Spinal Cord Injury Prevalence and Treatment Modalities

Abstract

Spinal cord injury (SCI) is a devasting neurological condition producing physical dependency, morbidity, psychological stress, and financial burden. During the last 30 years, its global prevalence has increased from 236 to 1298 cases per million populations. Two types of spinal cord injury are primary and secondary injury. Primary injury is mechanical damage to the cord itself whereas secondary injury results from one or more biochemical and cellular processes that are triggered by the primary lesion. In 1700 BC, in an Egyptian surgical papyrus, they describe the frustration of health care professionals in treating a severe spinal cord injury, the Papyrus reported spinal fractures as a “disease that should not be treated”. Most of these studies approach a patient with acute spinal cord injury (ASCI) in one of four manners: corrective surgery or a physical, biological, or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at a minimum, allow for partial functional recoveries for these patients, which could improve their quality of life. More studies were done on spinalized animals that indicate that most of these pharmacological agents may act on receptors present in the spinal cord, thus facilitate to produce coordinated locomotor movement, whereas some other drugs used to improve the neuropathological changes caused because of spinal cord injury (SCI), such as spasticity or demyelination, to improve walking.

1. Introduction

Spinal cord injury (SCI) has a very tremendous impact on the affected individuals and their families, within developed nation annual cases of SCI are 11.5–53.4 cases per million, whereas alone in North America, over 1 million people are affected with direct lifetime costs around $1.1–4.6 million USD each [1, 2, 3]. The incidence rate of SCI has bimodal distribution having a different mechanism of injury from high energy impact in which youngsters are mostly affected i.e., motor vehicle accidents and injuries related to sports, to low energy injuries in which mostly older are affected i.e., fall from standing in the context of pre-existing stenosis. In Tehran, the annual incidence of SCI is 44 cases per 1, 000, 000 [4], whereas in European countries 5.5–195.4 cases per million [5]. Due to sensory and motor impairments, immobility, prolonged hospital stay, and changes in skin composition these subjects are more prone to develop pressure ulcers [6, 7]. Around 30–40% of SCI subjects develop pressure ulcers during the acute phase of injury and rehabilitation [8]. Ludwig Guttmann one of the great pioneers in the field of SCI rehabilitation explains in the year 1976 that SCI is the greatest disaster for affected human beings as along with disability it also leads to dysfunction of many body organs such as respiratory system, GIT, urinary and autonomic system including Joints, bones, and Skin. Due to dysfunction of multiple organs leads to immobility, serious complications &high mortality rate during both chronic & acute phase of injury.

2. Pathophysiology of SCI

After spinal cord injury, cord compression is the most common mechanism of injury and it is continued after injury [9]. Due to mechanical injury, because of rotation dislocation, flexion, extension, or distraction forces give rise to penetrating injuries and strain in vascular structure and in neural tissues [9]. Mechanical damage to bone and ligaments is related to cord compression, which gives rise to hematomas in the channels of the spinal cord [10]. During the early period of injury, bleeding begin to occur after spinal trauma and is later followed by the interruption of blood supply to nearby tissues because of cord compression [11]. Hypoxia and local ischemic infraction are the two main causes that create hindrance in blood flow after SCI [12]. The grey matter of the spinal cord is mostly damaged because of hypoxia and local ischemic infraction, where the metabolic function is high. Physically fractured neurons and reduced thickness of myelin sheath are mostly found in the damaged area [13]. In the damaged tissues deterioration in the neuronal transmission is promoted by edema and macrophage accumulation [14].

Secondary damage can be initiated by primary damage, whereas a number of pathophysiological mechanisms can come into play even hours and days after developing SCIs [15]. At the cellular level most notable mechanism that occurs after a secondary injury is lack of energy because of ischemia and impaired perfusion [16], Mostly after the occurrence of Traumatic SCI ischemia occurs immediately, and if it is left untreated, within after 3 hours additional damages occur which continue for at least 24 h [17, 18]. After secondary injury other crucial changes such as hemorrhage, edema, demyelination, axonal and neuronal necrosis along with the formation of cavity occurs, along with a series of pathological changes in nerve tissue following SCI, which gives rise to infarction [19], excitotoxicity, oxidative damage and ischemia, mostly occurs due to increased level of glutamate, whereas secondary damage in spinal cord occurs due to synthesis of Ca2+-dependent nitric oxide [20, 21]. After secondary injury, oxidative damage and lipid peroxidation occur in the cell membrane and neuronal death occurs because of activation of secondary injury signaling cascades at the areas of injured tissue [12, 22]. N-methyl-D-aspartate (NMDA) receptors, throw a direct influence of the excitatory neurotransmitter in the spinal cord [23]. In animal models studies have revealed that the spinal cord affected by trauma and ischemia can be protected by blocking this NMDA receptor [23, 24], antagonists of NMDA receptor thus help in improving neurological outcomes and preventing the incidence of edema [25, 26], magnesium ions acts as antagonists of the NMDA receptor [14]. One of the previous studies has shown the role of antagonists of NMDA receptor i.e., α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA), in improving neurological function as well in reducing the injured area when it is administered [27]. One of the important excitatory neurotransmitters is glutamate located in the CNS, if over activation of this glutamate receptor occurs then it causes damage to neurons [28], so in the case of SCI, elevation in the level of excitatory amino acids including glutamate and aspartate occurs [29], within 15 min of SCI these excitatory amino acids reach to their toxic levels and it can last for more than 120 min [30]. After SCI, regeneration of axons in mammals is least, and they cannot regenerate correctly, which leads to permanent paralysis, soon after the injury at the injured site glial reactions occur and they form glial scar [31], microglia, oligodendrocyte precursors, meningeal cells, astrocytes and stem cells, as well as oligodendrocytes and myelin fragments are recruited by glial response [32, 33], but axon regeneration is inhibited by molecules release by these cells that hampers regeneration of neurons [34, 35]. Another important recovery inhibitory known as chondroitin sulfate proteoglycan (CSPG), is also produced by glial scar [36], so administration of natural bacterial enzyme Chondroitinase ABC (ChABC) helps in degrading the inhibitory carbohydrate side chains on CSPG, as well it also promotes regeneration of sensory axons and cortico spinal cord [37]. Growth-promoting effects of Chondroitinase ABC is because of the elimination of perineuronal nets, increased germination of spare axons, and the formation of new synaptic connections under the injured sites [38]. In the severed axon on the bridge side, ChABC promotes axonal regeneration [37]. Its potential therapeutic effect has been shown mostly in an animal model of SCI, nigrostriatal injury, and stroke [39, 40, 41]. PUFA or polyunsaturated are lipids have roles in the central nervous system, especially the major role is played by docosahexanoic acid, one of the major class of omega-3 fatty acids. Over the past decades, studies have proved the major role of omega-3 fatty acids in various CNS disorders including Zellweger syndrome, schizophrenia, depression, and Alzheimer’s disease [42]. Many studies on the animal model had proved its beneficial effect on different animals [43, 44, 45]. These mentioned studies have proven the neuroprotective effect of omega-3 fatty acids in ameliorating inflammatory responses [46, 47], decreasing oxidative stress, and suppressing glutamate-induced cytotoxicity, both in vivo and in vitro [48, 49, 50, 51].

