3. Pathophysiology of spinal cord injuries

A comprehensive understanding of the neuropathological alterations after a SCI is the crucial part in designing effective therapeutic strategies. The SCI is primarily due to either compression or contusion [8]. The fundamental mechanisms that are involved in initial and later stages of SCIs include vascular complications, inflammation, lipid peroxidation, demyelination and apoptosis [9].

### 3.1. Vascular disorders

1. Introduction

124 Essentials of Spinal Cord Injury Medicine

cord tumors [2, 3].

controversies and other emerging technologies.

2. Global prevalence of spinal cord injuries

Spinal cord injury (SCI) is an extremely devastating condition with no proper effective treatment strategies till date. Instead of all the recent comprehensive research, SCIs still remain as one of the most intimidating challenge in the field of neurological sciences [1]. The increasing prevalence of SCIs specifically in young generation has caused a serious clinical, social and economical burden across the globe. According to a report by World Health Organization, SCIs has affected people worldwide with an estimated incidence rate of ~80 cases per million population [2]. The causes for SCIs could be a result of traumatic (~90%) or non-traumatic (~10%) events. Although the percentages of traumatic SCIs are high, recently it has been estimated that percentages of non-traumatic SCIs are also increasing majorly due to spinal

Following SCIs, severe damages to the neural tissue occur followed by further damages to the neural circuitry, which results in loss of sensorimotor functions [4]. So much of the pathophysiological events cause serious failures in body system that makes it harder or nearly impossible to treat. In addition to neurorehabilitation, the highly established therapeutic strategies for SCIs focus on protocols that can induce early neurological protection and prevent secondary SCIs. While these procedures have revealed to encourage locomotional recovery in affected individuals with incomplete SCIs, the therapeutic outcome in patients with life-threatening incomplete and complete SCIs continues to be disappointing [5]. These kind of therapeutic failures are due to the deficiency of natural regeneration of injured axons where demyelination has occurred. Till date, various number of significant in vivo studies that are predominantly experimented on the model of mammalian SCIs in the recent years have contributed to the establishment of several regenerative approaches including neuroprotective therapeuticscoupled regeneration and cellular transplantation with neurotrophic activity. In this review, we are intended to cover pathophysiological mechanisms following SCI, preclinical and clinical updates of cellular transplantation that majorly involve cells population derived from human embryonic stem cells (hESCs), mesenchymal stem cells (MSCs) and human-induced pluripotent stem cells (iPSCs), the extent of success from cellular transplantation, associated

According to World Health Organization (WHO) report, individuals suffering from SCIs hold 2–5 times more chances of premature death compared to non-SCI individuals, whereas the ratio of survival rate get worsen in low and middle income countries [2]. The high morbidity ratio of SCIs has driven widespread exploration into treatments and rehabilitations to recover neural function after SCIs. The incidence and prevalence rate of SCIs, in particular of traumatic SCIs, varies widely among different regions across the globe, mainly due to fluctuating sources of facts and figures and missing or unrecorded data [6]. Apart from including sudden deaths from SCIs, the annual incidence rate of traumatic SCIs across the globe is 2.5–83 cases/per million Ischemia, hemorrhage, systemic hypotension and microcirculatory disturbances are the vascular manifestations due to SCI [10]. The major decrease in blood flow at the lesion site occurs immediately after SCI [11], while the ischemia becomes worsen in the first few hours [9]. After a period of ischemia, blood reperfusion occurs with increased free radicals that lead to reperfusion paradoxical damage [12]. The disruption of small blood vessels and hemorrhage affects more of the local microcirculation than the large arteries, which leads to a failure of glutamatemediated excitotoxicity and autoregulation. Additionally, severe systemic hypotension increases the microcirculation dysfunction and exacerbates injury [13].

#### 3.2. Inflammation

After a SCI, the perniciousness from inflammation to the nervous tissue influences the cells to get into necrosis in the injured site. At this stage, different immune cells, including neutrophils, monocytes, microglia and T-lymphocytes, secrete certain cytokines such as tumor necrosis factor-α, interleukin-1β and interleukin-6, which lead to apoptotic cell death [14]. First, the neutrophils aggregate at the damaged area and release cytokines, proteases and free radicals that lead to more inflammation while involving glial cells in the inflammatory process, which eventually induce cell death [9]. This is followed by the infiltration of monocytes into the injury site, which is followed by differentiation into macrophages. The monocytes and a recently triggered microglia secrete cytokines, free radicals and growth promoting factors. The Tlymphocytes secrete neurotrophins and modulate microglia to protect neurons from degeneration [15].
