Open access peer-reviewed chapter

Prerequisites for Mesenchymal Stem Cell Transplantation in Spinal Cord Injury

Written By

Sherif M. Amr

Reviewed: 03 May 2017 Published: 29 November 2017

DOI: 10.5772/intechopen.69554

From the Edited Volume

Mesenchymal Stem Cells - Isolation, Characterization and Applications

Edited by Phuc Van Pham

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Abstract

We have aimed at distinguishing obligatory prerequisites for mesenchymal stem cell transplantation in spinal cord injury from those prerequisites which are unnecessary or are prerequisites that have to be further investigated. Obligatory prerequisites include the following. First, the site of injury is extensively gliotic, constituting an unsuitable medium for stem cell transplantation. It has to be dissolved by neurolyzing agents, chondroitinase ABC as an example. Second, stem cells need a suitable biomaterial scaffold for their proper integration. Third, the biomaterial scaffold necessitates a tissue filler harboring stem cells, other cells and neurotrophic factors in a combinatorial approach. Fourth, the efficiency of mesenchymal stem cells themselves has to be increased (by reducing oxidative stress-induced apoptosis, by hypoxic preconditioning, by modulating the extracellular matrix and by other measures). Prerequisites that have to be further investigated include the ideal source, mode, quantity, time point and number of injections of mesenchymal stem cells; which growth factors and cells to be used in the combinatorial approach; transforming mesenchymal stem cells into motor neuron-like cells or Schwann cells; increasing the homing effect of stem cells and how to establish a continuous drug and cell delivery system.

Keywords

  • spinal cord injury
  • mesenchymal stem cells
  • scaffolds
  • nerve grafting
  • neurotrophic factors
  • chondroitinase ABC
  • continuous drug delivery systems

1. Introduction

Traumatic spinal cord injury results usually from cervical and lumbar fractures; it may be associated with complete paraplegia. Regeneration after such an injury is fairly limited mainly due to the inhibitory milieu (the gliosis) within the spinal cord. Cellular therapeutic strategies may overcome this milieu by neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration [1]. Clinically, in a meta-analysis on cellular therapy in traumatic spinal cord injury in humans published in 2012 [2], the authors reviewed eight bone marrow mesenchymal and hematopoietic stem cell studies, two olfactory ensheathing cell studies, one Schwann cell study and one fetal neurogenic tissue study. Three of these were Grade III and nine Grade IV level of evidence. It was concluded that improved preclinical studies and prospective, controlled clinical trials were needed. Nevertheless, ever since, the number of clinical trials have been increased. Mesenchymal stem cells, in particular, are easy to isolate, can be rapidly expanded in culture and can be cryopreserved without loss of potency [3, 4]. Clinical reports on their use have varied, starting from documenting their safety [5, 6] up to limited clinical efficacy [7], even partial or complete efficacy [811].

The aim of this review is to distinguish necessary prerequisites for effective mesenchymal stem cell transplantation in spinal cord injuries from those prerequisites which are unnecessary or are prerequisites that have to be further investigated.

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2. Establishing a suitable niche

2.1. Dissolving the gliosis

Axonal regeneration following spinal cord injury is limited not only because central nervous system neurons have a poor intrinsic capacity for growth but also because injured axons encounter a series of inhibitory factors that are non-permissive for growth. These include myelin inhibitors [Nogo-A, MAG108 (myelin-associated glycoprotein) and OMgp109 (oligodendrocyte myelin glycoprotein)]; chondroitin sulfate proteoglycans (neurocan, versican, aggrecan, brevican, phosphacan and NG2); semaphorins and ephrins. In the central nervous system, laminin is replaced by netrins [1215].

2.1.1. Chondroitinase ABC

Chondroitinase ABC [1618] has improved recovery of function in synergy with mesenchymal stromal cells without [19] or with the addition of an acellular nerve allograft [20] or in synergy with brain-derived neurotrophic factor (BDNF) secreting mesenchymal stem cells [21]. Chondroitinase ABC should be thermostabilized with the sugar trehalose to reduce its temperature-dependent loss of activity [22]; it should be injected in high doses (50 or 100 IUs) [2325], at multiple times [2629] and be combined with cell transplantation and growth factor infusion [30, 31].

2.1.2. Other measures to overcome the gliosis

In a rat model of spinal cord contusion injury [32], infused sialidase has acted robustly throughout the spinal cord gray and white matter, whereas chondroitinase ABC activity has been more intense superficially, thus raising the possible consideration that it might be superior to chondroitinase ABC. Blocking myelin-associated inhibitors with Nogo-A monoclonal antibodies or with Nogoreceptor competitive agonist peptide (NEP1-40) has been shown to increase axonal regeneration [33]. Bone marrow mesenchymal stem cells with Nogo-66 receptor gene silencing have been used for repair of spinal cord injury [34]. Blocking Rho-A with Rho inhibitor ‘cethrin’ might overcome its effect; a synthetic membrane-permeable peptide mimetic of the protein tyrosine phosphatase σ, wedge domain can bind to tyrosine phosphatase σ and relieve chondroitin sulfate proteoglycan-mediated inhibition [35]. Chondroitin sulfate proteoglycans inhibition of phosphoinositide 3-kinase (PI3K) signaling is reversed by cell permeable phosphopeptide (PI3Kpep) [36]; rolipram, a phosphodiesterase4 inhibitor, can increase intracellular cAMP levels [33]; taxol, a microtubule-stabilizing agent, increases neurite outgrowth [37, 38].

2.1.3. Emerging role of heparin in lysing the gliosis

There is an emerging role of heparin in lysing of the gliosis, as reviewed elsewhere [39]. Both unfractionated and low molecular weight heparins have a fibrolytic (gliolytic) effect, can modulate astrocyte function and are used as lumen fillers. Astrocytes release a variety of trophic factors. These trophic factors include nerve growth factor, basic fibroblast growth factor, transforming growth factor-β, platelet-derived growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor and others. Astrocyte stress response and trophic effects are mediated by the fibroblastic growth factor family member, on which heparin exerts a profound influence [4042].

2.2. Providing a suitable scaffold, both to bridge the gap and to harbor the cells

2.2.1. Biomaterial scaffolds in spinal cord injury

Biomaterial scaffolds in spinal cord injury have been reviewed elsewhere [43, 44]. Mesenchymal stromal cells have been grown onto fibrin scaffolds [45, 46]. The survival and neural differentiation of human bone marrow stromal cells have been tested on fibrin versus fibrin platelet-rich plasma scaffolds. The results have shown a clear superiority of platelet-rich plasma scaffolds, mainly after BDNF administration [47]. Mesenchymal stem cells have also been grown onto collagen scaffolds [48]. Rat adipose-derived stem cells have differentiated into olfactory ensheathing cell-like cells on collagen scaffolds by co-culturing with olfactory ensheathing cells [49]. Acellular spinal cord scaffolds [50, 51] and acellular muscle bioscaffolds [52] seeded with bone marrow stromal cells have promoted functional recovery in spinal cord-injured rats. Electro-acupuncture has been found to promote the survival and differentiation of transplanted bone marrow mesenchymal stem cells pre-induced with neurotrophin-3 and retinoic acid in gelatin sponge scaffold after rat spinal cord transaction [53]. Human bone marrow mesenchymal stem cells and endometrial stem cells have been found to differentiate better into motor neurons on electrospun poly(ε-caprolactone) scaffolds [54]. Nogo-66 receptor gene-silenced cells have been transplanted in a poly(D,L-lactic-co-glycolic acid) scaffold for the treatment of spinal cord injury [55]. Bone marrow mesenchymal stem cells seeded in chitosan-alginate scaffolds [56] and biodegradable chitin conduit tubulation combined with bone marrow mesenchymal stem cell transplantation have reduced glial scar and cavity formation in spinal cord injury [57]. In a comparative study investigating the efficacy of allogeneic mesenchymal stem cell transplantation via simple intralesional injection versus the use of a poly (lactic-co-glycolic acid) scaffold or a chitosan scaffold, higher mesenchymal stem cell engraftment rates have been reported in the scaffold groups, particularly, in the chitosan scaffold group [58].

Injectable extracellular matrix hydrogels have been used as scaffolds for spinal cord injury repair [59]. Matrix metalloproteinase-sensitive, hyaluronic acid-based biomimetic hydrogel scaffolds containing brain-derived neurotrophic factor have been implanted [60]. Cell-seeded alginate hydrogel scaffolds have promoted directed linear axonal regeneration in the injured rat spinal cord [61]. Multichannel polymer scaffolds fabricated from positively charged oligo[poly(ethylene glycol)fumarate] hydrogel and loaded with either syngeneic Schwann cells or mesenchymal stem cells derived from enhanced green fluorescent protein transgenic rats have been successfully implanted into rat spinal cords following T9 complete transection [62]. Highly superporous poly(2-hydroxyethyl methacrylate) scaffolds with oriented pores [63] and highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds have been developed for spinal cord injury repair [64].

Three-dimensional culture can mimic the stem cell niche compared to conventional two-dimensional culture. Bone marrow-derived mesenchymal stem cells cultured in three-dimensional collagen scaffold have exhibited distinctive features including significantly enhancing neurotrophic factor secretions and reducing macrophage activations challenged by lipopolysaccharide [65]. A polyhydroxybutaryl-hydroxyvinyl-based three-dimensional scaffold for a tissue engineering and cell-therapy combinatorial approach for spinal cord injury regeneration has been developed [66]. A three-dimensional biomimetic hydrogel has been implemented to deliver factors secreted by human mesenchymal stem cells in spinal cord injury [67]. Bone marrow mesenchymal stem cells in a three-dimensional gelatin sponge scaffold have attenuated inflammation, have promoted angiogenesis and have reduced cavity formation in experimental spinal cord injury [68].

2.2.2. Prerequisites for the use of biomaterial scaffolds in spinal cord injury

Biomaterial scaffolds should be biocompatible, non-toxic, chemically stable, of known absorption and degradation kinetics matching the degree of in vivo cell/tissue growth and should have adequate surface for cell access, proliferation and cell differentiation [69, 70]. They should meet macroengineering requirements being of proper form [71, 72], design (shape) [73] and size (diameter) [74]. They should be supplied with macrogrooves [43, 75, 76] and have a wall thickness of 0.6 mm, a porosity of 80% and a pore size range of 10–40 μm [7779]. They should meet microengineering requirements, microgrooves directing axonal growth [8087]. Prestretch-induced surface anisotropy has been beneficial in enhancing axon alignment, growth and myelination [88]. Also, filament inclusion has been more effective for bridging long nerve defect gaps [43, 89, 90]; Schwann cell migration over gaps exceeding 18 mm is superior in the presence of filaments. Yoshii et al. [91, 92] have tested collagen microfilaments with diameters of 20 μm to repair long gaps (20 or 30 mm) in the rat sciatic nerve. Increasing fiber number (4000 versus 2000 filaments) has enhanced nerve regeneration. Thus, increasing the whole filament surface area by increasing their number and reducing their diameter (increased surface area-to-volume ratio) is also critical [89, 93, 94].

Scaffolds should fulfill nearly the same mechanical conditions of the recipient spinal cord, exerting incremental tensile forces on intact cord segments to promote axonal regeneration while unloading gliotic segments to reduce gliosis and harbor cellular transplants (Figure 1a and b). A scaffold should possess sufficient toughness to resist compression or collapse, yet still be flexible and suturable [95]. A brittle scaffold that sustains little or no plastic deformation before fracture might break hampering axonal progression.

Figure 1.

(a) How a spinal cord lesion looks like; (1) cranial spinal cord; (2) rostral spinal cord and (3) the gliotic segment. (b) A biomaterial scaffold (4) should fulfill nearly the same mechanical conditions of the recipient spinal cord, exerting incremental tensile forces (5—arrows) on intact cord segments to promote axonal regeneration while unloading gliotic segments (6—arrows) to reduce gliosis and harbor cellular transplants. In addition, it should meet macro- and microengineering requirements; it should provide adequate space for the interplay and manipulation of the different molecular pathways for axonal regeneration through lumen filling technology and it should meet requirements based on spatial distribution of neurotrophic factor gradients. Lumen filling technology allows for the incorporation and gradual local release of stem cells (7), accessory cells (8), molecular growth factors (e.g. BDNF, neurotrophin-3, etc.) (9) and neurolyzing agents (e.g. chondroitinase ABC) (10), either by combining them with a growth-supporting matrix in the lumen (11), by crosslinking (12) them to nerve conduit walls or by using microspheres (13) to deliver them. Growth-supporting matrices (11) in the lumen include hydrogel-forming collagen, fibrin, laminin, alginate, heparin and heparin sulfate. A natural and low-toxicity crosslinking agent (12), genipin, is commonly used.

A scaffold should have an elastic modulus comparable with that of the recipient spinal cord. To approach appropriate mechanical properties, one strategy has been to form polymer composites with biopolymers such as chitosan [96], a polymer which has been established as being “softer” and biocompatible. The role of mechanical compliance in directing cell fate and function is a critical issue in material design [9799]. A low elasticity and hierarchically aligned fibrillar fibrin hydrogel fabricated through electrospinning and concurrent molecular self-assembly process has been tested. Matrix stiffness and aligned topography have instructed stem cell neurogenic differentiation and rapid neurite outgrowth [100].

Scaffolds should provide adequate space for the interplay and manipulation of the different molecular pathways for axonal regeneration [80, 81, 101103].

To provide adequate space and adherence for cells and molecules, biomaterial polymer nerve scaffolds should be porous [43]. Currently, ideal scaffolding should have 80–90% porosity with a pore size of 50–250 μm. Its pores should be interconnected so as to provide physical support to cells and guide their proliferation and differentiation, also facilitating neovascularization [69, 104]. The porous structure can be stabilized by adding glutaraldehyde, polyethylene glycol, heparin or collagen, allowing the structure to become more resistant and to maintain elasticity. A natural and low-toxicity cross-linking agent, genipin, has been used to immobilize nerve growth factor, a neurotrophic factor, onto chitosan-based neural scaffolds to generate a novel nerve graft, which has been beneficial for peripheral nerve repair [105]. A novel method has been introduced for standardized microcomputed tomography-guided evaluation of scaffold properties in bone and tissue research [106].

Scaffolds should provide adequate space for lumen fillers Methods of lumen filling allow for incorporation of cells and molecular factors either by combining them with a growth-supporting matrix in the lumen, by crosslinking them to nerve conduit walls or by using microspheres to deliver them [107]. Growth-supporting matrices in the lumen include hydrogel-forming collagen, fibrin, laminin, alginate, heparin, and heparin sulfate.

Scaffolds should meet requirements based on spatial distribution of neurotrophic factor gradients.

Spatial molecular concentration gradients of nerve growth factor [108] and laminin [43, 109, 110] promote axonal sprouting. Thus, axonal growth can be hypothetically made to bridge the whole length of the neural gap by seeding the scaffolds with multiple nerve growth factor/laminin spatial concentration gradients [111].

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3. Optimizing the therapeutic effect of mesenchymal stem cell transplantation

3.1. The ideal source for mesenchymal stem cells

Mesenchymal stem cells reside not only in various tissues of mesenchymal origin (e.g. bone marrow, adipose tissue, skin and peripheral blood) but also in perinatal sources (e.g. umbilical cord blood, umbilical cord matrix or Wharton’s jelly, amniotic fluid and placenta) [112].