3. Epidemiology

3.1 Indian epidemiological data

According to Chhabra HS [52] his retrospective study showed that (data between 2000 and 2016) during the study period the mortality rate was 10%, while the data from 16 years (758) subjects, quadriplegics, and paraplegics were 39% (294) or 61% (464). 679 subjects were approximately 81% male; the death rate from quadriplegia and paraplegia was 22% and 3%, respectively. Respiratory disease is the leading killer of hospital deaths. Due to the death rate in hospitals, there is a need to focus on respiratory management and the prevention of infections, especially in quadriplegics.

Jha RK, et al. [53], demonstrated in their prospective study observed that the major cause of spinal cord injury is RTA (road traffic accident) along with hills, roofs, trees, electricity pole, and stairs (70%) followed by fall from height, including trees, hills, stairs or roof of home (28%), most common age group is s 20–39 years followed by 50–59 years, cause of injury in age group 50–59 years is because of fall. Male is more prone to SCI, they collected data from march 2019 to march 2020 total of 198 cases (68 cases had thoracic injury. 86 patients had a lumbar spine injury and 22 patients had a cervical spine injury, and rest 22 patients had spine injury at more than one segment), 138 cases fall under the age group 25–50 years, whereas remaining 41 subjects were below 25 years of age and 19 subjects were found in 50 plus age group. Out of 198 cases, 136 cases were of RTA, 52 cases were of fall from height, 8 cases were of assault, 2 cases came after trivial injury who were later found to have atlantoaxial dislocation.

Sengupta D et al. [54] showed in their descriptive retrospective study that in patients with cervical spinal cord injury in low-middle-income countries (LMIC), ventilation exposure, hospitalization, and mortality are high and the main cause of mortality among them is due to poor AIS values, extended VD, intensive care and hospital stays, comprehensive CSCI rehabilitation programs are required to overcome this situation.

Jain M. et al. [55], in its retrospective observational study in the population of East India, collected data on August 15, 2018, and August 14, 2019, by including 103 patients with the injury in their study followed by RTA (37.9%), the ratio of men to Women (M: F) 5.87: 1, the most common age group in their study is 31–40 years, followed by 21–30 years and 41–50 year old.

According to Mittal S., et al RTA is the most common type of injury in men and FFH is the most common type of injury in women. The thoracolumbar junction (D10-L2) (37.5%) followed by the cervical spine (25.3%) is the most common injury site, and variations between the age group was 16–30 years were also observed in their study. Men were mainly affected in May/June (monsoons), while women mainly suffered trauma in March/April (summer).

Mathur and colleagues (2015) demonstrated in their study that occupational hazards like FFH (53%) & RTA (23%), carrying heavy object overhead (3.0%), and fall following electric shock (4.0%), and married couples are at high risk for spinal cord injury in comparison to singles, in their study married subjects were 58.3% which is similar to the studies from the Western countries (57.7%) [56].

Another study by Rai S et al., [57] also reported that the percentage of married couples was more in comparison to singles (70%).

Nirmala BP et al. [58] describe the socio-demographics of the subjects and showed that of 60 subjects, 36 were men (60%), while 23 subjects (38.3%) completed secondary school and 19 (31.7%) completed primary education level, 7 (11.7%) subjects have completed university education, 6 (10.0%) were illiterate. Students, day laborers, and housewives were 17 (28.3%), 16 (26.7%) and 13 (21.7%), respectively. 35 patients (58.3%) were married. 27 (45.0%) came from low-income families and 32 (53.3%) came from middle-income families. Both patients with traumatic SCS and non-traumatic SCS belong to the rural community compared to the urban community.

Krishnamurthy G, et al. [59] in his hospital-based cross-sectional study showed that younger age groups (20–49 years of age) were most often affected compared to older age groups of 50 years and over, while the most common injury site was at the level of the thorax (64.3%) followed by a lower cervical level in 21.4% of the cases. Patients with incomplete SCI (39.2%) were stronger compared those to a complete spinal cord. People with injuries (60.8%).

A study by Yusuf et al. [60] on 133 patients with traumatic paraplegia came to the conclusion that the majority of the patients were younger, in 72.2% of the cases road traffic injuries were the most common type of injury, the most common injury site is the cervical spine (62%) and complete spine injury (52.6%) is the most common type of injury in their study.

While in another study by Aswani Kumar et al. [61] in 152 SCI cases, adolescents were most affected, in which 71.7% of the cases were construction workers, this means in their study that a fall from a great height is a common form of injury (61.2%). Cases of cervical spine injury were 44.1%.

GZ et al. [62] showed in their review that in Asia the incidence rates of traumatic spinal cord injuries ranged from 12.06 to 61.6 per million and the mean age ranged from 26.8 to 56.6 years when male subjects were exposed to high risk are female and common types of injuries are motor vehicle collisions (MVCs) and falls, however, most countries have reported war injuries as the leading cause. The neurological level and extent of injury were mixed and subjects were classified based on AIS/Frankel grade A.

Chacko V, et al. [63] showed that of 218 subjects with spinal cord injuries who were admitted to a general hospital in rural India, 125 subjects were characterized by a neurological deficit. Infections and pressure ulcers were reported, and patients with injuries to the cervical spine were mostly eliminated, so their study emphasizes that general hospitals have no facilities.

