The effect of bone marrow derived cell therapies on hind limb perfusion, A systematic review and meta-analysis.

Abstract

Administration of bone marrow (BM) derived cells to restore perfusion showed promising results in preclinical studies. However, clinical studies in chronic limb threatening ischemia (CLTI) demonstrated conflicting results. We conducted a systematic review and meta-analysis on preclinical studies to assess the efficacy of BM-derived cell administration in restoring relative perfusion in the hind limb ischemia model (HLI) and identify possible determinants of therapeutic efficacy. In vivo animal studies that assessed BM MNCs or BM MSCs in the HLI model and included relative perfusion as an outcome measure were identified using a systematic search in PubMed and EMBASE on January 10th, 2022. Risk of bias was assessed using SYRCLE's risk of bias tool. Study characteristics and outcome data on relative perfusion were extracted. A random effects meta-analysis was performed using the mean difference calculated from the maximum relative perfusion for each study arm in each study. 85 studies that comprised 1053 animals were included. Our meta-analysis shows a significant increase in perfusion in the affected limb after BM cell administration compared to the control (effect size 18.3 (95% CI 15.9 - 20.7, p<0.001). However, we observed a high heterogeneity between studies (I2 91%), which could not be explained by dose, species, cell type or administration route. The risk of several types of bias was unclear due to incomplete reporting. We also detected a substantial risk of publication bias in this evidence base. There is a beneficial effect of BM-derived cell therapy in animal models for CLTI. However, the certainty of the evidence is low according to GRADE assessment. Translational implementation of this method should take this into account.