Therapy For Spinal Cord Injury Research Articles

A Review of Treatment Methods Focusing on Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation for Chronic Spinal Cord Injury.

Cell transplantation therapy using human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) has attracted attention as a regenerative therapy for spinal cord injury (SCI), and its efficacy in treating the subacute phase of SCI has been reported in numerous studies. However, few studies have focused on treatment in the chronic phase, which accounts for many patients, suggesting that there are factors that are difficult to overcome in the treatment of chronic SCI. The search for therapeutic strategies that focus on chronic SCI is fraught with challenges, and the combination of different therapies is thought to be the key to a solution. In addition, many issues remain to be addressed, including the investigation of therapeutic approaches for more severe injury models of chronic SCI and the acquisition of practical motor function. This review summarizes the current progress in regenerative therapy for SCI and discusses the prospects for regenerative medicine, particularly in animal models of chronic SCI.

Development of Guidelines for Occupational Therapy in Spinal Cord Injury

Development of Guidelines for Occupational Therapy in Spinal Cord Injury

Application of Conductive Hydrogels on Spinal Cord Injury Repair: A Review.

Spinal cord injury (SCI) causes severe motor or sensory damage that leads to long-term disabilities due to disruption of electrical conduction in neuronal pathways. Despite current clinical therapies being used to limit the propagation of cell or tissue damage, the need for neuroregenerative therapies remains. Conductive hydrogels have been considered a promising neuroregenerative therapy due to their ability to provide a pro-regenerative microenvironment and flexible structure, which conforms to a complex SCI lesion. Furthermore, their conductivity can be utilized for noninvasive electrical signaling in dictating neuronal cell behavior. However, the ability of hydrogels to guide directional axon growth to reach the distal end for complete nerve reconnection remains a critical challenge. In this Review, we highlight recent advances in conductive hydrogels, including the incorporation of conductive materials, fabrication techniques, and cross-linking interactions. We also discuss important characteristics for designing conductive hydrogels for directional growth and regenerative therapy. We propose insights into electrical conductivity properties in a hydrogel that could be implemented as guidance for directional cell growth for SCI applications. Specifically, we highlight the practical implications of recent findings in the field, including the potential for conductive hydrogels to be used in clinical applications. We conclude that conductive hydrogels are a promising neuroregenerative therapy for SCI and that further research is needed to optimize their design and application.

Thermosensitive hydrogel-based GPR124 delivery strategy for rebuilding blood-spinal cord barrier.

Spinal cord injury (SCI) causes blood-spinal cord barrier (BSCB) disruption, leading to secondary damage, such as hemorrhagic infiltration, inflammatory response, and neuronal cell death. It is of great significance to rebuild the BSCB at the early stage of SCI to alleviate the secondary injury for better prognosis. Yet, current research involved in the reconstruction of BSCB is insufficient. Accordingly, we provide a thermosensitive hydrogel-based G protein-coupled receptor 124 (GPR124) delivery strategy for rebuilding BSCB. Herein, we firstly found that the expression of GPR124 decreased post-SCI and demonstrated that treatment with recombinant GPR124 could partially alleviate the disruption of BSCB post-SCI by restoring tight junctions (TJs) and promoting migration and tube formation of endothelial cells. Interestingly, GPR124 could also boost the energy metabolism of endothelial cells. However, the absence of physicochemical stability restricted the wide usage of GPR124. Hence, we fabricated a thermosensitive heparin-poloxamer (HP) hydrogel that demonstrated sustained GPR124 production and maintained the bioactivity of GPR124 (HP@124) for rebuilding the BSCB and eventually enhancing functional motor recovery post-SCI. HP@124 hydrogel can encapsulate GPR124 at the lesion site by injection, providing prolonged release, preserving wounded tissues, and filling injured tissue cavities. Consequently, it induces synergistically efficient integrated regulation by blocking BSCB rupture, decreasing fibrotic scar formation, minimizing inflammatory response, boosting remyelination, and regenerating axons. Mechanistically, giving GPR124 activates energy metabolism via elevating the expression of phosphoenolpyruvate carboxykinase 2 (PCK2), and eventually restores the poor state of endothelial cells. This research demonstrated that early intervention by combining GPR124 with bioactive multifunctional hydrogel may have tremendous promise for restoring locomotor recovery in patients with central nervous system disorders, in addition to a translational approach for the medical therapy of SCI.

