Aug 2026· Neurosurgical review· Vol 49· 0 citations· 58 references
Medicine
TL;DR
This review catalogs recent conceptual and technological developments contributing to the emergence of brain-spine interfaces and suggests they may have potential to improve the quality of life for SCI patients.
Abstract
Spinal cord injuries (SCIs) profoundly impact millions globally, leading to loss of motor and sensory functions below the injury site. Brain-spine interfaces (BSIs) represent an early-stage neuroprosthetic strategy that attempts to restore functional communication between cortical motor-intention signals and spinal sensorimotor circuits below the level of injury. Although early preclinical and highly selected clinical studies have shown encouraging motor outcomes, the evidence remains preliminary, and routine clinical use is limited by questions regarding safety, durability, patient selection, accessibility, and long-term functional benefit. BSI approaches are based on the observation that residual spinal pathways and sensorimotor circuits may remain partially responsive to neuromodulation even after injury. Along the way, technological advancements have significantly bolstered SCI treatment strategies, ranging from surgical interventions to regenerative therapies. Approaches such as neurostimulation and biomaterial-based strategies have shown potential in experimental and early translational settings, although their clinical efficacy and generalizability remain incompletely established. Furthermore, exploring neuroplasticity and the body’s intrinsic ability to reorganize neural connections post-injury underscores the potential for spontaneous recovery in certain cases. However, integrating BSIs into clinical practice faces substantial hurdles, including technical challenges, ethical considerations, and the need for specialized training for healthcare providers. Despite these obstacles, BSIs and other novel treatments may have potential to improve the quality of life for SCI patients, although further clinical investigation is needed to establish their safety, efficacy, and generalizability. This review catalogs recent conceptual and technological developments contributing to the emergence of BSI.
With the continuous development of artificial intelligence, novel biomaterials, and immersive technologies such as virtual reality, BCIs are expected to evolve toward more personalized, home-based, and intelligent rehabilitation solutions, accelerating their clinical application and offering new therapeutic hope for SCI patients.
Xudong Zhao, Keyi Chen, Jinquan Ma et al.· Spine Research· 0 citations
A prospective multicenter comparative protocol was developed for adults with chronic cervical injury and neurological stability, and implanted brain–spine systems have enabled intention- driven standing and walking in an individual with chronic tetraplegia, whereas non-invasive cervical stimulation combined with task practice has improved hand strength and sensation in cohorts.
INTRODUCTION
Spinal cord injury (SCI) precipitates a multiphasic secondary injury cascade that establishes a hostile, inhibitory microenvironment, rendering the condition refractory to conventional surgical stabilization and rehabilitation. While cell-based therapies offer promise for neural reconstruction, their clinical translation is impeded by protocol heterogeneity and fragmented safety data. To address this, we mapped clinical trials for SCI to quantify patient demographic parameters, identify lineage-specific adverse-event patterns, evaluate objective motor and sensory efficacy outcomes, and analyze methodological trial designs to formulate concrete structural recommendations for future advanced-phase trials.
METHODS
We analyzed clinical trials from the Web of Science Core Collection (SCIE and ESCI) published since 2005. The dataset comprised 116 eligible studies involving patients with SCI receiving cellular therapies with reported safety outcomes. We employed a dual-method approach combining manual extraction of clinical characteristics (demographics, interventions, adverse events, efficacy outcomes) with quantitative data analysis. Statistical associations between therapeutic variables (cell type, route, dosage) and safety profiles were evaluated using Fisher's exact test.
RESULTS
The clinical landscape is predominantly defined by early-phase (Phase 1: 59.5%), single-arm investigations (63.8%) utilizing autologous bone marrow-derived cells. Reflecting a cautious paradigm to minimize severe complications, patient selection frequently targeted the hemodynamically stable chronic phase (58.3%) and thoracic SCI (21.6%). Safety analyses revealed lineage-specific profiles: mesenchymal stromal cells were significantly associated with transient fever (P = 0.038), whereas intrathecal administration correlated with procedural symptoms such as headache (P < 0.001). The observation of higher systemic adverse event rates in low-dose cohorts was likely confounded by the mandatory concurrent immunosuppressive regimens required for specific allogeneic lineages, rather than the absolute cell dose. Regarding therapeutic efficacy, outcomes were critically influenced by the chronological phase of injury. Patients treated in the acute or subacute phases exhibited higher rates of neurological improvement, though distinguishing this from spontaneous recovery remains challenging, whereas chronic phase interventions demonstrated more limited primary sensorimotor gains. Additionally, intrathecal administration showed an advantage in preserving sensory pathways due to minimized structural disruption, while dose requirements could not be generalized and varied fundamentally based on specific cellular mechanisms of action.