Sridharan N, et al. [64] examined the epidemiology of spinal cord injuries in indoor patients (245) of the Rajiv Gandhi Government General Hospital, Chennai, India, and showed in their study that men are most affected compared to women (216 men). Subjects), the ratio between the male and female population is 8.8: 1.2, and the most common age group is ages 20–40 and the most common type of injury is a fall from a height, such as an injury in men is in Area of the cervical spine (C5 and C6) was high, followed by injuries in the segments at the dorsal level and on the lumbar spine, whereas in women the most common injury site was on the lumbar spine.

According to Pandey V et al. [65], RTA is the second largest mode of injury in SCI it is because of increased number of vehicles in metropolitan cities of a developing country like India so to minimize this traffic-related accidents strict traffic rules must be enforced on the public.

In another retrospective study by Lalwani S et al. [66] a total of 341 such cases were identified between January 2008 and December 2011, of which 288 people were male and 53 people were female, most people were between 25 and 64 years old, followed in young adults between 16 and 24 years of age (19, 35%) the ratio between men and women is 5.4: 1, 55% of the cases had isolated spinal injuries, cases had isolated spine injuries, cervical spine injury was observed in 259 patients (75.95%), thoracic spine injury was observed in 56 patients (16.42%) and thoracic spine injury was observed in 26 patients (7.62%) a thoracic and lumbar spine was observed. A higher drop in energy (44.28%) is the most common type of injury, followed by an RTA (41.93%); the patient’s death mostly occurred in phase IV (secondary to tertiary complications of the trauma, i.e., > 1 week), while in phase I forty patients died (brought dead or survived 3–24 h) and 70 in phase III (> 24 h to 7 days).

3.2 Worldwide epidemiological data

One of the most recent retrospective studies by Chen J, et al. [67] in the Chinese province of Guangdong via TSCI showed that the male to female ratio was 3.4: 1, meaning that of 482 cases, 384 subjects were male and 112 were female. The most affected age group was 45–60 years (41.7%), followed by 31–45 years (23.8%), the most common type of injury was a fall from a height (49.3%), followed by motor vehicle collisions (MVCs) (34.8%), and the most common injury site was the cervical spinal cord, C4–C6, which accounted for 39.8%.

Another descriptive cross-sectional study from Korea by Kim HS et al. [68] has shown that of 221 patients with spinal cord injury (161 traumatic and 60 non-traumatic) the most frequently affected age group was between 40 and 49 years, while in the case of non-traumatic SCI the age group affected by traumatic SCI was between 70 and 79 years. Male subjects were mainly affected by TSCI, compared to non-TSCI, while the most common cause of TSCI was a drop (37.3%), followed by a car accident (35.4%).%) and stumbling (19.3%) and, in non-traumatic SCI, neoplasia (35.0%). Tripping is the main cause, especially in the elderly.

Johansson E, et al. [69] in their prospective cohort study on SCI subjects from Finland over a 4 year period they enrolled 346 subjects and observed that the leading cause of injury were low-level falls (36.2%), high-level falls (25.5%), and transport-related accidents (19.2%), fall from height is the common mode of injury in subjects above 60 years of age, whereas in subjects below 60 years of age 47.4% cases were alcohol-related. Cervical injury is the most common type of injury in subjects above 60 years of age (77.1%), while less common in subjects below 60 years of age (59.6%). In summer and autumn season, the incidence of TSCI is high.

According to Darain H, et al. [70], one of their retrospective study in Pakistan from 2011 to 2016 concluded that male subjects are prone to at least 3 times higher than the female population and 90%) of the subjects were paraplegics. The majority of the illiterate class are more affected and most of the subjects are labors (21.4%) and in the female population majority of affected subjects are housewives (21.3%), and fall from height (30.4%), RTA (25.5%) and firearm injury (21.1%) are major cause of injury. Their retrospective study thus showed that firearm injury in the spinal cord is distinctive in Pakistan, which has not been reported in other countries.

4. Therapeutic possibilities

In the case of SCI repair, surgical techniques are used for more than 40 years [71, 72], most commonly used approach is surgical decompression with or without arthrodesis, but the chances of cervical and thoracic SCI subjects to walk is only 1% to 1.8% after an attempted surgical decompression [73]. Surgery plays a major role in spinal alignment, nerve decompression, and stabilization of the spine, which helps to prevent additional neurological injury. In reconstructive surgeries use of improved implants plays a role in stabilizing unstable fractures. The major role of surgery is to prevent further damage and rehabilitating the subjects [74]. Earlier decompression improves the chances of neurological recovery [75], as proved by many experimental studies. However, these studies did not coincide with the findings of the best clinical studies [76]. One of the studies performed on 2012 corroborated the findings of these experimental studies, this study implies that if decompression is performed within 24 hours after trauma, then the chances of functional recovery improves [77]. The first 24–36 h after injury represents a crucial time window for optimal neurological recovery with decompressive surgery following acute SCI [78]. In one of the studies on decompression surgery, which was performed on 77 subjects with follow-up assessment of 5 years by Anjarwalla et al. [79], to determine the long-term outcome concerning pain and physical function. They reported that back and leg pain was sustained for one year with improved physical function.

4.1 Physical means

To minimize secondary spinal cord damage, physical approaches are accessed as a better treatment method. Hypothermia, hyperbaric oxygen, and exercise, particularly on a treadmill, are the most studied technique under physical means. Most studies have shown the beneficial effect of local cooling by perfusion or irrigation with hypothermic saline. However, this cooling therapy prevents potassium loss, such as in steroid therapy. This technique works on the principle that low temperature protects the central nervous tissues from hypoxia and ischemia. However, this technique is challenging due to its high mortality rate.