Advances in extracellular vesicle-based combination therapies for spinal cord injury.

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits. The currently available treatments involve surgical, medical, and rehabilitative strategies. However, none of these techniques can markedly reverse neurological deficits. Recently, extracellular vesicles from various cell sources have been applied to different models of spinal cord injury, thereby generating new cell-free therapies for the treatment of spinal cord injury. However, the use of extracellular vesicles alone is still associated with some notable shortcomings, such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons. Therefore, this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury, including the combination of extracellular vesicles with nanoparticles, exogenous drugs and/or biological scaffold materials, which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles. We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Hydrogel scaffolds in the treatment of spinal cord injury: a review.

Spinal cord injury (SCI) is a disease of the central nervous system often caused by accidents, and its prognosis is unsatisfactory, with long-term adverse effects on patients' lives. The key to its treatment lies in the improvement of the microenvironment at the injury and the reconstruction of axons, and tissue repair is a promising therapeutic strategy. Hydrogel is a three-dimensional mesh structure with high water content, which has the advantages of biocompatibility, degradability, and adjustability, and can be used to fill pathological defects by injectable flowing hydrophilic material in situ to accurately adapt to the size and shape of the injury. Hydrogels mimic the natural extracellular matrix for cell colonization, guide axon extension, and act as a biological scaffold, which can be used as an excellent carrier to participate in the treatment of SCI. The addition of different materials to make composite hydrogel scaffolds can further enhance their performance in all aspects. In this paper, we introduce several typical composite hydrogels and review the research progress of hydrogel for SCI to provide a reference for the clinical application of hydrogel therapy for SCI.

Clinical trials for neuroregenerative therapies for spinal cord injury: what have we learnt so far?

ABSTRACT Introduction There remains a lack of effective regenerative therapies to treat traumatic spinal cord injury (SCI). On a global level, patients living with SCI, their families, and the healthcare system are impacted by the extensive financial burden associated with the management of SCI. Clinical trials are crucial to assess the real-world efficacy of the different emerging neuroregenerative approaches that have shown promise in the pre-clinical stages of research. Areas covered This perspective summarizes and discusses potential solutions to several key challenges that clinical investigators evaluating novel therapeutic strategies to treat SCI might face: 1) the challenges in patient recruitment and meeting enrollment targets with adequate statistical power; 2) the loss of patients to follow-up; 3) the heterogeneity in patient presentation and recovery trajectories; 4) the complex multifaceted pathophysiology of SCI that renders investigations of single therapeutic approaches difficult; 5) the challenge of capturing positive treatment effects of investigative therapies; 6) the high costs associated with conducting clinical trials; 7) the implementation of current guidelines for treating SCI to optimize care delivery and clinical trial conduct; 8) the shift in SCI patient demographics reflective of an aging population; and 9) navigating regulatory bodies to translate therapies into the clinic. Expert opinion There are challenges when conducting SCI clinical trials that span broadly across medical, social, political, and economic considerations. Thus, we should employ an interdisciplinary approach when addressing these challenges in order to facilitate the evaluation of novel treatments for SCI.

A custom-made weight-drop impactor to produce consistent spinal cord injury outcomes in a rat model.