DISCUSSION
While the baseline safety of cellular transplantation for spinal cord injury is established, clinical translation remains hindered by methodological heterogeneity, imprecise patient stratification, and a reliance on single-arm trial designs. To navigate this translational bottleneck, future investigations should adopt multi-tiered methodological frameworks. First, study designs should transition toward controlled protocols, utilizing crossover designs for chronic cohorts and matched historical or synthetic controls for acute and subacute phases. Concurrently, patient selection must evolve from broad clinical grading to advanced stratification. Integrating biomarkers, electrophysiology, and imaging to objectively quantify tissue sparing can better identify responsive subgroups, thereby improving trial efficiency and accelerating clinical translation. Beyond cohort refinement, intervention parameters, specifically dosage and delivery routes, should be individualized according to cell lineage, as adverse events associate more with intrinsic cellular biology and procedural invasiveness. Furthermore, isolating the true therapeutic effect requires the standardization and reporting of confounding variables, such as immunosuppressive regimens and physical rehabilitation. Finally, by separating shorter-term efficacy measurements from long-term safety registries, the field can facilitate a more reliable and objective clinical translation.
Jun Kang, Senyu Yao, Songfu Zou et al.· BMC Medicine· 0 citations
Background and objectives Spinal cord injury (SCI) often results in permanent paralysis, leading to substantial long-term disability and loss of quality-adjusted life years. Strategies to preserve neural function in the hyperacute phase are needed. Transcutaneous spinal cord stimulation (tSCS) improves neurological function in chronic SCI. Earlier implementation in acute SCI may preserve or restore function and improve recovery. Methods STEP-RAISE is a Phase 1/2 prospective clinical trial evaluating the safety and preliminary efficacy of tSCS in acute moderate-to-severe traumatic SCI. Electrical current will be delivered to the lumbosacral spinal cord using the investigational ARC-Ex device (ONWARD Medical) via surface electrodes over the thoracolumbar region. Phase 2 is a randomized, triple-blinded, placebo-controlled trial designed to assess treatment effects. Safety outcomes include hemodynamics, spinal cord perfusion pressure, and skin reactions. Efficacy will be assessed using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) examination with electromyography at baseline, during stimulation, and at 6-month follow-up. Biomarkers include neuronal (UCH-L1) and glial (GFAP) markers and exploratory proteomics in blood and cerebrospinal fluid collected prior to stimulation and at discharge. Discussion The STEP-RAISE trial evaluates safety and preliminary efficacy of non-invasive tSCS initiated within 72 h of SCI to improve sensorimotor recovery. Neurophysiological and patient-reported outcomes will characterize recovery and assess whether early tSCS augments functional recovery. This study is designed to estimate treatment effects and inform subsequent trials in acute SCI. Planned enrollment includes 5 participants in Phase 1 and 10 in Phase 2. Clinical trial registration ClinicalTrial.gov: NCT07090473; first posted on 07/29/2025, first open to enrollment 04/2026. https://clinicaltrials.gov/study/NCT07090473
A. Keller, P. Kumar, Xuan Bradfield et al.· Frontiers in Neuroscience· 0 citations
Evidence indicates that EES may promote functional recovery in patients with chronic incomplete SCI and in a subset of those clinically classified as having “motor-complete” SCI; however, its therapeutic benefit is influenced by the complex interaction of multiple factors, including the integrity of spared pathways, the level of injury, stimulation parameters, electrode configuration, and rehabilitation intensity.
Fei Xie, Chao Bai, Xin-Ping Luan et al.· Frontiers in Medicine· 1 citation
Cervical spinal cord injury presents significant challenges in restoring motor function, particularly of the upper limbs, which are essential for daily activities and independence. Recent advances in neural stem/progenitor cell technologies have shown promise for restoring damaged neural circuits and improving hand function. However, clinical and preclinical evidence indicate that stem cell transplantation alone is often insufficient for optimal recovery, and the mechanisms by which rehabilitation can enhance stem cell integration and upper limb recovery after spinal cord injury remain poorly understood. Therefore, this review synthesizes current evidence on stem cell therapy and targeted rehabilitation and explores their combined potential to promote circuit reorganization and functional recovery. We discuss key developments in neural stem/progenitor cell applications, including optimal timing and delivery methods, alongside targeted rehabilitation approaches, such as task-specific training and environmental enrichment. By integrating findings across regenerative strategies and rehabilitative approaches, this review emphasizes the need for a multimodal approach that combines cellular therapies with effective rehabilitation protocols to overcome the inherent challenges of cervical spinal cord injury. Ultimately, this comprehensive perspective aims to guide future research and clinical practices, paving the way for improved outcomes for individuals living with cervical spinal cord injury.
Tenglin Li, T. A. de Santana, Erin Knock et al.· Regenerative Medicine Report...· 0 citations
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