In a comparative study using mesenchymal stem cells extracted from both bone marrow and adipose tissue for spinal cord injury, animals receiving adipose tissue cells have presented higher levels of tissue brain-derived neurotrophic factor, increased angiogenesis, higher number of preserved axons and a decrease in the number of macrophages, suggesting the superiority of mesenchymal stem cells extracted from adipose tissue [113]. In another study, however, no difference has been found between animals receiving mesenchymal stem cells derived from bone marrow or adipose tissue, whether in terms of axonal regeneration, neuroprotection or functional recovery [114].

Mesenchymal stem cells obtained from perinatal sources can proliferate more rapidly and extensively than adult mesenchymal stem cells and are easily obtained after normal and cesarean births, with low risk of viral contamination. They may be used for allogenic transplantation because they act by suppressing immune response and are, therefore, considered non-immunogenic cells [112].

In a study comparing mesenchymal stem cells derived from fat, bone marrow, Wharton’s jelly and umbilical cord blood for treating spinal cord injuries, dogs have been treated with only matrigel or matrigel mixed with each type of mesenchymal stem cells. Although there have been no significant differences in functional recovery among the mesenchymal stem cell groups, application of umbilical cord stem cells has led to more nerve regeneration, neuroprotection and less inflammation compared to other mesenchymal stem cells [115].

Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention. These cells not only display a mesenchymal stem cell phenotype in vitro but also have similar in vivo immunomodulatory effects after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells [116].

3.2. Increasing the efficiency of mesenchymal stem cells and their influence on spinal cord regeneration

3.2.1. Influence of mesenchymal stem cells on spinal cord regeneration in general

Present around blood vessels, mesenchymal stem cells respond more readily to tissue damage [3]. The transdifferentiation capacity of mesenchymal stem cells into neuronal and glial lineages has been debated; transplanted mesenchymal stem cells do not differentiate into a neuronal fate, even if they display weak expression of NeuN (a neuronal marker) [3]. Mesenchymal stem cell-based cell therapy, even when applied during the chronic phase of spinal cord injury, leads to changes in a number of structural and functional parameters, all of which indicate improved recovery [117]. Mesenchymal stem cells promote repair in the injured cord by secreting growth factors that overcome the inhibitory environment of the lesion. These cells have anti-inflammatory, immunomodulatory, vascular promoting oxidative stress reducing and neuroprotective effects. They can secrete trophic factors thus exerting a paracrine effect that can stimulate axon regeneration contributing to functional recovery enhancement [112, 118]. Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide [119]. Intrathecal transplantation of mesenchymal stem cells activates extracellular adjusting protein kinase1 and 2 in the spinal cord following ischemia reperfusion injury, partially improving spinal cord function and inhibiting apoptosis in rats [120].

Measures to increase the efficiency of mesenchymal stem cells include the following. Replacing fetal bovine serum has been proposed as a gold standard for human cell propagation [121]. Mechanical fibrinogen-depletion has been found to support heparin-free mesenchymal stem cell propagation in human platelet lysate [122]. A combination of electroacupuncture and grafted mesenchymal stem cells overexpressing tyrosine kinase C has been found to improve remyelination and function in demyelinated spinal cord of rats [123]. Arginine decarboxylase is a rate-limiting enzyme of agmatine synthesis and is known to exist in the central nervous system of mammals. Arginine decarboxylase-secreting human mesenchymal stem cells have been found to be more suitable candidates than human mesenchymal stem cell for stem cell therapy after spinal cord injury [124]. Heme oxygenase-1 is a stress-responsive enzyme that modulates immune response and oxidative stress associated with spinal cord injury. Functional recovery after spinal cord injury has been promoted by transplantation of mesenchymal stem cells overexpressing heme oxygenase-1 [125]. Hypothermia is known to improve the microenvironment of the injured spinal cord in a number of ways. Neural cell transplantation has promoted the recovery of hind limb function in rats, and a combination treatment with hypothermia has produced synergistic effects [126]. Extracorporeal shock wave can introduce alteration of microenvironment in cell therapy for chronic spinal cord injury [127].

3.2.2. Peculiarities of bone marrow stromal cells in spinal cord regeneration

Bone marrow stromal cell transplantation has been shown to overcome the gliosis [3]. They have been reported to enhance neuronal protection and cellular preservation via reduction in injury-induced sensitivity to mechanical trauma. They can attenuate astrocyte reactivity and chronic microglia/macrophage activation. They have been found to infiltrate primarily into the ventrolateral white matter tracts, spreading to adjacent segments rostrocaudal to the injury epicenter. However, bone marrow stromal cell transplantation present certain issues. Migration beyond the injection site after intraspinal delivery is limited and inter-donor variability in efficacy and immunomodulatory potency might affect clinical outcome [4].

Measures to increase the efficiency of bone marrow mesenchymal stem cells include mainly measures to reduce oxidative stress-induced apoptosis, hypoxic preconditioning, measures to modulate the extracellular matrix and other measures.

Studies have demonstrated that the inhibition of the Notch1 pathway in bone marrow mesenchymal stem cells contributes to the differentiation of these cells. Research findings that certain antioxidants induce bone marrow mesenchymal stem cells to differentiate into neuronal cells suggest that bone marrow mesenchymal stem cell differentiation is related to the level of reactive oxygen species in cells. After bone marrow mesenchymal stem cell induction with the antioxidant β-mercaptoethanol, Western blotting and immunofluorescence have revealed gradual increases in the expression of Nestin (a neural stem cell-specific protein) and neuron-specific enolase but decreases in Notch1 expression. The decreased expression levels of Notch1 have correlated positively with changes in reactive oxygen species [128]. The effects of a calpain inhibitor (MDL28170) on increasing survival of bone marrow mesenchymal stem cells transplanted into the injured rat spinal cord have been investigated. The protective effects of MDL28170 on survival of bone marrow mesenchymal stem cells have inhibited the activation of calpain and stress-induced apoptosis [129]. Treatment with bone marrow mesenchymal stem cells combined with plumbagin may alleviate spinal cord injury by affecting oxidative stress, inflammation, apoptosis and the activation of the Nrf2 pathway [130]. Polydatin, a glucoside of resveratrol, has been reported to possess potent antioxidative effects and can used in combination with bone marrow mesenchymal stem cell for the treatment of spinal cord injury. Polydatin significantly protects bone marrow mesenchymal stem cell against apoptosis due to its antioxidative effects and the regulation of Nrf 2/ARE pathway [131]. Carvedilol, a nonselective β-adrenergic receptor blocker, has been reported to exert potent anti-oxidative activities. It has been shown that carvedilol protects cell death of H2O2-induced bone marrow mesenchymal stem cells partly through PI3K-Akt pathway, suggesting its use in combination with bone marrow mesenchymal stem cells to improve cell survival in oxidative stress microenvironments [132].

Hypoxic preconditioning effectively increases the survival rate of bone marrow mesenchymal stem cells following transplantation and increases their protective effect on injured tissues. Hypoxic preconditioning has upregulated the expression of hypoxia-inducible factor 1α in spinal cord tissues [133].

Cytokines and extracellular matrix can trigger various types of neural differentiation. To highlight the current understanding of their effects on neural differentiation of human bone marrow-derived multipotent progenitor cells, extracellular matrix proteins, tenascin-cytotactin, tenascin-restrictin and chondroitin sulfate, with the cytokines, nerve growth factor/brain-derived neurotrophic factor/retinoic acid, have been incorporated to induce transdifferentiation of human bone marrow-derived multipotent progenitor cells. Greater amounts of neuronal morphology have appeared in cultures incorporated with tenascin-cytotactin and tenascin-restrictin than those with chondroitin sulfate. It has been suggested that the combined use of tenascin-cytotactin, nerve growth factor /brain-derived neurotrophic factor/retinoic acid and human bone marrow-derived multipotent progenitor cells offers a new feasible method for nerve repair [134]. Fibronectin secreted by mesenchymal stem cells in the early stage has been found to accumulate on gelatin sponge scaffolds and promote neurite elongation of neuronal differentiating mesenchymal stem cells as well as nerve fiber regeneration after spinal cord injury [135].

Transplanted bone mesenchymal stem cells can be mobilized by erythropoietin toward lesion sites following spinal cord injury [136]. Propofol injection combined with bone marrow mesenchymal stem cell transplantation has improved electrophysiological function in the hindlimb of rats with spinal cord injury than monotherapy [137]. Combining bone marrow stromal cells with green tea polyphenols has attenuated the blood-spinal cord barrier permeability in rats with compression spinal cord injury [138]. Bone marrow stromal cells transplantation combined with ultrashortwave therapy has promoted functional recovery in spinal cord injury in rats [139].

Microtubule-associated protein 1B plays an important role in axon guidance and neuronal migration. Phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 in bone marrow mesenchymal stem cells have been found to modulate the phosphorylation of microtubule-associated protein 1B via a cross-signaling network and have affected the migratory efficiency of bone marrow mesenchymal stem cells towards injured spinal cord [140]. Administration of valproic acid potentiates the therapeutic effect of mesenchymal stem cell therapy [141]. Interleukin-8 enhances the angiogenic potential of human bone marrow mesenchymal stem cells by increasing vascular endothelial growth factor production [142].

3.2.3. Peculiarities of adipose-derived stem cells in spinal cord regeneration

Human mesenchymal cells from adipose tissue have deposited laminin and have promoted regeneration of injured spinal cord in rats [143146]. Transplanted during the acute and subacute phases after spinal cord injury, they have enabled the remodulation and regeneration of the lesion site, decreasing the importance of transplantation time in the treatment of spinal cord injury [145]. Chondroitinase ABC-adipose-derived stem cells constructed using lentiviral vector transfection have stably expressed chondroitinase ABC, and chondroitinase ABC expression has significantly enhanced their migratory capacity [146]. Cytoplasmic extracts prepared from adipose tissue stromal cells have inhibited H2O2-mediated apoptosis of cultured spinal cord-derived neural progenitor cells and have improved cell survival. Predifferentiation of adipose tissue-derived stromal cells has promoted the protection of denuded axons and cellular repair. Such predifferentiated cells and hematopoietic stem cells have been successfully infused intrathecally [143]. Nevertheless, no evidence points to the superiority of neural differentiated adipose tissue-derived stromal over undifferentiated ones. Allogenic adipose-derived stem cells have improved neurological function in a canine model. All of the former evidence, however, is contradicted by a study in a rat C3–C4 hemisection in which adipose tissue-derived stromal cell transplantation has significantly reduced sprouting of the descending serotonergic fibers at the injured site [147].

Hypoxic preconditioning of adipose tissue-derived mesenchymal stem cells has increased their survival. Cotransplantation of such cells with engineered neural stem cells has improved both cell survival and gene expression of the engineered neural stem cells [4].

3.2.4. Peculiarities of human umbilical cord blood-derived mesenchymal stem cells in spinal cord regeneration

Human umbilical cord blood-derived mesenchymal stem cells (whether Wharton’s jelly mesenchymal stem cells or human umbilical cord perivascular cells) may reverse spinal cord injury pathophysiology by downregulating apoptotic genes and secreting neurotrophic factors in few days; they may transdifferentiate toward neuronal and oligodendroglial phenotypes [3]. Intrathecal transplantation of human amniotic mesenchymal stem cells has promoted functional recovery in a rat model of traumatic spinal cord injury [148] and in a chronic constrictive nerve injury model [149]. Placental mesenchymal stromal cells have rescued ambulation in ovine myelomeningocele [150]. Umbilical cord-derived mesenchymal stem cell therapy for neurological disorders may act via inhibition of mitogen-activated protein kinase pathway-mediated apoptosis [115]. Through the effect on glial cells(suppression of activated astrocytes and microglia), proinflammatory (Interleukin-1β and Interleukin-17A) and anti-inflammatory cytokines (anti-inflammatory cytokine Interleukin-10), intrathecal injection of human umbilical cord-derived mesenchymal stem cells has ameliorated neuropathic pain in rats [151]. Also, neurotrophic factors have been expressed in the injured spinal cord after transplantation of human-umbilical cord blood stem cells in rats [152].

Preconditioning of umbilical cord mesenchymal stem cells in physioxic environment can enhance the regenerative properties of these cells in the treatment of rat spinal cord injury. In a study on umbilical cord, mesenchymal stem cells pretreated with either atmospheric normoxia (21% O2) or physioxia (5% O2) have grown faster, whereas physioxia has upregulated the expression of trophic and growth factors, including hepatocyte growth factor, brain-derived neurotrophic factor and vascular endothelial growth factor. This has been associated with a significant increase in axonal preservation and a decrease in the number of caspase-3+ cells and ED-1+ macrophages [153].

Calcitonin gene-related peptide, a neural peptide synthesized in spinal cord, contributes to homing of human umbilical cord mesenchymal stem cells. The PI3K/Akt and p38MAPK signaling pathways have played a critical role in the calcitonin gene-related peptide-induced chemotactic migration of human umbilical mesenchymal stem cells [154].

Lavandula angustifolia has neuroprotective effects; it has potentiated the functional and cellular recovery with human umbilical mesenchymal stem cell treatment in rats after spinal cord injury [155]. The combined treatment with methylprednisolone and amniotic membrane mesenchymal stem cells after spinal cord injury in rats has potentiated the anti-inflammatory and anti-apoptotic effect of mesenchymal stem cell transplantation [156]. The neuroprotective effects of conditioned medium from cultured human CD34(+) cells have been similar to those of human CD34(+) cells and the conditioned medium has been found to enhance the neuroprotective effects of 17β-estradiol in rat spinal cord injury [157].

3.3. Inducing the transformation of mesenchymal stem cells into motor neuron-like cells or Schwann cells

A third method for optimizing the therapeutic effect of mesenchymal stem cell transplantation is inducing their transformation into motor neuron-like cells or Schwann cells [158169]. Their differentiation into motor neuron-like cells has been induced through a pre-induction step using β-mercaptoethanol followed by 4 days of induction with retinoic acid and sonic hedgehog [158]. Motor neuron axonal sprouting has been induced by adding different concentrations of a nerve growth factor to the differentiation media. In another study [159], such cells have been tested for 2′,3′-cyclic-nucleotide-3′-phosphodiesterase and microtubule-associated protein 2, as well as to glial fibrillary acidic protein and beta III tubulin. Cells have been injected percutaneously into the spinal cord of paraplegic dogs for two times separated by a 21-day interval. Optimal culture conditions have been investigated as to the production of neural cells and neural stem cells [160]. β-Mercaptoethanol has been used as the main inducer of the neurogenesis pathway. Three types of neural markers have been used: nestin as the immaturation stage marker, neurofilament light chain as the early neural marker, and microtubule-associated protein 2 as the maturation marker. Results have shown that the best exposure time for the production of neural stem cells is 6 hours. It has also been demonstrated that LY294002, a small molecule inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway, can promote neuronal differentiation of mesenchymal stem cells cultured on polycaprolactone/collagen scaffolds [161]. Similarly, microRNA-124 has promoted bone marrow mesenchymal stem cell differentiation into neurogenic cells for accelerating recovery in the spinal cord injury [166, 169]. Such induced motor neuron-like cells have promoted axonal regeneration into the injured spinal cord, whether derived from bone marrow [162, 163, 168], human chorion [164] and placenta [167]. Their in vivo tracking by magnetic resonance has been possible in rabbit models of spinal cord injury [169].