Studies have shown that after SCI, Hyperbaric Oxygen Therapy (HBO) treatment prevents oxidative damage to the spinal cord [80]. Many studies on an animal model of SCI have demonstrated the neuroprotective effect of HBO, as it downgraded the overproduction of tumor necrosis factor-α (TNF-α) and SCI-induced interleukin (I.L.)-1β. It also significantly alleviates the number of glial cells line-derived neurotrophic factor- and vascular endothelial growth factor (VEGF)-positive cells and spinal cord IL-10 production [81]. In a current metanalysis on R.C.T. by Huang, Liyi et al. 2021, a total of 1746 studies were identified by them in which 11 studies were included involving 875 participants, and they concluded that hyperbaric oxygen therapy might improve sensory, and motor function, as well as psychology after SCI, compared to conventional treatment. In contrast, it needs a large sample size and more R.C.T. to prove it.

4.2 Pharmacological therapy

Pharmacology plays a crucial role in treating SCI; the medication can play an essential role in treating secondary SCI, as many experimental and clinical trials prove. Corticosteroids and gangliosides are already approved for human use.

Michael G. Fehlings et al. 2017 in one of their systematic and meta-analysis, demonstrated that when methylprednisolone sodium succinate was administered within 24 hrs of postinjury has no relevant impact on long-term neurological recovery when all postinjury time points are considered. In contrast, within 8 hrs of injury, its administration showed an additional 3.2 points of motor recovery compared with patients receiving placebo or no treatment. Liu Z et al. 2019 have reported that in the case of acute traumatic SCI, high dose administration of methylprednisolone does not improve neurological outcomes despite increasing the risk of adverse events. Much work has been done with various secondary injury inhibitors, such as estrogen, in the hope of superior protection in secondary injury. Its analogues have been used in the case of the rat model to protect cells in culture and improve outcomes.

5. Effect of secretory leukocyte protease inhibitor

Due to primary injury, there is a dysfunction of blood supply in the cord due to the breakdown of blood spinal cord barrier (BSCB), because of which the spinal cord undergoes ischemia-reperfusion injury and oxidative stress [82, 83]. A recent study by Renzhe Tang et al. [84] demonstrated the protective role of Secretory Leukocyte Protease Inhibitor, which helps improve the S.C.I. by inhibiting the activity of the inflammatory signaling pathway, which releases a large number of inflammatory factors that can affect tissue repair. Hence, SLPI suppresses the Nuclear factor kappa beta (NF-κB) signaling pathway by binding to the tumor necrosis factor-α and interleukin-8 (IL-8) promoter region. In addition, due to its inflammatory anti-bacterial properties, SLPI promotes reducing secondary injury and other complications during SCI and helps in wound healing.

5.1 Brain-computer interfaces

Brain-computer interfaces play a vital role in restoring both gross and fine locomotion in paralyzed patients. It seeks to decode motor or cognitive intentions from the brain and translate the intentions to an effector: like a robotic arm and a mouse [85]. A BCI apparatus consists of the following parts: Electrodes that are placed directly on the brain tissue or in the epidural, subdural, or subarachnoid spaces, Decoder a device containing neural mapping algorithms, effector that the SCI patient would like to control (Jarosiewicz et al. Pre-made algorithms are used by the decoder to translate specific patterns of cortex excitement into a meaningful signal for the effector. In certain cases, presumably when the use of electrodes is contraindicated then in that case in place of electrodes magnetic resonance imaging is used to map blood-oxygen levels in the brain to transmit a signal to the decoder [86]. A study by Yang et al. [87]observed many multiple clinical studies where BCIs helped to momentarily restore locomotion to limbs. One of the clinical study showed that two quadriplegic subjects were able to control and perform 3D movements like grasping and stretching using a robotic arm that is connected to BCI successfully [87].

5.2 Cethrin

Rho signaling pathway is a significant barrier in axon regulation, and after SCI, this pathway is upregulated, hindering axon regeneration. (Forgoinen et al. 2014). A toxin produced by bacteria clostridium botulinum called c3 transferase has the property to block rho-mediated inhibition of axonal growth by blocking rho an (a type of rho protein) and promoting neuronal development [88]. The result of phase I/IIa clinical trial of a c3 transferase, ba-210 (trademarked as cethrin), was published by, Fehlings et al. 2011 when a single dose of the drug (0.3–9 mg), a permeable material, was applied at the time of decompressive surgery of SCI at dura matter, with acute complete injury of more than seven days on 48 patient then increased motor recovery and ais grade conversion from ASIA scale A to ASIA scale C or D at one year follow up was observed in approximately 6% of the thoracic spine injury patients and 66% of cervical spine injury, in spite that no serious events were reported regarding the drug.

5.3 Magnesium with polyethylene glycol

Magnesium is antagonistic of N-methyl-d-aspartate (NMDA) receptors, which help in reducing inflammation and excitotoxicity. After traumatic spinal cord injury, it has been observed clinically and experimentally in human blood and brain of animals that magnesium is continuously depleting. This depletion is the major cause of poor neurological outcomes in humans and animals. The study [89] demonstrated that in the serum of T.B.I. patients significant decline of Mg²⁺ levels was measured and is linked to the severity of T.B.I. Previous clinical studies showed that it’s a multifactorial pharmacological intervention with proven safety, but it has yet to be investigated. Interestingly, it was proved clinically that Mg²⁺ in P.E.G. formulation is currently available treatment in the case of SCI and is more effective than methylprednisolone [90].