The main objective of this study is to design a custom-made weight-drop impactor device to produce a consistent spinal cord contusion model in rats in order to examine the efficacy of potential therapies for post-traumatic spinal cord injuries (SCIs). Adult female Sprague-Dawley rats (n = 24, 11 weeks old) were randomly divided equally into two groups: sham and injured. The consistent injury pattern was produced by a 10 g stainless steel rod dropped from a height of 30 mm to cause (0.75 mm) intended displacement to the dorsal surface of spinal cord. The neurological functional outcomes were assessed at different time intervals using the following standardized neurobehavioral tests: Basso, Beattie, and Bresnahan (BBB) scores, BBB open-field locomotion test, Louisville Swim Scale (LSS), and CatWalk gait analysis system. Hind limb functional parameters between the two groups using BBB scores and LSS were significantly different (p < 0.05). There were significant differences (p < 0.05) between the SCI group and the sham group for the hind limb functional parameters using the CatWalk gait analysis. We developed an inexpensive custom-made SCI device that yields a precise adjustment of the height and displacement of the impact relative to the spinal cord surface.

Metformin promotes Schwann cell remyelination, preserves neural tissue and improves functional recovery after spinal cord injury

Patients with a spinal cord injury (SCI) usually suffer lifelong disability as a result. Considering this, SCI treatment and pathology study are urgently needed. Metformin, a widely used hypoglycemic drug, has been indicated for its important role in central nervous system diseases. This study aimed to investigate the potential effect of metformin on remyelination after SCI. In the present study, we established a cervical contusion SCI model and metformin treatment was applied after SCI. Biomechanical parameters and behavioral assessment were used to evaluate the severity of injury and the improvement of functional recovery after SCI, respectively. The immunofluorescence and western blot were performed at the terminal time point. Our results showed that treating with metformin after SCI improved functional recovery by reducing the white matter loss and promoting Schwann cell remyelination, and the Nrg1/ErbB signaling pathway may be involved in promoting remyelination mediated by oligodendrocytes and Schwann cells. In addition, the area of spared tissues was significantly increased in the metformin group. However, metformin had no significant effects on the glial scar and inflammation after SCI. In summary, these findings indicated that the role of metformin in Schwann cell remyelination after SCI was probably related to the regulation of the Nrg1/ErbB pathway. It is, therefore, possible to suggest that metformin may be a potential therapy for SCI.

Inhibited astrocytic differentiation in neural stem cell-laden 3D bioprinted conductive composite hydrogel scaffolds for repair of spinal cord injury

The emergence of three-dimensional (3D) bioprinting technology has attracted ever-increasing attention in engineered tissue fabrication for stem cell-based tissue repair. However, the in vivo performance of transplanted stem cells in the tissue engineering scaffolds is still a major concern for regenerative medicine researches. Especially for neural stem cell (NSC) transplantation, the uncontrollable differentiation of the NSCs in host often leads to a poor therapeutic effect in nerve tissue repair, such as spinal cord injury (SCI) repair. To address this issue, we have fabricated a conductive composite hydrogel (CCH) scaffold loading with NSCs by 3D bioprinting, for delivering the NSCs to injured spinal cord and repairing the propriospinal nerve circuit. In our strategy, a novel conductive polymer (PEDOT:CSMA,TA) was synthesized and introduced into a photocrosslinkable gelatin/polyethylene glycol physical-gel matrix, thereby forming a composite bioink with well shear-thinning and self-healing properties. The composite bioink we prepared was then printed into the NSC-laden CCH scaffold with high shape fidelity and similar physicochemical properties to native spinal cord tissues. The NSCs encapsulated in the bioprinted CCH scaffold extended their neurites to form superior physical contact with the neighboring cells as well as the electroconductive matrix, and maintained a predominant in vivo neuronal differentiation, accompanying with few astrocytic production in the lesion area after transplantation into the SCI sites. As a result, the removal of glial scar tissues and the regeneration of well-developed nerve fibres sequentially happened, which not only facilitated nerve tissue development, but also accelerated locomotor function recovery in the SCI rats. By exploring the application of conductive biomaterials in stem cell-based SCI therapy, this work represents a feasible, new approach to precisely construct tissue engineering scaffolds for stem cell-based therapy in traumatic SCI and other nervous system diseases.

