Effectiveness of biomaterial-based combination strategies for spinal cord repair - a systematic review and meta-analysis of preclinical literature

Abstract

Study design: Systematic review and meta-analysis of preclinical literature.

Objectives: To assess the effects of biomaterial-based combination (BMC) strategies for the treatment of Spinal Cord Injury (SCI), the effects of individual biomaterials in the context of BMC strategies, and the factors influencing their efficacy. To assess the effects of different preclinical testing paradigms in BMC strategies.

Methods: We performed a systematic literature search of Embase, Web of Science and PubMed. All controlled preclinical studies describing an in vivo or in vitro model of SCI that tested a biomaterial in combination with at least one other regenerative strategy (cells, drugs, or both) were included. Two review authors conducted the study selection independently, extracted study characteristics independently and assessed study quality using a modified CAMARADES checklist. Effect size measures were combined using random-effects models and heterogeneity was explored using meta-regression with tau², I² and R² statistics. We tested for small-study effects using funnel plot-based methods.

Results: 134 publications were included, testing over 100 different BMC strategies. Overall, treatment with BMC therapies improved locomotor recovery by 25.3% (95% CI, 20.3-30.3; n = 102) and in vivo axonal regeneration by 1.6 SD (95% CI 1.2-2 SD; n = 117) in comparison with injury only controls.

Conclusion: BMC strategies improve locomotor outcomes after experimental SCI. Our comprehensive study highlights gaps in current knowledge and provides a foundation for the design of future experiments.

Fig. 1. Formats for biomaterials.

A A spinal cord injury with a large, irregularly shaped lesion site or cavity typical of a crush injury. This injury type is suited to injection of materials, including (counter clockwise, from upper right) a hydrogel loaded with microparticles, an amorphous hydrogel, a soft hydrogel, or a gel seeded with a defined cell type. B A smaller, well defined injury site, more typical of a transection injury. This is suited to direct surgical insertion of scaffold materials, including (from top) fibrous materials with aligned or non-aligned matrices, a relatively firm hydrogel with or without a fibrous matrix, or a matrix with a porous character. The cavities in the material may form contiguous channels or be discontinuous. Created with icons from BioRender.com.

Fig. 2. Flow diagram of included studies.

Data from 134 publications were included in the meta-analysis and study quality/design assessment. Following data extraction, the analysis was conducted based on the set objectives. Of the included studies, 91 papers reported locomotor recovery outcomes, 72 reported in vivo axonal regeneration outcomes and 21 reported in vitro axonal regeneration. Objective 1 includes only comparisons that assessed the effect of biomaterials alone. Objective 2 includes studies that assessed BMC strategies in vitro, in vivo, and/or studied the biomaterial properties. Objective 3 includes studies that carried out investigations only in vivo.

Fig. 3. Influence of the testing paradigm used on locomotor recovery outcomes and percentage of reporting study quality parameters.

A Percentage of studies reporting study quality parameters. B Effect of the influence of testing biomaterial properties and performing in vitro and in vivo experiments testing combinations (n = 29) vs. in vivo experiments only (n = 47) on the effect size as a percentage of improvement in motor score. Vertical error bars represent the 95% CI for the individual estimates, and the horizontal shaded grey bar represents the 95% CI of the global estimate. The width of each vertical bar is normalised to the square root of number of animals contributing to that comparison.