5.4 Nanoparticle-based therapy

Nanoparticle-based approaches in SCI have also played a significant role; in one of the study Cho et al. [91]. In a guinea pig contusion model, showed that treatment by polyethene glycol coated silica nanoparticles helps in restoring the integrity of neuronal membrane and leads to recovery of conduction through the SCI lesion. Wang YT et al. [92] in one of their study on a rat SCI model, demonstrated that local administration of gold nanoparticles conjugated with human NgR–Fc (hNgR-Fc) fusion protein vaccine promotes and improves the efficacy of repair in this rat model. Besides having their risks nowadays, nanoparticles-based drug formulation is of great choice for treatment in the case of SCI. In their study Wilson S, F et al. 2019 demonstrated the most beneficial effect of Dexamethasone acetate (DA) micelles; it shows promising outcomes in replenishing hindlimb function, in minimizing deformity of glial cells, formation of cyst around the injured point, helps in axonal regeneration and reduce the loss of neurons in case of S.C.I. Rasti Boroojen and his co-workers have shown the effect of co-electrospinning of poly-εcaprolacton (P.C.L.)-containing dexamethasone sodium phosphate-albumin (DEXP-BSA)-loaded chitosan nanoparticles for the repair of SCI. polyethene glycol coupled with single-walled carbon nanotubes plays major role in filling of cavities caused after traumatic SCI and thus help in axonal regeneration& repair and promotes functional recovery of the hindlimbs [93]. Chitosan, a polysaccharide polymer, is non-toxic, biodegradable, biocompatible, and accessible for surface modification due to it being preferred in biomedical sciences for wound healing, drug delivery and surgical adhesion. Chitosan nanoparticles are the best key player for functional recovery of motor and sensory neurons and are named “membrane sealant” after neurotrauma or S.C.I. episodes [94]. Another nanoparticle known as Roilipram has emerged as a promising candidate for targeting C.N.S. regeneration because of its ability to cross the blood-brain barrier. It is a phosphodiesterase (P.D.E.) IV inhibitor, known to uphold an apoptotic cell death, deplete both inflammatory cytokine and immune cell infiltration, increase cAMP via PDE IV inhibitor, reduce neuronal sensitivity, spare white matter space, and improve locomotor revival in SCI [95]. A polymeric micelle nanoparticle PgP [poly (lactide-co-glycolide)-graft-polyethylenimine] acts as a carrier for rolipram in SCI improvement developed by Mack et al. 2018. It has been polymerized for combinational delivery of therapeutic nucleic acids and drugs for SCI. repair; it has a hydrophobic core and hydrophilic shell, which carries rolipram and small-interfering R.N.A. to the site of SCI. Zonisamide, an antiepileptic drug chemically known as 1,2-benzisoxazole-3-methanesulfonamide, is a clinically approved drug used worldwide; this drug has been used in treating psychiatric and other neurological impairments. Zonisamide-loaded MPEG-PLLA-PTMC [monomethyl poly (ethylene glycol)- poly (l-lactide)- poly (trimethylene carbonate)] nanomicelles in the SCI model have targeted and recovered motor dysfunction which was induced in this model. other nanoparticles such as Self-assembled monomethoxy poly (ethylene glycol) – poly (d, l-lactic acid) diblock copolymer micelles have also shown promising results in reducing the inflammatory response in motor function recovery in spinal cord injured rats [96]. In case of primary injury, these particles act as sealing agents. Fang C et al. showed promising results of zonisamide-encapsulated gold nanoparticles in neuronal and axonal regeneration, thus contributing to SCI recovery. In the case of SCI, for cellular survival, intracellular signaling, and axonal transport, microtubule stability is an urgent demand. A clinically accepted nano-drug known as Paclitaxel has a hydrophobic nature. It acts as a regulator for mitosis and microtubule formation. Due to its hydrophobic nature, it’s easy to deliver at the targeted injured site and has shown promising improvement in SCI [97]. April Cox et al. 2020 in one of their latest studies on rodents, showed the beneficial role of low dose estrogen delivery to the injury site to the spinal cord using an agarose gel patch embedded with estrogen-loaded nanoparticles and markedly found decreased post-injury lesion size, reactive gliosis, and glial scar formation. In contrast, with an increase in the levels of glial cell-derived neurotrophic factors and axonal regeneration, vascular endothelial growth factor production also increases.

5.5 Exosomes for spinal cord injury repair

It’s a membrane-bound vesicles having 30–150 nm in diameter released by various cells and can carry intracellular contents including proteins, lipids, mRNA, and microRNA [98].

In case of SCI many studies have reported the importance of micro RNAs (miRNA) as it regulates RNA silencing and post-transcriptional modification of gene expression. miRNA-126 has shown promising results after SCI as it promotes angiogenesis and suppresses inflammation. One of the recent studies by Huang et al. [76] used MSC derived exosomes to deliver miRNA-126, to cure SCI in rat model, its administration promoted angiogenesis and neurogenesis at the injury site of SCI, in addition, miRNA-126 treated SCI rats had elevated Bax, caspase-3 and Bcl2 expression these findings suggest that miRNA-126 loaded exosomes inhibited apoptosis. Similarly, another study by Zhong et al. 2020 reported the role of neural stem cell-derived exosomes in SCI mouse model that at the injured site it of the spinal cord it starts promoting angiogenesis by upregulating vascular endothelial growth factor-A.

A study by Li et al. 2020 transplantation of MSC-derived exosomes immobilized in a peptide-modified adhesive hydrogel in SCI mouse model promoted neural and bladder function recovery after 28 days of transplantation.

U-83836E (2-[[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl) piperazin-1-yl] methyl] -2,5,7,8-tetramethyl-3,4- dihydrochromen-6-ol dihydrochloride) is a second-generation of lazaroid (a class of lipophilic steroids that inhibits LPO), containing a non-steroidal structure and an α-tocopherol ring are some of the new antioxidants that plays role in neuroprotection as shown by many studies [99], U-83836E acts as neuroprotective played a major role in inhibiting the production of LPO, ROS, and RNS, in addition inhibiting calpain-dependent neurodegeneration and cascading events associated with secondary injury pathways [99]. melatonin (N-acetyl-5-methoxytryptophan), one of the drug plays a major role in scavenging away free radicals (ROS and RNS), suppressing lipid peroxidation and endogenous antioxidant enzyme expressions are also regulated by melatonin drug [100], It acts as a neuroprotectant by preserving the neuronal structure and increasing neuroprotection post-injury. In combination with dexamethasone (Melatonin + dexamethasone), it exerts a good neuroprotective effect by acting as an anti-inflammatory agent and improving locomotor function [100]. In case of the Traumatic Brain Injury model, this melatonin drug enhances the brain anti-oxidant level, suppress NF-kappa B activation, and enhances cognitive function [99]. Drug Resveratrol a natural phytoalexin exerts neuroprotective activity to suppress oxidative stress, post-SCI·oedema, Na+, K+-ATPase activity, glutamate excitotoxicity, neuro-regeneration and thus improves neurological activity during SCI [101].

5.6 Non-pharmacological approaches

Vitamins, growth factors, and cultured cells are categorized under non-pharmacological approaches as these help in reducing SCI complications such as pain, swelling, and improve locomotor activity through non-medication approaches. As these approaches are beneficial for a short duration so for long-term clinical efficacy they should be combined with pharmacological agents [102], That’s the reason in case of prevention and treatment of ischemic brain injury require multiple interventions.