Engineered extracellular vesicles for delivery of siRNA promoting targeted repair of traumatic spinal cord injury.

Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.

Evaluation of the Autologous Genetically Enriched Leucoconcentrate on the Lumbar Spinal Cord Morpho-Functional Recovery in a Mini Pig with Thoracic Spine Contusion Injury.

Pathological changes associated with spinal cord injury (SCI) can be observed distant, rostral, or caudal to the epicenter of injury. These remote areas represent important therapeutic targets for post-traumatic spinal cord repair. The present study aimed to investigate the following in relation to SCI: distant changes in the spinal cord, peripheral nerve, and muscles. The changes in the spinal cord, the tibial nerve, and the hind limb muscles were evaluated in control SCI animals and after intravenous infusion of autologous leucoconcentrate enriched with genes encoding neuroprotective factors (VEGF, GDNF, and NCAM), which previously demonstrated a positive effect on post-traumatic restoration. Two months after thoracic contusion in the treated mini pigs, a positive remodeling of the macro- and microglial cells, expression of PSD95 and Chat in the lumbar spinal cord, and preservation of the number and morphological characteristics of the myelinated fibers in the tibial nerve were observed and were aligned with hind limb motor recovery and reduced soleus muscle atrophy. Here, we show the positive effect of autologous genetically enriched leucoconcentrate-producing recombinant neuroprotective factors on targets distant to the primary lesion site in mini pigs with SCI. These findings open new perspectives for the therapy of SCI.

North American Clinical Trials Network for Spinal Cord Injury Registry: Methodology and Analysis.

The North American Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of neurosurgery departments at university affiliated hospitals with medical, nursing, and rehabilitation personnel who are skilled in the assessment, evaluation, and management of SCI. NACTN was established with the goal of consistently advancing the quality of life of people with SCI through clinical trials of new therapies that provide robust evidence of safety and effectiveness. A prospective multi-center Registry was created to collect the natural course of the acute traumatic SCI patient from time of injury to 12 months follow-up. NACTN's network of hospitals enrolls a significant number of patients, defines and adheres to standard protocols, and provides the infrastructure and highly skilled personnel to conduct trials of therapy for SCI. Registry data have been used by academic institutions and by the biotechnology and pharmaceutical sectors to create comparison datasets for Phase I clinical trials of new therapies.

Recent advances in the combination of cellular therapy with stem cells and nanoparticles after a spinal cord injury.

Currently, combined therapies could help to reduce long-term sequelae of spinal cord injury (SCI); stem cell therapy at the site of injury in combination with other therapies has shown very promising results that can be transferred to the clinical field. Nanoparticles (NPs) are versatile technologies with applications to medical research for treatments of SCI since they could deliver therapeutic molecules to the target tissue and may help to reduce the side effects of non-targeted therapies. This article's purpose is to analyze and concisely describe the diverse cellular therapies in combination with NPs and their regenerative effect after SCI. We reviewed the literature related to combinatory therapy for motor impairment following SCI that has been published by Web of Science, Scopus, EBSCO host, and PubMed databases. The research covers the databases from 2001 to December 2022. Animal models of SCI have shown that the combination of NPs plus stem cells has a positive impact on neuroprotection and neuroregeneration. Further research is required to better understand the effects and benefits of SCI on a clinical level; therefore, it is necessary to find and select the most effective molecules that are capable of exacerbating the neurorestorative effects of the different stem cells and then try them out on patients after SCI. On the other hand, we consider that synthetic polymers such as poly [lactic-co-glycolic acid] (PLGA) could be a candidate for the design of the first therapeutic strategy that combines NPs with stem cells in patients with SCI. The reasons for the selection are that PLGA has shown important advantages over other NPs, such as being biodegradable, having low toxicity levels, and high biocompatibility; In addition, researchers could control the release time and the biodegradation kinetics, and most importantly, it could be used as NMs on other clinical pathologies (12 studies on www.clinicaltrials.gov) and has been approved by the Federal Food, Drug, and Cosmetic Act (FDA). The use of cellular therapy and NPs may be a worthwhile alternative for SCI therapy; however, it is expected that the data obtained from interventions after SCI reflect an important variability of molecules combined with NPs. Therefore, it is necessary to properly define the limits of this research to be able to continue to work on the same line. Consequently, the selection of a specific therapeutic molecule and type of NPs plus stem cells are crucial to evaluate its application in clinical trials.

