Spinal cord injury (SCI) is a disabling condition that disrupts motor, sensory, and autonomic functions. The lack of effective therapeutic strategies for patients with SCI reflects its complex pathophysiology that leads to the point of no return in its function repair and regeneration capacity. Herein, a detailed description of the physiology and anatomy of the spinal cord and the pathophysiology of SCI is presented.
1. Spinal Cord Anatomy and Physiology
The spinal cord is the major communication channel between the body and the brain. Additionally, the spinal cord can independently respond to sensory information without input from the brain through reflex arcs and produce repetitive patterns of motor behavior using self-containing circuits known as Central Pattern Generators (CPGs). The spinal cord extends from the base of the brain in the medulla oblongata through the foremen magnum of the skull to the L1/L2 lumbar vertebra, where it terminates as the conus medullaris. Distal to this end of the spinal cord is a collection of nerve roots called the cauda equina. Like the brain, which is protected by the cranium, the spinal cord is likewise protected by a bone structure called vertebral column. The spinal cord is also protected by three membranes of connective tissue called meninges (dura mater, arachnoid mater, and pia mater). The subarachnoid space (between arachnoid and pia), which is filled with cerebrospinal fluid, and the epidural space (between dura and periosteum), which is filled with loose fibrous and adipose connective tissues, also helps to protect the spinal cord .
The spinal cord has numerous groups of nerve fibers going towards and coming from the brain. The tracts are described according to the funiculus within which they are located. The ascending tracts usually start with the prefix spino- and end with the name of the brain region where spinal cord fibers first synapse (e.g., spinothalamic tract). The descending motor tracts begin with the prefix denoting the brain region that gives rise to the fibers and ends with the suffix -spinal (e.g., corticospinal tract) .
2. Spinal Cord Injury
A spinal cord injury is a devastating event that leads to motor, sensory, and autonomic dysfunctions. The complexity of this event and the lack of an effective treatment make SCI a worldwide problem. A study performed by the Global Burden of Diseases, Injuries and Risk Factors (GBD) reported 0.93 million (0.78–1.16 million) new SCI cases globally, with a prevalence of 27.04 million cases (24.98–30.15 million) . The annual incidence of SCI varies greatly from region to region: 7 to 37 cases per 100,000 individuals . In the United States, traffic accidents are currently the leading cause of injury (38%), followed by falls (30%), violence (13.5%), and sports/recreation accidents (9%) . The average age at injury is 42 years, and 80% of spinal cord injuries occur in males .
2.1. Primary Injury
2.2. Secondary Injury
2.2.1. Permeability and Vascular Alterations
2.2.2. Ionic Disruption and Glutamate Excitotoxicity
2.2.3. Metabolic Alterations
Ischemia, oxygen deprivation, and oxidative stress lead to the production of high levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) . As a consequence, ROS and RNS are strongly reactive with polyunsaturated fatty acid of the cellular membrane, leading not only to lipid peroxidation, but also to damage at the protein and nucleic acid levels. Furthermore, the formation of free radicals also invokes architectonic alterations of the cytoskeleton and organelle membranes, mitochondrial dysfunction, and increased intracellular Ca2+ uptake .
2.2.4. Inflammatory Response
Inflammation is a major “secondary injury” event, and its dysregulated nature leads to more neuronal damage . Initiation of the “secondary injury” leads to cell activation of astrocytes, fibroblasts, pericytes, and microglia. The BSCB disruption further drives injury progression by facilitating the infiltration of non-resident cells. Peripheral immune cells invade the injury site and chronically persist within the spinal cord . Fibroblasts, which infiltrate from the periphery or differentiate from other resident cells, deposit inhibitory extracellular matrix (ECM) components that aggravate the inflammatory environment . Moreover, SCI generates cellular debris and releases intracellular proteins that induce potent inflammatory stimuli. This debris signal, also called damage-associated molecular patterns (DAMPs), is usually hidden from immune surveillance within the intact CNS . After an injury, DAMPs engage pattern recognition receptors (PRR) of inflammatory cells involved in foreign microbe detection . As a result of the rapid DAMP- and PRR-mediated activation, resident and peripheral inflammatory cells are recruited to the lesion site . Consequently, these cells release various oxidative stress regulators, cytokines, chemokines, and other inflammatory mediators that exacerbate the inflammatory response .
Regarding microglia, the cellular morphology and protein expression profiles are altered following SCI. Microglia cells retract their processes and assume an amoeboid morphology, making them better prepared for phagocytosis and debris clearance. Reactive microglia closely resemble circulating macrophages in terms of morphology, protein expression profile, and function . Together with morphological changes, the release of chemokines and cytokines recruits neutrophils and macrophages into the injured spinal cord . The first type of infiltrating immune cells are the neutrophils, which, in rodents and humans, have their peak within the spinal cord around 1-day post-injury . The by-products produced after neutrophil-mediated phagocytosis create a cytotoxic environment with the production of ROS and reactive nitrogen species (RNS) .
