Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord

Traumatic brain injury (TBI) and spinal cord injury (SCI) represent significant global health challenges, resulting in profound and often permanent disability. Unlike peripheral tissues, the central nervous system (CNS) has a very limited innate capacity for repair because neurons do not regenerate or replicate after damage. Recovery is further hindered by complex, secondary pathological responses that continue long after the initial injury. This paper reviews the pathophysiology of these injuries and outlines the current state of clinical management and regenerative research.

Damage in neurotrauma occurs in two phases. The primary injury is the immediate physical trauma, which is generally not modifiable. The secondary injury phase involves a cascade of deleterious processes that propagate cell loss and create a non-permissive environment for repair. Key mechanisms include mitochondrial dysfunction, oxidative stress, excitotoxicity (uncontrolled neurotransmitter release), and the formation of a glial scar. Following injury, microglia and astrocytes adopt reactive phenotypes—some of which are pro-inflammatory (e.g., M1 microglia, A1 astrocytes) and contribute to further tissue damage, while others attempt to support wound healing. The consolidation of the glial scar, rich in inhibitory proteins, creates a physical and chemical barrier that actively prevents axonal regrowth.

Currently, clinical management is largely supportive, focusing on mitigating secondary injury through methods such as intracranial or intraspinal pressure control and optimizing tissue perfusion. Pharmacological interventions targeting individual molecular pathways have consistently failed in clinical trials, likely because these isolated approaches cannot adequately address the multifaceted nature of the secondary injury cascade. The authors propose that future progress requires moving toward combinatorial therapies—such as combining stem cell transplantation with hydrogel scaffolds, or using multi-target drug strategies—to simultaneously protect neural tissue, modulate the local immune environment, and stimulate regeneration. Additionally, the development of early biomarkers for neuroregeneration is urgently needed to provide real-time validation of therapeutic efficacy in clinical settings.