- Open Access
An overview of tissue engineering approaches for management of spinal cord injuries
© Samadikuchaksaraei; licensee BioMed Central Ltd. 2007
- Received: 08 May 2006
- Accepted: 14 May 2007
- Published: 14 May 2007
Severe spinal cord injury (SCI) leads to devastating neurological deficits and disabilities, which necessitates spending a great deal of health budget for psychological and healthcare problems of these patients and their relatives. This justifies the cost of research into the new modalities for treatment of spinal cord injuries, even in developing countries. Apart from surgical management and nerve grafting, several other approaches have been adopted for management of this condition including pharmacologic and gene therapy, cell therapy, and use of different cell-free or cell-seeded bioscaffolds. In current paper, the recent developments for therapeutic delivery of stem and non-stem cells to the site of injury, and application of cell-free and cell-seeded natural and synthetic scaffolds have been reviewed.
- Spinal Cord
- Spinal Cord Injury
- Schwann Cell
- Neural Stem Cell
- Axonal Regeneration
Spinal cord injury (SCI) usually leads to devastating neurological deficits and disabilities. The data published by the National Spinal Cord Injury Statistical Center in 2005  showed that the annual incidence of SCI in the United States is estimated to be 40/milliion. It also estimated that the number of patients with SCI in US was estimated to be 225,000 to 288,000 persons in July 2005 (see Ackery et al  for a review on the worldwide epidemiology of SCI).
It has been shown that patients with SCI have more depressive feelings than general population . The marriage of patients who are married at the time of injury is more likely to be compromised than general population. Also, the likelihood of getting married after the injury is lower than the general population . In addition, there are significant reductions in rates of occupation and employment after injury, especially during the first year .
In addition, tremendous costs are imposed on community by the spinal cord injury. The costs include cost of initial and subsequent hospitalizations, rehabilitation and supportive equipment, home modifications, personal assistance, institutional care and loss of income. It has been shown that the average initial hospital expenses for a patient with SCI is around $95000 and the average yearly expenses after recovery and rehabilitation is around $14135 . The average lifetime cost that is directly attributed to SCI is estimated to be $620000–$2800000 for each patient aged 25 years at the time of injury, and $450000–1600000 for each patient aged 50 at the time of injury .
These data show that apart from the patients, SCI imposes high psychosocial and financial costs to the family of the patient and to the community. Therefore, investment for the development of any treatment modality that improves patients' signs and symptoms, and subsequently, diminishes the health care costs of SCI is quite justifiable.
The neurological damage that is incurred at the time of mechanical trauma to the spinal cord is called "primary injury". The primary injury provokes a cascade of cellular and biochemical reactions that leads to further damage. This provoked cascade of reactions is called "secondary injury".
Primary injury occurs following (1) blunt impact, (2) compression, and (3) penetrating trauma. Blunt impacts can lead to concussion, contusion, laceration, transection or intraparenchymal hemorrhage. Cord compression usually results from hyperflexion, hyperextension, axial loading, and severe rotation . Gunshot and stab wounds are examples of penetrating traumas. The immediate mechanical damage to the neurons leads to the cell necrosis at the point of impact .
Several mechanisms are involved in secondary injury of which, vascular changes at the site of injury are the most important events. The microvascular alterations include loss of autoregulation, vasospasm, thrombosis, hemorrhage and increased permeability. These, in combination with edema, lead to hypoperfusion, ischemia and necrosis . Other major mechanisms include: (1) free radicals formation and lipid peroxidation  (2) accumulation of excitatory neurotransmitters, e.g. glutamate (acting on N-methyl-D-aspartate [NMDA] and non-NMDA receptors), and neural damage due to excessive excitation (excitotoxicity)  (3) loss of intracellular balance of sodium, potassium, calcium and magnesium and subsequent increased intracellular calcium level  (4) increased level of opioids, especially dynorphins, at the site of injury, which contribute to the pathophysiology of secondary injury [12, 13] (5) depletion of energy metabolites leading to anaerobic metabolism at the site of injury and increasing of LDH activity  (6) provocation of an inflammatory response and recruitment and activation of inflammatory cells associated with secretion of cytokines, which contribute to further tissue damage , and (7) activation of calpains  and caspases and apoptosis [17, 18].
Primary and secondary injuries lead to the cell loss in the spinal cord. In penetrating injuries, this leads to scarring and tethering of the cord . Demyelination occurs following the loss of oligodendrocytes, which causes conduction deficits . In contusion injuries, a cystic cavity surrounded by an astrocytic scar is formed following this tissue loss. Where the injury extends to pia mater, collagen will also contribute in the formation of the scar tissue. As a physical barrier, the scar dos not allow the axons to grow across the cavity .
Crushed or transected nerve fibers exhibit regenerative activities by outgrowth of neurites. This is called regenerative sprouting. But, this would not be more than 1 mm, because there are inhibitory proteins in the CNS that inhibit this activity . Among these inhibitory proteins, the myelin proteins Nogo and MAG could be named, which are exposed after the injury [22, 23]. Inhibitory proteins have been identified in the extracellular matrix of the scar tissue as well, mainly chondroitin sulfate proteoglycans (CSPGs) secreted by reactive astrocytes [7, 24]. Permanent hyperexcitability is another mechanism that develops in many cells leading to different signs and symptoms .
Stabilization of the spine and restoration of its normal alignment together with surgical decompression of the cord is the subject of individual or institutional preferences; and there is no consensus regarding necessity, timing, nature, or approach of surgical intervention [25, 26].
There have been several attempts to target and modulate the mechanisms leading to the secondary injury by pharmacological interventions (see Sayer et al  and Baptiste and Fehlings  for review), neutralization of the effects of regenerative sprouting inhibitory proteins (see Scott et al  for review) and gene therapy (see Blits and Bunge  and Pearse and Bunge  for review).
The core approach of tissue engineering consists of provision of an interactive environment between cells, scaffolds and bioactive molecules to promote tissue repair. To achieve this goal, the ex vivo engineered cell-scaffold constructs could be transplanted to the site of injury. Alternatively, the repair is achieved by delivery of scaffold-free cells or acellular scaffolds to the damaged tissue.
Due to the immune privilege, recruitment of macrophages is limited in CNS and the resident microglia cells are the main immune cells that are activated after SCI . It has been shown that controlled boosting of local immune response by delivering of autologous macrophages, which were alternatively activated to a wound-healing phenotype, can promote recovery from the spinal cord injury. Initial experiments with implantation of macrophages activated by preincubation with peripheral nerve fragments lead to partial recovery of paraplegic rats . Improved motor recovery and reduced spinal cyst formation of rats was also observed by implantation of macrophages activated by incubation with autologous skin . The postulated mechanisms are activation of infiltrating T cells, and increased production of trophic factors such as brain-derived neurotrophic factor (BDNF) [33, 34] leading to removal of inhibitory myelin debris . Promotion of a permissive extracellular matrix containing laminin is another observation . Following these and subsequent positive results from animal experiments, autologous macrophages activated by incubation with autologous skin, under the brand name of ProCord, were entered into a multicentric clinical trial. The results of phase I studies show that out of eight patients in the study, three recovered clinically significant neurological motor and sensory function. Also, it has been shown that this cell therapy is well tolerated in patients with acute SCI .
In animal model studies, transplantation of dendritic cells into the injured spinal cord of mice led to better functional recovery as compared to controls . The implanted dendritic cells induced proliferation of endogenous neural stem/progenitor cells (NSPCs) and led to de novo neurogenesis. This observation was attributed to the action of secreted neurotrophic factors such as neurotrophin-3, cell-attached plasma membrane molecules, and possible activation of microglia/macrophages by implanted dendritic cells .
Dendritic cells pulsed (incubated) with encephalitogenic or non-encephalitogenic peptides derived from myelin basic protein when administered intravenously or locally to the site of injury, promoted recovery from SCI . The mechanisms proposed to explain this phenomenon is based on presentation of the loaded antigen to the naïve T cells by dendritic cells. The stimulated T cells start a cascade of events leading to "beneficial autoimmunity". They may secrete growth factors that protect the injured tissue. Also, they lead to a transient reduction in the nerve's electrophysiological activities, decreasing nerve's metabolic requirements and thus preserving neuronal viability . This explanation is in line with the finding that in those rats, which are unresponsive to myelin self-antigens, the outcome of CNS injury is worse than normal rats .
Olfactory ensheathing cells (OECs)
Olfactory ensheathing cells (OECs) are glial cells ensheathing the axons of the olfactory receptor neurons. These cells have properties of both Schwann cells and astrocytes, with a phenotype closer to the Schwann cells . OECs can be obtained from olfactory bulb or nasal mucosa (lamina propria). Cells from both sources have been used for treatment of spinal cord injury in animal models. Those from olfactory bulb origin lead to axonal regeneration and functional recovery after transplantation to animals with transected [41, 42], hemisected [43, 44] or contused  spinal cords. Similar results were also obtained by transplantation of OECs isolated from lamina propris in both transected  and hemisected  models. It has been shown that these cells are able to retain their regenerative ability after cryopreservation  and after establishment of a clonally derived cell line . Boosting of regenerative capability of OECs by overexpression of brain-derived neurotrophic factor (BDNF)  or glial cell line-derived neurotrophic factor (GDNF)  was also tried successfully in animal models.
OECs migrate after implantation , decrease neuronal apoptosis  and secrete a number of extracellular matrix molecules such as type IV collagen, and the chondroitin sulfate proteoglycan NG2 . They also secrete trophic factors such as vascular endothelial growth factor (VEGF) , nerve growth factor (NGF), and BDNF . Remyelination is also increased after transplantation of OECs [56–58]. A comparison of acute versus delayed transplantation of OECs has shown that acute transplantation leads to earlier recovery and better functional and histological results . The efficacy and behavior of olfactory bulb-derived cells were compared with lamina propria (LP)-derived cells after implantation. LP-derived cells showed superior ability to migrate within the spinal cord, and reduce the cavity formation and lesion size, but they enhanced autotomy . All the above properties can explain the observed histological and functional improvements following transplantation of olfactory ensheathing cells to the site of injury.
According to the promising results obtained from animal experiments, several clinical trials have been started. In a large series more than 400 patients underwent transplantation of fetal olfactory bulb-derived cells, of which the results of 171 operations were published , showing functional recovery, regardless of age and as early as the first day after implantation . But, an independent observational study of 7 cases from this series did not report any clinically useful sensorimotor, disability, or autonomic improvements . In a recent case report, a rapid functional recovery was noted within 48 hours of transplantation of olfactory bulb-derived cells . This reemphasizes the need for further studies into the mechanism of action of these cells, as according to the animal studies, such a rapid start of improvement is not expected. Nasal mucosal-derived OECs were also used in a phase I clinical trial conducted on 3 patients who were followed for one year after transplantation . The results confirm the safety and feasibility of this approach.
Schwann cells (SCs)
Schwann cells originating from dorsal and ventral roots are one of the cellular components that migrate to the site of tissue damage after spinal cord injury [65–68]. The remyelinating capability of Schwann cells has been demonstrated in a number of studies [66, 69] and the functioning status of this myelin in conduction of neural impulses was confirmed [70, 71]. SCs promote axonal regeneration by secretion of adhesion molecules such as L1 and N-CAM, extracellular matrix molecules such as collagen  and laminin (see Chernousov and Carey  for review), and a number of trophic factors such as FGF-2 , nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and NT3 (see Mirsky et al  for review). In addition to their on neural regeneration and remyelination, a number of unwanted effects were also reported following the use of these cells. It has been shown that when SCs come into contact with CNS astrocytes, their migration into the CNS is stopped . Also, corticospinal tracts (CST) show a delayed and poor regenerative activity in response to Schwann cells implantation when compared with OECs . The other unwanted issue in regard to SCs is that the damaged axons, which are stimulated by these cells to regenerate, grow into the grafted population of Schwann cells, but there is little evidence to support that they leave these cells and re-enter their original white matter pathways . When combining SCs transplantation with delivering of neurotrophic factors  or OECs plus chondroitinase  exit of regenerating axons could be observed from the transplanted population of grafted cells.
