Spinal Cord Injury and Its Future Therapy-A Perspective

Human and animal body comprises of various systems. These body physiological functions coordinated and regulated centrally and peripherally by central nervous system and peripheral nervous system respectively. The Central Nervous System (CNS) consists of brain and spinal cord. This nervous system is complicated network of mechanism which is the central processing unit of an entire nervous system. The nervous system is made up of neurons and neuoglias. The neurons are a specialised cell with membrane ability to generating electrical impulses. Neuoglias are an abundant cell type than neuron in CNS which provides more supports for neurons. Our body system knows about the significance of these cells, so only brain and spinal cord are protected by armour cover of cranium and vertebral column. Because limited regenerative capacity of a neuronal cells [1].


Faithful Model of SCI
Rat is a faithful animal for neuroscience, behavioural research and regenerative research for preclinical studies. The greater size of rat provides much more advantages than mice especially borne to surgical procedures and in studies of spinal cord injury, where rat models have been higher translational value [5]. It is much easier to handle and less stressed by human approaches than mice [6]. In the recent decades gene based neuroscience research growing with mice but rat and mice show drastic differences in basic studies like cognition, addiction, impulsive, social behaviour and demonstrate differences in extent of neuroregeneration, demonstrating the significance of appropriate model for a human wisely [7], moreover SCI injury changes in rats are similar to humans [8]. Human spinal cord injury much more complex than experimentally produced rat models although anatomical differences of axonal tracts should be taken into account with human, Rat is to be convenient model of spinal injury due to low incidence of surgical affections and wellestablished functional analysis techniques [9].

Type of Spinal Cord Injury Models in Rat
Still what we know about spinal cord injury pathophysiology mechanism is very little. So to know pathophysiological aspects of spinal cord injury and to evaluate CNS spinal cord regeneration, many model has been created for spinal cord injury related to interest [10], for example weight drop model that first described by Andrew [11], aneurysm clip compression [12], calibrated forceps compression [13], contusion [14], complete transaction model [15], excitotoxic model via chemically mediated [16], tractive model [17], epidural balloon inflation compression model [18], hemitransaction model [19]. This hemi transaction model commonly used to investigate nerve grafting in biomaterials research [20]. This partial transaction model simulates an injury more likely to be seen clinically than complete transaction and provides comparison between injured and healthy fibres in same animals [21]. This model relatively controlled injury environment, low morbidity, and the full transaction or crush injury models. Hence biomaterial scaffold, nerve grafting studies its being good model of choice [22].

Neurotrophins in SCI
Another approach of SCI therapy is borne to neurotrophins. It is the growth factor form the CNS, promotes the normal development

Cell Based Approaches in SCI
Cell based approaches in SCI mainly by two concepts (1) directly replace the cells lost due to injury (oligodendrocytes or neurons or meningial cells), (2)  can be used to obtain neurons and glial cells [64]. As stated, earlier demyelination of an intact axon is a major sequence of SCI [65].
Remyelination is needed for locomotor improvement and restore the salutatory conduction of neuron [66].
Notably human embryonic stem cell derived oligodendrocytes progenitor cells transplant remyelination and restore locomotion after spinal cord injury [67]. The problem of ESC derived immature lineage cells is ability to induce teratoma after transplantation [68].
But with the high purity production of ESC derived cells it can limits the tumour inducing potential of ESC [69]. Neural Stem Cells (NSC) are multipotent, having ability to produce complete neural lineages [45]. The NSC is a remnant of neuroectoderm present in the brain and spinal cord. In adult the source of NSC cell is Sub Ventricular Zone (SVZ) lining the lateral ventricles and the Subgranular Zone (SGZ) within the Dentate Gyrus (DG) of the hippocampus and spinal cord [70], These NSC contributes the remyelination [71] and inturn improves axonal conduction. In a different study on human neural stem cell transplants is found effective for SCI in primates [72] the limitation of NSC is that obtaining cells [73]. Other approach is to stimulate endogenous NSC, but in vivo microenvironment not good to stimulate NSC regeneration [74]. Although ESC derived NSC/NPC is an exogenous source, obtaining high purity is a mater.
Another type of somatic stem cell widely studied is mesenchymal stem cells. There are various sources for mesenchymal stem cells likely Wharton jelly of umbilical cord [75], bone marrow derived mesenchymal stem cells [76] and Dental pulp [77]. Human Dental Pulp Derived Stem Cells (DPSCs) having neuroprotective, neroregenerative, neurotrophic support in preclinical study [78].
This neural crest originated DPSCs could be an ideal stem cell candidate for treating neurological and neurodegenerative diseases [79]. Although, no reports of clinical study in human spinal cord injury, transplantation of human immature dental pulp in spinal injured dogs showed improvement [80]. So many things have to take into account required stem cell density and availability, desirable strategies, for their use. For example, DPSCs or exfoliated deciduous tooth stem cells are not available throughout a patient's lifetime.
Stem cell banking can overcome that, it is time-consuming and costly limits their use in clinical applications [81]. Human umbilical cord blood and Wharton's jelly isolated MSC transplantation reduces neuropathic pain [19] and improved sensory recovery [82] of SCI in rats.
The limitation of human UC blood isolated MSC is maternal cell contamination which negatively influence the utilization of this material for cell-based therapy due to Graft-Versus Host Disease (GVHD) [83]. Adipose tissue derived mesenchymal stem cells are easily can harvest from abundant adipose tissue [84]. These MSC secretes neurotrophic factor [85] which aids neuroprotection in ischemic spinal cord injury [86]. Bone marrow derived mesenchymal stem cell is a currently widely using MSC in spinal cord injury and regeneration due to its wide variety of study reports [87]. It lacks tumorogenic potential [88], neuroprotective ability [89] through expression of various kinds mRNA related to neurotrophic factors [90], immunosuppressive by low expression of MHC antiinflammatory, aiding in axonal regeneration, endogenous stem cell activating property [91] unlike ESC no ethical problem and induce remyelination [92]. The BMSC administration is safe and feasible [93]. The limitation of MSC is that it needs substrate to attach which will improve survivability because anchorage dependant property [94]. Hence MSC with scaffold increase survivability and overcome above stated limitation.

Stem Cells & Nerve Growth Factors (NGF)
Another approach is stem cell and NGF. Advantage of this approach is that the stem cell secretes certain neurotrophic factors which are substantial neuronal recovery from spinal cord injury.
Exogenous neurotrophic factor or over expressing NGF secreting cells are adding stem cell survivability [95,96] and helps in endogenous protective mechanism [97]. MSCs and NGF synergistic effect in promote axonal regeneration and improve functional recovery [98]. Limitation of this approach is that the injury site is not hospital environment for stem cell survival and attachment because injury site ECM related molecules and pathological state hampers advantage of this approach although various studies with significant results.  [100]. Notably acellular spinal cord seeded with mesenchymal stem cell improves robust long-distance axonal regeneration in spinal cord injured rodent study [101].

Conclusion
The spinal cord injury is a very complex mechanism so simply targeting a single mechanism does not give a good translational value. To improve the therapeutic strategies in spinal cord injury making lesion site like in vivo or mimic like environment by tissue engineering technology is focusing area. So the optimal multidisciplinary approach combining biomaterials, stem cells, and bio molecules offers a promising treatment for repairing the injured spinal cord [102]. From above review lack of combined therapeutic strategy are noticed regarding spinal cord injury strategy. Hence to fill the limitation, we hypothesis that the nerve growth factor