Toxic aldehyde-scavenging polypeptides mitigate secondary injury after spinal cord injury

Neuroprotective therapy for traumatic spinal cord injury (SCI) still faces formidable challenges in clinic. Immediately after traumatic SCI, toxic reactive aldehydes are largely produced by lipid peroxidation, which subsequently promotes a vicious cycle of oxidative stress and inflammation in injured spinal cord, leading to the worse secondary injury. Therefore, scavenging of toxic reactive aldehydes has become a promising strategy for treatment of secondary SCI. Here, a drug-free polypeptide (PPAH) containing hydrazide groups on the side chains is designed and synthesized for mitigating secondary SCI through scavenging toxic aldehydes. The prepared PPAH displayed the ability to scavenge reactive aldehydes both in vitro and in vivo. Specifically, PPAH exhibited a protective effect against acrolein-induced damage in neurocytes and the intrathecal injection of PPAH was able to suppress inflammation, protect neurons, inhibit demyelination and improve hindlimb functional recovery in a rat SCI model. Therefore, as an effective toxic aldehyde-scavenging agent, PPAH shows promising perspectives in therapies for SCI.

Evaluation of the Effectiveness of Systemic Therapy of Spinal Cord Injury of Moderate Severity with Human Umbilical Cord Placental Blood Mononuclear Cells Using Indicators of Dispersion of Articular Angles in the Swimming Test

Female Sprague-Dawley rats were used as models of moderate contusion spinal cord injury to evaluate the efficiency of single systemic (intravenous) infusion of human mononuclear cord blood cells for restoration of the motor function of hind limbs. The dynamics of recovery of hind limb motor function was assessed using a specially designed method based on calculation of selective dispersion and amplitude-dependent dispersion of hind limbs joint angles measured in the swimming test. The obtained data suggest that systemic application of human mononuclear cord blood cells significantly (p<0.05) promoted recovery of hind limb motor function in the animal models of contusion spinal cord injury of moderate severity in comparison with control animals (without cell therapy).

Combination therapy with ultrasound and 2D nanomaterials promotes recovery after spinal cord injury via Piezo1 downregulation

Spinal cord injury (SCI) causes severe neurological dysfunction and currently has no effective treatment. Due to the complex pathophysiological processes associated with SCI and the limited efficacy of single strategies, the need for combined strategies for effective SCI therapy is becoming increasingly apparent. In this study, we evaluated the combined effects of layered double hydroxide-coupled NT3 (MgFe-LDH/NT3) nanoparticles (NPs) and ultrasound (US) both in vitro and in vivo. Combined treatment promoted neural stem cell (NSC) differentiation into neurons and exerted anti-inflammatory effects in vitro. Furthermore, combined therapy promoted behavioural and electrophysiological performance at eight weeks in a completely transected murine thoracic SCI model. Additional RNA sequencing revealed that ultrasonic-induced Piezo1 downregulation is the core mechanism by which combined therapy promotes neurogenesis and inhibits inflammation, and the Piezo1/NF-κB pathways were identified. Hence, the findings of this study demonstrated that the combination of ultrasound and functional NPs may be a promising novel strategy for repairing SCI.

Sustained Release of Human Adipose Tissue Stem Cell Secretome from Star-Shaped Poly(ethylene glycol) Glycosaminoglycan Hydrogels Promotes Motor Improvements after Complete Transection in Spinal Cord Injury Rat Model.