3.4. Mode, quantity and number of injections; time point for injection age and donor variation; allo- and xenotransplantation

The mode, quantity and number of injections may influence the therapeutic effect of mesenchymal stem cell transplantation

3.4.1. Mode of injection

All methods for stem cell transplantation (intravenous, intrathecal, intramedullary, intranasal or skeletal muscle injection ) are based on the homing effect, the ability of implanted stem cells to move to the injured area [170180]. Mesenchymal progenitor cells have been injected intravenously in two models of cervical spinal cord injury, unilateral C5 contusion and complete unilateral C5 hemisection. Cells have been isolated from green fluorescence protein-luciferase transgenic mice and have been injected via the tail vein at D1, D3, D7, D10, or D14. Transplanted cells have been tracked via postmortem bioluminescence imaging. Cells have been found to accumulate in the lungs, irrespective of the time of injection or injury model. It has been proposed that they modulate the immune system via the lungs through secreted immune mediators [173]. The antioxidant and anti-inflammatory effects of intravenously injected adipose-derived mesenchymal stem cells have been proven in dogs with acute spinal cord injury [174]. Diffuse and persistent blood-spinal cord barrier disruption after contusive spinal cord injury has recovered following intravenous infusion of bone marrow mesenchymal stem cells [177]. Intravenous mesenchymal stem cell therapy has been effective after recurrent laryngeal nerve injury [179]. In a meta-analysis, the efficacy of intravenous bone marrow mesenchymal stem cell transplantation in spinal cord injury has been investigated. It has been concluded that the therapeutic window of intravenous bone marrow mesenchymal stem cell transplantation is wide [180]. The feasibility and safety of intrathecal transplantation of autologous bone marrow mesenchymal stem cells have been investigated in horses [175]. The intranasal delivery of bone marrow stromal cells to spinal cord lesions has been successfully tried out [176]. Stem cell injection in the hindlimb skeletal muscle has enhanced neurorepair in mice with spinal cord injury [178].

Although intrathecal is more effective than intravenous injection, it needs large stem cell numbers. Subarachnoid adhesions may prevent the cells from reaching the target site. The homing effect is absent in the chronic stage of spinal cord injury. Therefore, direct intramedullary injection into the injured site is the most effective method for delivering stem cells. Intramedullary injection proximal to the injured area is ideal for stem cell survival, but is hampered by volume effects caused by high tissue pressure and subsequent normal spinal cord damage. On the contrary, large volumes can be injected into the cavity area at the injured level. Injecting into the contused cavity may lead to resolution of the glial scar and may bridge for axonal regeneration. Therefore, Park et al. [171, 172] have injected into both the normal proximal spinal cord and the injured area. In addition, subdural stem cells have been applied in the hope the homing effect has been reinduced because of intramedullary injection.

3.4.2. Quantity, number and time point for mesenchymal stem cell transplantation

3.4.2.1. Quantity and number

Diversity of lesion models, animal types and route of cell administration influence the quantity of mesenchymal stem cells administered. Cell survival and enhancement in locomotor performance have been observed both after intravenous injection of one million cells in a volume of 0.5 mL of DMEM in a model of balloon compressive injury in rats and after transplantation of 600,000 cells in a volume of 6 μL directly into the injury site after contusive injury in rats [112]. Other studies have advocated intrathecal administration from 100 × 106 up to 230 × 106 cells followed by an additional 30 × 106 cell administration at 3 months [5], or the administration of two or three intrathecal injections with a median of 1.2 × 106 mesenchymal stem cells/kg body weight [6]. In a phase III clinical trial, limited efficacy has been proven after injecting 1.6 × 10 autologous mesenchymal stem cells into the intramedullary area at the injured level and 3.2 × 10 autologous mesenchymal stem cells into the subdural space. Single mesenchymal stem cell application to intramedullary and intradural space has had a very weak therapeutic effect compared to multiple injections [7]; partial efficacy has been demonstrated in other trials [811]. Continuous improvement after multiple mesenchymal stem cell transplantations has been observed in a patient with complete spinal cord injury [181]. Multiple injections of human umbilical cord-derived mesenchymal stromal cells through the tail vein have improved microcirculation and the microenvironment in a rat model of radiation myelopathy [182].

3.4.2.2. Time point

Acute phase is defined as the first three days after spinal cord injury and chronic phase is defined as more than 12 months after spinal cord injury. Subacute phase is defined as the period between acute and chronic phase. In the acute phase, reactive oxygen-free radicals, excitatory transmitters, inflammatory molecules and hypoxia caused by hypoperfusion are cytotoxic to implanted stem cells. In the chronic phase, glial scar tissue acts as a physical barrier to axonal regrowth. Thus, it is difficult for implanted stem cells to survive in chronic spinal cord injury. In contrast, in the subacute phase, the inflammatory response is reduced and the glial scar formation has not formed. Therefore, the subacute phase seems to be an optimal phase in the respect of timing of stem cell application [170]. Experimentally, bone marrow-derived stem cells have been infused intravenously 10 weeks after spinal cord injury [183].

3.4.3. Age and donor variation, allo- and xenotransplantation

3.4.3.1. Age and donor variation

The potency of mesenchymal stem cells exhibits significant age and donor variation [3, 184186]. A robust potency assay has been established based on pooling responder leukocytes to minimize individual immune response variability. It has highlighted significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radioresistance [184, 185].

3.4.3.2. Allo- and xenotransplantation

The neuroprotective and immunomodulatory effects of xenotransplantation of adipose tissue mesenchymal stem cells in Lewis rats after lumbar ventral root avulsion have been proven [187]. The therapeutic effects of autologous and allogenic bone marrow-derived mesenchymal stem cell transplantation have been established in canine spinal cord injury [188]. Immunosuppression of allogenic mesenchymal stem cells transplantation after spinal cord injury may improve graft survival [189].

3.4.4. Evaluating the therapeutic effect of mesenchymal stem cell transplantation

Although neurological evaluation of the spinal cord injured patient is usually conducted according to the International Standards for Neurological Classification of Spinal Cord Injury recommended by the American Spinal Cord Injury Association, it should be confirmed by electrophysiological studies (somatosensory evoked potentials and motor evoked potentials) and magnetic resonance imaging studies. Magnetic resonance imaging findings after stem cell therapy include widening of cord diameter, blurring of intramedullary cavity margin and appearance of fiber-like streak pattern in the injured spinal cord. Diffusion tensor imaging can perform accurate visualization and assessment of white matter tracts and is useful for the prediction of neurological recovery in spinal cord injury patients. Fiber continuity on diffusion tensor imaging not seen before stem cell therapy may be an indicator of axonal regeneration in stem cell therapy. Cell labeling techniques for in vivo visualization using biological indicators or contrast agents have helped monitoring the status of the transplanted stem cells in the body (survival, migration and exact location of implanted stem cells). Typical examples are supermagnetic iron oxide particle monitoring using magnetic resonance imaging and radionuclide monitoring using positron emission tomography or single-photon emission computed tomography [170, 190, 191].

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4. Supplying neurotrophic factors and accessory cells

A combinatorial approach has been agreed upon for effective treatment of spinal cord injury [192208].

The combination of neurotrophic factors such as BDNF and neurotrophin-3 has enhanced axonal regeneration and myelination [193]. Cyclic adenosine monophosphate (a neuronal stimulator) and neurotrophin-3 (neurotrophic factor) have been injected 5 days prior to a C4 transection at L4 to precondition the dorsal root ganglion soma. Bone marrow mesenchymal stem cells have been transplanted 7 days post injury. The effect of bone marrow mesenchymal stem cells on spinal cord regeneration has been augmented by modifying them to either express human brain-derived neurotrophic factor (BDNF) in an acute injury or neurotrophin-3 in a chronic injury model, by prestimulating them to secrete neurotrophic factors, e.g. by pretreating them with Schwann cell differentiating factors [3]. In an attempt to generate mesenchymal-derived differentiated neural cells expressing nerve growth factor or neurotrophin-3, mesenchymal stem cells have been infected with recombinant lentiviruses that express nerve growth factor both to induce their neural lineage genes and as a combinatorial approach [194]. Magnetic targeting of neurotrophin-3 gene-transfected bone marrow mesenchymal stem cells via lumbar puncture has enhanced their delivery to the site of injury and has significantly improved functional recovery and nerve regeneration compared to transplanting neurotrophin-3 gene-transfected bone marrow mesenchymal stem cells without magnetic targeting system [195, 196]. Pulsed electromagnetic field exposure near the injured site and for 8 hours per day over 4 weeks has been suggested as a suitable protocol for directing the cells to the site of injury [197]. Electro-acupuncture has promoted the survival and differentiation of transplanted bone marrow mesenchymal stem cells pre-induced with neurotrophin-3 and retinoic acid in gelatin sponge scaffold after rat spinal cord transection [53, 198].

A combination of other trophic factors, including epidermal growth factor, fibroblast growth factor type 2 and platelet-derived growth factor have enhanced the survival of implanted cells. Likewise has been the addition of granulocyte macrophage-colony stimulating factor [4, 170]. Co-transplantation of bone marrow-derived mesenchymal stem cells and nanospheres containing FGF-2 has improved cell survival and neurological function in the injured rat spinal cord [199]. Human ciliary neurotrophic factor overexpressing stable bone marrow stromal cells have proved effective in a rat model of traumatic spinal cord injury [200]. Bone marrow mesenchymal stem cells combined with minocycline have improved spinal cord injury in a rat model [201]. Propofol has enhanced the therapeutic effect of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats [202].

The addition of accessory cells includes combining mesenchymal stem cells with neural progenitor cells [3], neural crest stem cells [203], olfactory ensheathing cells [204, 205] or Schwann cells [207, 208]. The effects of mesenchymal stem cell and olfactory ensheathing cell transplantation at early or delayed time after a spinal cord contusion injury in the rat have been compared. Mesenchymal stem cell grafting seems a better option than olfactory ensheathing cell grafting [206].

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5. Establishing a continuous drug and cell delivery system

In spinal cord injury, the gap is usually extensive and associated with excessive scarring. The axonal growth cone would thus take years to reach the distal spinal cord. Consequently, the factors mentioned before have to be replenished continually.

This can take place through an intrathecal (possibly extradural) continuous cell and drug delivery system (catheter) [39, 209]. Catheter-related complications include tension headache, meningitis, fibrous track formation, catheter slippage, difficult catheter insertion and catheter blockage. Microsphere, nanosphere and nanoshell technology may help keep the catheter patent, dissolve fibrosis and replenish molecules and cells [43, 210215]. Co-transplantation of bone marrow-derived mesenchymal stem cells and nanospheres containing FGF-2 has improved cell survival and neurological function in the injured rat spinal cord [199]. Controlling surface tension as well as hydrophobic and hydrophilic properties of the conduit lumen and the microspheres may help us fulfill the three aims described previously. One method to achieve the latter aim is using magnetic nanoparticle-incorporated human bone marrow-derived mesenchymal stem cells exposed to pulsed electromagnetic fields [190, 191, 197] (Figure 2).

Figure 2.

An intrathecal continuous cell and drug delivery system (catheter) (14) allows for the replenishment of stem cells, accessory cells, molecular growth factors and neurolyzing agents. To avoid catheter-related complications, it had better be lined with a biomaterial used for vascular grafts (15). Hydrophobic microsphere, nanosphere and nanoshell technology may also help keep the catheter patent, dissolve fibrosis and replenish molecules and cells. Magnetic nanoparticles (16) incorporated into microspheres may help guide the latter to the gliotic segment. After their release from microspheres, magnetic nanoparticles may be made to attach to the scaffold and to the intact cord segments and to apply tension on them (17—arrows), thus promoting axonal regeneration and enhancing engraftment and differentiation of transplanted cells.

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6. Conclusion

We have attempted to identify the prerequisites for effective mesenchymal stem cell transplantation in spinal cord injuries. These fall into three categories (Table 1). The first category comprises those prerequisites, on which the literature is united. Research workers are thus obliged to follow them or provide a reasonable explanation for having not followed them.

1. Establishing a suitable niche
1.1. Dissolving the gliosis
Category I (prerequisites, on which the literature is united)
Chondroitinase ABC in high doses (50 or 100 IUs) and at multiple times (at 0, 1, 2 and 4 weeks)
Category II (prerequisites, on which the literature is still not united)
- Heparins, sialidase
- Blocking myelin-associated inhibitors with Nogo-A monoclonal antibodies or with Nogoreceptor competitive agonist peptide (NEP1-40)
- Blocking Rho-A with Rho inhibitor ‘cethrin’
- A synthetic membrane-permeable peptide mimetic of the protein tyrosine phosphatase σ can bind to protein tyrosine phosphatase σ and relieve proteoglycan-mediated inhibition
- Cell permeable phosphopeptide (PI3Kpep) reverses proteoglycans inhibition of phosphoinositide 3-kinase signaling in axons.
- Rolipram, a phosphodiesterase4 inhibitor, can increase intracellular cAMP levels
- Improving blood vessel formation might reduce cell death and promote angiogenesis within the injury zone
- Taxol, a microtubule-stabilizing agent, increases neurite outgrowth
1.2. Providing a suitable scaffold, both to bridge the gap and to harbor the cells
Category I (prerequisites, on which the literature is united)
- Scaffolds should meet macro- and microengineering requirements
- Scaffolds should fulfill the same mechanical conditions of the recipient spinal cord
- Scaffolds should provide adequate space for the different molecular pathways for axonal regeneration; they should be of ideal porosity
- Scaffolds should provide adequate space for lumen fillers
- Scaffolds should meet requirements based on spatial distribution of neurotrophic factor gradients
2. Optimizing the therapeutic effect of mesenchymal stem cell transplantation
2.1. The ideal source for mesenchymal stem cells
Category II (prerequisites, on which the literature is still not united)
Compared to stem cells of other mesenchymal origin (e.g. bone marrow, adipose tissue, skin), umbilical cord stem cells are superior
2.2. Increasing the efficiency of mesenchymal stem cells
Category I (prerequisites, on which the literature is united)
- Reducing oxidative stress-induced apoptosis
- Hypoxic preconditioning
- Modulating the extracellular matrix
Category II (prerequisites, on which the literature is still not united)
- Measures to reduce oxidative stress-induced apoptosis (arginine decarboxylase expressing cells; heme oxygenase-1 expressing cells; calpain inhibitor MDL28170; plumbagin; polydatin, a glucoside of resveratrol; carvedilol, a nonselective β-adrenergic receptor blocker)
- Measures during stem cell culture (replacing fetal bovine serum, mechanical fibrinogen-depletion)
- Measures during grafting (electroacupuncture, hypothermia, extracorporeal shock wave, propofol, green tea polyphenols, ultrashortwave therapy, valproic acid, IL-8)
- Measures increasing the homing effect and mobilization of stem cells (calcitonin gene-related peptide, erythropoietin)
2.3. Inducing the transformation of mesenchymal stem cells into motor neuron-like cells or Schwann cells
Category II (prerequisites, on which the literature is still not united)
2.4. Mode, quantity and number of injections; time point for injection; age and donor variation; allo- and xenotransplantation
Category I (prerequisites, on which the literature is united): intramedullary injection; injection during the subacute phase
Category II (prerequisites, on which the literature is still not united): all other issues
3. Supplying neurotrophic factors and accessory cells
Category I (prerequisites, on which the literature is united)
A combinatorial approach, including growth factors, cellular transplants and neurolyzing agents, has to be followed
Category II (prerequisites, on which the literature is still not united)
Which growth factors (epidermal growth factor, fibroblast growth factor type 2, platelet-derived growth factor, riluzole, minocycline, granulocyte-colony stimulating factor, BDNF, neurotrophin-3) and cells (embryonic stem cells, neural stem cells, induced pluripotent stem cells, neural crest stem cells, mesenchymal stromal cells, Schwann cells, olfactory ensheathing cells or macrophages) to be used in combination
4. Establishing a continuous drug and cell delivery system
Category III (prerequisites defective in the literature)

Table 1.