But, this approach needs more research, particularly those with few side effects [103]. Natural vitamins like vitamins A, E, and C are antioxidants that mostly attack the generation of ROS and RNS that further retard LPO and cellular damage. By retarding the formation of lipid hydroperoxides vitamin C contributes in protecting the membrane from destruction. It also enhances following neuroprotective pathways by diminishing the necrotic tissues and promotes functional recovery, suppressing the generation & expression of ROS, LPO, and proteins such as NF-kB, iNOS, and COX-2, downregulating the levels of TNFα and IL-1β, and controlling the antioxidant status and MPO activity[104]. Vitamin E also promotes functional recovery by suppressing the production of ROS, RNS, LPO, glutathione activity, and reducing peroxidases [105].

Gangliosides, a glycolipid molecule derived from sialic acid, in vitro studies have observed that gangliosides, help in increasing the formation and growth of neurites, protoplasmic expansions of axons that originate new functional connections, induce neuronal regeneration, and promote neuroplasticity [106]. In case of SCI most studied ganglioside is GM1, studies have observed that SCI subjects who are receiving GM1, ganglioside has much more improvement in sensory and motor functions along with sphincter function in comparison to subjects who are on placebos [107]. In incomplete SCI subjects who received GM1in combination with physical therapy have improved motor scores and walking velocity and distance in comparison to subjects who were either on placebo or physical therapy alone [108]. In traumatic SCI subjects with neurological damage, have recommended ganglioside loading dose is 300 mg for 30 days, i.e., 100 mg once daily via intravenous or intramuscular injection. Ganglioside should not be administered simultaneously with methylprednisolone [107].

5.7 Nimodipine

Nimodipine, an L type calcium channel blocker, showed a moderate result in the case of spasticity, one of the significant comorbidities of the spinal cord that hampers the quality of life and motor recovery. One of the studies performed by Maite Marcanton et al. [109] in a mouse model of chronic SCI showed that nimodipine ultimately hampers the development of spasticity measured as increased muscle tone and spontaneous spasms. Nimodipine improves blood flow to the injured spinal cord in the laboratory setting. The abnormal muscle activities associated with spasticity remain inhibited even after the stoppage of the treatment. Constitutive and conditional silencing of the L-type calcium channel CaV1.3 in neuronal subtypes demonstrated that this channel-mediated the preventive effect of nimodipine on spasticity after SCI This study identifies a treatment protocol and suggests targeting CaV1.3 could prevent spasticity after SCI [110].

5.8 Anti-nogo antibodies

Inhibitory molecules present in the myelin obstruct the regeneration of axon in the injured CNS myelin-associated protein nogo a is the most potent inhibitor, so after nervous system injury, neutralization of nogo-a exhibits axonal regeneration in the injured tract and compensatory sprouting of uninjured tracts in animal studies. Anti-nogo, an IgG antibody, has undergone a phase I safety trial in human subjects with acute sci as it also promotes axonal regeneration in C.N.S. injury. Zorner et al. [111] in his study showed the potent role of human anti-human-nogo-a antibody in 52 patients with ASIA A to C cervical or thoracic injuries by administrating it within 4–14 days of injury for periods ranging from 24 h to 4 weeks, intrathecally into the lumbar spine, no adverse event of this antibody was reported, but efficacy trials are still ongoing (www.clinicaltrials.gov, nct00406016). Loss of bladder control is a common problem after spinal cord injury. In ASCI subjects, a human phase-i safety and tolerability trial with the intrathecal application of anti-nogo-a antibodies has been successfully concluded [112]. In patients with acute tetraplegia for upper-limb motor recovery, a phase-two randomized European multicenter trial is still going on (https://nisci-2020.eu).Bladder parameters will be monitored as part of the panel of secondary readouts in this trial. Data addressing potential beneficial effects of nogo-suppression after SCI in humans should become available soon. Klaus Kutcher et al. [112] demonstrated the role of an anti-nogo antibody in humans. It assessed this antibody’s pharmacokinetics, tolerability, and feasibility ati35 by administrating it intrathecally in 52 patients with acute, complete traumatic paraplegia and tetraplegia. Treatment started 4 to 60 days post-injury in SCI subjects. There was no adverse event reported regarding ati355. In the case of paraplegic subjects, motor scores improved by 8 points, while in tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 19/27 points at week 48. In their review, Raihan Mohammed et al. 2020 describe the beneficial use of anti-nogo antibodies in rats and primates in upregulating C.N.S. regeneration and improving sensory and motor function. In treatment with anti-nogo antibodies in the case of sci subjects, no adverse event has been reported, although genetic evidence for its efficacy is mixed. Rong-Rong Zhao et al. 2013 in his study showed the effective response of combined treatment of anti-nogo-A and chondroitinase abc in the treatment of SCI subjects, anti-nogo a therapy promotes the growth of the more significant number of axons having a diameter of > 3 μm and growth of finer axons with varicosities is promoted by treatment of ch abc, these results point to different functions of nogo-a and chondroitin sulfate proteoglycans in axonal regeneration. In contrast, the combination of both shows enhanced functional recovery. According to their protocol, the first administered anti-nogo-a or the control antibody anti-cyclosporin a by intrathecal infusion from the osmotic pump for two weeks in rats. After that, the pump was removed two weeks after the lesion. After one week of removing the pump, rats were given ch abc or the control enzyme penicillinase above and below the lesion through intraspinal injection. Subsequently, the rats received five intrathecal infusions of enzyme on alternate days for ten days; the rats in all groups started rehabilitation training one month after the lesion, seven days after the first enzyme injection.

5.9 Cell transplantation therapies

It is the most promising therapeutic therapy for SCI treatment. Nowadays, various stem cells and mature somatic cells (neural stem cell, embryonic/pluripotent stem cells, mesenchymal/hematopoietic neural cells, oligodendrocytes, astrocytes, Schwann cells, and olfactory ensheathing cells) stem cells are used as transplantation therapy to treat various stages of SCI [113].