2.2.5. Inhibitory Environment
The regeneration of CNS following injury is reduced due to multiple inhibitory factors at the injury site. Several researchers have shown that there is an initial growth response following injury; however, once axons encounter this inhibitory environment, the growth is blocked, leaving dystrophic axonal end bulbs in their place . Within the CNS, cells are surrounded by an ECM composed of a complex and interactive network of glycoproteins, proteoglycans, and glycosaminoglycans . Under different circumstances, these molecules can either promote neurite outgrowth, such as during neuronal development , or inhibit it, such as after injury  or after neural degeneration .
Axonal retraction occurs in two phases: an early axon intrinsic, cytoskeleton-associated phase, in which Ca2+-dependent activation of calpain proteases leads to cytoskeletal breakdown , and a macrophage-dependent phase, in which infiltration of phagocytic macrophages correlates with retraction of dystrophic axons . Alongside this, there is an increase in the number of inhibitory proteins, including myelin-associated inhibitors (MAIs), chondroitin sulfate proteoglycans (CSPGs), as well as growth-inhibiting molecules such as proneurotrophins .
Nogo-A, oligodendrocytes myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG) have all been identified as MAIs that can collapse axonal growth cones and inhibit neurite outgrowth . Nogo-A was identified as a neurite growth inhibitor in the 1980s . The evidence of inhibitory effects of Nogo-A came from in vitro studies in which exposure of chicken retinal ganglion and rat dorsal root ganglion (DRG) neurons to Nogo-A was shown to inhibit neurite outgrowth and induce growth cone collapse . The OMgp is also expressed in oligodendrocytes and several types of CNS neurons, such as pyramidal cells in the hippocampus and Purkinje cells in the cerebellum, among others . Although less is known about OMgp in comparison to Nogo-A and MAG, it has also been shown to be a potent inhibitor of neurite outgrowth in multiple cell lines and primary neuronal cultures .
MAG is a minor component of mature, compact myelin, enriched in the periaxonal membrane of the myelin sheath, and is expressed by oligodendrocytes and Schwann cells . The inhibitory effect of MAG was found in studies investigating its interaction with primary neurons. Purified recombinant MAG was found to block neurite outgrowth and induce growth cone retraction . The inhibitory properties of MAG were further confirmed by Tang and colleagues, demonstrating that myelin from MAG knockout mice was not inhibitory to the growth of DRG neurons in vitro compared to myelin from wild-type mice . Furthermore, inhibition of neurite outgrowth was completely abolished by immunodepletion of MAG from the soluble fraction of myelin-conditioned media . These observations suggest that soluble MAIs, likely released after injury, can influence the growth capacity of neurons and axons in addition to myelin debris.
The ECM of the CNS is rich in CSPGs, some existing within the extracellular milieu and others associated with specific structures. Within the CNS, CSPGs can associate with specialized structures, denominated perineuronal nets (PNNs), which surround the soma and dendrites of mature neurons. The PNNs are ECM proteins including hyaluronan, CSPGs, and linking proteins . There are also a number of CSPGs, such as brevican, neurocan, aggrecan, and versican, which bind to the hyaluronan backbone of the PNN .
Maintenance of this specialized structure is important for synaptic and network stabilization and homeostasis. Specifically, PNNs stabilize mature neurons by reducing dendritic spine plasticity , forming a scaffold for synaptic inhibitory molecules  and also restricting the movement of receptors at the synapse . The formation and maturation of PNNs are concurrent with the development and maturation of the nervous system. After injury, CSPGs are actively secreted into the ECM, mainly by reactive astrocytes , but with a minor component secretion by macrophages and oligodendrocytes . This results in an abundance of CSPGs at the injury site, adding to the inhibitory milieu. The inhibitory effect of the CSPGs is mediated through the protein tyrosine phosphatase sigma (PTPσ) receptor. When CSPGs bind to PTPσ receptors, the GTPase Rho/ROCK signaling pathway is activated. In neurons, this inhibits axonal growth, leading the growth cone into a dystrophic state .
2.2.6. Spinal Cord Scarring
As referenced above, SCI activates astrocytes, pericytes, and fibroblasts, promoting the development of a glial/fibrotic scar. Astrocytes activation and subsequent glial scar boundaries are enhanced by the increase in transforming growth factor-beta (TGF-β) . TGF-β increases microglia/macrophage and astrocyte activation, as well as fibronectin and laminin deposition . Moreover, the signal transducer and activator of the transcription 3 (STAT3) transcription factor is important in establishing glial scar borders that isolate infiltrating cells into the lesion epicenter .
2.3. Chronic Phase
Following the secondary injury, the chronic phase is established, and this can lead to the continuous expansion of the lesion site of the patients with SCI. The chronic phase is characterized by scar maturation, cystic cavitation, and axonal dieback . The process of Wallerian degeneration of injured axons is ongoing, and it may take years for severed axons and their cell bodies to be entirely removed . The lesion may not remain static and syrinx formation may occur, commonly causing dissociated sensory reduction, deterioration of motor function, and neuropathic pain .