Prerequisites for effective mesenchymal stem cell transplantation in spinal cord injuries.

The literature is unanimous on the following: (1) the gliosis has to be dissolved prior to mesenchymal stem cell transplantation (e.g. through chondroitinase ABC in high doses (50 or 100 IUs) and at multiple times); (2) a suitable scaffold has to be used; this scaffold should meet both macro- and microengineering requirements and should provide adequate space for lumen fillers; (3) the efficiency of mesenchymal stem cells themselves has to be increased (by reducing oxidative stress-induced apoptosis, by hypoxic preconditioning, by modulating the extracellular matrix and by other measures); (4) a combinatorial approach including growth factors, cellular transplants and neurolyzing agents has to be followed.

There are many issues, however, on which the literature is still not united. These fall into the second category. Among others, they include (1) the ideal source for mesenchymal stem cells, mode, quantity, time point and number of injections; (2) which growth factors and cells to be used in the combinatorial approach; (3) optimizing the therapeutic effect of mesenchymal stem cell transplantation by inducing their transformation into motor neuron-like cells or Schwann cells; (4) increasing the homing effect of stem cells (by calcitonin gene-related peptide). In the third category, more research has to be stimulated, e.g. as to how to establish a continuous drug and cell delivery system.

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List of abbreviations

AktProtein kinase B (PKB), a serine/threonine-specific protein kinase
BDNFBrain-derived neurotrophic factor
cAMPCyclic adenosine monophosphate
DMEMDulbecco's Modified Eagle Medium ED-1+ macrophages: antibody against cellular marker CD68 macrophages
FGF-2Fibroblast growth factor type 2
LY294002Morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases
MAG108Myelin-associated glycoprotein
MDL28170Calpain inhibitor III
NEP1-40Nogoreceptor competitive agonist peptide
NeuNFeminizing locus on X-3, Fox-3, Rbfox3, or hexaribonucleotide binding protein-3
NG2Neural/glial antigen 2
Nogo-AReticulon-4, neurite outgrowth inhibitor
Nrf 2Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2
Nrf 2/ARE pathwayThe transcription factor Nrf2 (NF-E2-related factor 2) binds to the ARE, a cis-acting element called the antioxidant responsive element
OMgp109Oligodendrocyte myelin glycoprotein
PI3KPhosphatidylinositol 3-kinase
PI3KpepCell permeable phosphopeptide: p38MAPK P38 mitogen-activated protein kinases
Rho-Aras homolog gene family, member A

