***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: OBJECTIVES Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia ( CLI ) of the lower extremities and no other established treatment options . This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells ( TRCs ) . METHODS A prospect i ve , r and omized double-blinded , placebo controlled , multicenter study ( RESTORE-CLI ) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization . Enrollment of 86 patients began in April 2007 and ended in February 2010 . For the prospect ively planned interim analysis , conducted in February 2010 , 33 patients had the opportunity to complete the trial ( 12 months of follow-up ) , and 46 patients had completed at least 6 months of follow-up . The interim analysis included analysis of both patient population s. An independent physician performed the bone marrow or sham control aspiration . The aspirate was processed in a closed , automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells . An average of 136 ± 41 × 10(6 ) total viable cells or electrolyte ( control ) solution were injected into 20 sites in the ischemic lower extremity . The primary end point was safety as evaluated by adverse events , and serious adverse events as assessed at multiple follow-up time points . Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure ( defined as any of the following : major amputation , death , de novo gangrene , or doubling of wound size ) , as well as major amputation rate and measures of wound healing . RESULTS There was no difference in adverse or serious adverse events between the two groups . Statistical analysis revealed a significant increase in time to treatment failure ( log-rank test , P = .0053 ) and amputation-free survival in patients receiving TRC treatment , ( log-rank test , P = .038 ) . Major amputation occurred in 19 % of TRC-treated patients compared to 43 % of controls ( P = .14 , Fisher exact test ) . There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months . CONCLUSIONS Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options Background —Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality . There is no effective pharmacological therapy available . Injection of autologous bone marrow-derived mononuclear cells ( BM-MNC ) is a promising therapeutic option in patients with critical limb ischemia , but double-blind , r and omized trials are lacking . Methods and Results —Forty patients with critical limb ischemia were included in a multicenter , phase II , double-blind , r and omized-start trial to receive either intraarterial administration of BM-MNC or placebo followed by active treatment with BM-MNC ( open label ) after 3 months . Intraarterial administration of BM-MNC did not significantly increase ankle-brachial index and , thus , the trial missed its primary end point . However , cell therapy was associated with significantly improved ulcer healing ( ulcer area , 3.2±4.7 cm2 to 1.89±3.5 cm2 [ P=0.014 ] versus placebo , 2.92±3.5 cm2 to 2.89±4.1 cm2 [ P=0.5 ] ) and reduced rest pain ( 5.2±1.8 to 2.2±1.3 [ P=0.009 ] versus placebo , 4.5±2.4 to 3.9±2.6 [ P=0.3 ] ) within 3 months . Limb salvage and amputation-free survival rates did not differ between the groups . Repeated BM-MNC administration and higher BM-MNC numbers and functionality were the only independent predictors of improved ulcer healing . Ulcer healing induced by repeated BM-MNC administration significantly correlated with limb salvage ( r=0.8 ; P<0.001 ) . Conclusions —Intraarterial administration of BM-MNC is safe and feasible and accelerates wound healing in patients without extensive gangrene and impending amputation . These exploratory findings of this pilot trial need to be confirmed in a larger r and omized trial in patients with critical limb ischemia and stable ulcers . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00282646 Background Peripheral vascular disease of the lower extremities comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia ( CLI ) . Bone marrow derived Mesenchymal Stem Cells ( BM- MSCs ) may ameliorate the consequences of CLI due to their combinatorial potential for inducing angiogenesis and immunomodulatory environment in situ . The primary objective was to determine the safety of BM- MSCs in patients with CLI . Methods Prospect i ve , double blind r and omized placebo controlled multi-center study was conducted in patients with established CLI as per Rutherford classification in category II-4 , III-5 , or III-6 with infra-inguinal arterial occlusive disease and were not suitable for or had failed revascularization treatment . The primary end point was incidence of treatment – related adverse events ( AE ) . Exploratory efficacy end points were improvement in rest pain , increase in Ankle Brachial Pressure Index ( ABPI ) , ankle pressure , healing of ulcers , and amputation rates .  Twenty patients ( BM-MSC : Placebo = 1:1 ) were administered with allogeneic BM-MSCs at a dose of 2 million cells/kg or placebo ( PlasmaLyte A ) at the gastrocnemius muscle of the ischemic limb . Results Improvement was observed in the rest pain scores in both the arms . Significant increase in ABPI and ankle pressure was seen in BM-MSC arm compared to the placebo group . Incidence of AEs in the BM-MSC arm was 13 vs. 45 in the placebo arm where as serious adverse events ( SAE ) were similar in both the arms ( 5 in BM-MSC and 4 in the placebo group ) . SAEs result ed in death , infected gangrene , amputations in these patients . It was observed that the SAEs were related to disease progression and not related to stem cells . Conclusion BM-MSCs are safe when injected IM at a dose of 2 million cells/kg body weight . Few efficacy parameters such as ABPI and ankle pressure showed positive trend warranting further studies .Trial registration NIH website ( http://www . clinical trials.gov/ct2/show/NCT00883870 BACKGROUND AIMS CD133 + cells confer angiogenic potential and may be beneficial for the treatment of critical limb ischemia ( CLI ) . However , patient selection , blinding methods and end points for clinical trials are challenging . We hypothesized that bilateral intramuscular administration of cytokine-mobilized CD133 + cells in ambulatory patients with refractory CLI would be feasible and