Open research questions in Spinal Cord Injury Research

What the literature leaves open

• and Rau, G. Hofstoetter, U. S., Freundl, B., Binder, H., and Minassian, K. (2018). Common neural structures activated by epidural and transcutaneous lumbar spinal cord stimulation: elicitation of posterior root-muscle reflexes. PLoS ONE 13:e0192013. doi: 10.1371/journal.pone.0192013 Hofstoetter, U. S., Freundl, B., Lackner, P., and Binder, H. (2021). Transcutaneous spinal cord stimulation enhances walking performance and reduces spasticity in individuals with multiple sclerosis. Brain Sci. 11:472. doi: 10.3390/brainsci11040472 Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P., and Rothwell, J. C. (2005). Theta burst stimulation of the human motor cortex. Neuron 45, 201–206. doi: 10.1016/j.neuron.2004.12.033 Jackson, A. B., Carnel, C. T., Ditunno, J. F., Read, M. S., Boninger, M. L., Schmeler, M. R., et al. (2008). Outcome measures for gait and ambulation in the spinal cord injury population. J. Spinal Cord Med. 31, 487–499. doi: 10.1080/10790268.2008.11753644 Kirshblum, S. C., Burns, S. P., Biering-Sorensen, F., Donovan, W., Graves, D. E., Jha, A., et al. (2011). International standards for neurological classification of J. Spinal Cord Med. 34, 535–546. doi: 10.1179/204577211X13207446293695 cord injury (revised 2011). spinal Kumru, H., Benito-Penalva, J., Valls-Sole, J., Murillo, N., Tormos, J. M., Flores, C., et al. gait training for (2016). Placebo-controlled study of rTMS combined with Lokomat treatment in subjects with motor incomplete spinal cord injury. Exp. Brain Res. 234, 3447–3455. doi: 10.1007/s00221-016-4739-9 R(cid:13) Lam, T., Noonan, V. K., and Eng, J. J. (2008). A systematic review of functional ambulation outcome measures in spinal cord injury. Spinal Cord 46, 246–254. doi: 10.1038/sj.sc.3102134 Lefaucheur, J. P., Aleman, A., Baeken, C., Benninger, D. H., Brunelin, J., Di Lazzaro, V., et al. (2020). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018). Clin. Neurophysiol. 131, 474–528. doi: 10.1016/j.clinph.2019.11.002 Minassian, K., Hofstoetter, U. S., Danner, S. M., Mayr, W., Bruce, J. A., McKay, W. B., et al. (2016). Spinal rhythm generation by step-induced feedback and transcutaneous posterior root stimulation in complete spinal cord-injured individuals. Neurorehabil. Neural Repair 30, 233–243. doi: 10.1177/15459683155 91706 Nardone, R., Höller, Y., Brigo, F., Seidl, M., Christova, M., Bergmann, J., et al. (2013). Functional brain reorganization after spinal cord injury: systematic review of animal and human studies. Brain Res. 1504, 58–73. doi: 10.1016/j.brainres.2012. 12.034 Raithatha, R., Carrico, C., Powell, E. S., Westgate, P. M., Chelette Ii, K. C., Lee, K., et al. (2016). Non-invasive brain stimulation and robot-assisted gait training after incomplete spinal cord injury: a randomized pilot study. NeuroRehabilitation 38, 15–25. doi: 10.3233/NRE-151291 Rossi, S., Antal, A., Bestmann, S., Bikson, M., Brewer, C., Brockmöller, J., et al. (2021).

  Lower limb rehabilitation in chronic incomplete SCI: a randomized controlled trial protocol comparing combined TMS-tSCS neuromodulation vs. tSCS alone · 2026 · DOI

• Fourth, the single oral dose (50 mg/kg/day) highlights the need for future dose-response and pharmacokinetic studies to optimize blood-spinal cord barrier penetrance, where nano-formulations could be explored.

  Neuroprotective potential of the natural polyphenol Procyanidin B2 in spinal cord injury: a comprehensive study utilizing machine learning, network pharmacology, and in vivo validation · 2026 · DOI

• In contrast, limited research exists regarding RTW and stay-at-work policies in Canada, with only one Canadian study meeting the set inclusion criteria, compared to 9 retrieved studies U.