References

  1. 1. Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nature Neuroscience. 2017;20(5):637-647
  2. 2. Harrop JS, Hashimoto R, Norvell D, Raich A, Aarabi B, Grossman RG, Guest JD, Tator CH, Chapman J, Fehlings MG. Evaluation of clinical experience using cell-based therapies in patients with spinal cord injury: A systematic review. Journal of Neurosurgery: Spine. 2012 Sep;17(1 Suppl):230-246. DOI: 10.3171/2012.5.AOSPINE12115.Review. PubMed PMID: 22985383
  3. 3. Doulames VM, Marquardt LM, Jayaram B, Plant CD and Plant GW. Stem Cell Therapies for Cervical Spinal Cord Injury, Recovery of Motor Function Following Spinal Cord Injury. Heidi F, editor, InTech; 2016. DOI: 10.5772/63580. Available from: http://www.intechopen.com/books/recovery-of-motor-function-following-spinal-cord-injury/stem-cell-therapies-for-cervical-spinal-cord-injury
  4. 4. Dasari VR, Veeravalli KK, Dinh DH. Mesenchymal stem cells in the treatment of spinal cord injuries: A review. World Journal of Stem Cells. 2014 Apr 26;6(2):120-133. DOI: 10.4252/wjsc.v6.i2.120. Review. PubMed PMID: 24772239; PubMed Central PMCID: PMC3999770
  5. 5. Vaquero J, Zurita M, Rico MA, Bonilla C, Aguayo C, Montilla J, Bustamante S, Carballido J, Marin E, Martinez F, Parajon A, Fernandez C, Reina LD, Neurological Cell Therapy Group. An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy. 2016 Aug;18(8):1025-1036. DOI: 10.1016/j.jcyt.2016.05.003. PubMed PMID: 27311799
  6. 6. Satti HS, Waheed A, Ahmed P, Ahmed K, Akram Z, Aziz T, Satti TM, Shahbaz N, Khan MA, Malik SA. Autologous mesenchymal stromal cell transplantation for spinal cord injury: A phase I pilot study. Cytotherapy. 2016 Apr;18(4):518-522. DOI: 10.1016/j.jcyt.2016.01.004. PubMed PMID: 26971680
  7. 7. Oh SK, Choi KH, Yoo JY, Kim DY, Kim SJ, Jeon SR. A phase III clinical trial showing limited efficacy of autologous mesenchymal stem cell therapy for spinal cord injury. Neurosurgery. 2016 Mar;78(3):436-447; discussion 447. DOI: 10.1227/NEU.0000000000001056. PubMed PMID: 26891377
  8. 8. Hur JW, Cho TH, Park DH, Lee JB, Park JY, Chung YG. Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: A human trial. The Journal of Spinal Cord Medicine. 2015 Jul 24. [Epub ahead of print] PubMed PMID: 26208177
  9. 9. Miao X, Wu X, Shi W. Umbilical cord mesenchymal stem cells in neurological disorders: A clinical study. Indian Journal of Biochemistry & Biophysics. 2015 Apr;52(2):140-146. PubMed PMID: 26118125
  10. 10. Mendonça MV, Larocca TF, de Freitas Souza BS, Villarreal CF, Silva LF, Matos AC, Novaes MA, Bahia CM, de Oliveira Melo Martinez AC, Kaneto CM, Furtado SB, Sampaio GP, Soares MB, dos Santos RR. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Research & Therapy. 2014 Nov 17;5(6):126. DOI: 10.1186/scrt516. PubMed PMID: 25406723; PubMed Central PMCID: PMC4445989
  11. 11. Cheng H, Liu X, Hua R, Dai G, Wang X, Gao J, An Y. Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. Journal of Translational Medicine. 2014 Sep 12;12:253. DOI: 10.1186/s12967-014-0253-7. PubMed PMID: 25209445; PubMed Central PMCID:PMC4172930
  12. 12. Bradbury EJ, McMahon SB. Spinal cord repair strategies: Why do they work? Nature Reviews Neuroscience. 2006;7:644-653
  13. 13. Thuret S, Moon LDF, Gage FH. Therapeutic interventions after spinal cord injury. Nature Reviews Neuroscience. 2006;7:628-643
  14. 14. Harel NY, Strittmatter SM. Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nature Reviews Neuroscience. 2006;7:603-616
  15. 15. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience. 2006;7:617-627
  16. 16. Yamagata T, Saito H, Habuchi O, Suzuki S. Purification and properties of bacterial chondroitinases and chondrosulfatases. Journal of Biological Chemistry. 1968;243:15231535. [PubMed: 5647268]
  17. 17. Bradbury EJ, Carter LM. Manipulating the glial scar: Chondroitinase ABC as a therapy for spinal cord injury. Brain Research Bulletin. 2011;84:306316. [PubMed: 20620201]
  18. 18. Tom VJ, Sandrow-Feinberg HR, Miller K, Santi L, Connors T, Lemay MA, Houle JD. Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. The Journal of Neuroscience. 2009;29:14881-14890. [PMC free article] [PubMed]
  19. 19. Lee SH, Kim Y, Rhew D, Kuk M, Kim M, Kim WH, Kweon OK. Effect of the combination of mesenchymal stromal cells and chondroitinase ABC on chronic spinal cord injury. Cytotherapy. 2015 Oct;17(10):1374-1383. DOI: 10.1016/j.jcyt.2015.05.012. PubMed PMID: 26188966
  20. 20. Wang Y, Jia H, Li WY, Guan LX, Deng L, Liu YC, Liu GB. Molecular examination of bone marrow stromal cells and chondroitinase ABC-assisted acellular nerve allograft for peripheral nerve regeneration. Experimental and Therapeutic Medicine. 2016 Oct;12(4):1980-1992. PubMed PMID: 27698684; PubMed Central PMCID: PMC5038205
  21. 21. Xiong LL, Li Y, Shang FF, Chen SW, Chen H, Ju SM, Zou Y, Tian HL, Wang TH, Luo CZ, Wang XY. Chondroitinase administration and pcDNA3.1-BDNF-BMSC transplantation promote motor functional recovery associated with NGF expression in spinal cord-transected rat. Spinal Cord. 2016 Jun 28. DOI: 10.1038/sc.2016.55. [Epub ahead of print] PubMed PMID: 27349609
  22. 22. Lee H, McKeon RJ, Bellamkonda RV. Regenerative medicine special feature: Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proceedings of the National Academy of Sciences USA. 2009 Nov 2
  23. 23. Hunanyan AS, García-Alías G, Alessi V, Levine JM, Fawcett JW, Mendell LM, Arvanian VL. Role of chondroitin sulfate proteoglycans in axonal conduction in Mammalian spinal cord. The Journal of Neuroscience. 2010 Jun 9;30(23):7761-7769. DOI: 10.1523/JNEUROSCI.4659-09.2010
  24. 24. Cheng CH, Lin CT, Lee MJ, Tsai MJ, Huang WH, Huang MC, Lin YL, Chen CJ, Huang WC, Cheng H. Local delivery of high-dose chondroitinase ABC in the sub-acute stage promotes axonal outgrowth and functional recovery after complete spinal cord transection. PLoS One. 2015 Sep 22;10(9):e0138705. DOI: 10.1371/journal.pone.0138705. eCollection 2015
  25. 25. Shields LB, Zhang YP, Burke DA, Gray R, Shields CB. Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat. Surgical Neurology. 2008 Jun;69(6):568-577; discussion 577. DOI: 10.1016/j.surneu.2008.02.009
  26. 26. Iseda T, Okuda T, Kane-Goldsmith N, Mathew M, Ahmed S, Chang YW, Young W, Grumet M. Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion. Journal of Neurotrauma. 2008 Apr;25(4):334-349. DOI: 10.1089/neu.2007.0289
  27. 27. Caggiano AO, Zimber MP, Ganguly A, Blight AR, Gruskin EA. Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. Journal of Neurotrauma. 2005 Feb;22(2):226-239
  28. 28. Mondello SE, Jefferson SC, Tester NJ, Howland DR. Impact of treatment duration and lesion size on effectiveness of chondroitinase treatment post-SCI. Experimental Neurology. 2015 May;267:64-77. DOI: 10.1016/j.expneurol.2015.02.028
  29. 29. Ma Y, Liu M, Li Y. Secretion of bacterial chondroitinase ABC from bone marrow stromal cells by glycosylation site mutation: A promising approach for axon regeneration. Medical Hypotheses. 2011 Nov;77(5):914-916. DOI: 10.1016/j.mehy.2011.08.010. Epub 2011 Aug 31
  30. 30. Wilems TS, Pardieck J, Iyer N, Sakiyama-Elbert SE. Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury. Acta Biomaterialia. 2015 Sep 15. DOI: 10.1016/j.actbio.2015.09.018. PII: S1742-7061(15)30112-4. [Epub ahead of print]
  31. 31. Kumar P, Choonara YE, Modi G, Naidoo D, Pillay V. Multifunctional therapeutic delivery strategies for effective neuro-regeneration following traumatic spinal cord injury. Current Pharmaceutical Design. 2015;21(12):1517-1528
  32. 32. Mountney A, Zahner MR, Sturgill ER, Riley CJ, Aston JW, Oudega M, Schramm LP, Hurtado A, Schnaar RL. Sialidase, chondroitinase ABC, and combination therapy after spinal cord contusion injury. Journal of Neurotrauma. 2013 Feb 1;30(3):181-190. DOI: 10.1089/neu.2012.2353
  33. 33. McCreedy DA, Sakiyama-Elbert SE. Combination therapies in the CNS: Engineering the environment. Neuroscience Letters. 2012 Jun 25;519(2):115-121. DOI: 10.1016/j.neulet.2012.02.025. Epub 2012 Feb 17. Review. PMID: 22343313
  34. 34. Li Z, Zhang Z, Zhao L, Li H, Wang S, Shen Y. Bone marrow mesenchymal stem cells with Nogo-66 receptor gene silencing for repair of spinal cord injury. Neural Regeneration Research. 2014 Apr 15;9(8):806-814. DOI: 10.4103/1673-5374.131595. PubMed PMID: 25206893; PubMed Central PMCID: PMC4146260
  35. 35. Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck SM, Madalena KM, Brown BP, Weng YL, Li S, Karimi-Abdolrezaee S, Busch SA, Shen Y, Silver J. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature. 2015 Feb 19;518(7539):404-408. DOI: 10.1038/nature13974. Epub 2014 Dec 3. PubMed PMID: 25470046; PubMed Central PMCID: PMC4336236
  36. 36. Silver L, Michael JV, Goldfinger LE, Gallo G. Activation of PI3K and R-Ras signaling promotes the extension of sensory axons on inhibitory chondroitin sulfate proteoglycans. Developmental Neurobiology. 2014 Sep;74(9):918-933. DOI: 10.1002/dneu.22174. Epub 2014 Mar 27
  37. 37. Tetzlaff W, Alexander SW, Miller FD, Bisby MA. Response of facial and rubrospinal neurons to axotomy: Changes in mRNA expression for cytoskeletal proteins and GAP-43. The Journal of Neuroscience. 1991;11:2528-2544; [PubMed]
  38. 38. Sengottuvel V, Leibinger M, Pfreimer M, Andreadaki A, Fischer D. Taxol facilitates axon regeneration in the mature CNS. The Journal of Neuroscience. 2011;31:2688-2699 [PubMed]
  39. 39. Amr SM. Bridging Defects in Chronic Spinal Cord Injury Using Peripheral Nerve Grafts: From Basic Science to Clinical Experience, Recovery of Motor Function Following Spinal Cord Injury. Heidi F, editor. InTech; 2016. DOI: 10.5772/64211. Available from: http://www.intechopen.com/books/recovery-of-motor-function-following-spinal-cord-injury/bridging-defects-in-chronic-spinal-cord-injury-using-peripheral-nerve-grafts-from-basic-science-to-clinical-experience
  40. 40. Billings PC, Pacifici M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: Mechanisms and mysteries. Connective Tissue Research. 2015;56(4):272-280. DOI: 10.3109/03008207.2015.1045066
  41. 41. Olczyk P, Mencner Ł, Komosinska-Vassev K. Diverse roles of heparan sulfate and heparin in wound repair. BioMed Research International. 2015;2015:549417. DOI: 10.1155/2015/549417. Epub 2015 Jul 7. Review. PubMed PMID: 26236728; PubMed Central PMCID: PMC4508384
  42. 42. Santos-Silva A, Fairless R, Frame MC, Montague P, Smith GM, Toft A, Riddell JS, Barnett SC. FGF/heparin differentially regulates Schwann cell and olfactory ensheathing cell interactions with astrocytes: A role in astrocytosis. The Journal of Neuroscience. 2007 Jul 4;27(27):7154-7167
  43. 43. Madigan NN, McMahon S, O'Brien T, Yaszemski MJ, Windebank AJ. Current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury using polymer scaffolds. Respiratory Physiology & Neurobiology. 2009 Nov 30;169(2):183-199. DOI: 10.1016/j.resp.2009.08.015. Epub 2009 Sep 6. Review. PubMed PMID: 19737633; PubMed Central PMCID: PMC2981799
  44. 44. Straley KS, Foo CW, Heilshorn SC. Biomaterial design strategies for the treatment of spinal cord injuries. Journal of Neurotrauma. 2010 Jan;27(1):1-19. DOI: 10.1089/neu.2009.0948. Review. PubMed PMID: 19698073; PubMed Central PMCID: PMC2924783
  45. 45. Hyatt AJ, Wang D, van Oterendorp C, Fawcett JW, Martin KR. Mesenchymal stromal cells integrate and form longitudinally-aligned layers when delivered to injured spinal cord via a novel fibrin scaffold. Neuroscience Letters. 2014 May 21;569:12-17. DOI: 10.1016/j.neulet.2014.03.023. PubMed PMID: 24680849; PubMed Central PMCID: PMC4015360
  46. 46. Liu J, Chen Q, Zhang Z, Zheng Y, Sun X, Cao X, Gong A, Cui Y, He Q, Jiang P. Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury. Cells, Tissues, Organs. 2013;198(1):35-46. DOI: 10.1159/000351665. PubMed PMID: 23774080
  47. 47. Zurita M, Otero L, Aguayo C, Bonilla C, Ferreira E, Parajón A, Vaquero J. Cell therapy for spinal cord repair: Optimization of biologic scaffolds for survival and neural differentiation of human bone marrow stromal cells. Cytotherapy. 2010 Jul;12(4):522-537. DOI: 10.3109/14653241003615164. PubMed PMID: 20465485
  48. 48. Cholas R, Hsu HP, Spector M. Collagen scaffolds incorporating select therapeutic agents to facilitate a reparative response in a standardized hemiresection defect in the rat spinal cord. Tissue Engineering Part A. 2012 Oct;18(19-20):2158-2172. DOI: 10.1089/ten.TEA.2011.0577. PubMed PMID: 22827732
  49. 49. Wang B, Han J, Gao Y, Xiao Z, Chen B, Wang X, Zhao W, Dai J. The differentiation of rat adipose-derived stem cells into OEC-like cells on collagen scaffolds by co-culturing with OECs. Neuroscience Letters. 2007 Jun 29;421(3):191-196. PubMed PMID: 17574753
  50. 50. Chen J, Zhang Z, Liu J, Zhou R, Zheng X, Chen T, Wang L, Huang M, Yang C, Li Z, Yang C, Bai X, Jin D. Acellular spinal cord scaffold seeded with bone marrow stromal cells protects tissue and promotes functional recovery in spinal cord-injured rats. Journal of Neuroscience Research. 2014 Mar;92(3):307-317. DOI: 10.1002/jnr.23311. PubMed PMID: 24375695
  51. 51. Liu J, Chen J, Liu B, Yang C, Xie D, Zheng X, Xu S, Chen T, Wang L, Zhang Z, Bai X, Jin D. Acellular spinal cord scaffold seeded with mesenchymal stem cells promotes long-distance axon regeneration and functional recovery in spinal cord injured rats. Journal of Neurological Sciences. 2013 Feb 15;325(1-2):127-136. DOI: 10.1016/j.jns.2012.11.022. PubMed PMID: 23317924
  52. 52. Wei X, Wen Y, Zhang T, Li H. Effects of bone marrow mesenchymal stem cells with a cellular muscle bioscaffolds on repair of acute hemi-transection spinal cord injury in rats. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012 Nov;26(11):1362-1368. Chinese. PubMed PMID: 23230674
  53. 53. Zhang K, Liu Z, Li G, Lai BQ, Qin LN, Ding Y, Ruan JW, Zhang SX, Zeng YS. Electro-acupuncture promotes the survival and differentiation of transplanted bone marrow mesenchymal stem cells pre-induced with neurotrophin-3 and retinoic acid in gelatin sponge scaffold after rat spinal cord transection. Stem Cell Reviews. 2014 Aug;10(4):612-625. DOI: 10.1007/s12015-014-9513-4. PubMed PMID: 24789671
  54. 54. Shirian S, Ebrahimi-Barough S, Saberi H, Norouzi-Javidan A, Mousavi SM, Derakhshan MA, Arjmand B, Ai J. Comparison of capability of human bone marrow mesenchymal stem cells and endometrial stem cells to differentiate into motor neurons on electrospun poly(ε-caprolactone) scaffold. Molecular Neurobiology. 2016 Oct;53(8):5278-5287. doi: 10.1007/s12035-015-9442-5. PubMed PMID: 26420037
  55. 55. Wang D, Fan Y, Zhang J. Transplantation of Nogo-66 receptor gene-silenced cells in a poly(D,L-lactic-co-glycolic acid) scaffold for the treatment of spinal cord injury. Neural Regeneration Research. 2013 Mar 15;8(8):677-685. DOI: 10.3969/j.issn.1673-5374.2013.08.001. PubMed PMID: 25206713; PubMed Central PMCID: PMC4146076
  56. 56. Wang D, Wen Y, Lan X, Li H. Experimental study on bone marrow mesenchymal stem cells seeded in chitosan-alginate scaffolds for repairing spinal cord injury. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2010 Feb;24(2):190-196. Chinese. PubMed PMID: 20187451
