title: Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury: Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis.
abstract: Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8-29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3-5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI.
authors.affiliation: Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany.|Department of Neurosurgery, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Ralf
authors.identifier: 0000-0001-7886-3314
authors.initials: R
authors.lastname: Watzlawick
authors.affiliation: Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Julian
authors.identifier: 0000-0001-6456-7135
authors.initials: J
authors.lastname: Rind
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.|Stroke Division, Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Sena
authors.affiliation: Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, United States of America.
authors.forename: Benedikt
authors.identifier: 0000-0003-3362-9780
authors.initials: B
authors.lastname: Brommer
authors.affiliation: Center for Stroke Research Berlin, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Tian
authors.identifier: 0000-0001-8059-0677
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Center for Stroke Research Berlin, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Marcel A
authors.identifier: 0000-0001-6832-9599
authors.initials: MA
authors.lastname: Kopp
authors.affiliation: Center for Stroke Research Berlin, Charité-Universitätsmedizin, Berlin, Germany.|German Center for Neurodegenerative Diseases (DZNE) Berlin site, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Malcolm R
authors.identifier: 0000-0001-9187-9839
authors.initials: MR
authors.lastname: Macleod
authors.affiliation: Stroke Division, Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.|University of Tasmania, School of Medicine, Faculty of Health, Medical Sciences Precinct, Hobart, Tasmania, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Howells
authors.affiliation: Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany.|Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, United States of America.|Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, United States of America.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schwab
mesh_terms: D000818:Animals; D017690:Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D004195:Disease Models, Animal; D009830:Olfactory Bulb / Q000166:cytology* / Q000637:transplantation; D017594:Publication Bias; D013119:Spinal Cord Injuries / Q000628:therapy*; D016896:Treatment Outcome