safe . METHODS In this double-blind , r and omized sham-controlled trial , subjects received subcutaneous injections of granulocyte colony-stimulating factor ( 10 μg/kg per day ) for 5 days , followed by leukapheresis , and intramuscular administration of 50 - 400 million sorted CD133 + cells delivered into both legs . Control subjects received normal saline injections , sham leukapheresis and intramuscular injection of placebo buffered solution . Subjects were followed for 1 year . An aliquot of CD133 + cells was collected from each subject to test for genes associated with cell senescence . RESULTS Seventy subjects were screened , of whom 10 were eligible . Subject enrollment was suspended because of a high rate of mobilization failure in subjects r and omly assigned to treatment . Of 10 subjects enrolled ( 7 r and omly assigned to treatment , 3 r and omly assigned to control ) , there were no differences in serious adverse events at 12 months , and blinding was preserved . There were non-significant trends toward improved amputation-free survival , 6-minute walk distance , walking impairment question naire and quality of life in subjects r and omly assigned to treatment . Successful CD133 + mobilizers expressed fewer senescence-associated genes compared with poor mobilizers . CONCLUSIONS Bilateral administration of autologous CD133 + cells in ambulatory CLI subjects was safe , and blinding was preserved . However , poor mobilization efficiency combined with high CD133 + senescence suggests futility in this approach Case studies suggest that bone marrow-derived stem cells may improve  chronic wound healing .  A prospect i ve , r and omized , clinical study was conducted to compare the rate of healing chronic lower limb wounds in patients with diabetes mellitus whose wounds were treated with topically applied and locally injected bone marrow-derived cells or whole blood ( control ) . Of the 48 patients participating in the study , 25 were r and omized to study treatment and 23 to control treatment . At baseline , no significant differences were observed between the two groups for patient age ( average for treatment group was 54 years , 3 months ; range 33 to 76 years and for the control group 58 years , 7 months ; range 28 to 69 years ) , comorbidity ( 82 % in the treatment group and 78 % in the control group had diabetes mellitus ) , ulcer history ( mean duration was 14.28 months in the treatment group and 10.21 months in the control group ; SD 0.28 ) , or baseline area ( mean was 65.32 cm2 in the treatment group and 48.83 cm2 in the control group ) . After obtaining informed consent , all wounds were surgically debrided . Wounds of study participants r and omized to the treatment group were injected and oversprayed with a total of 5 cc of autologous bone marrow-derived cells . Using a similar procedure , the wounds of patients r and omized to the control group were injected with 5 cc of autologous peripheral blood . All wounds were covered with saline-moistened gauze and cotton pads . Patients were followed for a maximum of 3 months . The average decrease in wound area at 2 weeks was 17.4 % ( 39.6 - 43.4 cm2 ) in the treatment group compared to 4.84 % ( 41.6 - 42.8 cm2 ) in the control group . After 12 weeks , the average decrease in wound area was 36.4 % ( SD 0.48 ) in the treatment group compared to 27.32 % ( SD 0.32 ) in the control group . No adverse events were observed . None of the patients complained of significant pain or discomfort following the procedure , no wound infections occurred , and all patients reported resumption of normal daily activity the day after the procedure . The results of this study show that a single application of autologous bone marrow-derived cells increases the rate of healing chronic lower extremity wounds in the early weeks of treatment . Additional studies to eluci date the treatment mode of action and optimal application frequency as well as comparisons between this and other treatment modalities are warranted BACKGROUND Pre clinical studies have established that implantation of bone marrow-mononuclear cells , including endothelial progenitor cells , into ischaemic limbs increases collateral vessel formation . We investigated efficacy and safety of autologous implantation of bone marrow-mononuclear cells in patients with ischaemic limbs because of peripheral arterial disease . METHODS We first did a pilot study , in which 25 patients ( group A ) with unilateral ischaemia of the leg were injected with bone marrow-mononuclear cells into the gastrocnemius of the ischaemic limb and with saline into the less ischaemic limb . We then recruited 22 patients ( group B ) with bilateral leg ischaemia , who were  r and omly injected with bone marrow-mononuclear cells in one leg and peripheral blood-mononuclear cells in the other as a control . Primary outcomes were safety and feasibility of treatment , based on ankle-brachial index ( ABI ) and rest pain , and analysis was per protocol . FINDINGS Two patients were excluded from group B after r and omisation . At 4 weeks in group B patients , ABI was significantly improved in legs injected with bone marrow-mononuclear cells compared with those injected with peripheral blood-mononuclear cells ( difference 0.09 [ 95 % CI 0.06 - 0.11 ] ; p<0.0001 ) . Similar improvements were seen for transcutaneous oxygen pressure ( 13 [ 9 - 17 ] ; p<0.0001 ) , rest pain ( -0.85 [ -1.6 to -0.12 ] ; p=0.025 ) , and pain-free walking time ( 1.2 [ 0.7 - 1.7 ] ; p=0.0001 ) . These improvements were sustained at 24 weeks . Similar improvements were seen in group A patients . Two patients in group A died after myocardial infa rct ion unrelated to treatment . INTERPRETATION Autologous implantation of bone marrow-mononuclear cells could be safe and effective for achievement of therapeutic angiogenesis , because of the natural ability of marrow cells to supply endothelial progenitor cells and to secrete various angiogenic factors or cytokines CONTEXT Few data document current cardiovascular ( CV ) event rates in stable patients with atherothromb 
    Output:
    
Conclusions Based on the review , autologous stem cell therapy may have a positive effect on “ no-option ” patients with PAD , but presented no significant improvement in major limb salvage .