SCI biology and pathobiology

SCI is difficult to treat because the injured spinal cord develops several interacting lesion compartments, including the non-neural lesion core, the astrocytic scar border, and the surrounding reactive neural tissue. Each region contributes differently to repair failure and recovery potential [6]. The non-neural lesion core forms at the center of injury and contains inflammatory cells, fibroblast-like cells, pericytes, newly formed blood vessels, extracellular matrix, and connective-tissue-like scar components. This environment is generally poorly permissive to axonal regrowth. The astrocytic scar border forms around the lesion core and separates the damaged tissue from surrounding spared neural tissue. This border can inhibit axonal extension through extracellular matrix molecules and scar-associated inhibitors, but it also helps contain inflammation and limit lesion expansion [7]. Animal studies suggest that spared neural tissue surrounding incomplete lesions may retain greater capacity for axonal sprouting, synaptic remodeling, and circuit reorganization than tissue surrounding complete lesions [8].

The observation that some individuals experience partial spontaneous recovery after SCI has prompted research into the mechanisms underlying residual circuit function, neuroplasticity, and endogenous repair. Recovery depends on injury severity, neurologic completeness, injury level, age, medical comorbidities, preserved descending pathways, and the extent of spared spinal circuitry [5, 9]. Studies of neurotrophic factors, cytokine signaling, immune-cell activation, and cellular remodeling within the injured spinal cord have helped identify therapeutic targets for enhancing plasticity and limiting secondary injury [10]. Spontaneous recovery is also shaped by the temporal evolution of inflammation. In the acute phase, resident microglia activate and peripheral immune cells, including neutrophils and monocyte-derived macrophages, infiltrate the injured cord. These cells can worsen secondary injury through pro-inflammatory cytokines, reactive oxygen species, proteases, and other cytotoxic mediators [11]. During later subacute and chronic phases, immune cells may also contribute to debris clearance, extracellular matrix remodeling, and trophic support. However, persistent inflammation can maintain an inhibitory microenvironment that limits axonal regeneration and functional recovery.

Neuroregeneration after SCI is challenging because the injured spinal cord contains both intrinsic limitations to axonal growth and extrinsic barriers created by inflammation, scar formation, demyelination, and inhibitory extracellular matrix molecules. SCI pathology is commonly divided into primary and secondary injury mechanisms. Primary injury refers to the initial mechanical trauma, which disrupts axons, neurons, glia, blood vessels, and spinal cord parenchyma. Secondary injury evolves over hours to weeks and includes ionic imbalance, calcium influx, glutamate-mediated excitotoxicity, mitochondrial dysfunction, oxidative stress, blood-spinal cord barrier disruption, edema, ischemia, demyelination, apoptosis, and inflammatory-cell recruitment. Over time, astrocytes, immune cells, fibroblast-like cells, pericytes, and extracellular matrix components contribute to formation of a structured lesion border often referred to as the glial or astrocytic scar [12]. This scar has a dual role. It can inhibit axonal regrowth through physical obstruction and growth-inhibitory molecules such as chondroitin sulfate proteoglycans, but it also helps contain inflammation, restrict lesion expansion, and protect surrounding spared tissue. Neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 have been investigated for their ability to support neuronal survival, axonal growth, and activity-dependent plasticity, although their effects depend on timing, delivery method, and injury model [13–15]. Overall, the immune response after SCI is dynamic rather than uniformly harmful or beneficial. Early inflammation can amplify secondary injury through cytotoxic mediators, while later immune activity may support debris clearance, tissue remodeling, and trophic signaling. However, if inflammation persists, it can sustain an inhibitory lesion environment and limit axonal regeneration. Understanding the timing, cellular composition, and molecular signaling of this immune response is essential for developing therapies that reduce secondary injury while preserving repair-supportive functions.

Contemporary translational research in SCI increasingly focuses on strategies that enhance neuroplasticity, axonal sprouting, circuit reorganization, and regeneration rather than simply preventing secondary injury. These approaches include activity-based rehabilitation, neuromodulation, molecular pathway modulation, biomaterial scaffolds, and cell-based grafting strategies. However, the translational landscape remains complex because many interventions that demonstrate axonal growth or functional recovery in animal models have not yet shown reproducible, generalizable benefit in large human clinical trials [16].

Terminology and conceptual distinctions

Several related but distinct technologies are discussed in the context of SCI rehabilitation. Brain-computer interfaces (BCIs), also referred to as brain-machine interfaces (BMIs), decode neural activity to control an external device, computer, prosthesis, or stimulation system. In contrast, brain-spine interfaces (BSIs) specifically establish a closed-loop connection between decoded cortical motor intent and targeted spinal cord stimulation, thereby attempting to restore communication between supraspinal motor centers and spinal sensorimotor circuits [17].

Neuromodulation is a broader umbrella term that refers to therapeutic alteration of nervous system activity through electrical, magnetic, pharmacologic, or other targeted interventions [18]. Epidural electrical stimulation (EES) involves surgically implanted electrodes placed in the epidural space to stimulate spinal circuits, whereas transcutaneous spinal cord stimulation (tSCS) is a noninvasive approach that delivers stimulation through surface electrodes placed over the spine [19].

Functional electrical stimulation (FES) applies electrical currents to peripheral nerves or muscles to generate task-specific movements such as grasping, cycling, or stepping. Neuromuscular electrical stimulation (NMES) similarly activates peripheral nerves or muscles, often with the goal of strengthening, preventing atrophy, or improving conditioning, although it may overlap with FES when used for functional movement tasks [20]. As peripheral muscle and nerve stimulation approaches are mechanistically distinct from spinal-circuit neuromodulation and BSI, they are discussed here only to clarify terminology rather than as a major focus of the review.