5.10 Autologous mesenchymal stem cells (MSC)

Ling Ling Liau et al. 2020, in their recent review, concluded the beneficial role of mesenchymal stem cell therapy in the case of sci, including novel biological therapies that can be applied along with MSC to enhance its efficacy. MSC’s application in the injured spinal cord helps reduce secondary injury and protects the neural elements that survived the initial mechanical insult by suppressing the inflammation. M.S.C.s are also shown to differentiate into neuron-like cells and help rebuild damaged nerve tissues by stimulating neural stem cell proliferation. As M.S.C.s secretes paracrine factors that help protect the remaining axon and promote the regeneration of axons, it helps replace damaged cells by differentiating them into nerve cells [114]. The secretion of VEGF, H.G.F., IGF-I, stanniocalcin-1, TGF-β, and GM-CSF promotes the survival of damaged neurons and oligodendrocytes M.S.C.s. [115]. Hur et al. [116] in one of their studies demonstrated the role of an autologous adipose tissue-derived mesenchymal stem cell by intrathecal transplantation of it in 14 subjects with SCI; there was improvement shown in sensory function in 10 subjects, motor function improvement was shown in 5 subjects, whereas improved voluntary anal contraction was reported in 2 subjects with SCI. But in the M.R.I. examination, the lesion size remained unchanged. Bydon et al. 2020 demonstrated the beneficial role of 100 million autologous ADSCs in treating SCI subjects. ADSCs were delivered intrathecally in the subjects. There was improvement shown in ASIA sensory and motor score and quality of life, as indicated by the higher Global Health Score. Jarocha et al. 2015 reported that after SCI injury in a 15 years old patient with complete injury AIS (A) transplantation of BMNCs at ten weeks and then subsequent transplantation of autologous BMSCs at every 3–4 months for five times, and in 2 years follow up, AIS grade improved from C to D (score increased from 112 to 231), and patient also received bladder filling sensation, control over the bladder, the anal sensation was restored, control over the body trunk, improvement in muscle strength of lower extremities from plegia to deep paresis and subject began to stand and walk with support. Sharma et al. 2013 in his study of 56 subjects with chronic SCI (mean duration of injury 64 months), transplanted BMNCs in them and found improvement in A.I.S. grade of 4 patients while improvement in Functional Independence Measure (F.I.M.) score was observed in 24 patients. Marcus Vinícius Pinheiro Mendonça et al. 2014 conducted a non-control study in 14 subjects of both genders of traumatic injury of fewer than six months of thoracic or lumbar level. Bone marrow-derived mesenchymal stem cell was directly injected into the lesion following laminectomy and durotomy after culturing and characterizing it by flow cytometry, cell differentiation assays, and G-band karyotyping. In all the subjects, improvement in tactile sensitivity was observed, gain in motor function in the lower limb, especially in the hip flexor, was observed in 8 subjects, sacral sparing was presented in 7 subjects, and improved (A.I.S.) grades to B or C – incomplete injury. In contrast, improvement in urologic function was observed in 9 subjects, while in 1 subject, improvement in somatosensory evoked potentials (SSEP) was observed. Zhilai Zhou et al. 2020, in their study on a mouse model, demonstrated the role of adipose-derived mesenchymal stem cell (ADSC) transplantation on the inflammatory reaction after SCI and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression. Zengjie Fan et al. 2020. Design fabricated pre vascularized nerve conduits (P.N.C.) based on the pre vascularized stem cell sheet. They demonstrated its repair effect in transected SCI rats; they found that for promoting better healing of SCI, improving the condition of ischemia and hypoxia, and inhibiting glial scar formation P.N.C. is potential alternative material biomaterials and the best effective solution for SCI rehabilitation. Many studies have shown that stem cells revealed their therapeutic role by secreting factors into their surroundings via a paracrine mechanism, like extracellular vesicles, one of the emerging extracellular vesicles has diameter 40–150 nm. They have attracted increasing attention in regenerative medicine called exosomes [98]. They act as the communication medium between cells by carrying different proteins, lipids, R.N.A. (mRNA, noncoding R.N.A., etc.), and other biological macromolecules and regulating the gene expression or protein synthesis of target cells; they influence the physiological function of the targeted cell [117]. Studies also showed that when human adipose mesenchymal stem cells (hADSCs)-derived exosomes were injected in and around the wounds in rodents’ skin, they significantly promoted angiogenesis at the lesion site and accelerated wound healing [116]. Besides that, exogenous stem cell exosomes also facilitate tissue regeneration and repair at the injured site when directly administered [118]. Rong Y et al. 2019 demonstrated that neural stem cell-derived exosomes (NSCs-Exos) after traumatic spinal cord injury reduce neuroinflammation and cell apoptosis by mediating the activation of autophagy. Dong Zhong et al. 2020 demonstrated in their study that after traumatic spinal cord injury, the weakly physical strength of spinal cord microvascular endothelial cells (SCMECs) is one of the leading causes of augmentation of the spinal cord. Therefore, to promote recovery after spinal cord injury, it is crucial to improve the plasticity and regeneration of SCMECs, So they focused on the influence of exosomes derived from neural stem cells. So, they extracted primary SCMECs from the spinal cord tissue of C57 mice and neural stem cells from 14 days pregnant C57 mouse after that, exosomes were isolated from N.S.C.s conditioned medium. After that co-incubated with the SCMECs in vitro, the result showed that NSCs-Exos could enhance the angiogenic activities of SCMECs and were highly enriched in VEGF-A; they accelerated the microvascular regeneration, reduced the spinal cord cavity and improved Basso mouse scale scores in spinal cord injury mice (Table 1).