  Vocational rehabilitation and return to work after spinal cord injury: a scoping review of policies in the U.S. and Canada · 2026 · DOI

• Individuals with chronic cervical spinal cord injury (SCI) retain voluntary motor unit (MU) activation below the level of the lesion despite profound impairments in muscle relaxation, yet the MU-level mechanisms underlying this dissociation remain unclear.

  Physiological and pathological motor unit phenotypes coexist within single motor pools after cervical SCI · 2026 · DOI

• from fully evaluating its relative efficacy and safety in treatment. Second, this study does not provide evidence that TIIA-PLGA SRMs can remain in the lesion site for an extended period and sustained release TIIA. Although we aimed to enhance the local concentration of the drug in the injury area through intrathecal injection, the lack of direct observation of the retention of microspheres in the cerebrospinal fluid over time limits our ability to confirm their sustained release effects. In response to these issues, we are conducting in vivo pharmacokinetic studies of TIIA-PLGA SRMs after intrathecal administration, observing their retention and degradation timelines as well as in vivo release behavior. PLGA is regarded as a medical polymer material with good biodegradability and biocompatibility, and is applied as a high-quality drug carrier in basic research (Tang et al., 2026). However, the potential inflammatory response during intrathecal administration has not been clearly identified, so the clinical safety of this intrathecal delivery system still needs to be considered. Third, In this study, there were some in the evaluation methods of pathological morphology results such as HE and Nissl staining. For instance, the pathological morphology score based on HE staining used five integers ranging from 0 to 4 to evaluate pathological morphological changes of the injured spinal cord. The evaluation method was relatively coarse and subjective, and the infiltrating immune or inflammatory cells were difficult to identify. In subsequent studies, more detailed, objective, and repeatable pathological morphology evaluation methods should be explored. Next, in vitro experiments targeting microglia or intervention experiments with Notch signaling pathway agonists, which restricts our further understanding of the mechanism of the Notch signaling pathway involvement in the treatment of SCI with TIIA-PLGA SRMs and its roles in regulating microglial phenotypic polarization. Finally, our study used Iba1 as a standard microglia marker, but Iba1 is expressed by both resident microglia and infiltrating monocytederived macrophages after SCI. In the future, specific microglia markers such as TMEM119 or P2RY12 should be used to distinguish these populations and reduce the interference from macrophages in the results.

  Regulation of microglial polarization via notch signaling pathway by intrathecal administration of tanshinone IIA-PLGA sustained-release microspheres to promote neurological recovery after spinal cord injury · 2026 · DOI

• One important confounder is that prehospital mortality was not included in this study. Patients who have multisystem injuries and spinal injuries may be pronounced dead at the scene and are thus inadvertently excluded from the study cohort. This would have led to selection bias and hindered the objective analysis of the outcomes of spinal injury in polytrauma. Our cohort of patients with spine trauma was well represented in “moderate” and “severe” injuries based on ISS scores. However, a confounder would be that patients with “profound” injuries based on an ISS score of ≥25 only accounted for 6.8% of patients with spinal trauma. Patients in this group who died may have had undiagnosed spinal trauma if they could not be imaged (x-ray, computed tomography, magnetic resonance imaging) prior to their death. The study did not analyze the specific management of trauma patients after admission. As there is no fixed protocol for management of spinal injuries in the setting of multisystem injury in the study hospital, patients may have been managed by different specialties with different approaches. This could lead to varying outcomes. Furthermore, there were no data with regard to postadmission complications, such as acute myocardial infarction, adult respiratory distress syndrome, and deep vein thrombosis, which are known to have significant mortality risks [18]. The development and subsequent management of these complications may have contributed to mortality in ways independent of the initial mechanism of injury; thus, their exclusion may limit the accuracy of the study’s correlation between mechanism of injury, type of injury sustained, and subsequent mortality. The authors suggest that future research is required to verify the findings reported in this study. Including trauma victims who do not survive to be admitted to the hospital would allow a more objective analysis of the survivability of spinal injury in polytrauma. Another area of potential future research is the implementation of preventive strategies for age-range-specific mechanisms of injury, as this study has shown a pattern in the type of injuries sustained across different age groups.

  A Retrospective Analysis of Concomitant Spinal Injuries in the Setting of Polytrauma at a Tertiary Hospital in Singapore · 2026 · DOI

• Additional changes in the bowels and bladder items in the BI-SR-TH would enhance understanding and validity, potentially by adding phrases such as 'completely managed alone' and including the phrase 'in the past week' in the descriptions.

