critical limb ischemia and chronic kidney disease. Diabetes mellitus. 2013;16(4):85-94. (In Russ.) doi: https://doi.org/10.14341/DM2013485-94

8. Jeyaraman M, Nagarajan S, Maffulli N, et al. Stem Cell Therapy in Critical Limb Ischemia. Cureus. 2023;15(7):e41772. doi: https://doi.org/10.7759/cureus.41772

9. Spreen MI, Gremmels H, Teraa M, et al. Diabetes Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia: Pooled Data From Two Randomized Controlled Trials. Diabetes Care. 2016;39(11):2058-2064. doi: https://doi.org/10.2337/dc16-0850

10. High lower limb amputations in gangren. Russsian Consensus. Wounds and wound infections. The prof. B.M. Kostyuchenok journal. 2020;7(4):6-55. (In Russ.) doi: https://doi.org/10.25199/2408-9613-2020-7-4-6-55

11. RuemenapfG, Morbach S, Sigl M. Therapeutic Alternatives in Diabetic Foot Patients without an Option for Revascularization: A Narrative Review. J Clin Med. 2022. doi: https://doi.org/10.3390/jcm11082155

12. Shi H, Yuan X, Fan W, Yang X, Liu G. Stem Cell Therapy for Diabetic Foot: An Umbrella Review of Systematic Reviews and Meta-Analyses. Adv Wound Care. 2024;13(5):201-216. doi: https://doi.org/10.1089/wound.2023.0136

13. Lozano Navarro LV, Chen X, Giratá Viviescas LT, et al. Mesenchymal stem cells for critical limb ischemia: their function, mechanism, and therapeutic potential. Stem Cell Res Ther. 2022;13(1):345. doi: https://doi.org/10.1186/s13287-022-03043-3

14. Zhi K, Gao Z, Bai J, et al. Application of adipose-derived stem cells in critical limb ischemia. Front Biosci (Landmark Ed). 2014;19(5):768-76. doi: https://doi.org/10.2741/4243

15. Teraa M, Gremmels H, Wijnand JGJ, Verhaar MC. Cell Therapy for Chronic Limb-Threatening Ischemia: Current Evidence and Future Directions. Stem Cells Transl Med. 2018;7(12):842-846. doi: https://doi.org/10.1002/sctm.18-0025

16. Beegle JR, Magner NL, Kalomoiris S, et al. Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia. Mol Ther Methods Clin Dev. 2016;3:16053. doi: https://doi.org/10.1038/mtm.2016.53

17. Maksimova N, Krasheninnikov M, Zhang Y, et al. Early passage autologous mesenchymal stromal cells accelerate diabetic wound re-epithelialization: A clinical case study. Cytotherapy. 2017;19(12):1548-1550. doi: https://doi.org/10.1016/j.jcyt.2017.08.017.

18. Krasilnikova OA, Baranovskii DS, Lyundup AV, et al. Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action. Stem Cell Rev Rep. 2022;18(6):1974-1985. doi: https://doi.org/10.1007/s12015-022-10379-z

19. Soria-Juan B, Escacena N, Capilla-González V, et al. Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus. Front Immunol. 2019;10:1151. doi: https://doi.org/10.3389/fimmu.2019.01151

20. Niebergall-Roth E, Frank NY, Ganss C, et al. Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine. International Journal of Molecular Sciences. 2023; 24(1):66. doi: https://doi.org/10.3390/ijms24010066.

21. Gupta PK, Shivashankar P, Rajkumar M, et al. Label extension, single-arm, phase III study shows efficacy and safety of stempeucel® in patients with critical limb ischemia due to atherosclerotic peripheral arterial disease. Stem Cell Res Ther. 2023;14(1):60. doi: https://doi.org/10.1186/s13287-023-03292-w

22. Lu D, Chen B, Liang Z, 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 Res Clin Pract. 2011;92(1):26-36. doi: https://doi.org/10.1016/j.diabres.2010.12.010

23. Gupta PK, Chullikana A, Parakh R, et al. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013;11:143. doi: https://doi.org/10.1186/1479-5876-11-143

24. Ruiz-Salmeron R, de la Cuesta-Diaz A, Constantino-Bermejo M, et al. Angiographic demonstration of neoangiogenesis after intra-arterial infusion of autologous bone marrow mononuclear cells in diabetic patients with critical limb ischemia. Cell Transplant. 2011;20(10):1629-39. doi: https://doi.org/10.3727/096368910X0177

25. Shirbaghaee Z, Heidari Keshel S, Rasouli M, et al. Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI). Stem Cell Res Ther. 2023;14(1):174. doi: https://doi.org/10.1186/s13287-023-03390-9

26. Mohamed SA, Howard L, McInerney V, et al. Autologous bone marrow mesenchymal stromal cell therapy for «no-option» critical limb ischemia is limited by karyotype abnormalities. Cytotherapy. 2020;22(6):313-321. doi: https://doi.org/10.1016/j.jcyt.2020.02.007

27. Schiavetta A, Maione C, Botti C, et al. A phase II trial of autologous transplantation of bone marrow stem cells for critical limb ischemia: results of the Naples and Pietra Ligure Evaluation of Stem Cells study. Stem Cells Transl Med. 2012;1(7):572-8. doi: https://doi.org/10.5966/sctm.2012-0021

