title: Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia.
abstract: OBJECTIVE
  Recent evidence indicates that bone marrow mononuclear cells (BMC) promote collateral vessel formation in patients with severe peripheral arterial disease (PAD). However, aspects concerning optimal administration mode, durability and long-term safety require consideration. Combined intra-arterial (IA) plus intramuscular (IM) BMC delivery may be more effective than exclusive intramuscular injections. The aim of this study was to evaluate feasibility, safety and effect of exclusive IM versus combined IM+IA delivery of autologous BMC in patients who were not candidates for surgical or endovascular treatment.
  
  
  METHODS
  Twenty-seven patients were treated with either combined IA+IM (N=12) or sole IM (N=15) administration of autologous BMC. Efficacy was assessed after 1, 6 and 12 months. Limb salvage, pain-free walking distance, ankle-brachial pressure index (ABI) and pain scores were evaluated.
  
  
  RESULTS
  There were no adverse reactions related to injection of the cells. Three patients died within the first year of follow-up due to non-procedure related causes. Two patients in the IA+IM group required limb amputation because of ongoing critical ischemia versus 7 patients in the IM group (P=0.17). BMC treatment in the remaining patients resulted in a significant and sustained (>12 months) improvement. Pain-free walking distance improved from 81+/-56 meters at baseline to 257+/-126 meters at t=6 months (P=0.0002). Mean ABI increased 23% after 6 months (P=0.01) and pain score reduced for up to 50% as shown by Brief Pain Inventory (P=0.001).
  
  
  CONCLUSIONS
  Both IM and combined IM/IA delivery of autologous BMC are safe, and result in relevant and sustained improvement in a considerable proportion of patients with severe PAD who are not amenable for conventional treatment.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. r.b.m.van_tongeren@lumc.nl
authors.forename: R B
authors.initials: RB
authors.lastname: Van Tongeren
authors.forename: J F
authors.initials: JF
authors.lastname: Hamming
authors.forename: W E
authors.initials: WE
authors.lastname: Fibbe
authors.forename: V
authors.initials: V
authors.lastname: Van Weel
authors.forename: S J G C
authors.initials: SJ
authors.lastname: Frerichs
authors.forename: A M
authors.initials: AM
authors.lastname: Stiggelbout
authors.forename: J H
authors.initials: JH
authors.lastname: Van Bockel
authors.forename: J H
authors.initials: JH
authors.lastname: Lindeman
mesh_terms: D000328:Adult; D000368:Aged; D000671:Amputation, Surgical; D000842:Ankle / Q000098:blood supply; D001794:Blood Pressure; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D001916:Brachial Artery / Q000503:physiopathology; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D007273:Injections, Intramuscular; D007383:Intermittent Claudication / Q000209:etiology / Q000503:physiopathology; D007511:Ischemia / Q000150:complications / Q000401:mortality / Q000503:physiopathology / Q000601:surgery*; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D023821:Limb Salvage; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D020127:Recovery of Function; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D016138:Walking