In animal model studies, Schwann cells are isolated from either newborn or adult sciatic nerve and cultured in the presence of mitogens. Upon transplantation to the damaged spinal cord of adult animals, they stimulate tissue repair by causing regenerating axons and astroglia to express developmentally related molecules. When compared with the effects of OECs in an acute SCI setting, it was concluded that the degree of functional recovery achieved by SCs is less than OECs . It has been shown that delayed transplantation leads to a higher survival of SCs in host tissue as compared with acute transplantation; meanwhile, implanted Schwann cells cause extensive infiltration of endogenous SCs to the site of injury . Schwann cells are usually transplanted by direct injection to the site of injury, which can add to the inflammatory process in the region. Recently, as an alternative route, transplantation to the subarachnoid space was tried and led to a favorable outcome . The results of a phase I human clinical trial in patients with chronic SCI will be presented in the next annual meeting of the Congress of Neurological Surgeons in Chicago .
Neural stem cells in CNS
Neural stem cells (NSCs) are present in adult and developing central nervous system of mammals and can be isolated and expanded in vitro . Neurosphere technique is the most common method for isolation of NSCs. Using this technique, stem cells have been isolated from developing spinal cord , cerebral cortex  and brain , and from adult subependymal, subventricular zone of the lateral ventricle [88, 89], cerebral cortex  and spinal cord . Also, there was a widely held assumption that dentate gyrus of the hippocampus contains neural stem cells in adults. But, it has been shown recently that dentate gyrus is a source of neural-restricted progenitors (NRPs) and not multipotent stem cells . NRPs are different from neural stem cells as they are committed to neural lineage at time of isolation. It has been shown that NSCs differentiate to neural and glial cells both in vitro [93, 94] and in vivo [93–95]. Also, following a clonal study, it has been reported that neural stem cells from the adult mouse brain can contribute to the formation of chimeric embryos and give rise to cells of all germ layers .
The fate of in vivo differentiation of neural stem cells depends on the niche they have been transplanted to. When transplanted into a neurogenic region e.g. dentate gyrus [95, 97] or subventricular zone , they will differentiate into neurons. Transplantation into other, so called, non-neurogenic regions, such as spinal cord , will induce them to differentiate into glial cells. Although a few studies report limited differentiation in non-neurogenic regions [84, 85], most reports are consistent with differentiation into glial fate. This shows the importance of environmental cues in directing the differentiation of NSCs. NRPs isolated from fetal spinal cord were transplanted into normal and injured spinal cord and differentiated into neurons in normal cords. But, the injured spinal cord niche restricted their differentiation and the cells remained undifferentiated or partially differentiated in this niche . In an interesting study, a mixed population of NRPs and GRPs were transplanted into the injured spinal cord. The mixed population was provided by either direct isolation from fetal spinal cord or pre-differentiation of NSCs in vitro. This approach resulted in generation of a microenvironment that led to an excellent survival, migration out of the injury site and differentiation of the cells into both neural and glial phenotypes [99, 100]. Functional improvements have been reported after transplantation of NSCs derived from embryonic spinal cord  and brain , adult brain  and spinal cord , and a mixed population of NRPs and GRPs isolated from fetal spinal cord .
Hematopoietic stem cells and marrow stromal cells
As hematopoietic stem cells (HSCs) and marrow stromal cells (also known as mesenchymal stem cells) (MSCs) are more accessible than other cells mentioned in this review, they have attracted much attention as the potential cell sources in management of spinal cord injury. Bone marrow is a rich source of these cells; although, HSCs have also been obtained from umbilical cord blood  and fetal tissues .
Much of the evidence used to support the potential of HSCs and MSCs to differentiate into neural and glial cells comes from in vivo studies. Transplantation of unfractioned bone marrow has led to detection of bone marrow-derived cells that expressed neural markers in CNS, in both animal models [107–109] and humans [110, 111]. In a recent clinical trial  bone marrow cells were delivered to patients with acute and chronic SCI intravenously or via vertebral artery. The study demonstrated the safety of the procedure. Partial improvement in the ASIA score and partial recovery of electrophysiological recordings of motor and somatosensory potentials have been observed in all subacute patients (n = 4) who received cells via vertebral artery and in one out of four subacute patients who received cells intravenously. Improvement was also found in one out of two chronic patients who received cells via vertebral artery. In another clinical trial unfractioned bone marrow cells were transplanted in conjunction with the administration of granulocyte macrophage-colony stimulating factor (GM-CSF) in six complete SCI patients and followed for 6–18 months. The procedure was safe and led to sensory improvements immediately. Also, AIS scores improved in 5 patients .
As unfractioned bone marrow is a mixture of different progenitor cells that might show different behavior in the same condition, more detailed studies have been performed on isolated fractions of HSCs and MSCs. Derivation of cells which have been phenotypically defined as neurons [106, 114] and glial cells [105, 106] has been reported after in vitro differentiation of HSCs. But, the point to be remembered is the fact that subsets of hematopoietic stem cells express neuronal and oligodendroglial marker genes [115, 116] and this should be considered in interpretation of results of any differentiation study.
It was reported that transplanted hematopoietic stem cells transdifferentiate in vivo into neurons and glial cells without fusion . But, dissimilar results were obtained from in vivo transdifferentiation studies. For example Koshizuka et al  have shown that HSCs only differentiate into glial cells not neurons. Lack of transdifferentiation into neurons, which is a matter of controversy [119–121], was also reported by Wagers et al  and Castro et al . A recent electrophysiological study on neuron-like cells derived from HSCs failed to detect generation of action potentials in these cells . But, locomotor improvement has been reported in the mice with contused spinal cord after transplantation of hematopoietic stem cells [118, 125]. Also, it was shown that implantation of HSCs into developing spinal cord lesion of chicken embryos directs these cells to differentiate into neurons with no apparent fusion to the host cells . These apparently disparate findings may be due to the issues such as the employed technique, the subpopulation of the HSCs used, and the experimental model. A phase I clinical trial in which CD34+ cells were delivered into the injured spinal cord via lumbar puncture technique demonstrated feasibility and safety of the procedure after 12 weeks of follow up .
The capacity of marrow stromal cells (MSCs) to differentiate in vitro into cells expressing neuronal markers have been shown in a number of studies [128, 129], and the potential of these cells to generate voltage-sensitive ionic current was confirmed by electrophysiological recording . In vitro differentiation into glial cells was also reported . In vivo differentiation into neurons [132, 133] and glial cells [134–136] has been reported in a number of studies. But a few studies have failed to demonstrate this transdifferentiation [125, 137, 138]. Fusion is another observation that needs to be considered. The question that bone marrow cells may adopt the phenotype of other cells by cell fusion was raised by in vitro observations [139, 140] and tested in an in vivo model in which fusion of marrow stromal cells with Purkinje neurons was detected . It has been shown that transplanted cells are capable not only to migrate in the injured tissue [135, 142] but also to attract host cells to the site of transplantation . Also, they form cell bridges within the traumatic cavity [134, 137]. To address the best rout of delivery of these cells, chronic paraplegic rats received MSCs either locally or intravenously and it was concluded that transplantation of the cells to the spinal cord leads to superior functional recovery . Locomotor improvements have been reported in most of the above studies even in those that did not detect transdifferentiation. This observation was attributed to secretion of cytokines and growth factors from MSCs [138, 144], which might be subjected to batch-to-batch variation . The point to be considered is that in most studies locomotor function was assessed by the Basso-Beattie-Breshnahan (BBB) test, which is a subjective test. More objective tests such as electrophysiological studies should be considered for achieving to more conclusive results. To the author's knowledge, no peer-reviewed clinical trial using MSCs for SCI patients has been published yet. But, a clinical trial involving transplantation of in vitro expanded MSCs to the spinal cord of the patients with amyotrophic lateral sclerosis revealed that the procedure is safe and feasible .
Embryonic stem (ES) cells
Embryonic stem (ES) cells are pluripotent cells derived from inner cell mass of the blastocyst, an early embryonic stage. It has been known for many years that pluripotent embryonic stem cells can proliferate indefinitely in vitro and are able to differentiate into derivatives of all three germ layers .
Neural stem cells derived from ES cells can lead to behavioral improvement after transplantation to the site of injury in the spinal cord . It has been shown that after prolonged in vitro expansion of ES cells-derived neural stem cells, they remain able to differentiate into neurons and astrocytes both in vitro and upon transplantation into brain . Transplantation of motor neuron-committed ES cells to the injured spinal cord combined with pharmacological inhibition of myelin-mediated axon repulsion and provision of attractive cues within the peripheral nerves led to extension of transplanted axons out of the spinal cord. The axons reached the muscle, formed neuromuscular junctions and their functionality was confirmed by electrophysiological studies . Transfection of ES cells with MASH1 gene is another strategy that caused ES cells to differentiated into motor neurons lacking Nogo receptor after transplantation into the transected spinal cord of mice and led to functional improvements confirmed by electrophysiological assessment . Myelination was also addressed in a number of studies; for example, it was shown that neural cells derived in vitro from ES cells can myelinate the demyelinated rat spinal cord upon transplantation . Oligodendrocyte-restricted progenitor cells were also derived from ES cells and were able to enhance remyelination and led to functional improvements after transplantation into a rat model of acute spinal cord injury .
As, lack of extracellular matrix at lesion site that directs and organizes the wound healing cells is one of the mechanisms that interferes with regenerative process after spinal cord injury, different studies have been conducted to investigate the potential of bioscaffold grafts to promote regeneration in the injured spinal cord, and to provide a bridge through which the regenerating axons can be properly guided from one end of the injury to the other end. Scaffolds were applied either alone or, to increase their healing effects, in combination with different growth factors or cellular components.
As the major constituent of extracellular matrix, collagen supports neural cells attachment and growth . NeuraGen™ Nerve Gide, a commercial peripheral nerve graft made of type I collagen, received FDA clearance for marketing in 2001. In spinal cord injuries, collagen has been used to fill the gap and the present evidence shows that it supports axonal regeneration. Collagen is a component of inhibitory glial scar and there is some evidence that it might inhibit nerve growth . But, it has been suggested that collagen is not inhibitory to axonal regeneration per se and its effects depend on whether it contains inhibitory or trophic factors (see Klapka and Müller  for review). Application of cross-linked collagen and collagen filaments [156, 157] have been studied in animal models of SCI. They increased regenerative activity in the spinal cord and improved the functional disability. It was observed that if the orientation of the grafted collagen fibers was parallel to the axis of the spinal cord, they promoted the growth of the regenerating axons into the graft from both proximal and distal ends. In this model, regenerating axons were also observed parallel to the axis of implant at the proximal host-implant interface. But, at the distal interface the running regenerating axons were entangled [156, 157]. The results of implantation of a collagen tube in the injured spinal cords of rats were also promising showing that regenerating spinal axons regrow into the ventral root through this tube . It has also been shown that impregnation of collagen with neurotrophin-3, increased the growth of corticospinal tract fibers into the implant and led to significant recovery of function of rats under investigation despite absence of regrowth of these fibers into the host tissue . Surgical reconstruction of transected cat spinal cord using collagen plus omental transposition increased regenerative activity and led to functional recovery . Functional recovery has also been observed by collagen implantation and omental transposition in a patient with SCI . It has been shown that inclusion of collagen, supplemented with fibroblast growth factor-1 (FGF-1) or neurotrophin-3 (NT-3), within the hydrogel guidance channels improves axonal regeneration. FGF-1 increases axonal regeneration from reticular and vestibular brainstem motor neurons. But, NT-3 decreases the regeneration rate of brainstem motor neurons and only increases local axonal regeneration .
Alginate is an extracellular matrix derived from the brown seaweed from which a sponge has been developed by cross-linking of its fibers with covalent bonds . In an in vitro study, it has been shown that when olfactory ensheathing cells, Schwann cells and bone marrow stromal cells are cultured on alginate hydrogel, they are transformed into atypical cells with spherical shape and their metabolic activities are inhibited; it has also been shown that alginate inhibits growth of dorsal root ganglia neurons .
But, when alginate sponge was implanted in the spinal cord of rats, it promoted axonal elongation, and the axons establish electrophysiologically functional projections and lead to functional improvements [163, 164]. Also, interestingly, it was found that the axons that entered the sponge from the rostral and caudal stumps were able to leave the sponge from the opposite side and establish functional synapses with local neurons . When compared with collagen, alginate reduced glial scar formation at the construct-tissue interface . Also, the number of axons entered the alginate sponge were significantly higher than collagen . In another experiment, alginate and fibronectin were used to coat poly-β-hydroxybutyrate (PHB) fibers obtained from bacterial cultures. When this construct was implanted to the rats with SCI, it increased the survival rate of rubrospinal tract axons. But, it did not lead to ingrowth of nerve fibers into the construct . Recently, an alginate-based anisotropic capillary hydrogel (ACH) was implanted into the cervical spinal cord injury of rats and robustly increased the ingrowth of longitudinally directed regenerating axons into this implant .
Poly(α-hydroxy acids) are synthetic biodegradable polymers with excellent biocompatibility and the possibility of changing their specifications, and especially their mechanical properties and degradation rates, by alteration of the composition and distribution of their repeating units . The advantages of synthetic scaffolds over the natural scaffolds are their lower batch-to-batch variation, more predictable and reproducible mechanical and physical properties and higher potential for control of materials impurities. It has been shown when the poly(D, L-lactic-co-glycolic acid) 50:50 (PLA25GA50) is applied to the completely transected spinal cord of rats, it demonstrates good mechanical properties and encourages axonal regeneration. The regenerated axons were observed penetrating the graft and the glial and inflammatory response near the lesion was similar to the controls . For provision of a better 3-dimensional construct, macroporous scaffolds (foams) were made of poly(D, L-lactic acid) (PDLLA) containing poly(ethylene oxide)-block-poly(D, L-lactide) (PELA) copolymer (PDLLA-PELA foams). The foams were molded into small diameter rods and 14–20 rods were assembled using acidic fibroblast growth factor (aFGF)-containing fibrin glue and used to bridge the transected rat spinal cord. The construct was invaded by blood vessels and axons from proximal and distal spinal stumps, and axonal regrowth preferentially occurred along the main pore direction [170, 171]. In another experiment, the same foam was made with the same diameter as rat spinal cord, treated with the neuroprotective brain-derived neurotrophic factor (BDNF), and embedded in fibrin glue containing aFGF. Apart from easier handling, this construct possessed a good flexibility and was able to support formation of blood vessels and migration of astrocytes, Schwann cells, and axons. BDNF led to the ingrowth of more regenerating axons to the implant, mainly at the rostral part. But the implants did not improve functional performance .
Synthetic hydrogels, such as poly [N-2-(hydroxypropyl) methacrylamide] (PHPMA) hydrogel (NeuroGel™)  and poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA) , consist of crosslinked networks of hydrophilic co-polymers that swell in water and provide three-dimensional substrates for cell attachment and growth. Their ability to retain substantial amount of water with respect to the network density makes them suitable for transport of small molecules. These materials show low interfacial tension with biological fluids and can be formulated to have the same mechanical properties similar to the spinal cord [175–177]. They are nonbiodegradable materials. The advantage of these materials over the biodegradable materials is that they do not expose the tissues to the intermediary breakdown products, which may adversely affect the regeneration process .
After implantation of NeuroGel into the transected cat spinal cord, it was infiltrated by blood vessels, glial cells and regenerating descending supraspinal axons of the ventral funiculus and afferent fibers of the dorsal column, and most of regenerating axons were myelinated, mainly by Schwann cells. The regenerating axons were able to leave the implant both rostrally and caudally. The animals showed variable degrees of locomotor improvements . Hydrogel decreased the gliotic scar formation at the interface between cord stump and the implant. Also, it considerably reduced the damage to the distal cord stump manifested by presence of more intact myelinated fibers and reduction of myelin degradation . NeuroGel was also implanted in the post-traumatic lesion cavity in a rat model of chronic compression-produced injury of spinal cord. The hydrogel was invaded by blood vessels and glial cells. Also, ingrowth of regenerating axons was observed from the rostral stump into the NeuroGel. The axons were associated with well-organized myelin sheets and Schwann cells. Functional recovery was also observed . In another interesting study, the cell-adhesive sequence Arg-Gly-Asp (RGD) of the central-binding domain of the extracellular matrix (ECM) glycoprotein fibronectin was incorporated into the NeuroGel (PHPMA-RGD hydrogel). This core tripeptide sequence plays a central role in the adhesion-mediated cell migration required for tissue construction during development and repair. The PHPMA-RGD hydrogel was implanted in the transected cord of rats and led to angiogenesis and axonal growth. It was shown that axons enter the construct from the rostral cord and leave it into the caudal stump. The axons were myelinated by Schwann cells, and supraspinal axons and synaptic connections were observed in the reconstructed cord segment. The rats showed some degrees of functional improvements .
PHEMA has a lower volume fraction compared with NeuroGel. When both NeuroGel and PHEMA were implanted into the rat cortex, NeuroGel was invaded by various connective tissue elements, but PHEMA hindered ingrowth of connective tissue and only allowed astrocyte invasion . Unfilled PHEMA-MMA channels were used to bridge the transected spinal cord of rats using fibrin glue. A tissue bridge formed inside the channel between two stumps and brainstem motor neurons regenerated through this bridge to the distal stump. Also, the channel limited the ingrowth of scar tissue. But, the channels did not improve the functional recovery . In another experiment, PHEMA soaked in brain-derived neurotrophic factor (BDNF) solution was implanted in hemisected rat spinal cords. BDNF did not have any effect on the scarring and angiogenesis but, it promoted axonal regeneration . Axonal regeneration into the implant is also improved when PHEMA-MMA channels are filled with the matrices such as collagen, fibrin and Matrigel .
Polyethylene glycol (PEG) is a water-soluble surfactant polymer. Brief application of aqueous solution of this polymer to the site of injury in the spinal cord seals and repairs cell membrane breaches, reverses the permeabilization of the membrane produced by injury, inhibits production of free radicals [182–184], and decreases oxidative stress [185, 186]. PEG was able to re-establish the anatomical continuity and lead to functional recovery of severed guinea pig spinal cord . It has been shown that brief application of PEG to the injured spinal cord of guinea pigs reduces cystic cavitation and the extent of the injury , and improves behavioral function [189, 190]. But, prolonged application can induce conduction block .
Fibrin is derived from blood and is the major component of clots. Fibrin functions as bridging molecule for many types of cell-cell interactions. At the site of injury, many cells directly bind to the fibrin via their surface receptors. This helps localization of these cells to the site of injury and carrying out their specialized function . In the treatment of SCI, the fibrin is usually enriched with acidic fibroblast growth factor (aFGF) and is used in conjunction with other modalities. Its application in combination with poly(α-hydroxy acids) and synthetic hydrogels has been described in the above paragraphs. When the site of cord injury was filled with a fibrin gel, which was engineered to release neurotrophin-3 after degradation by the invading cells, vigorous cellular infiltration of the fibrin and diminished formation of the glial scar was observed . In addition to the above applications, fibrin glue is regularly used for stabilization of cellular bridges to the implantation site (see below).
Matrigel is an extracellular matrix extracted from the Engelbreth Holm Swarm (EHS) sarcoma and contains laminin, fibronectin, and proteoglycans, with laminin predominating . In an in vitro study, it has been shown that Matrigel stimulates cell proliferation and preserves the typical morphological features of olfactory ensheathing cells, Schwann cells and bone marrow stromal cells in culture; and it also supports growth of dorsal root ganglia neurons . Implantation of Matrigel alone does not increase regenerative activities in the spinal cord . But, Matrigel combined with vascular endothelial growth factor (VEGF) or a replication-defective adenovirus coding for VEGF decreases retrograde degeneration of corticospinal tract axons and increases axonal regenerative activities in rats. Regenerating axons growing from the rostral part of the lesion cross the implant and can be found in the distal cord . Also, inclusion of Matrigel within hydrogel guidance channels increases the number of regenerating axons penetrating the construct. But, this inhibits regeneration of brainstem motor neurons . Also, it has been shown that implantation of PAN/PVC guidance channels (see below) containing Matrigel enriched with glial cell line-derived neurotrophic factor (GDNF) enhances growth of regenerating axons into the implant . Matrigel has been used as regular scaffold for construction of bridges made of Schwann cells and also for delivery of human adult olfactory neuroepithelial-derived progenitors (see below).
Fibronectin (Fn) is a glycoprotein found in many extracellular matrices and in plasma. It is involved in cell attachment and migration due to its interaction with cell surface receptors . Fibrous aggregates of plasma fibronectin have been used to make fibronectin mats. These mats contain pores oriented in a single direction . The rate of resorption of these mats can be modified by incorporation of copper and zinc ions . When Fn mats were implanted in hemisected rats spinal cords, they well integrated with the spinal cord and showed little cavitation either within or adjacent to the implant. Orientated growth of GABAergic, cholinergic, glutamatergic, noradrenergic axons and calcitonin gene-related peptide (CGRP)-positive neurons occurred into the mat and axons were myelinated by Schwann cells. Incubation of mats with BDNF and NT-3 increased neurofilament-positive and glutaminergic fibers. Incorporation of nerve growth factor into the mats increased the number of CGRP-positive neurons. But, there was little axonal outgrowth from the mats into the host spinal cord . After implantation, Fn mats are vascularized and infiltrated by macrophages, axons and Schwann cells that myelinate the axons, oligodendrocytes and their precursors and astrocytes. Laminin deposition is also observed in the mats . This failure of outgrowth of axons from the mat to the surrounding tissue was attributed to the astrocytosis and glial scar formation around the implant. The attempts to decrease this astrocytosis by incubation of mats with antibodies to transforming growth factor β (TGFβ) not only did not solve the problem, but also exacerbated the extent of secondary damage .
In an in vitro study, it has been shown that combination of fibronectin with alginate hydrogel supports olfactory ensheathing cells proliferation. But, the proliferation rate was significantly lower than what was observed on Matrigel . Incorporation of the central binding domain of fibronectin i.e. Arg-Gly-Asp (RGD) to the NeuroGel (PHPMA-RGD hydrogel) has been performed in an interesting study to enhance its cell adhesion and guidance capacity. Implantation of this construct into the spinal cord of rats led to angiogenesis and axonal growth into the implant (see above) . Fibronectin has also been used to make fibronectin cables with parallel fibril alignment. It has been shown that these cables support Schwann cells growth in vitro and these cells align with the axis of the fibrils .
Agarose is a polysaccharide derived from seaweed. Recently, a freeze-dried agarose scaffold with uniaxial linear pores extending through its full length was manufactured and its biocompatibility and ability to function as a depot for growth factors was confirmed by in vitro studies . These scaffolds retain their microstructure without the use of chemical cross-linkers. Also, they can retain their guidance capabilities within the spinal cord for at least 1 month. Implantation of BDNF-incorporated scaffolds in a rat model of spinal cord injury, led to organized and linear axonal growth into the agarose. The implant was also penetrated with Schwann cells, blood vessels and macrophages. Agarose did not evoke fibrous tissue encapsulation in host tissue .
Another recent approach is to use in situ gelling agarose hydrogel. An irregular, dorsal over-hemisection spinal cord defect in adult rats was filled with agarose solution embedded with BDNF-loaded microtubules and was cooled until gelation. This allowed the gel to conformally fill the defect by adopting its shape and minimized the gap between tissue and scaffold. The implant was penetrated by axons only in the presence of BDNF. But, no outgrowth of axons from the implant to the host distal cord was observed. The other observed effect was reduction of the intensity of reactive astrocytosis and deposition of chondroitin sulfate proteoglycans (CSPGs) by BDNF .
Matrigel has been used as a scaffold for in vivo delivery of Schwann cells in several experiments. Purified Schwann cells were mixed with Matrigel and inserted in semipermeable non-degradable 60/40 polyacrylonitrile/polyvinylchloride (PAN/PVC) copolymer guidance channels. This construct was used to bridge a transected rat spinal cord. Histological studies demonstrated penetration of the implanted bridge by myelinated axons, blood vessels, macrophages and fibroblasts. When the models underwent electrophysiological studies, stimulus-evoked cord potentials were clearly identified in a few models, showing functionality of regenerating axons . When this model was combined by infusion of BDNF or NT-3 to the distal cord stump, axonal growth from the implant into the distal host spinal cord stump was effectively promoted for several cord segments. In the absence of BDNF or NT-3 only a few axons were able to enter the distal stump . In another experiment, instead of infusion of BDNF distal to the implant, the BDNF was added to the SC/Matrigel cable inside the PAN/PVC guidance channels. This approach led to increased growth of regenerating axons into the construct as well. Also, GDNF decreased the extent of reactive gliosis and cystic cavitation at the graft-host interface . Recently, a combination of SC/Matrigel cable inside PAN/PVC channels with implantation of olfactory ensheathing cells (OECs) in the distal and proximal cord stumps and infusion of chondroitinase ABC to the SC bridge/host spinal cord interface was studied in a rat model of spinal cord transection . OECs were implanted to enable regenerating axons to exit the SC/Matrigel bridge, and chondroitinase ABC was used to reduce the axonal regeneration inhibitory effect of chondroitin sulfate proteoglycan (CSPG) in the glial scar. This combined implantation therapy significantly increased the number of myelinated axons and serotonergic fibers in the bridge, and the latter grow in the distal cord stump. Also, significant functional improvement was observed. In another experiment carried out by implantation of SC/Matrigel cables contained in biodegradable scaffolds made of poly(alpha-hydroxy acids) (PHAs) such as poly(D, L-lactic acid) (PLA50) or high molecular weight poly(L-lactic acid) mixed with 10% poly(L-lactic acid) oligomers (PLA100/10), the intervention led to axonal ingrowth into the implant but, it was not as effective as the PAN/PVC experiment . In another experiment, Matrigel was used for seeding of Schwann cells derived from human bone marrow stromal cells in an ultra-filtration membrane (Millipore) tube. This construct promoted axonal regeneration into the bridge and resulted in recovery of hind limb function in rats .
Recently, the potential of delivering human adult olfactory neuroepithelial-derived progenitors with Matrigel was studied in a rat model of hemisected spinal cord injury. This approach has led to regeneration of rubrospinal neurons through the transplant within the white matter for several segments caudal to the graft so that a few rubrospinal axons terminated in gray matter close to motor neurons. Improvements in functional recovery were also observed in this experiment .
The ease of manipulation of collagen into various shapes allows precise application of the cells to the injured site. Cortical neonatal rat astrocytes were embedded in collagen type I gel and transplanted to the hemisected rat spinal cords. Collagen prevented migration of astrocytes into the host tissue, which was believed to be an advantage, as their presence could attract more regenerating axons into the implant. This approach has resulted in significant increase of number of ingrowing neurofilament-positive fibers (including corticospinal axons) into the implant. But, the fibers did not reenter the host tissue. Modest temporary improvements of locomotor recovery were observed in this study which was hypothetically attributed to the factors secreted from transplanted astrocytes .
Recently, it has been shown that adult neural progenitor cells harvested from rats cervical spine can be mounted on an alginate-based anisotropic capillary hydrogel (ACH) and this construct supports axonal regeneration in vitro .
In another experiment, neurospheres prepared from fetal rat hippocampus were injected into the alginate sponge, and implanted in the injured spinal cord of rats. Alginate increased the survival of neurospheres after transplantation and supported their migration, differentiation and integration to the host spinal cord . Microencapsulation of fibroblasts producing brain-derived neurotrophic factor (BDNF) in alginate-poly-L-ornithine is another method for application of alginate in treatment of SCI. Microcapsules protect fibroblasts from the host immune response and eliminate the need for immunosuppressive therapy. These constructs were injected to the spinal cord in a rat model of SCI and promoted growth of regenerating axons into the cellular matrix that developed between the capsules. They also led to improvement of the function of the affected limbs [210, 211]. In another study, neonatal Schwann cells were seeded on alginate and fibronectin-coated poly-β-hydroxybutyrate (PHB) fibers and supported ingrowth of regenerating axons, which extended along the entire length of the graft .
Fibrin has been used to enhance the effects of cell-scaffold constructs. In most instances, fibrin is used with acidic fibroblast growth factor (aFGF). It has been shown that basic fibroblast growth factor (bFGF) is not efficient in this setting . Fibrin containing aFGF has been applied to both ends of Schwann cells/Matrigel cables in PAN/PVC guidance channels. They increased sprouting of corticospinal tracts in rats; and the axons that entered the graft left the implant and entered the host spinal cord from the opposite end . Preparation of a mixture of cell suspension and fibrinogen for direct transplantation to the injured spinal cord is another approach for application of fibrin in clotted form. But, such a preparation made of olfactory ensheathing cells (OECs) did not prove to be effective in a rat model of SCI . Fibrin clots have been used for delivery of Schwann cells as well. SC/fibrin clot has been inserted in PAN/PVC guidance channels and were used to bridge a transected rat spinal cords. This was combined by transduction of caudal spinal cord stump cells with adeno-associated viral (AAV) vectors encoding for brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (AAV-NT-3). Histological sections have shown the ingrowth of axons from the rostral stump into the bridge, but the axons did not leave the bridge. On the other hand, the transduced neurons in the caudal stump extended their processes into the implant. This combined treatment led to significant improvement of hind limb function in treated animals .
A two-component scaffold was made of a blend of 50:50 poly(lactic-co-glycolic acid) (PLGA) (75%) and a block copolymer of poly(lactic-co-glycolic acid)-polylysine (25%). The scaffold's inner portion emulated the gray matter via a porous polymer layer and its outer portion emulated the white matter with long, axially oriented pores for axonal guidance and radial porosity to allow fluid transport while inhibiting ingrowth of scar tissue. The inner layer was seeded with a clonal multipotent neural precursor cell line originally derived from the external germinal layer of neonatal mouse cerebellum. Implantation of this construct into the hemisection adult rat model of spinal cord injury led to a long-term functional improvement accompanied by reduction of epidural and glial scar formation and growing of regenerating corticospinal tract fibers through the construct, from the injury epicenter to the caudal cord .
The complicated pathophysiology of spinal cord injury and its consequent disability had made the pace of therapeutic interventions in this field very slow for many years. But, in the last decade, the rapid progress that has been made in the field of tissue engineering as the result of advances made in areas of cell biology and biomaterials, opened up the way for new therapeutic strategies. These new strategies have shown promising results and the scientists are hoped to cure the patients with spinal cord injury before long.
- National Spinal Cord Injury Statistical Center: Spinal cord injury. Facts and figures at a glance. J Spinal Cord Med. 2005, 28: 379-380.Google Scholar
- Ackery A, Tator C, Krassioukov A: A global perspective on spinal cord injury epidemiology. J Neurotrauma. 2004, 21: 1355-1370. 10.1089/neu.2004.21.1355.PubMedGoogle Scholar
- Dryden DM, Saunders LD, Rowe BH, May LA, Yiannakoulias N, Svenson LW, Schopflocher DP, Voaklander DC: Depression following traumatic spinal cord injury. Neuroepidemiology. 2005, 25: 55-61. 10.1159/000086284.PubMedGoogle Scholar
- Meade MA, Lewis A, Jackson MN, Hess DW: Race, employment, and spinal cord injury. Arch Phys Med Rehabil. 2004, 85: 1782-1792. 10.1016/j.apmr.2004.05.001.PubMedGoogle Scholar
- Sekhon LH, Fehlings MG: Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine. 2001, 26: S2-12. 10.1097/00007632-200112151-00002.PubMedGoogle Scholar
- Dubendorf P: Spinal cord injury pathophysiology. Crit Care Nurs Q. 1999, 22: 31-35.PubMedGoogle Scholar
- Hulsebosch CE: Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ. 2002, 26: 238-255.PubMedGoogle Scholar
- Winkler T, Sharma HS, Gordh T, Badgaiyan RD, Stalberg E, Westman J: Topical application of dynorphin A (1-17) antiserum attenuates trauma induced alterations in spinal cord evoked potentials, microvascular permeability disturbances, edema formation and cell injury: an experimental study in the rat using electrophysiological and morphological approaches. Amino Acids. 2002, 23: 273-281. 10.1007/s00726-001-0138-y.PubMedGoogle Scholar
- Bao F, John SM, Chen Y, Mathison RD, Weaver LC: The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord. Neuroscience. 2006, 140: 1011-1022. 10.1016/j.neuroscience.2006.02.061.PubMedGoogle Scholar
- Park E, Velumian AA, Fehlings MG: The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma. 2004, 21: 754-774. 10.1089/0897715041269641.PubMedGoogle Scholar
- Chanimov M, Berman S, Gofman V, Weissgarten Y, Averbukh Z, Cohen ML, Vitin A, Bahar M: Total cell associated electrolyte homeostasis in rat spinal cord cells following apparently irreversible injury. Med Sci Monit. 2006, 12: BR63-BR67.PubMedGoogle Scholar
- Abraham KE, Brewer KL, McGinty JF: Opioid peptide messenger RNA expression is increased at spinal and supraspinal levels following excitotoxic spinal cord injury. Neuroscience. 2000, 99: 189-197. 10.1016/S0306-4522(00)00150-0.PubMedGoogle Scholar
- Abraham KE, McGinty JF, Brewer KL: The role of kainic acid/AMPA and metabotropic glutamate receptors in the regulation of opioid mRNA expression and the onset of pain-related behavior following excitotoxic spinal cord injury. Neuroscience. 2001, 104: 863-874. 10.1016/S0306-4522(01)00134-8.PubMedGoogle Scholar
- Yang YB, Piao YJ: Effects of resveratrol on secondary damages after acute spinal cord injury in rats. Acta Pharmacol Sin. 2003, 24: 703-710.PubMedGoogle Scholar
- Conti A, Cardali S, Genovese T, Di Paola R, La Rosa G: Role of inflammation in the secondary injury following experimental spinal cord trauma. J Neurosurg Sci. 2003, 47: 89-94.PubMedGoogle Scholar
- Ray SK, Matzelle DD, Sribnick EA, Guyton MK, Wingrave JM, Banik NL: Calpain inhibitor prevented apoptosis and maintained transcription of proteolipid protein and myelin basic protein genes in rat spinal cord injury. J Chem Neuroanat. 2003, 26: 119-124. 10.1016/S0891-0618(03)00044-9.PubMedGoogle Scholar
- Knoblach SM, Huang X, VanGelderen J, Calva-Cerqueira D, Faden AI: Selective caspase activation may contribute to neurological dysfunction after experimental spinal cord trauma. J Neurosci Res. 2005, 80: 369-380. 10.1002/jnr.20465.PubMedGoogle Scholar
- Takagi T, Takayasu M, Mizuno M, Yoshimoto M, Yoshida J: Caspase activation in neuronal and glial apoptosis following spinal cord injury in mice. Neurol Med Chir (Tokyo). 2003, 43: 20-29. 10.2176/nmc.43.20.Google Scholar
- Barami K, Diaz FG: Cellular transplantation and spinal cord injury. Neurosurgery. 2000, 47: 691-700. 10.1097/00006123-200009000-00033.PubMedGoogle Scholar
- Houle JD, Tessler A: Repair of chronic spinal cord injury. Exp Neurol. 2003, 182: 247-260. 10.1016/S0014-4886(03)00029-3.PubMedGoogle Scholar
- Schwab ME: Repairing the injured spinal cord. Science. 2002, 295: 1029-1031. 10.1126/science.1067840.PubMedGoogle Scholar
- Schwab ME: Nogo and axon regeneration. Curr Opin Neurobiol. 2004, 14: 118-124. 10.1016/j.conb.2004.01.004.PubMedGoogle Scholar
- Filbin MT: Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci. 2003, 4: 703-713. 10.1038/nrn1195.PubMedGoogle Scholar
- David S, Lacroix S: Molecular approaches to spinal cord repair. Annu Rev Neurosci. 2003, 26: 411-440. 10.1146/annurev.neuro.26.043002.094946.PubMedGoogle Scholar
- Silber JS, Vaccaro AR: Summary statement: the role and timing of decompression in acute spinal cord injury: evidence-based guidelines. Spine. 2001, 26: S110-10.1097/00007632-200112151-00018.PubMedGoogle Scholar
- Fehlings MG, Sekhon LH, Tator C: The role and timing of decompression in acute spinal cord injury: what do we know? What should we do?. Spine. 2001, 26: S101-S110. 10.1097/00007632-200112151-00017.PubMedGoogle Scholar
- Sayer FT, Kronvall E, Nilsson OG: Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature. Spine J. 2006, 6: 335-343. 10.1016/j.spinee.2005.11.001.PubMedGoogle Scholar
- Baptiste DC, Fehlings MG: Pharmacological approaches to repair the injured spinal cord. J Neurotrauma. 2006, 23: 318-334. 10.1089/neu.2006.23.318.PubMedGoogle Scholar
- Scott AL, Ramer LM, Soril LJ, Kwiecien JM, Ramer MS: Targeting myelin to optimize plasticity of spared spinal axons. Mol Neurobiol. 2006, 33: 91-111. 10.1385/MN:33:2:91.PubMedGoogle Scholar
- Blits B, Bunge MB: Direct gene therapy for repair of the spinal cord. J Neurotrauma. 2006, 23: 508-520. 10.1089/neu.2006.23.508.PubMedGoogle Scholar
- Pearse DD, Bunge MB: Designing cell- and gene-based regeneration strategies to repair the injured spinal cord. J Neurotrauma. 2006, 23: 438-452. 10.1089/neu.2006.23.437.PubMedGoogle Scholar
- Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M: Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 1998, 4: 814-821. 10.1038/nm0798-814.PubMedGoogle Scholar
- Bomstein Y, Marder JB, Vitner K, Smirnov I, Lisaey G, Butovsky O, Fulga V, Yoles E: Features of skin-coincubated macrophages that promote recovery from spinal cord injury. J Neuroimmunol. 2003, 142: 10-16. 10.1016/S0165-5728(03)00260-1.PubMedGoogle Scholar
- Franzen R, Schoenen J, Leprince P, Joosten E, Moonen G, Martin D: Effects of macrophage transplantation in the injured adult rat spinal cord: a combined immunocytochemical and biochemical study. J Neurosci Res. 1998, 51: 316-327. 10.1002/(SICI)1097-4547(19980201)51:3<316::AID-JNR5>3.0.CO;2-J.PubMedGoogle Scholar
- Knoller N, Auerbach G, Fulga V, Zelig G, Attias J, Bakimer R, Marder JB, Yoles E, Belkin M, Schwartz M, Hadani M: Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine. 2005, 3: 173-181.PubMedGoogle Scholar
- Mikami Y, Okano H, Sakaguchi M, Nakamura M, Shimazaki T, Okano HJ, Kawakami Y, Toyama Y, Toda M: Implantation of dendritic cells in injured adult spinal cord results in activation of endogenous neural stem/progenitor cells leading to de novo neurogenesis and functional recovery. J Neurosci Res. 2004, 76: 453-465. 10.1002/jnr.20086.PubMedGoogle Scholar
- Hauben E, Gothilf A, Cohen A, Butovsky O, Nevo U, Smirnov I, Yoles E, Akselrod S, Schwartz M: Vaccination with dendritic cells pulsed with peptides of myelin basic protein promotes functional recovery from spinal cord injury. J Neurosci. 2003, 23: 8808-8819.PubMedGoogle Scholar
- Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M: Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med. 1999, 5: 49-55. 10.1038/4734.PubMedGoogle Scholar
- Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M: Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci U S A. 2002, 99: 15620-15625. 10.1073/pnas.232565399.PubMed CentralPubMedGoogle Scholar
- Gudino-Cabrera G, Nieto-Sampedro M: Schwann-like macroglia in adult rat brain. Glia. 2000, 30: 49-63. 10.1002/(SICI)1098-1136(200003)30:1<49::AID-GLIA6>3.0.CO;2-M.PubMedGoogle Scholar
- Ramon-Cueto A, Cordero MI, Santos-Benito FF, Avila J: Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron. 2000, 25: 425-435. 10.1016/S0896-6273(00)80905-8.PubMedGoogle Scholar
- Shen H, Tang Y, Wu Y, Chen Y, Cheng Z: Influences of olfactory ensheathing cells transplantation on axonal regeneration in spinal cord of adult rats. Chin J Traumatol. 2002, 5: 136-141.PubMedGoogle Scholar
- Li Y, Decherchi P, Raisman G: Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing. J Neurosci. 2003, 23: 727-731.PubMedGoogle Scholar
- Polentes J, Stamegna JC, Nieto-Sampedro M, Gauthier P: Phrenic rehabilitation and diaphragm recovery after cervical injury and transplantation of olfactory ensheathing cells. Neurobiol Dis. 2004, 16: 638-653. 10.1016/j.nbd.2004.04.009.PubMedGoogle Scholar
- Plant GW, Christensen CL, Oudega M, Bunge MB: Delayed transplantation of olfactory ensheathing glia promotes sparing/regeneration of supraspinal axons in the contused adult rat spinal cord. J Neurotrauma. 2003, 20: 1-16. 10.1089/08977150360517146.PubMedGoogle Scholar
- Lu J, Feron F, Ho SM, Mackay-Sim A, Waite PM: Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. Brain Res. 2001, 889: 344-357. 10.1016/S0006-8993(00)03235-2.PubMedGoogle Scholar
- Ramer LM, Au E, Richter MW, Liu J, Tetzlaff W, Roskams AJ: Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J Comp Neurol. 2004, 473: 1-15. 10.1002/cne.20049.PubMedGoogle Scholar
- Shen HY, Yin DZ, Tang Y, Wu YF, Cheng ZA, Yang R, Huang L: Influence of cryopreserved olfactory ensheathing cells transplantation on axonal regeneration in spinal cord of adult rats. Chin J Traumatol. 2004, 7: 179-183.PubMedGoogle Scholar
- DeLucia TA, Conners JJ, Brown TJ, Cronin CM, Khan T, Jones KJ: Use of a cell line to investigate olfactory ensheathing cell-enhanced axonal regeneration. Anat Rec B New Anat. 2003, 271: 61-70. 10.1002/ar.b.10014.PubMedGoogle Scholar
- Ruitenberg MJ, Plant GW, Hamers FP, Wortel J, Blits B, Dijkhuizen PA, Gispen WH, Boer GJ, Verhaagen J: Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord. J Neurosci. 2003, 23: 7045-7058.PubMedGoogle Scholar
- Cao L, Liu L, Chen ZY, Wang LM, Ye JL, Qiu HY, Lu CL, He C: Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. Brain. 2004, 127: 535-549. 10.1093/brain/awh072.PubMedGoogle Scholar
- Deng C, Gorrie C, Hayward I, Elston B, Venn M, Mackay-Sim A, Waite P: Survival and migration of human and rat olfactory ensheathing cells in intact and injured spinal cord. J Neurosci Res. 2006, 83: 1201-1212. 10.1002/jnr.20817.PubMedGoogle Scholar
- Sasaki M, Hains BC, Lankford KL, Waxman SG, Kocsis JD: Protection of corticospinal tract neurons after dorsal spinal cord transection and engraftment of olfactory ensheathing cells. Glia. 2006, 53: 352-359. 10.1002/glia.20285.PubMed CentralPubMedGoogle Scholar
- Au E, Roskams AJ: Olfactory ensheathing cells of the lamina propria in vivo and in vitro. Glia. 2003, 41: 224-236. 10.1002/glia.10160.PubMedGoogle Scholar
- Boruch AV, Conners JJ, Pipitone M, Deadwyler G, Storer PD, Devries GH, Jones KJ: Neurotrophic and migratory properties of an olfactory ensheathing cell line. Glia. 2001, 33: 225-229. 10.1002/1098-1136(200103)33:3<225::AID-GLIA1021>3.0.CO;2-Y.PubMedGoogle Scholar
- Sasaki M, Lankford KL, Zemedkun M, Kocsis JD: Identified olfactory ensheathing cells transplanted into the transected dorsal funiculus bridge the lesion and form myelin. J Neurosci. 2004, 24: 8485-8493. 10.1523/JNEUROSCI.1998-04.2004.PubMed CentralPubMedGoogle Scholar
- Imaizumi T, Lankford KL, Kocsis JD: Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord. Brain Res. 2000, 854: 70-78. 10.1016/S0006-8993(99)02285-4.PubMedGoogle Scholar
- Lakatos A, Smith PM, Barnett SC, Franklin RJ: Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells. Brain. 2003, 126: 598-609. 10.1093/brain/awg055.PubMedGoogle Scholar
- Lopez-Vales R, Fores J, Verdu E, Navarro X: Acute and delayed transplantation of olfactory ensheathing cells promote partial recovery after complete transection of the spinal cord. Neurobiol Dis. 2006, 21: 57-68. 10.1016/j.nbd.2005.06.011.PubMedGoogle Scholar
- Richter MW, Fletcher PA, Liu J, Tetzlaff W, Roskams AJ: Lamina propria and olfactory bulb ensheathing cells exhibit differential integration and migration and promote differential axon sprouting in the lesioned spinal cord. J Neurosci. 2005, 25: 10700-10711. 10.1523/JNEUROSCI.3632-05.2005.PubMedGoogle Scholar
- Huang H, Chen L, Wang H, Xiu B, Li B, Wang R, Zhang J, Zhang F, Gu Z, Li Y, Song Y, Hao W, Pang S, Sun J: Influence of patients' age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury. Chin Med J (Engl ). 2003, 116: 1488-1491.Google Scholar
- Dobkin BH, Curt A, Guest J: Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury. Neurorehabil Neural Repair. 2006, 20: 5-13. 10.1177/1545968305284675.PubMed CentralPubMedGoogle Scholar
- Guest J, Herrera LP, Qian T: Rapid recovery of segmental neurological function in a tetraplegic patient following transplantation of fetal olfactory bulb-derived cells. Spinal Cord. 2006, 44: 135-142. 10.1038/sj.sc.3101820.PubMedGoogle Scholar
- Feron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S, Geraghty T, Mackay-Sim A: Autologous olfactory ensheathing cell transplantation in human spinal cord injury. Brain. 2005, 128: 2951-2960. 10.1093/brain/awh657.PubMedGoogle Scholar
- Brook GA, Houweling DA, Gieling RG, Hermanns T, Joosten EA, Bar DP, Gispen WH, Schmitt AB, Leprince P, Noth J, Nacimiento W: Attempted endogenous tissue repair following experimental spinal cord injury in the rat: involvement of cell adhesion molecules L1 and NCAM?. Eur J Neurosci. 2000, 12: 3224-3238. 10.1046/j.1460-9568.2000.00228.x.PubMedGoogle Scholar
- Jasmin L, Janni G, Moallem TM, Lappi DA, Ohara PT: Schwann cells are removed from the spinal cord after effecting recovery from paraplegia. J Neurosci. 2000, 20: 9215-9223.PubMedGoogle Scholar
- von Euler M, Janson AM, Larsen JO, Seiger A, Forno L, Bunge MB, Sundstrom E: Spontaneous axonal regeneration in rodent spinal cord after ischemic injury. J Neuropathol Exp Neurol. 2002, 61: 64-75.PubMedGoogle Scholar
- O'Brien DF, Farrell M, Fraher JP, Bolger C: Schwann cell invasion of the conus medullaris: case report. Eur Spine J. 2003, 12: 328-331.PubMed CentralPubMedGoogle Scholar
- Guest JD, Hiester ED, Bunge RP: Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp Neurol. 2005, 192: 384-393. 10.1016/j.expneurol.2004.11.033.PubMedGoogle Scholar
- Pinzon A, Calancie B, Oudega M, Noga BR: Conduction of impulses by axons regenerated in a Schwann cell graft in the transected adult rat thoracic spinal cord. J Neurosci Res. 2001, 64: 533-541. 10.1002/jnr.1105.PubMedGoogle Scholar
- Kohama I, Lankford KL, Preiningerova J, White FA, Vollmer TL, Kocsis JD: Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci. 2001, 21: 944-950.PubMed CentralPubMedGoogle Scholar
- Chernousov MA, Rothblum K, Tyler WA, Stahl RC, Carey DJ: Schwann cells synthesize type V collagen that contains a novel alpha 4 chain. Molecular cloning, biochemical characterization, and high affinity heparin binding of alpha 4(V) collagen. J Biol Chem. 2000, 275: 28208-28215.PubMedGoogle Scholar
- Chernousov MA, Carey DJ: Schwann cell extracellular matrix molecules and their receptors. Histology and Histopathology. 2000, 15: 593-601.PubMedGoogle Scholar
- Grothe C, Meisinger C, Claus P: In vivo expression and localization of the fibroblast growth factor system in the intact and lesioned rat peripheral nerve and spinal ganglia. J Comp Neurol. 2001, 434: 342-357. 10.1002/cne.1181.PubMedGoogle Scholar
- Mirsky R, Jessen KR, Brennan A, Parkinson D, Dong Z, Meier C, Parmantier E, Lawson D: Schwann cells as regulators of nerve development. J Physiol Paris. 2002, 96: 17-24. 10.1016/S0928-4257(01)00076-6.PubMedGoogle Scholar
- Shields SA, Blakemore WF, Franklin RJ: Schwann cell remyelination is restricted to astrocyte-deficient areas after transplantation into demyelinated adult rat brain. J Neurosci Res. 2000, 60: 571-578. 10.1002/(SICI)1097-4547(20000601)60:5<571::AID-JNR1>3.0.CO;2-Q.PubMedGoogle Scholar
- Keyvan-Fouladi N, Raisman G, Li Y: Delayed repair of corticospinal tract lesions as an assay for the effectiveness of transplantation of Schwann cells. Glia. 2005, 51: 306-311. 10.1002/glia.20211.PubMedGoogle Scholar
- Bamber NI, Li H, Lu X, Oudega M, Aebischer P, Xu XM: Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur J Neurosci. 2001, 13: 257-268. 10.1046/j.1460-9568.2001.01387.x.PubMedGoogle Scholar
- Fouad K, Schnell L, Bunge MB, Schwab ME, Liebscher T, Pearse DD: Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J Neurosci. 2005, 25: 1169-1178. 10.1523/JNEUROSCI.3562-04.2005.PubMedGoogle Scholar
- Garcia-Alias G, Lopez-Vales R, Fores J, Navarro X, Verdu E: Acute transplantation of olfactory ensheathing cells or Schwann cells promotes recovery after spinal cord injury in the rat. J Neurosci Res. 2004, 75: 632-641. 10.1002/jnr.20029.PubMedGoogle Scholar
- Hill CE, Moon LD, Wood PM, Bunge MB: Labeled Schwann cell transplantation: cell loss, host Schwann cell replacement, and strategies to enhance survival. Glia. 2006, 53: 338-343. 10.1002/glia.20287.PubMedGoogle Scholar
- Firouzi M, Moshayedi P, Saberi H, Mobasheri H, Abolhassani F, Jahanzad I, Raza M: Transplantation of Schwann cells to subarachnoid space induces repair in contused rat spinal cord. Neurosci Lett. 2006, 402: 66-70. 10.1016/j.neulet.2006.03.070.PubMedGoogle Scholar
- Saberi H, Firoozi M, Moshayedi P: Preliminary results of Schwann cell transplantation for chronic spinal cord injuries: 2006/10/9. Chicago, Illinois, Congress of Neurological Surgeons, 2006Google Scholar
- Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y, Okano H: Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res. 2002, 69: 925-933. 10.1002/jnr.10341.PubMedGoogle Scholar
- Iwanami A, Kaneko S, Nakamura M, Kanemura Y, Mori H, Kobayashi S, Yamasaki M, Momoshima S, Ishii H, Ando K, Tanioka Y, Tamaoki N, Nomura T, Toyama Y, Okano H: Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res. 2005, 80: 182-190. 10.1002/jnr.20436.PubMedGoogle Scholar
- Hung CH, Lin YL, Young TH: The effect of chitosan and PVDF substrates on the behavior of embryonic rat cerebral cortical stem cells. Biomaterials. 2006, 27: 4461-4469. 10.1016/j.biomaterials.2006.04.021.PubMedGoogle Scholar
- Kanemura Y, Mori H, Kobayashi S, Islam O, Kodama E, Yamamoto A, Nakanishi Y, Arita N, Yamasaki M, Okano H, Hara M, Miyake J: Evaluation of in vitro proliferative activity of human fetal neural stem/progenitor cells using indirect measurements of viable cells based on cellular metabolic activity. J Neurosci Res. 2002, 69: 869-879. 10.1002/jnr.10377.PubMedGoogle Scholar
- Mishra SK, Braun N, Shukla V, Fullgrabe M, Schomerus C, Korf HW, Gachet C, Ikehara Y, Sevigny J, Robson SC, Zimmermann H: Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation. Development. 2006, 133: 675-684. 10.1242/dev.02233.PubMedGoogle Scholar
- Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999, 97: 703-716. 10.1016/S0092-8674(00)80783-7.PubMedGoogle Scholar
- Akiyama Y, Honmou O, Kato T, Uede T, Hashi K, Kocsis JD: Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord. Exp Neurol. 2001, 167: 27-39. 10.1006/exnr.2000.7539.PubMedGoogle Scholar
- Lu F, Wong CS: A clonogenic survival assay of neural stem cells in rat spinal cord after exposure to ionizing radiation. Radiat Res. 2005, 163: 63-71. 10.1667/RR3285.PubMedGoogle Scholar
- Seaberg RM, van der KD: Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci. 2002, 22: 1784-1793.PubMedGoogle Scholar
- Mokry J, Karbanova J, Filip S: Differentiation potential of murine neural stem cells in vitro and after transplantation. Transplant Proc. 2005, 37: 268-272. 10.1016/j.transproceed.2004.12.233.PubMedGoogle Scholar
- Cao QL, Zhang YP, Howard RM, Walters WM, Tsoulfas P, Whittemore SR: Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol. 2001, 167: 48-58. 10.1006/exnr.2000.7536.PubMedGoogle Scholar
- Shihabuddin LS, Horner PJ, Ray J, Gage FH: Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J Neurosci. 2000, 20: 8727-8735.PubMedGoogle Scholar
- Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, Lendahl U, Frisen J: Generalized potential of adult neural stem cells. Science. 2000, 288: 1660-1663. 10.1126/science.288.5471.1660.PubMedGoogle Scholar
- Fricker RA, Carpenter MK, Winkler C, Greco C, Gates MA, Bjorklund A: Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain. J Neurosci. 1999, 19: 5990-6005.PubMedGoogle Scholar
- Cao QL, Howard RM, Dennison JB, Whittemore SR: Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp Neurol. 2002, 177: 349-359. 10.1006/exnr.2002.7981.PubMedGoogle Scholar
- Lepore AC, Han SS, Tyler-Polsz CJ, Cai J, Rao MS, Fischer I: Differential fate of multipotent and lineage-restricted neural precursors following transplantation into the adult CNS. Neuron Glia Biol. 2004, 1: 113-126. 10.1017/S1740925X04000213.PubMed CentralPubMedGoogle Scholar
- Lepore AC, Fischer I: Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord. Exp Neurol. 2005, 194: 230-242. 10.1016/j.expneurol.2005.02.020.PubMedGoogle Scholar
- Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH, Anderson AJ: Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A. 2005, 102: 14069-14074. 10.1073/pnas.0507063102.PubMed CentralPubMedGoogle Scholar
- Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG: Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci. 2006, 26: 3377-3389. 10.1523/JNEUROSCI.4184-05.2006.PubMedGoogle Scholar
- Hofstetter CP, Holmstrom NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J, Olson L: Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci. 2005, 8: 346-353. 10.1038/nn1405.PubMedGoogle Scholar
- Mitsui T, Shumsky JS, Lepore AC, Murray M, Fischer I: Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J Neurosci. 2005, 25: 9624-9636. 10.1523/JNEUROSCI.2175-05.2005.PubMedGoogle Scholar
- McGuckin CP, Forraz N, Allouard Q, Pettengell R: Umbilical cord blood stem cells can expand hematopoietic and neuroglial progenitors in vitro. Exp Cell Res. 2004, 295: 350-359. 10.1016/j.yexcr.2003.12.028.PubMedGoogle Scholar
- Hao HN, Zhao J, Thomas RL, Parker GC, Lyman WD: Fetal human hematopoietic stem cells can differentiate sequentially into neural stem cells and then astrocytes in vitro. J Hematother Stem Cell Res. 2003, 12: 23-32. 10.1089/152581603321210109.PubMedGoogle Scholar
- Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg GW, Dirnagl U: Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J Cell Biol. 2001, 155: 733-738. 10.1083/jcb.200105103.PubMed CentralPubMedGoogle Scholar
- Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR: Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000, 290: 1779-1782. 10.1126/science.290.5497.1779.PubMedGoogle Scholar
- Brazelton TR, Rossi FM, Keshet GI, Blau HM: From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000, 290: 1775-1779. 10.1126/science.290.5497.1775.PubMedGoogle Scholar
- Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM: Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A. 2003, 100: 2088-2093. 10.1073/pnas.0337659100.PubMed CentralPubMedGoogle Scholar
- Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B: Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci U S A. 2003, 100: 1364-1369. 10.1073/pnas.0336479100.PubMed CentralPubMedGoogle Scholar
- Syková E, Jendelová P, Urdzíková L, Lesný P, Hejcl A: Bone Marrow Stem Cells and Polymer Hydrogels-Two Strategies for Spinal Cord Injury Repair. Cell Mol Neurobiol. 2006Google Scholar
- Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, Park HS: Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng. 2005, 11: 913-922. 10.1089/ten.2005.11.913.PubMedGoogle Scholar
- Locatelli F, Corti S, Donadoni C, Guglieri M, Capra F, Strazzer S, Salani S, Del Bo R, Fortunato F, Bordoni A, Comi GP: Neuronal differentiation of murine bone marrow Thy-1- and Sca-1-positive cells. J Hematother Stem Cell Res. 2003, 12: 727-734. 10.1089/15258160360732740.PubMedGoogle Scholar
- Goolsby J, Marty MC, Heletz D, Chiappelli J, Tashko G, Yarnell D, Fishman PS, Dhib-Jalbut S, Bever CT, Pessac B, Trisler D: Hematopoietic progenitors express neural genes. Proc Natl Acad Sci U S A. 2003, 100: 14926-14931. 10.1073/pnas.2434383100.PubMed CentralPubMedGoogle Scholar
- Steidl U, Bork S, Schaub S, Selbach O, Seres J, Aivado M, Schroeder T, Rohr UP, Fenk R, Kliszewski S, Maercker C, Neubert P, Bornstein SR, Haas HL, Kobbe G, Tenen DG, Haas R, Kronenwett R: Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators. Blood. 2004, 104: 81-88. 10.1182/blood-2004-01-0373.PubMedGoogle Scholar
- Cogle CR, Yachnis AT, Laywell ED, Zander DS, Wingard JR, Steindler DA, Scott EW: Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet. 2004, 363: 1432-1437. 10.1016/S0140-6736(04)16102-3.PubMedGoogle Scholar
- Koshizuka S, Okada S, Okawa A, Koda M, Murasawa M, Hashimoto M, Kamada T, Yoshinaga K, Murakami M, Moriya H, Yamazaki M: Transplanted hematopoietic stem cells from bone marrow differentiate into neural lineage cells and promote functional recovery after spinal cord injury in mice. J Neuropathol Exp Neurol. 2004, 63: 64-72.PubMedGoogle Scholar
- Mezey E, Nagy A, Szalayova I, Key S, Bratincsak A, Baffi J, Shahar T: Comment on "Failure of bone marrow cells to transdifferentiate into neural cells in vivo". Science. 2003, 299: 1184-10.1126/science.1079318.PubMedGoogle Scholar
- Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD: Response to Comment on "Failure of Bone Marrow Cells to Transdifferentiate into Neural Cells in Vivo". Science. 2003, 299: 1184c-10.1126/science.1080631.Google Scholar
- Blau H, Brazelton T, Keshet G, Rossi F: Something in the eye of the beholder. Science. 2002, 298: 361-362. 10.1126/science.298.5592.361c.PubMedGoogle Scholar
- Wagers AJ, Sherwood RI, Christensen JL, Weissman IL: Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002, 297: 2256-2259. 10.1126/science.1074807.PubMedGoogle Scholar
- Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD: Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science. 2002, 297: 1299-10.1126/science.297.5585.1299.PubMedGoogle Scholar
- Roybon L, Ma Z, Asztely F, Fosum A, Jacobsen SE, Brundin P, Li JY: Failure of transdifferentiation of adult hematopoietic stem cells into neurons. Stem Cells. 2006, 24: 1594-1604. 10.1634/stemcells.2005-0548.PubMedGoogle Scholar
- Koda M, Okada S, Nakayama T, Koshizuka S, Kamada T, Nishio Y, Someya Y, Yoshinaga K, Okawa A, Moriya H, Yamazaki M: Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. Neuroreport. 2005, 16: 1763-1767. 10.1097/01.wnr.0000183329.05994.d7.PubMedGoogle Scholar
- Sigurjonsson OE, Perreault MC, Egeland T, Glover JC: Adult human hematopoietic stem cells produce neurons efficiently in the regenerating chicken embryo spinal cord. Proc Natl Acad Sci U S A. 2005, 102: 5227-5232. 10.1073/pnas.0501029102.PubMed CentralPubMedGoogle Scholar
- Callera F, do Nascimento RX: Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury: a preliminary safety study. Exp Hematol. 2006, 34: 130-131. 10.1016/j.exphem.2005.11.006.PubMedGoogle Scholar
- Woodbury D, Schwarz EJ, Prockop DJ, Black IB: Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000, 61: 364-370. 10.1002/1097-4547(20000815)61:4<364::AID-JNR2>3.0.CO;2-C.PubMedGoogle Scholar
- Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR: Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000, 164: 247-256. 10.1006/exnr.2000.7389.PubMedGoogle Scholar
- Hung SC, Cheng H, Pan CY, Tsai MJ, Kao LS, Ma HL: In vitro differentiation of size-sieved stem cells into electrically active neural cells. Stem Cells. 2002, 20: 522-529. 10.1634/stemcells.20-6-522.PubMedGoogle Scholar
- Bossolasco P, Cova L, Calzarossa C, Rimoldi SG, Borsotti C, Deliliers GL, Silani V, Soligo D, Polli E: Neuro-glial differentiation of human bone marrow stem cells in vitro. Exp Neurol. 2005, 193: 312-325. 10.1016/j.expneurol.2004.12.013.PubMedGoogle Scholar
- Deng YB, Yuan QT, Liu XG, Liu XL, Liu Y, Liu ZG, Zhang C: Functional recovery after rhesus monkey spinal cord injury by transplantation of bone marrow mesenchymal-stem cell-derived neurons. Chin Med J (Engl ). 2005, 118: 1533-1541.Google Scholar
- Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ, Olson L: Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A. 2002, 99: 2199-2204. 10.1073/pnas.042678299.PubMed CentralPubMedGoogle Scholar
- Zurita M, Vaquero J: Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation. Neuroreport. 2004, 15: 1105-1108. 10.1097/00001756-200405190-00004.PubMedGoogle Scholar
- Lee J, Kuroda S, Shichinohe H, Ikeda J, Seki T, Hida K, Tada M, Sawada K, Iwasaki Y: Migration and differentiation of nuclear fluorescence-labeled bone marrow stromal cells after transplantation into cerebral infarct and spinal cord injury in mice. Neuropathology. 2003, 23: 169-180. 10.1046/j.1440-1789.2003.00496.x.PubMedGoogle Scholar
- Akiyama Y, Radtke C, Kocsis JD: Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci. 2002, 22: 6623-6630.PubMed CentralPubMedGoogle Scholar
- Wu S, Suzuki Y, Ejiri Y, Noda T, Bai H, Kitada M, Kataoka K, Ohta M, Chou H, Ide C: Bone marrow stromal cells enhance differentiation of cocultured neurosphere cells and promote regeneration of injured spinal cord. J Neurosci Res. 2003, 72: 343-351. 10.1002/jnr.10587.PubMedGoogle Scholar
- Neuhuber B, Timothy HB, Shumsky JS, Gallo G, Fischer I: Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res. 2005, 1035: 73-85. 10.1016/j.brainres.2004.11.055.PubMedGoogle Scholar
- Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002, 416: 542-545. 10.1038/nature730.PubMedGoogle Scholar
- Ying QL, Nichols J, Evans EP, Smith AG: Changing potency by spontaneous fusion. Nature. 2002, 416: 545-548. 10.1038/nature729.PubMedGoogle Scholar
- Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A: Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003, 425: 968-973. 10.1038/nature02069.PubMedGoogle Scholar
- Yano S, Kuroda S, Lee JB, Shichinohe H, Seki T, Ikeda J, Nishimura G, Hida K, Tamura M, Iwasaki Y: In vivo fluorescence tracking of bone marrow stromal cells transplanted into a pneumatic injury model of rat spinal cord. J Neurotrauma. 2005, 22: 907-918. 10.1089/neu.2005.22.907.PubMedGoogle Scholar
- Vaquero J, Zurita M, Oya S, Santos M: Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration?. Neurosci Lett. 2006, 398: 129-134. 10.1016/j.neulet.2005.12.072.PubMedGoogle Scholar
- Lu P, Jones LL, Tuszynski MH: BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol. 2005, 191: 344-360. 10.1016/j.expneurol.2004.09.018.PubMedGoogle Scholar
- Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, Pastore I, Marasso R, Madon E: Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003, 4: 158-161. 10.1080/14660820310014653.PubMedGoogle Scholar
- Conley BJ, Young JC, Trounson AO, Mollard R: Derivation, propagation and differentiation of human embryonic stem cells. Int J Biochem Cell Biol. 2004, 36: 555-567. 10.1016/j.biocel.2003.07.003.PubMedGoogle Scholar
- Kimura H, Yoshikawa M, Matsuda R, Toriumi H, Nishimura F, Hirabayashi H, Nakase H, Kawaguchi S, Ishizaka S, Sakaki T: Transplantation of embryonic stem cell-derived neural stem cells for spinal cord injury in adult mice. Neurol Res. 2005, 27: 812-819. 10.1179/016164105X63629.PubMedGoogle Scholar
- Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A: Niche-Independent Symmetrical Self-Renewal of a Mammalian Tissue Stem Cell. PLoS Biol. 2005, 3: e283-10.1371/journal.pbio.0030283.PubMed CentralPubMedGoogle Scholar
- Deshpande DM, Kim YS, Martinez T, Carmen J, Dike S, Shats I, Rubin LL, Drummond J, Krishnan C, Hoke A, Maragakis N, Shefner J, Rothstein JD, Kerr DA: Recovery from paralysis in adult rats using embryonic stem cells. Ann Neurol. 2006, 60: 32-44. 10.1002/ana.20901.PubMedGoogle Scholar
- Hamada M, Yoshikawa H, Ueda Y, Kurokawa MS, Watanabe K, Sakakibara M, Tadokoro M, Akashi K, Aoki H, Suzuki N: Introduction of the MASH1 gene into mouse embryonic stem cells leads to differentiation of motoneuron precursors lacking Nogo receptor expression that can be applicable for transplantation to spinal cord injury. Neurobiol Dis. 2006, 22: 509-522. 10.1016/j.nbd.2005.12.020.PubMedGoogle Scholar
- Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW: Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci U S A. 2000, 97: 6126-6131. 10.1073/pnas.97.11.6126.PubMed CentralPubMedGoogle Scholar
- Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O: Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005, 25: 4694-4705. 10.1523/JNEUROSCI.0311-05.2005.PubMedGoogle Scholar
- Harley BA, Spilker MH, Wu JW, Asano K, Hsu HP, Spector M, Yannas IV: Optimal degradation rate for collagen chambers used for regeneration of peripheral nerves over long gaps. Cells Tissues Organs. 2004, 176: 153-165. 10.1159/000075035.PubMedGoogle Scholar
- Tsai EC, Dalton PD, Shoichet MS, Tator CH: Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 2006, 27: 519-533. 10.1016/j.biomaterials.2005.07.025.PubMedGoogle Scholar
- Klapka N, Müller HW: Collagen matrix in spinal cord injury. J Neurotrauma. 2006, 23: 422-435. 10.1089/neu.2006.23.422.PubMedGoogle Scholar
- Yoshii S, Oka M, Shima M, Akagi M, Taniguchi A: Bridging a spinal cord defect using collagen filament. Spine. 2003, 28: 2346-2351. 10.1097/01.BRS.0000085302.95413.16.PubMedGoogle Scholar
- Yoshii S, Oka M, Shima M, Taniguchi A, Taki Y, Akagi M: Restoration of function after spinal cord transection using a collagen bridge. J Biomed Mater Res A. 2004, 70: 569-575. 10.1002/jbm.a.30120.PubMedGoogle Scholar
- Liu S, Said G, Tadie M: Regrowth of the rostral spinal axons into the caudal ventral roots through a collagen tube implanted into hemisected adult rat spinal cord. Neurosurgery. 2001, 49: 143-150. 10.1097/00006123-200107000-00022.PubMedGoogle Scholar
- Houweling DA, Lankhorst AJ, Gispen WH, Bar PR, Joosten EA: Collagen containing neurotrophin-3 (NT-3) attracts regrowing injured corticospinal axons in the adult rat spinal cord and promotes partial functional recovery. Exp Neurol. 1998, 153: 49-59. 10.1006/exnr.1998.6867.PubMedGoogle Scholar
- Goldsmith HS, Fonseca A, Porter J: Spinal cord separation: MRI evidence of healing after omentum-collagen reconstruction. Neurol Res. 2005, 27: 115-123. 10.1179/016164105X21995.PubMedGoogle Scholar
- Kataoka K, Suzuki Y, Kitada M, Hashimoto T, Chou H, Bai H, Ohta M, Wu S, Suzuki K, Ide C: Alginate enhances elongation of early regenerating axons in spinal cord of young rats. Tissue Eng. 2004, 10: 493-504. 10.1089/107632704323061852.PubMedGoogle Scholar
- Novikova LN, Mosahebi A, Wiberg M, Terenghi G, Kellerth JO, Novikov LN: Alginate hydrogel and matrigel as potential cell carriers for neurotransplantation. J Biomed Mater Res A. 2006, 77: 242-252.PubMedGoogle Scholar
- Kataoka K, Suzuki Y, Kitada M, Ohnishi K, Suzuki K, Tanihara M, Ide C, Endo K, Nishimura Y: Alginate, a bioresorbable material derived from brown seaweed, enhances elongation of amputated axons of spinal cord in infant rats. J Biomed Mater Res. 2001, 54: 373-384. 10.1002/1097-4636(20010305)54:3<373::AID-JBM90>3.0.CO;2-Q.PubMedGoogle Scholar
- Suzuki K, Suzuki Y, Ohnishi K, Endo K, Tanihara M, Nishimura Y: Regeneration of transected spinal cord in young adult rats using freeze-dried alginate gel. Neuroreport. 1999, 10: 2891-2894. 10.1097/00001756-199909290-00003.PubMedGoogle Scholar
- Suzuki Y, Kitaura M, Wu S, Kataoka K, Suzuki K, Endo K, Nishimura Y, Ide C: Electrophysiological and horseradish peroxidase-tracing studies of nerve regeneration through alginate-filled gap in adult rat spinal cord. Neurosci Lett. 2002, 318: 121-124. 10.1016/S0304-3940(01)02359-X.PubMedGoogle Scholar
- Novikov LN, Novikova LN, Mosahebi A, Wiberg M, Terenghi G, Kellerth JO: A novel biodegradable implant for neuronal rescue and regeneration after spinal cord injury. Biomaterials. 2002, 23: 3369-3376. 10.1016/S0142-9612(02)00037-6.PubMedGoogle Scholar
- Prang P, Muller R, Eljaouhari A, Heckmann K, Kunz W, Weber T, Faber C, Vroemen M, Bogdahn U, Weidner N: The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials. 2006, 27: 3560-3569.PubMedGoogle Scholar
- Wu L, Ding J: In vitro degradation of three-dimensional porous poly(D,L-lactide-co-glycolide) scaffolds for tissue engineering. Biomaterials. 2004, 25: 5821-5830. 10.1016/j.biomaterials.2004.01.038.PubMedGoogle Scholar
- Gautier SE, Oudega M, Fragoso M, Chapon P, Plant GW, Bunge MB, Parel JM: Poly(alpha-hydroxyacids) for application in the spinal cord: resorbability and biocompatibility with adult rat Schwann cells and spinal cord. J Biomed Mater Res. 1998, 42: 642-654. 10.1002/(SICI)1097-4636(19981215)42:4<642::AID-JBM22>3.0.CO;2-K.PubMedGoogle Scholar
- Maquet V, Martin D, Scholtes F, Franzen R, Schoenen J, Moonen G, Jer R: Poly(D,L-lactide) foams modified by poly(ethylene oxide)-block-poly(D,L-lactide) copolymers and a-FGF: in vitro and in vivo evaluation for spinal cord regeneration. Biomaterials. 2001, 22: 1137-1146. 10.1016/S0142-9612(00)00357-4.PubMedGoogle Scholar
- Blacher S, Maquet V, Schils F, Martin D, Schoenen J, Moonen G, Jerome R, Pirard JP: Image analysis of the axonal ingrowth into poly(D,L-lactide) porous scaffolds in relation to the 3-D porous structure. Biomaterials. 2003, 24: 1033-1040. 10.1016/S0142-9612(02)00423-4.PubMedGoogle Scholar
- Patist CM, Mulder MB, Gautier SE, Maquet V, Jerome R, Oudega M: Freeze-dried poly(D,L-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord. Biomaterials. 2004, 25: 1569-1582. 10.1016/S0142-9612(03)00503-9.PubMedGoogle Scholar
- Woerly S: Restorative surgery of the central nervous system by means of tissue engineering using NeuroGel implants. Neurosurg Rev. 2000, 23: 59-77.PubMedGoogle Scholar
- Tsai EC, Dalton PD, Shoichet MS, Tator CH: Synthetic hydrogel guidance channels facilitate regeneration of adult rat brainstem motor axons after complete spinal cord transection. J Neurotrauma. 2004, 21: 789-804. 10.1089/0897715041269687.PubMedGoogle Scholar
- Bakshi A, Fisher O, Dagci T, Himes BT, Fischer I, Lowman A: Mechanically engineered hydrogel scaffolds for axonal growth and angiogenesis after transplantation in spinal cord injury. J Neurosurg Spine. 2004, 1: 322-329.PubMedGoogle Scholar
- Dalton PD, Flynn L, Shoichet MS: Manufacture of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) hydrogel tubes for use as nerve guidance channels. Biomaterials. 2002, 23: 3843-3851. 10.1016/S0142-9612(02)00120-5.PubMedGoogle Scholar
- Woerly S, Doan VD, Sosa N, de Vellis J, Espinosa A: Reconstruction of the transected cat spinal cord following NeuroGel implantation: axonal tracing, immunohistochemical and ultrastructural studies. Int J Dev Neurosci. 2001, 19: 63-83. 10.1016/S0736-5748(00)00064-2.PubMedGoogle Scholar
- Woerly S, Doan VD, Sosa N, de Vellis J, Espinosa-Jeffrey A: Prevention of gliotic scar formation by NeuroGel allows partial endogenous repair of transected cat spinal cord. J Neurosci Res. 2004, 75: 262-272. 10.1002/jnr.10774.PubMedGoogle Scholar
- Woerly S, Doan VD, Evans-Martin F, Paramore CG, Peduzzi JD: Spinal cord reconstruction using NeuroGel implants and functional recovery after chronic injury. J Neurosci Res. 2001, 66: 1187-1197. 10.1002/jnr.1255.PubMedGoogle Scholar
- Woerly S, Pinet E, de Robertis L, Van Diep D, Bousmina M: Spinal cord repair with PHPMA hydrogel containing RGD peptides (NeuroGel). Biomaterials. 2001, 22: 1095-1111. 10.1016/S0142-9612(00)00354-9.PubMedGoogle Scholar
- Lesny P, De Croos J, Pradny M, Vacik J, Michalek J, Woerly S, Sykova E: Polymer hydrogels usable for nervous tissue repair. J Chem Neuroanat. 2002, 23: 243-247. 10.1016/S0891-0618(02)00011-X.PubMedGoogle Scholar
- Shi R, Borgens RB: Anatomical repair of nerve membranes in crushed mammalian spinal cord with polyethylene glycol. J Neurocytol. 2000, 29: 633-643. 10.1023/A:1010879219775.PubMedGoogle Scholar
- Shi R, Borgens RB: Acute repair of crushed guinea pig spinal cord by polyethylene glycol. J Neurophysiol. 1999, 81: 2406-2414.PubMedGoogle Scholar
- Luo J, Borgens R, Shi R: Polyethylene glycol immediately repairs neuronal membranes and inhibits free radical production after acute spinal cord injury. J Neurochem. 2002, 83: 471-480. 10.1046/j.1471-4159.2002.01160.x.PubMedGoogle Scholar
- Luo J, Shi R: Diffusive oxidative stress following acute spinal cord injury in guinea pigs and its inhibition by polyethylene glycol. Neurosci Lett. 2004, 359: 167-170. 10.1016/j.neulet.2004.02.027.PubMedGoogle Scholar
- Luo J, Borgens R, Shi R: Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury. J Neurotrauma. 2004, 21: 994-1007. 10.1089/0897715041651097.PubMedGoogle Scholar
- Shi R, Borgens RB, Blight AR: Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol. J Neurotrauma. 1999, 16: 727-738.PubMedGoogle Scholar
- Duerstock BS, Borgens RB: Three-dimensional morphometry of spinal cord injury following polyethylene glycol treatment. J Exp Biol. 2002, 205: 13-24.PubMedGoogle Scholar
- Borgens RB, Shi R: Immediate recovery from spinal cord injury through molecular repair of nerve membranes with polyethylene glycol. FASEB J. 2000, 14: 27-35.PubMedGoogle Scholar
- Borgens RB, Shi R, Bohnert D: Behavioral recovery from spinal cord injury following delayed application of polyethylene glycol. J Exp Biol. 2002, 205: 1-12.PubMedGoogle Scholar
- Cole A, Shi R: Prolonged focal application of polyethylene glycol induces conduction block in guinea pig spinal cord white matter. Toxicol In Vitro. 2005, 19: 215-220. 10.1016/j.tiv.2004.10.007.PubMedGoogle Scholar
- Laurens N, Koolwijk P, de Maat MP: Fibrin structure and wound healing. J Thromb Haemost. 2006, 4: 932-939. 10.1111/j.1538-7836.2006.01861.x.PubMedGoogle Scholar
- Taylor SJ, McDonald JW, Sakiyama-Elbert SE: Controlled release of neurotrophin-3 from fibrin gels for spinal cord injury. J Control Release. 2004, 98: 281-294. 10.1016/j.jconrel.2004.05.003.PubMedGoogle Scholar
- Freshney RI: Culture of Animal Cells: a Manual of Basic Technique. 2000, New York, Wiley-Liss, 4thGoogle Scholar
- Xiao M, Klueber KM, Lu C, Guo Z, Marshall CT, Wang H, Roisen FJ: Human adult olfactory neural progenitors rescue axotomized rodent rubrospinal neurons and promote functional recovery. Exp Neurol. 2005, 194: 12-30. 10.1016/j.expneurol.2005.01.021.PubMedGoogle Scholar
- Facchiano F, Fernandez E, Mancarella S, Maira G, Miscusi M, D'Arcangelo D, Cimino-Reale G, Falchetti ML, Capogrossi MC, Pallini R: Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor. J Neurosurg. 2002, 97: 161-168.PubMedGoogle Scholar
- Iannotti C, Li H, Yan P, Lu X, Wirthlin L, Xu XM: Glial cell line-derived neurotrophic factor-enriched bridging transplants promote propriospinal axonal regeneration and enhance myelination after spinal cord injury. Exp Neurol. 2003, 183: 379-393. 10.1016/S0014-4886(03)00188-2.PubMedGoogle Scholar
- Ahmed Z, Underwood S, Brown RA: Nerve guide material made from fibronectin: assessment of in vitro properties. Tissue Eng. 2003, 9: 219-231. 10.1089/107632703764664693.PubMedGoogle Scholar
- King VR, Henseler M, Brown RA, Priestley JV: Mats made from fibronectin support oriented growth of axons in the damaged spinal cord of the adult rat. Exp Neurol. 2003, 182: 383-398. 10.1016/S0014-4886(03)00033-5.PubMedGoogle Scholar
- Ahmed Z, Idowu BD, Brown RA: Stabilization of fibronectin mats with micromolar concentrations of copper. Biomaterials. 1999, 20: 201-209. 10.1016/S0142-9612(98)00015-5.PubMedGoogle Scholar
- King VR, Phillips JB, Hunt-Grubbe H, Brown R, Priestley JV: Characterization of non-neuronal elements within fibronectin mats implanted into the damaged adult rat spinal cord. Biomaterials. 2006, 27: 485-496. 10.1016/j.biomaterials.2005.06.033.PubMedGoogle Scholar
- King VR, Phillips JB, Brown RA, Priestley JV: The effects of treatment with antibodies to transforming growth factor beta1 and beta2 following spinal cord damage in the adult rat. Neuroscience. 2004, 126: 173-183. 10.1016/j.neuroscience.2004.03.035.PubMedGoogle Scholar
- Stokols S, Tuszynski MH: The fabrication and characterization of linearly oriented nerve guidance scaffolds for spinal cord injury. Biomaterials. 2004, 25: 5839-5846. 10.1016/j.biomaterials.2004.01.041.PubMedGoogle Scholar
- Stokols S, Tuszynski MH: Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury. Biomaterials. 2006, 27: 443-451. 10.1016/j.biomaterials.2005.06.039.PubMedGoogle Scholar
- Jain A, Kim YT, McKeon RJ, Bellamkonda RV: In situ gelling hydrogels for conformal repair of spinal cord defects, and local delivery of BDNF after spinal cord injury. Biomaterials. 2006, 27: 497-504. 10.1016/j.biomaterials.2005.07.008.PubMedGoogle Scholar
- Oudega M, Gautier SE, Chapon P, Fragoso M, Bates ML, Parel JM, Bunge MB: Axonal regeneration into Schwann cell grafts within resorbable poly(alpha-hydroxyacid) guidance channels in the adult rat spinal cord. Biomaterials. 2001, 22: 1125-1136. 10.1016/S0142-9612(00)00346-X.PubMedGoogle Scholar
- Kamada T, Koda M, Dezawa M, Yoshinaga K, Hashimoto M, Koshizuka S, Nishio Y, Moriya H, Yamazaki M: Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after complete transection of adult rat spinal cord. J Neuropathol Exp Neurol. 2005, 64: 37-45.PubMedGoogle Scholar
- Joosten EA, Veldhuis WB, Hamers FP: Collagen containing neonatal astrocytes stimulates regrowth of injured fibers and promotes modest locomotor recovery after spinal cord injury. J Neurosci Res. 2004, 77: 127-142. 10.1002/jnr.20088.PubMedGoogle Scholar
- Wu S, Suzuki Y, Kitada M, Kitaura M, Kataoka K, Takahashi J, Ide C, Nishimura Y: Migration, integration, and differentiation of hippocampus-derived neurosphere cells after transplantation into injured rat spinal cord. Neurosci Lett. 2001, 312: 173-176. 10.1016/S0304-3940(01)02219-4.PubMedGoogle Scholar
- Tobias CA, Dhoot NO, Wheatley MA, Tessler A, Murray M, Fischer I: Grafting of encapsulated BDNF-producing fibroblasts into the injured spinal cord without immune suppression in adult rats. J Neurotrauma. 2001, 18: 287-301. 10.1089/08977150151070937.PubMedGoogle Scholar
- Tobias CA, Han SS, Shumsky JS, Kim D, Tumolo M, Dhoot NO, Wheatley MA, Fischer I, Tessler A, Murray M: Alginate encapsulated BDNF-producing fibroblast grafts permit recovery of function after spinal cord injury in the absence of immune suppression. J Neurotrauma. 2005, 22: 138-156. 10.1089/neu.2005.22.138.PubMedGoogle Scholar
- Meijs MF, Timmers L, Pearse DD, Tresco PA, Bates ML, Joosten EA, Bunge MB, Oudega M: Basic fibroblast growth factor promotes neuronal survival but not behavioral recovery in the transected and Schwann cell implanted rat thoracic spinal cord. J Neurotrauma. 2004, 21: 1415-1430. 10.1089/neu.2004.21.1415.PubMedGoogle Scholar
- Guest JD, Hesse D, Schnell L, Schwab ME, Bunge MB, Bunge RP: Influence of IN-1 antibody and acidic FGF-fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts. J Neurosci Res. 1997, 50: 888-905. 10.1002/(SICI)1097-4547(19971201)50:5<888::AID-JNR24>3.0.CO;2-W.PubMedGoogle Scholar
- Blits B, Oudega M, Boer GJ, Bartlett BM, Verhaagen J: Adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function. Neuroscience. 2003, 118: 271-281. 10.1016/S0306-4522(02)00970-3.PubMedGoogle Scholar
- Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY: Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A. 2002, 99: 3024-3029. 10.1073/pnas.052678899.PubMed CentralPubMedGoogle Scholar
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