  57. 57. Xue F, Wu EJ, Zhang PX, Li-Ya A, Kou YH, Yin XF, Han N. Biodegradable chitin conduit tubulation combined with bone marrow mesenchymal stem cell transplantation for treatment of spinal cord injury by reducing glial scar and cavity formation. Neural Regeneration Research. 2015 Jan;10(1):104-111. DOI: 10.4103/1673-5374.150715. PubMed PMID: 25788929; PubMed Central PMCID:PMC4357092
  58. 58. Kim YC, Kim YH, Kim JW, Ha KY. Transplantation of mesenchymal stem cells for acute spinal cord injury in rats: Comparative study between intralesional injection and scaffold based transplantation. Journal of Korean Medical Science. 2016 Sep;31(9):1373-1382. DOI: 10.3346/jkms.2016.31.9.1373. PubMed PMID: 27510379; PubMed Central PMCID: PMC4974177
  59. 59. Tukmachev D, Forostyak S, Koci Z, Zaviskova K, Vackova I, Vyborny K, Sandvig I, Sandvig A, Medberry CJ, Badylak SF, Sykova E, Kubinova S. Injectable extracellular matrix hydrogels as scaffolds for spinal cord injury repair. Tissue Engineering Part A. 2016 Feb;22(3-4):306-317. DOI: 10.1089/ten.TEA.2015.0422. PubMed PMID: 26729284; PubMed Central PMCID: PMC4799710
  60. 60. Park J, Lim E, Back S, Na H, Park Y, Sun K. Nerve regeneration following spinal cord injury using matrix metalloproteinase-sensitive, hyaluronic acid-based biomimetic hydrogel scaffold containing brain-derived neurotrophic factor. Journal of Biomedical Materials Research. Part A. 2010 Jun 1;93(3):1091-1099. DOI: 10.1002/jbm.a.32519. PubMed PMID: 19768787
  61. 61. Günther MI, Weidner N, Müller R, Blesch A. Cell-seeded alginate hydrogel scaffolds promote directed linear axonal regeneration in the injured rat spinal cord. Acta Biomaterialia. 2015 Nov;27:140-150. DOI: 10.1016/j.actbio.2015.09.001. PubMed PMID: 26348141
  62. 62. Madigan NN, Chen BK, Knight AM, Rooney GE, Sweeney E, Kinnavane L, Yaszemski MJ, Dockery P, O'Brien T, McMahon SS, Windebank AJ. Comparison of cellular architecture, axonal growth, and blood vessel formation through cell-loaded polymer scaffolds in the transected rat spinal cord. Tissue Engineering. Part A. 2014 Nov;20(21-22):2985-2997. DOI: 10.1089/ten.TEA.2013.0551. PubMed PMID: 24854680;PubMed Central PMCID: PMC4229864
  63. 63. Kubinová Š, Horák D, Hejčl A, Plichta Z, Kotek J, Proks V, Forostyak S, Syková E. SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores for spinal cord injury repair. Journal of Tissue Engineering and Regenerative Medicine. 2015 Nov;9(11):1298-1309. DOI: 10.1002/term.1694. PubMed PMID: 23401421
  64. 64. Kubinová S, Horák D, Hejčl A, Plichta Z, Kotek J, Syková E. Highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds for spinal cord injury repair. Journal of Biomedical Materials Research. Part A. 2011 Dec 15;99(4):618-629. DOI: 10.1002/jbm.a.33221. PubMed PMID: 21953978
  65. 65. Han S, Wang B, Li X, Xiao Z, Han J, Zhao Y, Fang Y, Yin Y, Chen B, Dai J. Bone marrow-derived mesenchymal stem cells in three-dimensional culture promote neuronal regeneration by neurotrophic protection and immunomodulation. Journal of Biomedical Materials Research. Part A. 2016 Jul;104(7):1759-1769. DOI: 10.1002/jbm.a.35708. PubMed PMID: 26990583
  66. 66. Ribeiro-Samy S, Silva NA, Correlo VM, Fraga JS, Pinto L, Teixeira-Castro A, Leite-Almeida H, Almeida A, Gimble JM, Sousa N, Salgado AJ, Reis RL. Development and characterization of a PHB-HV-based 3D scaffold for a tissue engineering and cell-therapy combinatorial approach for spinal cord injury regeneration. Macromolecular Bioscience. 2013 Nov;13(11):1576-1592. DOI: 10.1002/mabi.201300178. PubMed PMID:24038969
  67. 67. Caron I, Rossi F, Papa S, Aloe R, Sculco M, Mauri E, Sacchetti A, Erba E, Panini N, Parazzi V, Barilani M, Forloni G, Perale G, Lazzari L, Veglianese P. A new three dimensional biomimetic hydrogel to deliver factors secreted by human mesenchymal stem cells in spinal cord injury. Biomaterials. 2016 Jan;75:135-147. DOI: 10.1016/j.biomaterials.2015.10.024. PubMed PMID: 26497428
  68. 68. Zeng X, Zeng YS, Ma YH, Lu LY, Du BL, Zhang W, Li Y, Chan WY. Bone marrow mesenchymal stem cells in a three-dimensional gelatin sponge scaffold attenuate inflammation, promote angiogenesis, and reduce cavity formation in experimental spinal cord injury. Cell Transplantation. 2011;20(11-12):1881-1899. DOI: 10.3727/096368911X566181. PubMed PMID: 21396163
  69. 69. Rodríguez-Vázquez M, Vega-Ruiz B, Ramos-Zúñiga R, Saldaña-Koppel DA, Quiñones-Olvera LF. Chitosan and Its Potential Use as a Scaffold for Tissue Engineering in Regenerative Medicine. BioMed Research International. 2015;2015:821279. DOI: 10.1155/2015/821279. Epub 2015 Oct 4. Review. PubMed PMID: 26504833; PubMed Central PMCID: PMC4609393
  70. 70. Langer R and Tirrell DA. Designing materials for biology and medicine. Nature. 2004:428(6982):487-492. View at Publisher DOI:10.1038/nature02388. View at Google Scholar. View at Scopus
  71. 71. Zeng W, Rong M, Hu X, Xiao W, Qi F, Huang J, Luo Z. Incorporation of chitosan microspheres into collagen-chitosan scaffolds for the controlled release of nerve growth factor. PLoS One. 2014 Jul 1;9(7):e101300. DOI: 10.1371/journal.pone.0101300. eCollection 2014. PubMed PMID: 24983464; PubMed Central PMCID: PMC4077743
  72. 72. Hiroshi N, Tator CH, Shoichet MS. Bioengineered strategies for spinal cord repair. Journal of Neurotrauma. 2006;23:496-507. [PubMed: 16629632]
  73. 73. Wong DY, Leveque JC, Brumblay H, Krebsbach PH, Hollister SJ, Lamarca F. Macro-architectures in spinal cord scaffold implants influence regeneration. Journal of Neurotrauma. 2008;25:1027-1037. [PubMed: 18721107]
  74. 74. Krych AJ, Rooney GE, Chen B, Schermerhorn TC, Ameenuddin S, Gross LA, Moore MJ, Currier BL, Friedman JA, Spinner RJ, Yaszemski MJ, Windebank AJ. Relationship between scaffold channel diameter and number of regenerating axons in the transected rat spinal cord. Acta Biomaterialia. 2009. (Epub March 27, 2009)
  75. 75. Moore MJ, Friedman JA, Lewellyn EB, Mantila SM, Krych AJ, Ameenuddin S, Knight AM, Lu L, Currier BL, Spinner RJ, Marsh RW, Windebank AJ, Yaszemski MJ. Multiple-channel scaffolds to promote spinal cord axon regeneration. Biomaterials. 2006;27:419-429. [PubMed: 16137759]
  76. 76. Ducker TB, and Hayes GJ. Experimental improvements in the use of Silastic cuff for peripheral nerve repair. Journal of Neurosurgery. 1968;28:582
  77. 77. Rutkowski GE, and Heath CA. Development of a bioartificial nerve graft. II Nerve regeneration in vitro. Biotechnology Progress. 2002;18:373
  78. 78. Kokai LE, Lin YC, Oyster NM, and Marra KG. Diffusion of soluble factors through degradable polymer nerve guides: Controlling manufacturing parameters. Acta Biomaterialia. 2009:5:2540
  79. 79. Nectow AR, Marra KG, Kaplan DL. Biomaterials for the development of peripheral nerve guidance conduits. Tissue Engineering. Part B, Reviews. 2012 Feb;18(1):40-50. DOI: 10.1089/ten.TEB.2011.0240. Epub 2011 Sep 23. Review. PubMed PMID: 21812591; PubMed Central PMCID: PMC3262974
  80. 80. Bellamkonda R. Peripheral nerve regeneration: An opinion on channels, scaffolds and anisotropy. Biomaterials. 2006;27:3515-3518. [PubMed: 16533522]
  81. 81. Bellamkonda R, Ranieri JP, Bouche N, Aebischer P. Hydrogel-based three-dimensional matrix for neural cells. Journal of Biomedical Materials Research. 1995;29:663-671. [PubMed: 7622552]
  82. 82. Khademhosseini A, Langer R. Microengineered hydrogels for tissue engineering. Biomaterials. 2007;28:5087-5092. [PubMed: 17707502]
  83. 83. Clark P, Connolly P, Curtis A, Dow J, Wilkinson C. Cell guidance by ultrafine topography in vitro. Journal of Cell Science. 1991;99:73-77. [PubMed: 1757503]
  84. 84. Goldner JS, Bruder JM, Li G, Gazzola D. Neurite bridging across micropatterned grooves. Biomaterials. 2006;27:460-472. [PubMed: 16115675]
  85. 85. Yao L, Damodaran G, Nikolskaya N, Gorman AM, Windebank AJ, Pandit A. The effect of laminin peptide gradient of enzymatically cross-linked collagen scaffold on neurite growth. Journal of Biomedical Materials Research. Part A. 2009;11 (Epub February 11, 2009)
  86. 86. Yao L, O’Brien N, Windebank A, Pandit A. Orienting neurite growth in electrospun fibrous neural conduits. Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 2009;90(2):483-491. [PubMed: 19130615]
  87. 87. Yao L, Wang S, Cui W, Sherlock R, O’Connell C, Damodaran G, Gorman A, Windebank A, Pandit A. Effect of functionalized micropatterned PLGA on guided neurite growth. Acta Biomaterialia. 2009;5:580-588. [PubMed: 18835227]
  88. 88. Liu C, Pyne R, Kim J, Wright NT, Baek S, Chan C. The impact of prestretch induced surface anisotropy on axon regeneration. Tissue Engineering. Part C, Methods. 2016 Jan 8. [Epub ahead of print] PubMed PMID: 26563431; PubMed Central PMCID:PMC4744876
  89. 89. Lundborg G, Dahlin L, Dohi D, Kanje M, Terada N. A new type of “bioartificial” nerve graft for bridging extended defects in nerves. The Journal of Hand Surgery: British & European Volume. 1997;22:299-303
  90. 90. Cai J, Peng X, Nelson KD, Eberhart R, Smith GM. Permeable guidance channels containing microfilament scaffolds enhance axon growth and maturation. Journal of Biomedical Materials Research. Part A. 2005;75:374-386
  91. 91. Yoshii S, Oka M, Shima M, Taniguchi A, Akagi M. Bridging a 30-mm nerve defect using collagen filaments. Journal of Biomedical Materials Research. 2003;67A:467-474
  92. 92. Yoshii S, Oka M, Ikeda N, Akagi M, Matsusue Y, Nakamura T. Bridging a peripheral nerve defect using collagen filaments. The Journal of Hand Surgery. 2001;26:52-59
  93. 93. Chew SY, Mi R, Hoke A, Leong KW. Aligned protein–polymer composite fibers enhance nerve regeneration: A potential tissue-engineering platform. Advanced Functional Materials. 2007;17:1288-1296
  94. 94. Zhang BG, Quigley AF, Myers DE, Wallace GG, Kapsa RM, Choong PF. Recent advances in nerve tissue engineering. International Journal of Artificial Organs. 2014 Apr;37(4):277-291. DOI: 10.5301/ijao.5000317. Epub 2014 Apr 15. Review. PubMed PMID: 24811182
  95. 95. Hudson TW, Evans GR, Schmidt CE. Engineering strategies for peripheral nerve repair. Clinics in Plastic Surgery. 1999;26:617-628, ix
  96. 96. Xie F, Li QF, Gu B, Liu K, and Shen GX. In vitro and in vivo evaluation of a biodegradable chitosan-PLA composite composite peripheral nerve guide conduit material. Microsurgery. 2008;28:471
  97. 97. Discher DE, Janmey P, and Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310:1139
  98. 98. Engler AJ, Sen S, Sweeney HL, and Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;726:677
  99. 99. Mammoto A, and Ingber DE. Cytoskeletal control of growth and cell fate switching. Current Opinion in Cell Biology. 2009;21:864
  100. 100. Yao S, Liu X, Yu S, Wang X, Zhang S, Wu Q, Sun X, Mao H. Co-effects of matrix low elasticity and aligned topography on stem cell neurogenic differentiation and rapid neurite outgrowth. Nanoscale. 2016 May 21;8(19):10252-10265. DOI: 10.1039/c6nr01169a. PubMed PMID: 27124547
  101. 101. Frostick SP, Yin Q, Kemp G: Schwann cells, neurotrophic factors, and peripheral nerve regeneration. Microsurgery. 1998;18:397-405
  102. 102. Blottner D, Baumgarten HG: Neurotrophy and regeneration in vivo. Acta Anatomica. 1994;150:235-245
  103. 103. Li G, Che MT, Zhang K, Qin LN, Zhang YT, Chen RQ, Rong LM, Liu S, Ding Y, Shen HY, Long SM, Wu JL, Ling EA, Zeng YS. Graft of the NT-3 persistent delivery gelatin sponge scaffold promotes axon regeneration, attenuates inflammation, and induces cell migration in rat and canine with spinal cord injury. Biomaterials. 2016 Mar;83:233-248. DOI: 10.1016/j.biomaterials.2015.11.059. PubMed PMID:26774562
  104. 104. Liu H, Yao F, Zhou Y, et al. Porous poly (DL-lactic acid) modified chitosan-gelatin scaffolds for tissue engineering. Journal of Biomaterials Applications. 2005;19(4):303-322
  105. 105. Yang Y, Zhao W, He J, Zhao Y, Ding F, Gu X. Nerve conduits based on immobilization of nerve growth factor onto modified chitosan by using genipin as a crosslinking agent. European Journal of Pharmaceutics and Biopharmaceutics. 2011;79(3):519-525
  106. 106. Westhauser F, Weis C, Hoellig M, Swing T, Schmidmaier G, Weber MA, Stiller W, Kauczor HU, Moghaddam A. Heidelberg-mCT-Analyzer: A novel method for standardized microcomputed-tomography-guided evaluation of scaffold properties in bone and tissue research. Royal Society Open Science. 2015 Nov 11;2(11):150496. DOI: 10.1098/rsos.150496. PubMed PMID: 26716008; PubMed Central PMCID: PMC4680623
  107. 107. Pabari A, Yang SY, Mosahebi A, Seifalian AM. Recent advances in artificial nerve conduit design: Strategies for the delivery of luminal fillers. Journal of Controlled Release. 2011 Nov 30;156(1):2-10. DOI: 10.1016/j.jconrel.2011.07.001. Epub 2011 Jul 6. Review. PubMed PMID: 21763371
  108. 108. Rosoff WJ, Urbach JS, Esrick MA, McAllister RG, Richards LJ, Goodhill GJ. A new chemotaxis assay shows the extreme sensitivity of axons to molecular gradients. Nature Neuroscience. 2004 Jun;7(6):678-682. Epub 2004 May 25. Erratum in: Nat Neurosci. 2004 Jul;7(7):785
  109. 109. Adams DN, Kao EY, Hypolite CL, Distefano MD, Hu WS, Letourneau PC. Growth cones turn and migrate up an immobilized gradient of the laminin IKVAV peptide. Journal of Neurobiology. 2005;62:134-147. [PubMed: 15452851]
  110. 110. Dodla MC, Bellamkonda RV. Anisotropic scaffolds facilitate enhanced neurite extension in vitro. Journal of Biomedical Materials Research. Part A. 2006;78A:213-221. [PubMed: 16892507]
  111. 111. Tse TH, Chan BP, Chan CM, Lam J. Mathematical modeling of guided neurite extension in an engineered conduit with multiple concentration gradients of nerve growth factor (NGF). Annals of Biomedical Engineering. 2007 Sep;35(9):1561-1572. Epub 2007 May 23
  112. 112. Ng TK, Fortino VR, Pelaez D, Cheung HS. Progress of mesenchymal stem cell therapy for neural and retinal diseases. World Journal of Stem Cells. 2014 Apr 26;6(2):111-119. DOI: 10.4252/wjsc.v6.i2.111. Review. PubMed PMID: 24772238; PubMedCentral PMCID: PMC3999769
  113. 113. Ichim TE, Solano F, Glenn E, Morales F, Smith L, Zabrecky G, Riordan NH. Stem cell therapy for autism. Journal of Translational Medicine. 2007;5:30. DOI: 10.1186/1479-5876-5-30. PMID: 17597540
  114. 114. Ng TK, Lam DS, Cheung HS. Prospects of stem cells for retinal diseases. Asia-Pacific Journal of Ophthalmology. 2013;2:57-63 DOI: 10.1097/APO.0b013e31827e3e5d
  115. 115. Zhang R, Chen H, Zheng Z, Liu Q, Xu L. Umbilical cord-derived mesenchymal stem cell therapy for neurological disorders via inhibition of mitogen-activated protein kinase pathway-mediated apoptosis. Molecular Medicine Reports. 2015 Mar;11(3):1807-1812.DOI: 10.3892/mmr.2014.2985. PubMed PMID: 25412281
  116. 116. Badner A, Vawda R, Laliberte A, Hong J, Mikhail M, Jose A, Dragas R, Fehlings M. Early intravenous delivery of human brain stromal cells modulates systemic inflammation and leads to vasoprotection in traumatic spinal cord injury. Stem Cells Translational Medicine. 2016 Aug;5(8):991-1003. DOI: 10.5966/sctm.2015-0295. PubMed PMID: 27245367; PubMed Central PMCID: PMC4954452
