23 Perfusion measured with ABI and TcPO2 at baseline and after 6 months increased in patients with consecutive limb salvage (ABI 0.33±0.18 to 0.46±0.15, TcPO2 12±12 mmHg to 25±15 mmHg) but did not change in patients eventually undergoing major amputation. Clinically most important, patients who did not require amputation saw an improvement in mean Rutherford category from a baseline of 4.9 to 3.3 at 6 months (P = 0.0001). Furthermore, analgesics consumption
was reduced by 62%.23 In BONMOT-1 and the subsequent placebo-controlled, double-blind study (BONMOT-CLI), BM-MNC injections were placed along the axial Inhibitors,research,lifescience,medical line of the occluded native arteries; this maximizes efficacy because the density of preformed collaterals is highest in parallel orientation to the axial arteries, which is the location for collateral growth. In BONMOT-1 and BONMOT-CLI, the number of injections was also increased corresponding to the length of the arterial occlusion, from 40 injections for infra-popliteal disease only to 60 injections when femoral, popliteal, Inhibitors,research,lifescience,medical and infra-popliteal disease was present. In the RESTORE–CLI trial of 77 patients, Ixmyelocel-T treatment led to a significantly prolonged first occurrence of treatment failure (e.g., major amputation of injected leg, all-cause mortality, Inhibitors,research,lifescience,medical doubling of total wound surface area from baseline, de novo gangrene) (P = 0.0032, logrank test). Amputation-free
survival (major amputation of injected leg; all-cause mortality) saw a 32% reduction, but this was not statistically significant (P = 0.3). Treatment
effect in post hoc analyses of patients with baseline wounds was more pronounced.24 In the interim Inhibitors,research,lifescience,medical analysis of the HARVEST trial, the BMAC (bone marrow aspirate concentrate) group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI when compared with controls.25 INTRA-ARTERIAL BM-MNC: In the Inhibitors,research,lifescience,medical PROVASA (Intra-arterial Progenitor Cell Transplantation of Bone Marrow Mononuclear Cells for Induction of Neovascularization in Patients With Peripheral Arterial Occlusive Disease) study, 40 patients were randomized to intra-arterial delivery of either BM-MNC or placebo.26 There was a significant improvement in VX-680 price ulcer healing and significant rest pain reduction in subjects treated with BM-MNC versus placebo. The trial also demonstrated that multiple treatments of BM-MNC were associated with significantly greater improvements in ulcer healing and rest pain than a single treatment. However, patients with Rutherford class ischemia (Sunitinib cell line gangrene or major tissue loss) at baseline did not respond to therapy. The major predictors of successful ulcer healing were total cell number delivered, repeated cell administration, and greater cell functionality measured by in vitro assays. INTRA-ARTERIAL AND INTRAMUSCULAR BM-MNC: Combined intra-arterial (IA) plus intramuscular (IM) BMC delivery may be more effective than exclusive intramuscular injections.