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Importantly, their larger size provides a more relevant platform for drug development, bioengineering inventions, and electrophysiological and rehabilitation studies. Patients in Grade C and D had different degrees of motor function preservation and Grade E represented normal sensory and motor function. As time passes, SCI patients experience some spontaneous recovery of motor and sensory functions. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. In complete SCI, neurological assessments show no spared motor or sensory function below the level of injury 4. Patients with incomplete tetraplegia will gain better recovery than complete tetra- and paraplegia Patients generally reach a plateau of recovery within 9—12 months after injury Regaining some motor function within the first month after the injury is associated with a better neurological outcome Moreover, appearance of muscle flicker a series of local involuntary muscle contractions in the lower extremities is highly associated with recovery of function Importantly, initial muscle strength is an important predictor of functional recovery in these patients An association between sensory and motor recovery has been demonstrated in SCI where spontaneous sensory recovery usually follows the pattern of motor recovery 20 , Maintenance of pinprick sensation at the zone of partial preservation or in sacral segments has been shown as a reliable predictor of motor recovery One proposed reason for this association is that pinprick fibers in lateral spinothalamic tract travel in proximity of motor fibers in the lateral corticospinal tract, and thus, preservation of sensory fibers can be an indicator of the integrity of motor fiber Diagnosis of an incomplete injury is of great importance and failure to detect sensory preservation at sacral segments results in an inaccurate assessment of prognosis In the past few decades, various animal models have been developed to allow understanding the complex biomedical mechanisms of SCI and to develop therapeutic strategies for this condition. However, lack of clear distinction between Grades C and D and inaccurate categorization of motor improvements in patients over time, led to its replacement by other scoring systems Other classification methods followed Frankel's system. SCI commonly results from a sudden, traumatic impact on the spine that fractures or dislocates vertebrae. Grade B represented complete motor loss with preserved sensory function and sacral sparing. ASIA classification combines the assessments of motor, sensory and sacral functions, thus addressing the shortcomings of previous scoring systems The validity and reproducibility of ASIA system combined with its accuracy in prediction of patients' outcome have made it the most accepted and reliable clinical scoring system utilized for neurological classification of SCI This time-point has shown to provide a more precise assessment of neurological impairments after SCI One important predictor of functional recovery is to determine whether the injury was incomplete or complete. However, the majority of these trials failed to reproduce the same efficacy in human SCI. Notably, most injuries do not completely sever the spinal cord The most common form of primary injury is impact plus persistent compression, which typically occurs through burst fractures with bone fragments compressing the spinal cord or through fracture-dislocation injuries 8 , 12 , Impact alone with transient compression is observed less frequently but most commonly in hyperextension injuries 8. A precise record of ZPP enables the examiners to distinguish spontaneous from treatment-induced functional recovery, thus, essential for evaluating the therapeutic efficacy of treatments Complete loss of motor and preservation of some sensory functions below the neurological level of the injury is categorized as AIS B If motor function is also partially spared below the level of the injury, AIS score can be C or D The AIS is scored D when the majority of the muscle groups below the level of the injury exhibit strength level of 3 or higher for more details see Figure 1. Distraction injuries occur when two adjacent vertebrae are pulled apart causing the spinal column to stretch and tear in the axial plane 8 , Lastly, laceration and transection injuries can occur through missile injuries, severe dislocations, or sharp bone fragment dislocations and can vary greatly from minor injuries to complete transection 8. In SCI rats, infiltration of neutrophils, the first responders, peaks at 6 h post injury, followed by a significant decline at 24—48 h after SCI Similarly, in mouse SCI, neutrophil infiltration occurs within 6 h following injury; however, their numbers continue to rise and do not peak until 3—14 days post injury T cell infiltration also varies between rat and mouse SCI models Regardless of their pathophysiological relevance, mice have been used extensively in SCI studies primarily due to the availability of transgenic and mutant mouse models that have allowed uncovering molecular and cellular mechanisms of SCI In recent years, there has been emerging interest in employment of non-human primates and other larger animals such as pig, dog and cat as intermediate pre-clinical models 51 — 53 to allow more effective translation of promising treatments from rodent models to human clinical trials Although rodents have served as invaluable models for studying SCI mechanisms and therapeutic development, larger mammals, in particular non-human primates, share a closer size, neuroanatomy, and physiology to humans. Adults older than 60 years of age whom suffer SCI have considerably worse outcomes than younger patients, and their injuries usually result from falls and age-related bony changes 1. Lower thoracic lesions can cause paraplegia while lesions at cervical level are associated with quadriplegia 4. In the past decades, several scoring systems have been employed for clinical classification of neurological deficits following SCI. However, this scoring system failed to account for sacral function Moreover, integration of motor and sensory classifications was impossible in this system and it was abandoned due to complexity and impracticality in clinical settings These scoring systems also became obsolete due to their disadvantage in evaluation of sacral functions, difficulty of use or discrepancies between their motor and sensory scoring sub-systems In this system, sensory function is scored from 0—2 and motor function from 0 to 5 In this assessment, except upper cervical vertebrae that closely overlay the underlying spinal cord segments, the anatomical relationship between the spinal cord segments and their corresponding vertebra is not reciprocally aligned along the adult spinal cord At thoracic and lumbar levels, each vertebra overlays a spinal cord segment one or two levels below and as the result, a T11 vertebral burst fracture results in neurological deficit at and below L1 spinal cord segment. Over the past decades, a wealth of research has been conducted in preclinical and clinical SCI with the hope to find new therapeutic targets for traumatic SCI. Most of the functional recovery occurs during the first 3 months and in most cases reaches a plateau by 9 months after injury However, additional recovery may occur up to 12—18 months post-injury Long term outcomes of SCI are closely related to the level of the injury, the severity of the primary injury and progression of secondary injury, which will be discussed in this review. With recent advancements in medical procedures and patient care, SCI patients often survive these traumatic injuries and live for decades after the initial injury 5. They assessed the severity and prognosis of SCI using numerical sensory and motor scales This was a 5-grade system in which Grade A was the most severe SCI with complete loss of sensory and motor function below the level of injury. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. In , Bracken et al. One important factor is high degree of variability in the nature of SCI incidence, severity and location of the injury in human SCI, while in laboratory animal models, these variabilities are less Values acquired by clinical scoring systems such as ASIA or Frankel scoring systems lack the consistency of the data acquired from laboratory settings, which makes the translation of therapeutic interventions from experimental to clinical settings challenging A significant effect from an experimental treatment in consistent laboratory settings may not be reproducible in clinical settings due to high variability and heterogeneity in human populations and their injuries To date, several pharmacological and cellular preclinical discoveries have led to human clinical trials based on their efficacy in improving the outcomes of SCI in small animal models. Depending on the level of SCI, patients experience paraplegia or tetraplegia. Nonetheless, both small and large animal models of SCI have limitations in their ability to predict the outcome in human SCI. Demographically, men are mostly affected during their early and late adulthood 3rd and 8th decades of life 2 , while women are at higher risk during their adolescence 15—19 years and 7th decade of their lives 2. Compared to civilian SCI, blast injury is the common cause of SCI in battlefield that usually involves multiple segments of the spinal cord Blast SCI also results in higher severity scores and is associated with longer hospital stays A study on American military personnel, who sustained SCI in a combat zone from to , showed increased severity and poorer neurological recovery compared to civilian SCI Moreover, lower lumbar burst fractures and lumbosacral dissociation happen more frequently in combat injuries 1. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. Paraplegia is defined as the impairment of sensory or motor function in lower extremities 27 , Complete paraplegic patients, however, experience limited recovery of lower limb function if their NLI is above T9 Tetraplegia is defined as partial or total loss of sensory or motor function in all four limbs. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. An ideal animal model should have several characteristics including its relevance to the pathophysiology of human SCI, reproducibility, availability, and its potential to generate various severities of injury Small rodents are the most frequently employed animals in SCI studies due to their availability, ease of use and cost-effectiveness compared to primates and larger non-primate models of SCI 36 , Among rodents, rats more closely mimic pathophysiological, electrophysiological, functional, and morphological features of non-primate and human SCI In rat 39 , cat 40 , monkey 41 , and human SCI 17 , a cystic cavity forms in the center of the spinal cord, which is a surrounded by a rim of anatomically preserved white matter. The age distribution is bimodal, with a first peak involving young adults and a second peak involving adults over the age of 60 3. There is a reported male-to-female ratio of for SCI, which happens more frequently in adults compared to children 2. Regardless of the form of primary injury, these forces directly damage ascending and descending pathways in the spinal cord and disrupt blood vessels and cell membranes 11 , 16 causing spinal shock, systemic hypotension, vasospasm, ischemia, ionic imbalance, and neurotransmitter accumulation Overall, the extent of the primary injury determines the severity and outcome of SCI 20 , Functional classification of SCI has been developed to establish reproducible scoring systems by which the severity of SCI could be measured, compared, and correlated with the clinical outcomes Generally, SCI can be classified as either complete or incomplete. Thus, in pre-clinical studies, animal models, and study designs should be carefully chosen to reflect the reality of clinical setting as closely as possible {/INSERTKEYS}{/PARAGRAPH} Reports on the clinical outcomes of patients who suffered SCI between and in Australia demonstrated that survival rates for those suffering from tetraplegia and paraplegia is The life expectancy of SCI patients highly depends on the level of injury and preserved functions. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. {PARAGRAPH}{INSERTKEYS}Traumatic spinal cord injury SCI is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Therefore, it is critical to unravel the cellular and molecular mechanisms of SCI and develop new effective treatments for this devastating condition. Spinal cord injury SCI is a debilitating neurological condition with tremendous socioeconomic impact on affected individuals and the health care system. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. There are also distinct differences between the outcomes of SCI in military and civilian cases. A study by Metz and colleagues compared the functional and anatomical outcomes of rat contusive injuries and human chronic SCI High resolution MRI assessments identified that SCI-induced neuroanatomical changes such as spinal cord atrophy and size of the lesion were significantly correlated with the electrophysiological and functional outcomes in both rat and human contusive injuries Histological assessments in rats also showed a close correlation between the spared white matter and functional preservation following injury These studies provide evidence that rat models of contusive SCI could serve as an adequate model to develop and evaluate the structural and functional benefits of therapeutic strategies for SCI Mice show different histopathology than human SCI in which the lesion site is filled with dense fibrous connective-like tissue 43 — Another key difference between rat and mice SCI is the time-point of inflammatory cell infiltration.