Adipose tissue-derived stem cells (ASCs) have been shown to assist regenerative processes after spinal cord injury (SCI) through their secretome, which promotes several regenerative mechanisms, such as inducing axonal growth, reducing inflammation, promoting cell survival, and vascular remodeling, thus ultimately leading to functional recovery. However, while systemic delivery (e.g., i.v. [intravenous]) may cause off-target effects in different organs, the local administration has low efficiency due to fast clearance by body fluids. Herein, a delivery system for human ASCs secretome based on a hydrogel formed of star-shaped poly(ethylene glycol) (starPEG) and the glycosaminoglycan heparin (Hep) that is suitable to continuously release pro-regenerative signaling mediators such as interleukin (IL)-4, IL-6, brain-derived neurotrophic factor, glial-cell neurotrophic factor, and beta-nerve growth factor over 10 days, is reported. The released secretome is shown to induce differentiation of human neural progenitor cells and neurite outgrowth in organotypic spinal cord slices. In a complete transection SCI rat model, the secretome-loaded hydrogel significantly improves motor function by reducing the percentage of ameboid microglia and systemically elevates levels of anti-inflammatory cytokines. Delivery of ASC-derived secretome from starPEG-Hep hydrogels may therefore offer unprecedented options for regenerative therapy of SCI.

Hydralazine plays an immunomodulation role of pro-regeneration in a mouse model of spinal cord injury

Spinal cord injury (SCI) results in severe motor and sensory dysfunction with no effective therapy. Spinal cord debris (sp) from injured spinal cord evokes secondary SCI continuously. We and other researchers have previously clarified that it is mainly bone marrow derived macrophages (BMDMs) infiltrating in the lesion epicenter to clear sp, rather than local microglia. Unfortunately, the pro-inflammatory phenotype of these infiltrating BMDMs is predominant which impairs wound healing. Hydralazine, as a potent vasodilator and scavenger of acrolein, has protective effects in many diseases. Hydralazine is also confirmed to promote motor function and hypersensitivity in SCI rats through scavenging acrolein. However, few studies have explored the effects of hydralazine on immunomodulation, as well as spontaneous pain and emotional response, the important syndromes in clinical patients. It remains unclear whether hydralazine affects infiltrating BMDMs after SCI. In this study, we targeted BMDMs to explore the influence of hydralazine on immune cells in a mouse model of SCI, and also investigated the contribution of polarized BMDMs to hydralazine-induced neurological function recovery after SCI in male mice. The adult male mice underwent T10 spinal cord compression. The results showed that in addition to improving motor function and hypersensitivity, hydralazine relieved SCI-induced spontaneous pain and emotional response, which is a newly discovered function of hydralazine. Hydralazine inhibited the recruitments of pro-inflammatory BMDMs and educated infiltrated BMDMs to a more reparative phenotype involving in multiple biological processes associated with SCI pathology, including immune/inflammation response, neurogenesis, lipid metabolism, oxidative stress, fibrosis formation, and angiogenesis, etc. As an overall effect, hydralazine-treated BMDMs loaden with sp partially rescued neurological function after SCI. It is concluded that hydralazine plays an immunomodulation role of educating pro-inflammatory BMDMs to a more reparative phenotype; and hydralazine-educated BMDMs contribute to hydralazine-induced improvement of neurological function in SCI mice, which provides support for drug and cell treatment options for SCI therapy.

Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential.

Spinal cord injury (SCI) is an as yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential, but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and which cell types result in higher neurological and functional recovery remains under debate. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analysed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages and various types of stem cells have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale, motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic aetiology and did not display a randomized comparative control arm. Bone marrow stem cells and OECs were the most commonly tested cells, while open surgery and injection were the main methods of delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest ASIA Impairment Scale (AIS) grade conversion rates (improvements in ∼40% of transplanted patients), which surpassed the spontaneous improvement rate expected for complete chronic SCI patients within 1 year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated and neural stem cells, offer potential for improving patient recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may contribute highly to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials and how these are reported. It is therefore crucial to standardize these trials when aiming for higher value clinical evidence-based conclusions.