Bridging the gap: a translational perspective in spinal cord injury

Abstract

Traumatic spinal cord injury (SCI) is a devastating and complex condition to treat with no curative options. In the past few decades, rapid advancements in our understanding of SCI pathophysiology as well as the mergence of new treatments has created more optimism. Focusing on clinical translation, this paper provides a comprehensive overview of SCI through its epidemiology, pathophysiology, currently employed management strategies, and emerging therapeutic approaches. Additionally, it emphasizes the importance of addressing the heavy quality of life (QoL) challenges faced by SCI patients and their desires, providing a basis to tailor patient-centric forms of care. Furthermore, this paper discusses the frequently encountered barriers in translation from preclinical models to clinical settings. It also seeks to summarize significant completed and ongoing SCI clinical trials focused on neuroprotective and neuroregenerative strategies. While developing a cohesive regenerative treatment strategy remains challenging, even modest improvements in sensory and motor function can offer meaningful benefits and motivation for patients coping with this highly debilitating condition.

Keywords: animal models; clinical trials; neuroregeneration; pathophysiology; spinal cord injury.

FIGURE 1

Timeline of the pathophysiological developments of spinal cord injury (SCI). (A) The initial mechanical forces that contribute to lesion formation and necrosis, initiating SCI. (B) The acute phase of injury occurs following the initial injury. It is characterized by inflammation, ischemia, blood-spinal cord barrier (BSCB) disruption, immune cell infiltration and recruitment, demyelination, as well as excitotoxicity. This leads to further damage of the parenchyma beyond the initial lesion. (C) The subacute phase sees the recruitment of astrocytes from their quiescent state to reactive. Astrocytes are also derived from resident ependymal cells through neural stem/progenitor cell (epNSPC) differentiation. Predominantly epNSPCs differentiate into astrocytes, with few becoming oligodendrocytes and even less becoming neurons. The reactive astrocytes then contribute to further disruption of the BSCB, reduced glutamate uptake involved in excitotoxicity, and chondroitin sulfate proteoglycan (CSPG) deposition. Inflammation and ischemia also persist in this phase. (D) During intermediate and chronic phases of SCI, the reactive astrocyte border and fibrotic scar is formed and consolidated. The fibrotic scar contains type A pericytes, abnormal vasculature growth, and CSPG deposits. The scarring and cystic formation inhibits recovery. Created with Biorender.com.