  117. 117. de Almeida FM, Marques SA, Ramalho Bdos S, Massoto TB, Martinez AM. Chronic spinal cord lesions respond positively to transplants of mesenchymal stem cells. Restorative Neurology and Neuroscience. 2015;33(1):43-55. DOI: 10.3233/RNN-140431. PubMed PMID:25537259
  118. 118. Zhang LX, Yin YM, Zhang ZQ, Deng LX. Grafted bone marrow stromal cells: A contributor to glial repair after spinal cord injury. The Neuroscientist. 2015 Jun;21(3):277-289. DOI: 10.1177/1073858414532171. Review. PubMed PMID: 24777423
  119. 119. Tsumuraya T, Ohtaki H, Song D, Sato A, Watanabe J, Hiraizumi Y, Nakamachi T, Xu Z, Dohi K, Hashimoto H, Atsumi T, Shioda S. Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP). Journal of Neuroinflammation. 2015 Feb 22;12:35. DOI: 10.1186/s12974-015-0252-5. PubMed PMID: 25889720; PubMed Central PMCID: PMC4346126
  120. 120. Wang Y, Liu H, Ma H. Intrathecally Transplanting Mesenchymal Stem Cells(MSCs) Activates ERK1/2 in spinal cords of ischemia-reperfusion injury rats and improves nerve function. Medical Science Monitor. 2016 May 2;22:1472-1479. PubMed PMID: 27135658; PubMed Central PMCID: PMC4917313
  121. 121. Burnouf T, Strunk D, Koh MB, Schallmoser K. Human platelet lysate: Replacing fetal bovine serum as a gold standard for human cell propagation? Biomaterials. 2016 Jan;76:371-387. DOI: 10.1016/j.biomaterials.2015.10.065. Review. PubMed PMID:26561934
  122. 122. Laner-Plamberger S, Lener T, Schmid D, Streif DA, Salzer T, Öller M, Hauser-Kronberger C, Fischer T, Jacobs VR, Schallmoser K, Gimona M, Rohde E. Mechanical fibrinogen-depletion supports heparin-free mesenchymal stem cell propagation in human platelet lysate. Journal of Translational Medicine. 2015 Nov 10;13:354. DOI: 10.1186/s12967-015-0717-4. PubMed PMID: 26554451; PubMed Central PMCID: PMC4641400
  123. 123. Ding Y, Zhang RY, He B, Liu Z, Zhang K, Ruan JW, Ling EA, Wu JL, Zeng YS. Combination of electroacupuncture and grafted mesenchymal stem cells overexpressing TrkC improves remyelination and function in demyelinated spinal cord of rats. Scientific Reports. 2015 Mar 16;5:9133. DOI: 10.1038/srep09133. PubMed PMID:25779025
  124. 124. Park YM, Han SH, Seo SK, Park KA, Lee WT, Lee JE. Restorative benefits of transplanting human mesenchymal stromal cells overexpressing arginine decarboxylase genes after spinal cord injury. Cytotherapy. 2015 Jan;17(1):25-37. DOI: 10.1016/j.jcyt.2014.08.006. PubMed PMID: 25442787
  125. 125. Lee SH, Kim Y, Rhew D, Kim A, Jo KR, Yoon Y, Choi KU, Jung T, Kim WH, Kweon OK. Effect of canine mesenchymal stromal cells overexpressing heme oxygenase-1 in spinal cord injury. The Journal of Veterinary Science. 2016 Sep 1. [Epub ahead of print] PubMed PMID: 27586469
  126. 126. Wang D, Zhang J. Effects of hypothermia combined with neural stem cell transplantation on recovery of neurological function in rats with spinal cord injury. Molecular Medicine Reports. 2015 Mar;11(3):1759-1767. DOI: 10.3892/mmr.2014.2905. PubMed PMID: 25385306; PubMed Central PMCID: PMC4270334
  127. 127. Lee JY, Ha KY, Kim JW, Seo JY, Kim YH. Does extracorporeal shock wave introduce alteration of microenvironment in cell therapy for chronic spinal cord injury? Spine (Phila Pa 1976). 2014 Dec 15;39(26):E1553-E1559. DOI: 10.1097/BRS.0000000000000626. PubMed PMID: 25271504
  128. 128. Shi Y, Hu Y, Lv C, Tu G. Effects of reactive oxygen species on differentiation of bone marrow mesenchymal stem cells. Annals of Transplantation. 2016 Nov 14;21:695-700
  129. 129. Wang C, Shi D, Song X, Chen Y, Wang L, Zhang X. Calpain inhibitor attenuates ER stress-induced apoptosis in injured spinal cord after bone mesenchymal stem cells transplantation. Neurochemistry International. 2016 Jul;97:15-25. DOI: 10.1016/j.neuint.2016.04.015. PubMed PMID: 27137651
  130. 130. Yang W, Yang Y, Yang JY, Liang M, Song J. Treatment with bone marrow mesenchymal stem cells combined with plumbagin alleviates spinal cord injury by affecting oxidative stress, inflammation, apoptosis and the activation of the Nrf2 pathway. International Journal of Molecular Medicine. 2016 Apr;37(4):1075-1082. DOI: 10.3892/ijmm.2016.2498. PubMed PMID: 26936518
  131. 131. Chen M, Hou Y, Lin D. Polydatin protects bone marrow stem cells against oxidative injury: Involvement of Nrf 2/ARE pathways. Stem Cells International. 2016;2016:9394150. DOI: 10.1155/2016/9394150. PubMed PMID: 27022401; PubMed Central PMCID: PMC4684894
  132. 132. Chen M, Chen S, Lin D. Carvedilol protects bone marrow stem cells against hydrogen peroxide-induced cell death via PI3K-AKT pathway. Biomedicine and Pharmacotherapy. 2016 Mar;78:257-263. DOI: 10.1016/j.biopha.2016.01.008. PubMed PMID: 26898450
  133. 133. Wang Z, Fang B, Tan Z, Zhang D, Ma H. Hypoxic preconditioning increases the protective effect of bone marrow mesenchymal stem cells on spinal cord ischemia/reperfusion injury. Molecular Medicine Reports. 2016 Mar;13(3):1953-1960. DOI: 10.3892/mmr.2016.4753. PubMed PMID: 26783161; PubMed Central PMCID: PMC4768971
  134. 134. Deng WP, Yang CC, Yang LY, Chen CW, Chen WH, Yang CB, Chen YH, Lai WF, Renshaw PF. Extracellular matrix-regulated neural differentiation of human multipotent marrow progenitor cells enhances functional recovery after spinal cord injury. The Spine Journal. 2014 Oct 1;14(10):2488-2499. DOI: 10.1016/j.spinee. 2014.04.024. PubMed PMID: 24792783; PubMed Central PMCID:PMC4692164
  135. 135. Zeng X, Ma YH, Chen YF, Qiu XC, Wu JL, Ling EA, Zeng YS. Autocrine fibronectin from differentiating mesenchymal stem cells induces the neurite elongation in vitro and promotes nerve fiber regeneration in transected spinal cord injury. Journal of Biomedical Materials Research. Part A. 2016 Aug;104(8):1902-1911. DOI: 10.1002/jbm.a.35720. PubMed PMID: 26991461; PubMed Central PMCID: PMC5101622
  136. 136. Li J, Guo W, Xiong M, Han H, Chen J, Mao D, Tang B, Yu H, Zeng Y. Effect of SDF-1/CXCR4 axis on the migration of transplanted bone mesenchymal stem cells mobilized by erythropoietin toward lesion sites following spinal cord injury. International Journal of Molecular Medicine. 2015 Nov;36(5):1205-1214. DOI: 10.3892/ijmm.2015.2344. PubMed PMID: 26398409; PubMed Central PMCID: PMC4601746
  137. 137. Wang YX, Sun JJ, Zhang M, Hou XH, Hong J, Zhou YJ, Zhang ZY. Propofol injection combined with bone marrow mesenchymal stem cell transplantation better improves electrophysiological function in the hindlimb of rats with spinal cord injury than monotherapy. Neural Regeneration Research. 2015 Apr;10(4):636-643. DOI: 10.4103/1673 5374.155440. PubMed PMID: 26170827; PubMed Central PMCID:PMC4424759
  138. 138. Yu DS, Liu LB, Cao Y, Wang YS, Bi YL, Wei ZJ, Tong SM, Lv G, Mei XF. Combining bone marrow stromal cells with green tea polyphenols attenuates the blood-spinal cord barrier permeability in rats with compression spinal cord injury. Journal of Molecular Neuroscience. 2015 Jun;56(2):388-396. DOI: 10.1007/s12031-015-0564-z. PubMed PMID: 26007330
  139. 139. Yin YM, Lu Y, Zhang LX, Zhang GP, Zhang ZQ. Bone marrow stromal cells transplantation combined with ultrashortwave therapy promotes functional recovery on spinal cord injury in rats. Synapse. 2015 Mar;69(3):139-147. DOI: 10.1002/syn.21802. PubMed PMID: 25600592
  140. 140. Xia P, Pan S, Cheng J, Yang M, Qi Z, Hou T, Yang X. Factors affecting directional migration of bone marrow mesenchymal stem cells to the injured spinal cord. Neural Regeneration Research. 2014 Sep 15;9(18):1688-1695. DOI: 10.4103/1673-5374.141804. PubMed PMID: 25374590; PubMed Central PMCID: PMC4211189
  141. 141. Chen L, Cui X, Wu Z, Jia L, Yu Y, Zhou Q, Hu X, Xu W, Luo D, Liu J, Xiao J, Yan Q, Cheng L. Transplantation of bone marrow mesenchymal stem cells pretreated with valproic acid in rats with an acute spinal cord injury. Bioscience Trends. 2014 Apr;8(2):111-119. PubMed PMID: 24815388
  142. 142. Hou Y, Ryu CH, Jun JA, Kim SM, Jeong CH, Jeun SS. IL-8 enhances the angiogenic potential of human bone marrow mesenchymal stem cells by increasing vascular endothelial growth factor. Cell Biology International. 2014 Sep;38(9):1050-1059. DOI: 10.1002/cbin.10294. PubMed PMID: 24797366
  143. 143. Thakkar UG, Vanikar AV, Trivedi HL, Shah VR, Dave SD, Dixit SB, Tiwari BB, Shah HH. Infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and hematopoietic stem cells in post-traumatic paraplegia offers a viable therapeutic approach. Advanced Biomedical Research. 2016 Mar 16;5:51. DOI: 10.4103/2277-9175.178792. PubMed PMID: 27110548; PubMed Central PMCID: PMC4817398
  144. 144. Menezes K, Nascimento MA, Gonçalves JP, Cruz AS, Lopes DV, Curzio B, Bonamino M, de Menezes JR, Borojevic R, Rossi MI, Coelho-Sampaio T. Human mesenchymal cells from adipose tissue deposit laminin and promote regeneration of injured spinal cord in rats. PLoS One. 2014 May 15;9(5):e96020. DOI: 10.1371/journal. pone.0096020. PubMed PMID: 24830794; PubMed Central PMCID:PMC4022508
  145. 145. Aras Y, Sabanci PA, Kabatas S, Duruksu G, Subasi C, Erguven M, Karaoz E. The effects of adipose tissue-derived mesenchymal stem cell transplantation during the acute and subacute phases following spinal cord injury. Turkish Neurosurgery. 2016;26(1):127-139. DOI: 10.5137/1019-5149.JTN.15724-15.0. PubMed PMID: 26768879
  146. 146. Wu JH, Li M, Liang Y, Lu T, Duan CY. Migration of adipose-derived mesenchymal stem cells stably expressing chondroitinase ABC in vitro. Chinese Medical Journal (England). 2016 Jul 5;129(13):1592-1599. DOI: 10.4103/0366-6999.184464. PubMed PMID: 27364797; PubMed Central PMCID: PMC4931267
  147. 147. Kolar MK, et al. The therapeutic effects of human adipose-derived stem cells in a rat cervical spinal cord injury model. Stem Cells and Development. 2014;23(14):1659-1674
  148. 148. Zhou HL, Zhang XJ, Zhang MY, Yan ZJ, Xu ZM, Xu RX. Transplantation of human amniotic mesenchymal stem cells promotes functional recovery in a rat model of traumatic spinal cord injury. Neurochemical Research. 2016 Oct;41(10):2708-2718. PubMed PMID: 27351200
  149. 149. Chiang CY, Liu SA, Sheu ML, Chen FC, Chen CJ, Su HL, Pan HC. Feasibility of human amniotic fluid derived stem cells in alleviation of neuropathic pain in chronic constrictive injury nerve model. PLoS One. 2016 Jul 21;11(7):e0159482. DOI: 10.1371/journal.pone.0159482. PubMed PMID: 27441756; PubMed Central PMCID:PMC4956194
  150. 150. Wang A, Brown EG, Lankford L, Keller BA, Pivetti CD, Sitkin NA, Beattie MS, Bresnahan JC, Farmer DL. Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele. Stem Cells Translational Medicine. 2015 Jun;4(6):659-669. DOI: 10.5966/sctm.2014-0296. PubMed PMID: 25911465; PubMed Central PMCID: PMC4449103
  151. 151. Chen C, Chen F, Yao C, Shu S, Feng J, Hu X, Hai Q, Yao S, Chen X. Intrathecal injection of human umbilical cord-derived mesenchymal stem cells ameliorates neuropathic pain in rats. Neurochemical Research. 2016 Sep 21. [Epub ahead of print]PubMed PMID: 27655256
  152. 152. Chung HJ, Chung WH, Lee JH, Chung DJ, Yang WJ, Lee AJ, Choi CB, Chang HS, Kim DH, Suh HJ, Lee DH, Hwang SH, Do SH, Kim HY. Expression of neurotrophic factors in injured spinal cord after transplantation of human-umbilical cord blood stem cells in rats. The Journal of Veterinary Science. 2016 Mar;17(1):97-102. DOI: 10.4142/jvs.2016.17.1.97. PubMed PMID: 27051345; PubMed Central PMCID: PMC4808649
  153. 153. Zhilai Z, Biling M, Sujun Q, Chao D, Benchao S, Shuai H, Shun Y, Hui Z. Preconditioning in lowered oxygen enhances the therapeutic potential of human umbilical mesenchymal stem cells in a rat model of spinal cord injury. Brain Research. 2016 Jul 1;1642:426-435. DOI: 10.1016/j.brainres.2016.04.025. PubMed PMID:27085204
  154. 154. Zhang Y, Yang J, Zhang P, Liu T, Xu J, Fan Z, Shen Y, Li W, Zhang H. Calcitonin gene-related peptide is a key factor in the homing of transplanted human MSCs to sites of spinal cord injury. Scientific Reports. 2016 Jun 14;6:27724. DOI: 10.1038/srep27724. PubMed PMID: 27296555; PubMed Central PMCID: PMC4906351
  155. 155. Yaghoobi K, Kaka G, Mansouri K, Davoodi S, Sadraie SH, Hosseini SR. Lavandula angustifolia extract improves the result of human umbilical mesenchymal Wharton's jelly stem cell transplantation after contusive spinal cord injury in Wistar rats. Stem Cells International. 2016;2016:5328689. DOI: 10.1155/2016/5328689. PubMed PMID: 27057171; PubMed Central PMCID: PMC4769777
  156. 156. Gao S, Ding J, Xiao HJ, Li ZQ, Chen Y, Zhou XS, Wang JE, Wu J, Shi WZ. Anti-inflammatory and anti-apoptotic effect of combined treatment with methylprednisolone and amniotic membrane mesenchymal stem cells after spinal cord injury in rats. Neurochemical Research. 2014 Aug;39(8):1544-1552. DOI: 10.1007/s11064-014-1344-9. PubMed PMID: 24890008
  157. 157. Yeng CH, Chen PJ, Chang HK, Lo WY, Wu CC, Chang CY, Chou CH, Chen SH. Attenuating spinal cord injury by conditioned medium from human umbilical cord blood-derived CD34+ cells in rats. Taiwanese Journal of Obstetrics & Gynecology. 2016 Feb;55(1):85-93. DOI: 10.1016/j.tjog.2015.12.009. PubMed PMID: 26927256
  158. 158. Abdullah RH, Yaseen NY, Salih SM, Al-Juboory AA, Hassan A, Al-Shammari AM. Induction of mice adult bone marrow mesenchymal stem cells into functional motor neuron-like cells. Journal of Chemical Neuroanatomy. 2016 Nov;77:129-142. DOI: 10.1016/j.jchemneu.2016.07.003. PubMed PMID: 27417692
  159. 159. Besalti O, Aktas Z, Can P, Akpinar E, Elcin AE, Elcin YM. The use of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells for the treatment of paraplegic dogs without nociception due to spinal trauma. Journal of Veterinary Medical Science. 2016 Oct 1;78(9):1465-1473. PubMed PMID: 27301583; PubMed Central PMCID: PMC5059374
  160. 160. Mohammad MH, Al-Shammari AM, Al-Juboory AA, Yaseen NY. Characterization of neural stemness status through the neurogenesis process for bone marrow mesenchymal stem cells. Stem Cells and Cloning : Advances and Applications. 2016 Apr 18;9:1-15. DOI: 10.2147/SCCAA.S94545. PubMed PMID: 27143939; PubMed Central PMCID: PMC4846075
  161. 161. Ebrahimi-Barough S, Hoveizi E, Yazdankhah M, Ai J, Khakbiz M, Faghihi F, Tajerian R, Bayat N. Inhibitor of PI3K/Akt signaling pathway small molecule promotes motor neuron differentiation of human endometrial stem cells cultured on electrospun biocomposite polycaprolactone/collagen scaffolds. Molecular Neurobiology. 2016 Mar 18. [Epub ahead of print] PubMed PMID: 26993294
  162. 162. Qiu XC, Jin H, Zhang RY, Ding Y, Zeng X, Lai BQ, Ling EA, Wu JL, Zeng YS. Donor mesenchymal stem cell-derived neural-like cells transdifferentiate into myelin-forming cells and promote axon regeneration in rat spinal cord transection. Stem Cell Research & Therapy. 2015 May 27;6:105. DOI: 10.1186/s13287-015-0100-7. PubMed PMID: 26012641; PubMed Central PMCID: PMC4482203
  163. 163. Zeng X, Qiu XC, Ma YH, Duan JJ, Chen YF, Gu HY, Wang JM, Ling EA, Wu JL, Wu W, Zeng YS. Integration of donor mesenchymal stem cell-derived neuron-like cells into host neural network after rat spinal cord transection. Biomaterials. 2015 Jun;53:184-201. DOI: 10.1016/j.biomaterials.2015.02.073. PubMed PMID: 25890718