  Validity and Reliability of the Thai Version of the Barthel Index Self-Report (BI-SR-TH) for People with Spinal Cord Injury · 2026 · DOI

• Spinal cord injury (SCI) imposes a remarkable burden on affected cases and their families, while current treatment options remain insufficient.

  Betulinic Acid Promotes Motor Function Recovery After Spinal Cord Injury by Inhibiting Apoptosis Through Myc/NF-κB Signaling Pathway · 2026 · DOI

• Despite numerous studies, substantial success in reducing neurological consequences in such patients has not yet been achieved, and several aspects remain understudied, particularly the response of the spinal cord to injury at different anatomical levels.

  Influence of the anatomical level of spinal cord injury on the severity of neurological impairments in spinal cord trauma · 2024 · DOI

• Skill and attitudinal reasons were offered for the lack of evidence to practice transfer including: the absence of patient self-management, poor access to specialists, lack of education for family practice physicians, fragmentation of community resources and co-ordination upon hospital discharge.

  Why do challenges still exist in primary care for patients with spinal cord injury? · 2020 · DOI

• Moreover, when exploring SUD, it has not been systematically studied in accordance with CIE or DSM criteria.

  Lesión medular y uso de sustancias: una revisión sistemática · 2015 · DOI

Most-cited papers in Spinal Cord Injury Research

• A Randomized, Controlled Trial of Methylprednisolone or Naloxone in the Treatment of Acute Spinal-Cord Injury · New England Journal of Medicine · 1990 · 2,243 citations
• Epidural stimulation of the cervical spinal cord for post-stroke upper-limb paresis · Nature Medicine · 2023 · 166 citations
• Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial · Nature Medicine · 2024 · 152 citations
• In Situ Piezoelectric‐Catalytic Anti‐Inflammation Promotes the Rehabilitation of Acute Spinal Cord Injury in Synergy · Advanced Materials · 2024 · 107 citations
• Engineered Multifunctional Zinc–Organic Framework-Based Aggregation-Induced Emission Nanozyme for Accelerating Spinal Cord Injury Recovery · ACS Nano · 2024 · 106 citations
• Multifunctional Conductive and Electrogenic Hydrogel Repaired Spinal Cord Injury via Immunoregulation and Enhancement of Neuronal Differentiation · Advanced Materials · 2024 · 97 citations
• Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial · Nature Communications · 2024 · 91 citations
• A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on Hemodynamic Management · Global Spine Journal · 2024 · 90 citations
• Integrating hydrogels manipulate ECM deposition after spinal cord injury for specific neural reconnections via neuronal relays · Science Advances · 2024 · 86 citations
• Pregnancy and women with spinal cord injuries · Acta Obstetricia Et Gynecologica Scandinavica · 2008 · 71 citations

Most recent work

• Validity and Reliability of the Thai Version of the Barthel Index Self-Report (BI-SR-TH) for People with Spinal Cord Injury · Biomedical Sciences and Clinical Medicine · 2026
• The Effect of Overground Locomotor Training on Self-Efficacy Following Spinal Cord Injury: An Exploratory Study · Occupational Therapy In Health Care · 2026
• Identification of repopulated microglia-associated genes in microglia depleted/repopulated mice after spinal cord injury · Brain Research · 2026
• Trichosanthis peel injection improves functional recovery after spinal cord injury associated with the modulation of neuroinflammation and oxidative stress · Figshare · 2026
• Comment on: advances in nanomaterial-based therapeutic research for spinal cord injuries: an overview · Advanced Composites and Hybrid Materials · 2026
• Observation on the efficacy of combined electrical stimulation in the treatment of incomplete spinal cord injury: a randomized controlled trial · Frontiers in Neurology · 2026
• Identification of PANoptosis-Related Biomarkers in Spinal Cord Injury (SCI) through Multi-Omics Analysis and Machine Learning · International Journal of Neuroscience · 2026
• Identification of a mitochondrial biomarker signature linking neuroinflammation to neuronal dysfunction in spinal cord injury · Scientific Reports · 2026
• A Retrospective Analysis of Concomitant Spinal Injuries in the Setting of Polytrauma at a Tertiary Hospital in Singapore · Cureus · 2026
• Feasibility of Remote High-Intensity Interval Exercise Training in People with Spinal Cord Injury: A Pilot Study · Disabilities · 2026

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