Evaluation of bone marrow-derived cell-based therapies in the hindlimb ischaemia model: a protocol for a systematic review and meta-analysis.

Objective: Bone marrow(BM)-derived cell-based therapies for critical limb ischamia showed less clinical benefit than expected. While this might be due to patient-specific factors, it remains possible that important details were lost in the bench-to-clinic translation. The hindlimb ischaemia model is the golden standard to evaluate cell-based therapies aimed at promoting neovascularisation. To inform future trial design and identify potential knowledge gaps, we propose a systematic review and meta-analysis of preclinical evidence to assess the efficacy of BM-derived cell administration in restoring relative perfusion in the hind limb model and identify determinants of therapeutic efficacy.

Search strategy: PubMed and EMBASE were searched for prospective studies in which the hindlimb ischaemia model was used to assess BM-derived therapies.

Screening and annotation: Studies with an outcome measure related to relative perfusion of the hindlimb will be included. Study characteristics which include model-related factors as well as details on BM therapy will be extracted.

Data management and reporting: For the primary analysis, a random effects model will be constructed using the mean difference calculated from the maximum relative perfusion for each study arm in each study. A separate model will be constructed using the relative perfusion at the latest time point in each study. We will also assess the risk of bias using the SYRCLE tool for internal validity. Subgroup analysis will be performed on animal characteristics, administration route, dose and cell characteristics such as the cell donor.

Prospero registration number: This protocol has been registered at PROSPERO (CRD2021226592).