  164. 164. Faghihi F, Mirzaei E, Ai J, Lotfi A, Sayahpour FA, Ebrahimi-Barough S, Joghataei MT. Differentiation potential of human chorion-derived mesenchymal stem cells into motor neuron-like cells in two- and three-dimensional culture systems. Molecular Neurobiology. 2016 Apr;53(3):1862-1872. DOI: 10.1007/s12035-015-9129-y. Erratum in: Mol Neurobiol. 2016 Apr;53(3):1873. Barough, Somayeh Ebrahimi [Corrected to Ebrahimi-Barough, Somayeh]. PubMed PMID: 25790953
  165. 165. Wakao S, Matsuse D, Dezawa M. Mesenchymal stem cells as a source of Schwann cells: Their anticipated use in peripheral nerve regeneration. Cells, Tissues, Organs. 2014;200(1):31-41. DOI: 10.1159/000368188. Review. PubMed PMID: 25765009
  166. 166. Zhao Y, Jiang H, Liu XW, Xiang LB, Zhou DP, Chen JT. MiR-124 promotes bone marrow mesenchymal stem cells differentiation into neurogenic cells for accelerating recovery in the spinal cord injury. Tissue and Cell. 2015 Apr;47(2):140-146. DOI: 10.1016/j.tice.2015.01.007. PubMed PMID: 25697062
  167. 167. Li Z, Zhao W, Liu W, Zhou Y, Jia J, Yang L. Transplantation of placenta-derived mesenchymal stem cell-induced neural stem cells to treat spinal cord injury. Neural Regeneration Research. 2014 Dec 15;9(24):2197-2204. DOI: 10.4103/1673-5374.147953. PubMed PMID: 25657742; PubMed Central PMCID: PMC4316454
  168. 168. Mannoji C, Koda M, Kamiya K, Dezawa M, Hashimoto M, Furuya T, Okawa A, Takahashi K, Yamazaki M. Transplantation of human bone marrow stromal cell-derived neuroregenerative cells promotes functional recovery after spinal cord injury in mice. Acta Neurobiologiae Experimentalis (Warsaw). 2014;74(4):479-488. PubMed PMID:25576978
  169. 169. Zou D, Chen Y, Han Y, Lv C, Tu G. Overexpression of microRNA-124 promotes the neuronal differentiation of bone marrow-derived mesenchymal stem cells. Neural Regeneration Research. 2014 Jun 15;9(12):1241-1248. DOI: 10.4103/1673-5374.135333. PubMed PMID: 25206789; PubMed Central PMCID: PMC4146284
  170. 170. Oh SK, Jeon SR. Current concept of stem cell therapy for spinal cord injury: A review. Korean Journal of Neurotrauma. 2016 Oct;12(2):40-46. Review. PubMed PMID: 27857906; PubMed Central PMCID: PMC5110917
  171. 171. Park JH, Kim DY, Sung IY, Choi GH, Jeon MH, Kim KK, et al. Long-term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery. 2012;70:1238-1247
  172. 172. Parr AM, Kulbatski I, Tator CH. Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. Journal of Neurotrauma. 2007;24:835-845
  173. 173. White SV, Czisch CE, Han MH, Plant CD, Harvey AR, Plant GW. Intravenous transplantation of mesenchymal progenitors distribute solely to the lungs and improve outcomes in cervical spinal cord injury. Stem Cells. 2016 Jul;34(7):1812-1825. DOI: 10.1002/stem.2364. PubMed PMID: 26989838
  174. 174. Kim Y, Jo SH, Kim WH, Kweon OK. Antioxidant and anti-inflammatory effects of intravenously injected adipose derived mesenchymal stem cells in dogs with acute spinal cord injury. Stem Cell Research & Therapy. 2015 Nov 26;6:229. DOI: 10.1186/s13287-015-0236-5. PubMed PMID: 26612085; PubMed Central PMCID: PMC4660672
  175. 175. Maia L, da Cruz Landim-Alvarenga F, Taffarel MO, de Moraes CN, Machado GF, Melo GD, Amorim RM. Feasibility and safety of intrathecal transplantation of autologous bone marrow mesenchymal stem cells in horses. BMC Veterinary Research. 2015 Mar 15;11:63. DOI: 10.1186/s12917-015-0361-5. PubMed PMID: 25879519; PubMed CentralPMCID: PMC4369105
  176. 176. Ninomiya K, Iwatsuki K, Ohnishi Y, Ohkawa T, Yoshimine T. Intranasal delivery of bone marrow stromal cells to spinal cord lesions. Journal of Neurosurgery: Spine. 2015 Jul;23(1):111-119. DOI: 10.3171/2014.10.SPINE14690. PubMed PMID: 25840039
  177. 177. Matsushita T, Lankford KL, Arroyo EJ, Sasaki M, Neyazi M, Radtke C, Kocsis JD. Diffuse and persistent blood-spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells. Experimental Neurology. 2015 May;267:152-164. DOI: 10.1016/j.expneurol.2015.03.001. PubMed PMID: 25771801
  178. 178. Cruz-Martinez P, Pastor D, Estirado A, Pacheco-Torres J, Martinez S, Jones J. Stem cell injection in the hindlimb skeletal muscle enhances neurorepair in mice with spinal cord injury. Regenerative Medicine. 2014;9(5):579-591. DOI: 10.2217/rme.14.38. PubMed PMID: 25372077
  179. 179. Lerner MZ, Matsushita T, Lankford KL, Radtke C, Kocsis JD, Young NO. Intravenous mesenchymal stem cell therapy after recurrent laryngeal nerve injury: a preliminary study. Laryngoscope. 2014 Nov;124(11):2555-2560. DOI: 10.1002/lary.24798. PubMed PMID: 25043703
  180. 180. Zhang D, He X. A meta-analysis of the motion function through the therapy of spinal cord injury with intravenous transplantation of bone marrow mesenchymal stem cells in rats. PLoS One. 2014 Apr 1;9(4):e93487. DOI: 10.1371/journal.pone.0093487. PubMed PMID: 24690752; PubMed Central PMCID:PMC3972121
  181. 181. Jarocha D, Milczarek O, Wedrychowicz A, Kwiatkowski S, Majka M. Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury. Cell Transplantation. 2015;24(4):661-672. DOI: 10.3727/096368915X687796. PubMed PMID: 25807231
  182. 182. Wei L, Zhang J, Xiao XB, Mai HX, Zheng K, Sun WL, Wang L, Liang F, Yang ZL, Liu Y, Wang YQ, Li ZF, Wang JN, Zhang WJ, You H. Multiple injections of human umbilical cord-derived mesenchymal stromal cells through the tail vein improve microcirculation and the microenvironment in a rat model of radiation myelopathy. Journal of Translational Medicine. 2014 Sep 8;12:246. DOI: 10.1186/s12967-014-0246-6. PubMed PMID:25196350; PubMed Central PMCID: PMC4174271
  183. 183. Morita T, Sasaki M, Kataoka-Sasaki Y, Nakazaki M, Nagahama H, Oka S, Oshigiri T, Takebayashi T, Yamashita T, Kocsis JD, Honmou O. Intravenous infusion of mesenchymal stem cells promotes functional recovery in a model of chronic spinal cord injury. Neuroscience. 2016 Oct 29;335:221-231. DOI: 10.1016/j.neuroscience.2016.08.037. PubMed PMID: 27586052
  184. 184. Schimke MM, Marozin S, Lepperdinger G. Patient-specific age: The other side of the coin in advanced mesenchymal stem cell therapy. Frontiers in Physiology. 2015 Dec 2;6:362. DOI: 10.3389/fphys.2015.00362. Review. PubMed PMID: 26696897; PubMed Central PMCID: PMC4667069
  185. 185. Ketterl N, Brachtl G, Schuh C, Bieback K, Schallmoser K, Reinisch A, Strunk D. A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio-resistance. Stem Cell Research & Therapy. 2015 Dec 1;6:236. DOI: 10.1186/s13287-015-0233-8. PubMed PMID: 26620155; PubMed Central PMCID:PMC4666276
  186. 186. Neuhuber B, et al. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Research. 2005;1035(1):73-85
  187. 187. Ribeiro TB, Duarte AS, Longhini AL, Pradella F, Farias AS, Luzo AC, Oliveira AL, Olalla Saad ST. Neuroprotection and immunomodulation by xenografted human mesenchymal stem cells following spinal cord ventral root avulsion. Scientific Reports. 2015 Nov 9;5:16167. DOI: 10.1038/srep16167. PubMed PMID: 26548646; PubMed Central PMCID: PMC4637826
  188. 188. Jung DI, Ha J, Kang BT, Kim JW, Quan FS, Lee JH, Woo EJ, Park HM. A comparison of autologous and allogenic bone marrow-derived mesenchymal stem cell transplantation in canine spinal cord injury. Journal of Neurological Sciences. 2009 Oct 15;285(1-2):67-77. DOI: 10.1016/j.jns.2009.05.027. PubMed PMID: 19555980
  189. 189. Torres-Espín A, Redondo-Castro E, Hernandez J, Navarro X. Immunosuppression of allogenic mesenchymal stem cells transplantation after spinal cord injury improves graft survival and beneficial outcomes. Journal of Neurotrauma. 2015 Mar 15;32(6):367-380. DOI: 10.1089/neu.2014.3562. PubMed PMID: 25203134; PubMed Central PMCID: PMC4361361
  190. 190. Vaněček V, Zablotskii V, Forostyak S, Růžička J, Herynek V, Babič M, Jendelová P, Kubinová S, Dejneka A, Syková E. Highly efficient magnetic targeting of mesenchymal stem cells in spinal cord injury. International Journal of Nanomedicine. 2012;7:3719-3730. DOI: 10.2147/IJN.S32824. PubMed PMID: 22888231; PubMed CentralPMCID: PMC3414205
  191. 191. Hu SL, Zhang JQ, Hu X, Hu R, Luo HS, Li F, Xia YZ, Li JT, Lin JK, Zhu G, Feng H. In vitro labeling of human umbilical cord mesenchymal stem cells with superparamagnetic iron oxide nanoparticles. Journal of Cellular Biochemistry. 2009 Oct 1;108(2):529-535. DOI: 10.1002/jcb.22283. PubMed PMID: 19623584
  192. 192. Siddiqui AM, Khazaei M, Fehlings MG. Translating mechanisms of neuroprotection, regeneration, and repair to treatment of spinal cord injury. Progress in Brain Research. 2015;218:15-54. DOI: 10.1016/bs.pbr.2014.12.007. Review. PubMedPMID: 25890131
  193. 193. Morales II, Toscano-Tejeida D, Ibarra A. Non pharmacological strategies to promote spinal cord regeneration: A view on some individual or combined approaches. Current Pharmaceutical Design. 2016;22(6):720-727. Review. PubMed PMID: 26635267
  194. 194. Dong Y, Yang L, Yang L, Zhao H, Zhang C, Wu D. Transplantation of neurotrophin-3-transfected bone marrow mesenchymal stem cells for the repair of spinal cord injury. Neural Regeneration Research. 2014 Aug 15;9(16):1520-1524. DOI: 10.4103/1673-5374.139478. PubMed PMID: 25317169; PubMed Central PMCID: PMC4192969
  195. 195. Zhang RP, Wang LJ, He S, Xie J, Li JD. Effects of magnetically guided, SPIO-labeled, and neurotrophin-3 gene-modified bone mesenchymal stem cells in a rat model of spinal cord injury. Stem Cells International. 2016;2016:2018474. DOI: 10.1155/2016/2018474. PubMed PMID: 26649047; PubMed Central PMCID: PMC4663356
  196. 196. Gong Y, Wang H, Xia H. Stable transfection into rat bone marrow mesenchymal stem cells by lentivirus-mediated NT-3. Molecular Medicine Reports. 2015 Jan;11(1):367-373. DOI: 10.3892/mmr.2014.2727. PubMed PMID: 25333669
  197. 197. Cho H, Choi YK, Lee DH, Park HJ, Seo YK, Jung H, Kim SC, Kim SM, Park JK. Effects of magnetic nanoparticle-incorporated human bone marrow-derived mesenchymal stem cells exposed to pulsed electromagnetic fields on injured rat spinal cord. Biotechnology and Applied Biochemistry. 2013 Nov-Dec;60(6):596-602. DOI: 10.1002/bab.1109. PubMed PMID: 24033637
  198. 198. Liu Z, He B, Zhang RY, Zhang K, Ding Y, Ruan JW, Ling EA, Wu JL, Zeng YS. Electroacupuncture promotes the differentiation of transplanted bone marrow mesenchymal stem cells preinduced with neurotrophin-3 and retinoic acid into oligodendrocyte-like cells in demyelinated spinal cord of rats. Cell Transplantation. 2015;24(7):1265-1281. DOI: 10.3727/096368914X682099. PubMed PMID: 24856958
  199. 199. Shin DA, Pennant WA, Yoon DH, Ha Y, Kim KN. Co-transplantation of bone marrow-derived mesenchymal stem cells and nanospheres containing FGF-2 improve cell survival and neurological function in the injured rat spinal cord. Acta Neurochirurgica (Wien). 2014 Feb;156(2):297-303. DOI: 10.1007/s00701-013-1963-y. PubMed PMID: 24352373225
  200. 200. Abbaszadeh HA, Tiraihi T, Noori-Zadeh A, Delshad AR, Sadeghizade M, Taheri T. Human ciliary neurotrophic factor-overexpressing stable bone marrow stromal cells in the treatment of a rat model of traumatic spinal cord injury. Cytotherapy. 2015 Jul;17(7):912-921. DOI: 10.1016/j.jcyt.2015.03.689. PubMed PMID: 25939801
  201. 201. Chen D, Zeng W, Fu Y, Gao M, Lv G. Bone marrow mesenchymal stem cells combined with minocycline improve spinal cord injury in a rat model. International Journal of Clinical and Experimental Pathology. 2015 Oct 1;8(10):11957-11969. PubMed PMID: 26722382; PubMed Central PMCID: PMC4680327
  202. 202. Zhou YJ, Liu JM, Wei SM, Zhang YH, Qu ZH, Chen SB. Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation. Neural Regeneration Research. 2015 Aug;10(8):1305-1311. DOI: 10.4103/1673-5374.162765. PubMed PMID: 26487860; PubMed Central PMCID: PMC4590245
  203. 203. Neirinckx V, Agirman G, Coste C, Marquet A, Dion V, Rogister B, Franzen R,Wislet S. Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury. Stem Cell Research & Therapy. 2015 Nov 4;6:211. DOI: 10.1186/s13287-015-0202-2. PubMed PMID: 26530515; PubMed Central PMCID: PMC4632651
  204. 204. Ge L, Liu K, Liu Z, Lu M. Co-transplantation of autologous OM-MSCs and OM-OECs: A novel approach for spinal cord injury. Reviews in the Neurosciences. 2016 Apr 1;27(3):259-270. DOI: 10.1515/revneuro-2015-0030. PubMed PMID: 26574889
  205. 205. Wu S, Cui G, Shao H, Du Z, Ng JC, Peng C. The Cotransplantation of olfactory ensheathing cells with bone marrow mesenchymal stem cells exerts antiapoptotic effects in adult rats after spinal cord injury. Stem Cells International. 2015;2015:516215. DOI: 10.1155/2015/516215. PubMed PMID: 26294918; PubMed Central PMCID: PMC4532957
  206. 206. Torres-Espín A, Redondo-Castro E, Hernández J, Navarro X. Bone marrow mesenchymal stromal cells and olfactory ensheathing cells transplantation after spinal cord injury – A morphological and functional comparison in rats. European Journal of Neuroscience. 2014 May;39(10):1704-1717. DOI: 10.1111/ejn.12542. PubMed PMID: 24635194
  207. 207. Oraee-Yazdani S, Hafizi M, Atashi A, Ashrafi F, Seddighi AS, Hashemi SM, Seddighi A, Soleimani M, Zali A. Co-transplantation of autologous bone marrow mesenchymal stem cells and Schwann cells through cerebral spinal fluid for the treatment of patients with chronic spinal cord injury: Safety and possible outcome. Spinal Cord. 2016 Feb;54(2):102-109. DOI: 10.1038/sc.2015.142. PubMed PMID: 26526896
  208. 208. Kanno H, Pearse DD, Ozawa H, Itoi E, Bunge MB. Schwann cell transplantation for spinal cord injury repair: Its significant therapeutic potential and prospectus. Reviews in the Neurosciences. 2015;26(2):121-128. DOI: 10.1515/revneuro-2014-0068. Review. PubMed PMID: 25581750
  209. 209. Amr S, Amr H. Bridging defects in chronic spinal cord injury using peripheral nerve grafts; results of indwelling catheter implantation; a comparative clinical study. In: Research on Complication – Current Issues and Technology. Brisbane, Australia: iConcept Press Limited; 2016. ISBN 978-1-922227-37-9
  210. 210. Georgiou M, Bunting SCJ, Davies HA, Loughlin AJ, Golding JP, Phillips JB. Engineered neural tissue for peripheral nerve repair. Biomaterials. 2013;34:7335-7343
  211. 211. Goraltchouk A, Scanga V, Morshead CM, Shoichet MS. Incorporation of protein eluting microspheres into biodegradable nerve guidance channels for controlled release. Journal of Controlled Release. 2006;110(2):400-407
  212. 212. Yang Y, De LL, Rives CB, Jang JH, Lin WC, Shull KR, Shea LD. Neurotrophin releasing single and multiple lumen nerve conduits. Journal of Controlled Release. 2005;104(3):433-446
  213. 213. Xu X, Yee WC, Hwang PY, Yu H, Wan AC, Gao S, Boon KL, Mao HQ, Leong KW, Wang S. Peripheral nerve regeneration with sustained release of poly (phosphoester) microencapsulated nerve growth factor within nerve guide conduits. Biomaterials. 2003:24(13):2405-2412
  214. 214. Benoit JP, Faisant N, Venier-Julienne MC, Menei P. Development of micro-spheres for neurological disorders: From basics to clinical applications. Journal of Controlled Release. 2000;65:285-296. [PubMed: 10699288]
  215. 215. Chan JM, Zhang L, Yuet KP, Liao G, Rhee JW, Langer R, Farokhzad OC. PLGA-lecithin-PEG coreshell nanoparticles for controlled drug delivery. Biomaterials. 2009;30:1627-1634. [PubMed: 19111339]

Written By

Sherif M. Amr

Reviewed: 03 May 2017 Published: 29 November 2017