**6. Study limitations and future directions for MSCs**

Overall, the use of MSCs in SCI appears to be safe and without any major evidence of severe adverse reactions. However, the results obtained in the clinical trials so far do not concrete the promising results obtained in the preclinical trials. This may be due to the fact that preclinical studies normally utilize specific animal models with standardized protocols to produce the injury as well as preestablished treatments and timing of the transplantation which cannot be replicated in a human study. In clinical trials, most of these conditions depend heavily on chance, the traumatic event, and the emergency setting which may differ a lot from the controlled atmosphere of an animal experiment. In addition, there is a great lack of phase III clinical trials due to financial and ethical reasons. As mentioned before, one of the few phase III clinical trials held by Oh et al*.* showed weak and limited therapeutic efficacy [92]. Further investigation is needed to determine accurate parameters for its clinical use in SCI such as optimal therapeutic protocols involving type, preparation, number of cells administered, timing of transplantation, and administration route.

On the other hand, thanks to the technological revolution, scientists have now started to investigate the use of MSCs in combination with new biomaterials in order to promote tissue repair and to improve cell survival [6]. A study conducted by Xiao et al. analyzed the therapeutic effect of MSC transplantation in combination with a collagen scaffold which is known to support cell migration and adhesion [93]. After the transplant the injury status of the patients changed from ASIA A to ASIA C accompanied by a significant improvement in motor, sensory, and urinary functions [94]. Furthermore, the possibility of combining MSCs with hydrogels is particularly appealing due to their capacity to be injected with minimal invasion and to be loaded with specific drugs that can be furtherly released in a controlled manner [95]. Moreover, MSCs' ability to induce the production of neurotrophic, immunomodulating, and neuroprotective factors needs further investigation in order to be fully understood and furtherly enhanced, aiming to improve the clinical outcomes. Lastly, the homing properties of the MSCs could be useful to transport specific target drugs to the site of the lesion and thus acting as a vector [96].
