Therapeutic Angiogenesis by Autologous Bone Marrow Cell Implantation for Refractory Chronic Peripheral Arterial Disease Using Assessment of Neovascularization by 99mTc-Tetrofosmin (TF) Perfusion Scintigraphy

Abstract

We investigated efficacy and safety of implantation of autologous bone marrow mononuclear cells plus platelets, including endothelial progenitor cells (EPCs), for recovering refractory chronic peripheral arterial disease (PAD) using visual and quantitative analyses by Tc-tetrofosmin (TF) perfusion scintigraphy, and also investigated various quantitative assessments objectively. We performed 12 consecutive cases and 19 limbs and hands with severe chronic PAD that were almost Fontaine class IV (11/12 cases, about 92%) in this trial. This treatment was very effective in relieving severe pain of PAD, especially for Buerger's disease. We used a visual analog scale (VAS) for measurement of pain level. The maximum pain level before implantation was 66.5 ± 5.0 mm, and it decreased to 12.1 ± 2.2 mm after implantation ( p < 0.001). Rest pain in legs and fingers was resolved in 11 cases (11/12 cases, 92%). All patients could measure pain-free walking time on a treadmill, which improved remarkably (140 ± 53 s before implantation vs. 451 ± 74 s after implantation, p = 0.034). Resting ankle brachial pressure index (ABI) in legs implanted with bone marrow mononuclear cells was also improved (0.65 ± 0.08 before implantation vs. 0.73 ± 0.07 after implantation, p = 0.055). According to 99m Tc-TF perfusion scintigraphy, the proximal area (region from knee to ankle) was 1.32 ± 0.10 before implantation versus 1.56 ± 0.11 after implantation ( p = 0.007). Tc-TF perfusion scintigraphy in the distal area (region from ankle to end of toes, or from wrist to end of fingers) was 0.79 ± 0.06 before implantation versus 0.83 ± 0.06 after implantation ( p = 0.29). Ischemic legs and hands that were injected showed increased perfusion blood flow. Tc-TF perfusion scintigraphy was effective to estimate visual and quantitative analysis of collateral vessels in neovascularization. We were successful with this new treatment for the most severe, chronic PAD that was not curable by any of the current treatments. Thus, this therapeutic angiogenesis could be a new strategy for saving severe ischemic limbs and hands.

Bone marrow mononuclear cells versus G-CSF-mobilized peripheral blood mononuclear cells for treatment of lower limb ASO: pooled analysis for long-term prognosis

“…21 Although BMMNC or M-PBMNC intramuscular implantation has been used most often, both therapies have some risk: to collect about 500 mL of BMMNC, general anesthesia of about 4 h duration is necessary, and to collect PBMNC, about 3 h of apheresis with G-CSF treatment is required. [2][3][4][5][6][7][8][9][10][11][14][15][16][17][18] In a first cell-therapy trial, results of which were published in 2002, 22 ASO patients (44 limbs) were implanted with either BMMNC or PBMNC. 2 At 6 months after implantation, both therapies yielded improvements in terms of rest pain, ABI and transcutaneous oxygen pressure, but the clinical outcomes for BMMNC were significantly better than those for PBMNC.…”

Stem Cell Transplantation for the Treatment of Peripheral Arterial Disease

“…Specifically, there was an increase in pain-free walking time (from 140±53 s to 451±74 s, p=0.034), ABI (from 0.65±0.08 to 0.73±0.07, p=0.055) and perfusion index (proximal area from 1.32±0.10 to 1.56±0.11, p=0.007) [56]. Perfusion scintigraphy could identify new collaterals after BMMNC transplantation [56]. The second work showed increased ABI (from 0.54±0.47 to 0.61±0.50, p<0.05) and TcPO 2 (28.4±15.4 mmHg to 37.1±24.4 mmHg) following BMNNC transplantation in 8 patients with PAD [57].…”

“…The beneficial effect of stem cell therapy has been evaluated by diverse outcomes. These include alleviation of pain [19,23,46,47,51,63,69], increased walking distance [19,20,23,47,51,53,55,56,63,68,69,77,78,80], improved ABI and TcPO 2 [19,20,23,47,53,55,56,50,63,68,69,73,74,77,78,80,81], but also hard endpoints, notably ulcer healing [19,20,47,49,63,69,74,78,80], quality of life [72] and limb salvage [20,…”

“…The first work showed that these cells improved blood flow in 12 patients with PAD staged Fontaine IV [56]. Specifically, there was an increase in pain-free walking time (from 140±53 s to 451±74 s, p=0.034), ABI (from 0.65±0.08 to 0.73±0.07, p=0.055) and perfusion index (proximal area from 1.32±0.10 to 1.56±0.11, p=0.007) [56]. Perfusion scintigraphy could identify new collaterals after BMMNC transplantation [56].…”

Recent Innovation in Pretreatment for Skin Grafts Using Regenerative Medicine in the East

“…Iba et al (2002) demonstrated that implantation of Peripheral blood mononuclear cells and platelets into ischemic limbs effectively induced collateral vessel formation using rat models, suggesting that this cell therapy is useful for therapeutic angiogenesis. Some reports indicated the efficacy and feasibility of the clinical use of cell therapy (TateishiYuyama et al, 2002;Kajiguchi et al, 2007;Matoba et al, 2008;Miyamoto et al, 2004). Therapeutic angiogenesis using cell transplantation (TACT) is a treatment strategy for nooption patients with CLI in Japan.…”