Compound	Class	Mode of action
Indomethacin	Non-steroidal anti-inflammatory drug (NSAID) is a nonselective cyclooxygenase inhibitor (COX)	Prostaglandin production is inhibited and tissue necrosis is prevented. This drug also blocks RhoA synthesis that involves in preventing axonal regeneration, loss of oligodendrocytes & axonal myelination is prevented by Indomethacin [119, 120].
Meloxicam	COX2 inhibitor	Prostaglandin production is inhibited, reduction in oxidative stress and exerts neuroprotective effect by suppressing the production of ROS, LPO, GSH, an DNA fragmentation [121].
Cyclosporine A	Immunosuppressant	It inhibits helper T lymphocytes, cytotoxic and inflammatory responses in macrophages, suppress the expression of nitric oxide synthase suppresses the production of tumor necrosis factor (TNF-α) and expression of IL-1, IL-2, and IL-6 [122].
Tacrolimus (FK506)	Immunosuppressant (isolated from Streptomyces tsukubanensis)	It exerts a neuroprotective effect on T cells and modulates inflammation, in addition, suppress caspase-3, NF-kB and promotes survival of oligodendrocytes [119].
A91 (87–99 immunogenic sequence)	Neural peptide INDP	It promotes neuroprotection by activating T-lymphocytes, Th2 anti-inflammatory activity, and promote brain-derived neurotropic factor (BDNF). iNOS expression production of ON, LPO generation is inhibited by INDP after SCI thus prevents apoptosis [119, 123].
Metformin	Hypoglycemic drug, AMP-protein kinase (AMPK), an agonist.	Apoptosis is prevented by this drug by suppressing the activity of two pathways i.e., mTOR and p70S6K promoting autophagy and inhibiting NF-kB inflammation, also regulate TNFα and IL-1β inflammatory cytokines [119].

Table 1.

Immunosuppressive or immunomodulatory drugs are commonly reported to use during SCI.

5.11 Nutritional supplementation

Mostafa Hosseini et al. 2020 in one of their meta-analyses on the role of nutritional supplementation of Vit C &E on spinal cord injury animal model and concluded that daily supplementation of both nutraceuticals either alone or in combination significantly helps in improving motor function in animals suffering from SCI, in addition, studies proved that supplementation of vitamin C is only effective when administered intraperitoneally, whereas concomitant supplementation of both vitamins does not show better efficacy than treatment of both vitamins alone. Due to its antioxidative properties, Vitamin C or ascorbic acid protects other organs, including the spinal cord, in an animal model. Wang et al. 2015 in their study demonstrated that supplementation of vitamin C is effective against renal damage induced due to SCI by inhibiting proinflammatory cytokines and nuclear factor-kappa. In another study conducted by Chao Chen et al. 2020 on nutritional supplementation of combined effects of taurine and Ascorbic acid in SCI induced rats. They divided the rats into four groups: sham, control, 100 mg/kg of taurine, 100 mg/kg of ascorbic acid, and 100 mg/kg of taurine + 100 mg/kg of ascorbic acid, and continued his treatment daily for 45 consecutive days and reported that the combined treatment of taurine and ascorbic acid decreased the activity of caspase-3 by 33.7% and p53 by 44% respectively, as well as activity of pro-NGF, mRNA expression of interleukin-6 (IL-6), cyclooxygenase-2, tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS as compared to the individual treatment of both taurines as well as vitamin C. Whereas changed antioxidant markers were recovered and induced lipid peroxidation comes to its normal level after the combined treatment of both. In his study on adult Sprague-Dawley rats, Kathia Cordero et al. 2018 demonstrated when fed with a normal diet. In another group, when fed with a dietary regiment supplemented with vitamin E (51 IU/g) for eight weeks after that, the rats were exposed to contusive SCI or sham operation; they reported that rats that were administered with vitamin E enriched diet showed accelerated bladder recovery, as well as improved locomotory function compared to rats that were fed with normal diets, as well as several oligodendrocytes in the ventral horns, were also increased. In one of the latest studies, K Pritchett et al. 2019 demonstrated the beneficial role of Vit D supplementation in athletes with spinal cord injury because athletes with SCI have insufficient status of 25(O.H.) vitamin D (25(O.H.)D) that is associated with decreased muscle strength. In their study, Thirty-four members (age: 33  ±  15 years, weight: 69.6  ±  28.2 kg, and height: 170.2  ±  25.4 cm) of the U.S. and Canadian Paralympic program participated in the study. After pre and post supplementation of Vitamin D(50,000 IU/week) for eight weeks to subjects deficient in 25(OH) D, and to subjects showing the insufficient status of 25(O.H.), D received 35,000 IU/week for four weeks, after that, both groups received a maintenance dose of 15,000 IU/week. They received supplementation of Vitamin D totally for 12- to 16-week. It was observed that 26% of athletes had sufficient 25(O.H.)D concentrations pre supplementation. In contrast, about 91% had sufficient concentrations post supplementation, whereas handgrip strength is improved post supplementation in about 62% of participants, whereas no change in 20-m wheelchair sprint performance was observed. Bi J, et al. [105] demonstrated the antioxidant & anti-inflammatory role of omega-3 fatty acid in spinal cord injury in the rat model, their study showed that as the concentration of omega-3 fatty was increased more effective result was obtained such as reduced oxidative stress markers, inflammatory markers, and apoptosis. As omega-3 fatty acid usually modify multiple pathways that are responsible for secondary damage following SCI. Studies have confirmed that subjects who are administrating long-chain omega-3 fatty acid before injury they restore cord lipid homeostasis, exerts neuroprotection, dysfunction of sensorimotor, and neuropathic pain is prevented by omega-3 fatty acid as well it promotes locomotor recovery both in acute & sensory phase of SCI [73]. One of the studies on SCI-induced rats has proved the neuroprotective effect of omega-3 fatty acid, it mainly suppresses the activation of inflammasomes following SCI. Their study showed that PUFA mainly suppresses activation of microgliosis, whereas oligodendrocytes number got increased with its consumption, and demyelination got suppressed [74].

6. Conclusion

Mammalian nervous system was unable to regenerate or repair itself as axons have least capacity to regenerate after devasting injury. Science is continuously searching the mechanism of protecting cell and axonal regeneration, but clinically still we are only providing support to SCI Subjects. Therapeutic approaches made in the last decades have only open field in the experimental work in the field of spinal cord regeneration. The combination of several strategies, either pharmacological or non-pharmacological should make minimum or partial functional recovery in SCI subjects, which might facilitate in improving their quality of life. Research has proved that above mentioned therapeutic approaches have proved very beneficial in these subjects.

Acknowledgments

The authors are thankful to the Indian Council of Medical Research (ICMR), New Delhi, (F.N.5/9/1311/2020-Nut) for the financial assistance.

Conflict of interest

The authors have no potential conflict of interest. The disclosure of potential conflict of interest in the prescribed format has been obtained from all the authors.