28. Klepanec A, Mistrik M, Altaner C, et al. No difference in intra-arterial and intramuscular delivery of autologous bone marrow cells in patients with advanced critical limb ischemia. Cell Transplant. 2012;21(9):1909-18. doi: https://doi.org/10.3727/096368912X636948

29. Madaric J, Klepanec A, Valachovicova M, et al. Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia. Stem Cell Res Ther. 2016;7(1):116. doi: https://doi.org/10.1186/s13287-016-0379-z

30. Powell RJ, Comerota AJ, Berceli SA, et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg. 2011;54(4):1032-41. doi: https://doi.org/10.1016/j.jvs.2011.04.006

31. Arango-Rodríguez ML, Mateus LC, Sossa CL, et al. novel therapeutic management for diabetes patients with chronic limb-threatening ischemia: comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly-derived mesenchymal stem cells. Stem Cell Res Ther. 2023;14(1):221. doi: https://doi.org/10.1186/s13287-023-03427-z

32. Lu D, Jiang Y, Deng W, et al. Long-Term Outcomes of BMMSC Compared with BMMNC for Treatment of Critical Limb Ischemia and Foot Ulcer in Patients with Diabetes. Cell Transplant. 2019;28(5):645-652. doi: https://doi.org/10.1177/0963689719835177

33. Tournois C, Pignon B, Sevestre MA, et al. Cell therapy in critical limb ischemia: A comprehensive analysis of two cell therapy products. Cytotherapy. 2017;19(2):299-310. doi: https://doi.org/10.1016/j.jcyt.2016.10.013

34. Yusoff FM, Kajikawa M, Matsui S, et al. Review of the Long-term Effects of Autologous Bone-Marrow Mononuclear Cell Implantation on Clinical Outcomes in Patients with Critical Limb Ischemia. Sci Rep. 2019;9(1):7711. doi: https://doi.org/10.1038/s41598-019-44176-5

35. Liu H, Fang Y, Pan T, et al. Autologous Stem Cells Transplantation for No-Option Angiitis-Induced Critical Limb Ischemia: Recurrence and New Lesion. Stem Cells Transl Med. 2022;11(5):504-512. doi: https://doi.org/10.1093/stcltm/szac017

36. Li M, Zhou H, Jin X, et al. Autologous bone marrow mononuclear cells transplant in patients with critical leg ischemia: preliminary clinical results. Exp Clin Transplant. 2013;11(5):435-9. doi: https://doi.org/10.6002/ect.2012.0129

37. Panunzi A, Madotto F, Sangalli E, et al. Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers. Cardiovasc Diabetol. 2022;21(1):196. doi: https://doi.org/10.1186/s12933-022-01629-y

38. Fang G, Jiang X, Fang Y, et al. Autologous peripheral blood-derived stem cells transplantation for treatment of no-option angiitis-induced critical limb ischemia: 10-year management experience. Stem Cell Res Ther. 2020;11(1):458. doi: https://doi.org/10.1186/s13287-020-01981-4

39. Liu H, Pan T, Fang Y, et al. 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. Stem Cells Transl Med. 2021;10(5):647-659. doi: https://doi.org/10.1002/sctm.20-0033

40. Madaric J, Valachovicova M, Paulis L, et al. Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia. Stem Cell Res Ther. 2017;8(1):165. doi: https://doi.org/10.1186/s13287-017-0622-2

41. Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circ Res. 2017;120(8):1326-1340. doi: https://doi.org/10.1161/CIRCRESAHA.116.309045

42. Benoit E, O’Donnell TF, Patel AN. Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transplant. 2013;22(3):545-62. doi: https://doi.org/10.3727/096368912X636777

43. Bondarenko ON, Ayubova NL, Galstyan GR, Dedov II. Preoperative visualization of peripheral arteries with duplex ultrasonography in patients with diabetes mellitus and critical limb ischemia. Diabetes mellitus. 2013;16(2):52-61. (In Russ.) doi: https://doi.org/10.14341/2072-0351-3756

44. Bondarenko ON, Ayubova NL, Galstyan GR, Dedov II. Transcutaneous oximetry monitoring in patients with type 2 diabetes mellitus and critical limb ischemia. Diabetes mellitus. 2013;16(1):33-42. (In Russ.) doi: https://doi.org/10.14341/2072-0351-3594

45. Dzhemilova ZN, Bondarenko ON, Galstyan GR. Diagnostic value of ankle peak systolic velocity in diabetic patients with critical limb ischemia. Diabetes mellitus. 2019;22(2):131-140. (In Russ.) doi: https://doi.org/10.14341/DM9776

46. Jaluvka F, Ihnat P, Madaric J, et al. Current Status of Cell-Based Therapy in Patients with Critical Limb Ischemia. Int J Mol Sci. 2020;21(23):8999. doi: https://doi.org/10.3390/ijms21238999

47. Beltrán-Camacho L, Rojas-Torres M, Durán-Ruiz MC. Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia. Int J Mol Sci. 2021;22(5):2335. doi: https://doi.org/10.3390/ijms22052335