The results of several published studies which were carried out on animal models have shown a positive clinical effect of bone marrow mononuclear cell application in order to treat ischemic diseases by producing collateral vessels:
Kamihata H, Matsubara H, Nishiue T, FujiyamaS, tsutsumiY, Ozone R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T. Implantation of bone marrowmononuclearcells into ischemic myocardium enhances collateral perfuzion and regional function via side supply of angioblasts, angiogenic ligans,andcytokines. Circ 2001;104:1046-1052
Shintani S, Murohara T, Ikeda H, UenoT, Sasaki K, Duan J, Imaizumi T. Augmentation of postnatal neovascularization with autologous bone marrow transplantation, Circ. 2001; 103:897-895
The subjects of the study were both models of heart ischemia:
Kajstura J, Rota M, Whang B, Cascapera S, Hosoda T, Bearzi C, Nurznska D, KasaharaH, Zias E, Bonafe M, Nadal-Ginard B, Torella D, Nascimbene A, Quaini F, Urbanek K, Leri A, Anversa P Bone marrow cells differentiate in cardiac cell lineages after infarction independently ofcell fusion; Circ Res. 2005; 96: 127-137
– and backlimb ischemia in mice.
These studies have proven the safety and effectivity of this cell composition application. Tateishi-Yuyama considered the effect of cell cytokines release applied by injection into ischemic tissues. He found that this procedure does not result in tissue damage or in cell development into other, less desired tissue types such as bones or scarred tissue.
Tareishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T, Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bone-marrowcells: a pilot study and a randomized controlled trial. The Lancet; 2002; 360: 427-435
1. Grant project IGA MZ n. 8047-3/2004
There was a grant project in General Teaching Hospital (VFN) in the Czech Republic called Therapeutic vasculogenesis in CLI patients. Standard collection by bone marrow puncture from lumbar bone scapula was used for the isolation of stem cells, usually in general anesthesia. With the sampling volume of the collected portions kept the same, maximum of 500 ml of bone blood was collected which is the same amount as is usually collected at blood establishments from blood donors and which is not an indication for transfusion.
The amount of adult endothelial cells, monocytes and endothelial precursors was evaluated with flow cytometry using signs CD14 (monocytes), CD133 and CD34 (endothelial precursor, CD117 (immature progenitor cells) and CD146 (adult endothelial cells).
The most commonly used cells for implantation are monocytic CD34+ cells. The amount of cells positive for endothelial markers was expressed in percentage of cells simultaneously positive for CD34 (Picture 5). Inter-arterial application with a perfusor into an artery after performing puncture angiography is used to return the cells. The implantation effect was monitored after 3, 6, 12 months when the defect healing, claudication test, joint pressure, transcutaneous oxygen tension, life quality according to the questionnaire were evaluated. From the methods displayed, angiographic examination was performed to objectify the state of artery course. Especially in young patients, the method of autologous application of stem cells seemed very promising.
The vessel wall’s ability to react to application of growths factors or stem cells indicates that it is a very promising therapeutic method to eliminate or reduce manifests of tissue ischemia (whether it was caused by a vessel injury, inflammation or progression of atherosclerotic process). However before it is implemented into regular practice, there is a need to carry out many researches on regulation of growth of blood vessels in adult tissues and on various therapeutic use of these acknowledgements, but also other major studies with careful selection of target group of patients, knowledge of pharmacokinetics, objectification and monitoring of effects, respectively side effects of this treatment.
2. Cell Therapy, a New Standard in Management of Chronic Critical Limb Ischemia and Foot Ulcer. Procházka V, et al. Cell Transplantation, Vol. 19, pp. 1413–1424 (2010)
96 patients with CLI and a limb defect (foot ulcer) in total were randomized into study Groups I and II. Patients in Group I (N=42, 36 men, 6 women, 66,2 ± 1,6 years) underwent local treatment with ABMSC while the patients in Group II (n=54, control subjects of evaluation, 42 men, 12 women, 64,1 ± 8,6 years) were treated with standard methods.
The result of the treatment with ABMSC was saving the limb in 79 % of patients suffering from critical limb ischemia related to occurrence of leg defect. In the remaining 21 % of patients, lymphopenia and thrombocytopenia were detected as potential causative factors indicating that at least a partial correction with patelet replacements can represent an advantage for the patient.
3. No Difference in Intra-arterial and Intra-muscular Delivery of Autologous Bone Marrow Cells. Klepanec A., et al. Cell Transplantation, Vol. 21, pp. 1909–1918 (2012)
41 patients with critical limb ischemia (category 5 and 6 according to Rutherford) who were not indicated for revascularization treatment were selected for the study (average age = 66 ± 10 years, 35 men). The patients were randomized into the treatment groups with 40 ml BMC administered through IM (n=21) or selective IA infusion (n=20). The primary end factors were preservation of the limb and healing of the defect. The secondary factors were the changes in values of transcutaneous oxygen pressure (tcpO2), life quality questionnaire (EQ5D), application binary interface (ABI) and pain evaluation according to a scale (0-10). Patients whose limbs were preserved and there were evident signs of healing, were assumed to respond to the treatment with BMC.
Both the intramuscular and intraarterial way of application of autologous cells represent effective treatment strategies in patients suffering from CLI. Higher concentration of CD34+ cells and lower amount of inflammation complications are associated with better clinical response to the treatment.
4. Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Non-Randomized, and Non-Controlled Studies. Circ Res. 2017 Jan 17. pii: CIRCRESAHA.116.309045.
From meta-analysis in which 2.334 patients were involved followed:
- Intramuscular implantation of bone marrow core cells concentrates or mobilized peripheral blood mononuclear cells concentrate should be considered as standard technique.
- Cell therapy of CLI has a potential to positively change natural fate of the ill and therefore most importantly reduce the necessity of amputation.
- The cell therapy cannot be expected to positively influence mortality of the patients because it has other causes (even though they can be connected to CLI).
- The cell treatment of CLI is safe.
- Primary analysis RCT (randomized controlled trials) with including all studies has shown that cell therapy reduces the risk of amputation by 50 %, respectively yearly frequency of amputations in the cell therapy Group was 50 % lower compared to controls (yearly frequency of amputations in control group was 70,8 %, it was 27,2 % in cell therapy group, p<0,0005).
- Primary analysis RCT (randomized controlled trials) with including all studies has shown that cell therapy increases the probability of successful healing of chronical trophic defects in CLI by 67 %.
- Primary analysis RCT (randomized controlled trials) with including all studies has shown that cell therapy prolongs interval to amputation by 33 %.
- Cell therapy of CLI should become a standard treatment in patients with progressive state of CLI, in whom it is not possible to perform revascularization.
5. Other important case studies
- Bone Marrow Aspirate Concentrate in Critical Limb Ischemia: Results of an Abridged Prospective Randomized Pivotal Trial in No Option CLI
- Safety and efficacy of cell-based therapy on critical limb ischemia: A meta-analysis
- Effectiveness of Autologous Stem Cell Therapy for the Treatment of Lower Extremity Ulcers
- Autologous bone marrow mononuclear cell therapy for critical limb ischemia is effective and durable
- Cell Therapy for Critical Limb Ischemia: A Meta-Analysis of Randomized Controlled Trials
- Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia
- Administration of Autologous Bone Marrow Cells for Limb Salvage in Patients With Critical Limb Ischemia: Results of the Multicenter Phase III MOBILE Trial
- Administration of ALDH Bright Cells to Patients With Intermittent Claudication: The NHLBI CCTRN PACE Trial
- Cell therapy in critical limb ischemia: A comprehensive analysis of two cell therapy products
- Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials