Spinal Repair Research Articles

The Center of the Spinal Cord May Be Central to Its Repair

A recent PLoS Biology report from Meletis et al. (2008) strongly suggests that ependymal cells are a key source of endogenous stem cells in the spinal cord. Advances in understanding endogenous neural stem cells may facilitate repair of the injured central nervous system.

The lumbar vertebral disc

In a time of a virtually endless number of spine meetings, many of interest to only a small group of researchers or scientists because of the restricted focus of the topics, AOSpine 2005 supported two unique symposia. These symposia differed from the general forum construct: in concept challenging the scientific community to integrate compelling mechanistic evidence for its clinical relevance and at the same time asking clinicians to focus their needs through the lens of the scientific community. Spotlighting the Lumbar Intervertebral Disc and the Lumbar Motion Segment for these initial forums could not have been more topical. Integrative symposia such as those recently held offer the opportunity to unite scientists and clinicians who might otherwise drift apart despite the seemingly thematic unity of common topics. The two symposia successfully counteracted this fragmentation between bench and bedside. Expertise from both segments resulted in a clear and mutual stimulation that extended beyond mercantile interests and project-protecting pettiness and engaged the potential for a new era of well-applied research. The topics ranged from the genetic principles of intervertebral disc degeneration to forward-looking applications involving intervertebral disc implantation. Basic science, which from the mid-1970s to the 1990s mainly concentrated on the natural history and pathophysiology of intervertebral disc degeneration, has been complemented in the past 10 years by notions emerging from clinical research—thinking that understood that repair is possible. This new and exciting treatment philosophy evolved in the climate of increasing spinal complaints among patients in the industrialized countries and the resultant rise in invasive interventions. More importantly, however, it was clinicians recognizing that decompressing, minimally invasive surgical procedures failed to provide convincing long-term results that ultimately served as a catalyst for more comprehensive treatment considerations. The logical consequence has been for them to consider regenerative treatment approaches to counteract the degenerative changes they have seen in their patients, especially in conjunction with the developing potential for preventative therapeutic approaches. Genetic analysis, gene therapy, greater understanding of growth factors and their function and the advent of cell therapy now offer different approaches to repair and regeneration, all of them aligned with the aim of seeking to deter disc degeneration as early as possible. Other therapeutic approaches, such as fusion and more recently arthoplastic interventions, have been developed to offer symptomatic relief; although much more invasive, their development has been fostered to meet the needs of the more advanced degenerative processes. In the context of developing therapeutic intervention, it is imperative to understand when the changes occur and what can be done to prevent further degeneration. Should not early symptoms of biological attrition therefore be correctly diagnosed non-invasively and reparative procedures initiated in this phase of change? Unfortunately, such early changes cannot be visualized with the currently available diagnostic procedures. In order to maximize the potential for disc repair and endplate research in the coming years, an accompanying need for structural visualization at the highest resolution that can be anticipated in the intervention needs to be achieved. The inherent aim is to seek detection of changes in the nano-range. Visualization diagnostics in nano-medicine has been made a main segment of the 7th European Research Framework Program. The musculoskeletal segment of regenerative medicine has been successfully expanded with the inclusion of Spinal Repair in this framework program, which will go into effect in 2007. This area is thus firmly anchored in nano-medicine and appreciated as an important and necessary research area that will demand an integrated approach to achieve its maximum potential in clinical application. These developments should stimulate our community to more forcefully state our research activities and to better coordinate bench and bedside in order to work out common reparative approaches that will enable us in the next 10 years to make disc repair clinically effective. May this supplement promote our common interests, for us it was the reason for organizing two meetings with very similar topics that generated a vivid interest in our community. We would like to thank the European Spine Journal for offering us a forum to communicate these state-of-the-art research endeavours. Hans Jorg Meisel Guest Editor

Olfactory neural cells: an untapped diagnostic and therapeutic resource. The 2000 Ogura Lecture.

This is an overview of the cellular biology of upper nasal mucosal cells that have special characteristics that enable them to be used to diagnose and study congenital neurological diseases and to aid neural repair. After mapping the distribution of neural cells in the upper nose, the authors' investigations moved to the use of olfactory neurones to diagnose neurological diseases of development, especially schizophrenia. Olfactory-ensheathing glial cells (OEGs) from the cranial cavity promote axonal penetration of the central nervous system and aid spinal cord repair in rodents. The authors sought to isolate these cells from the more accessible upper nasal cavity in rats and in humans and prove they could likewise promote neural regeneration, making these cells suitable for human spinal repair investigations. The schizophrenia-diagnosis aspect of the study entailed the biopsy of the olfactory areas of 10 schizophrenic patients and 10 control subjects. The tissue samples were sliced and grown in culture medium. The ease of cell attachment to fibronectin (artificial epithelial basement membrane), as well as the mitotic and apoptotic indices, was studied in the presence and absence of dopamine in those cell cultures. The neural repair part of the study entailed a harvesting and insertion of first rat olfactory lamina propria rich in OEGs between cut ends of the spinal cords and then later the microinjection of an OEG-rich suspension into rat spinal cords previously transected by open laminectomy. Further studies were done in which OEG insertion was performed up to 1 month after rat cord transection and also in monkeys. Schizophrenic patients' olfactory tissues do not easily attach to basement membrane compared with control subjects, adding evidence to the theory that cell wall anomalies are part of the schizophrenic "lesion" of neurones. Schizophrenic patient cell cultures had higher mitotic and apoptotic indices compared with control subjects. The addition of dopamine altered these indices enough to allow accurate differentiation of schizophrenics from control patients, leading to, possibly for the first time, an early objective diagnosis of schizophrenia and possible assessment of preventive strategies. OEGs from the nose were shown to be as effective as those from the olfactory bulb in promoting axonal growth across transected spinal cords even when added 1 month after injury in the rat. These otherwise paraplegic rats grew motor and proprioceptive and fine touch fibers with corresponding behavioral improvement. The tissues of the olfactory mucosa are readily available to the otolaryngologist. Being surface cells, they must regenerate (called "neurogenesis"). Biopsy of this area and amplification of cells in culture gives the scientist a "window to the developing brain," including early diagnosis of schizophrenia. The "Holy Grail" of neurological disease is the cure of traumatic paraplegia and OEGs from the nose promote that repair. The otolaryngologist may become the necessary partner of the neurophysiologist and spinal surgeon to take the laboratory potential of paraplegic cure into the day-to-day realm of clinical reality.

Spinal repair in immature animals: a novel approach using the South American opossum Monodelphis domestica.

1. The adult mammalian central nervous system (CNS) is unable to regenerate following injury and repair has only been seen when implants of peripheral nervous tissue, fetal tissue or Schwann cells are used, or antibodies or trophic molecules applied. However, the immature mammalian CNS has revealed a capacity to repair without extrinsic influence. 2. The marsupial mammal provides a unique opportunity to access the immature CNS without invasive in utero surgery. In particular, the South American opossum Monodelphis domestica is an ideal animal for spinal cord injury studies examining the ability of the immature CNS to repair after injury. 3. The Monodelphis spinal cord may be examined for its response to injury either as an in vitro or in vivo system and, therefore, is a flexible model, allowing many different questions to be addressed by the most suitable approach. 4. The immature Monodelphis CNS was able to support fibre growth that reappeared 4 days after a crush at P3-P8 in vitro. Conduction was also restored at this time, accompanied by synaptic connections. 5. A cut lesion performed in vivo on Monodelphis spinal cords at P7 took longer to repair, with fibres reappearing across the injury site 2 weeks after the lesion; greater disruption to structure was noted both during early stages of repair and in adulthood. 6. Neural pathway tracing with dextran amine from the lumbar cord to the brain in adult Monodelphis, which received spinal lesions at P7, revealed a similar distribution of labelled cells in brainstem and mid-brain nuclei to that of control animals. 7. Studies of the locomotor behaviour of adult Monodelphis that had received either a cut or crush lesion at P7-P8 showed remarkably similar abilities to control animals when performing complex tasks. 8. The results of spinal cord injury studies with the immature Monodelphis CNS may help in the development of treatments for spinal injury patients.

The International Spinal Research Trust's strategic approach to the development of treatments for the repair of spinal cord injury.

The International Spinal Research Trust (ISRT) has selected a sub-set of the key molecular and cellular events underlying spinal injury and nerve regeneration, to be focus of their funding and other means of research support. These priority targets are (i) to understand and to minimise the damage caused by spinal injury and the resulting inflammatory and fibrotic events, in order to prevent the establishment of a post-acute situation that is ill-placed for regeneration; and (ii) to understand and then to manipulate the integrated environment for regrowth that is created by the interplay of soluble and matrix- or membrane-associated factors, both trophic and inhibitory. Investigation and, ultimately, exploitation of these targets requires the development of standardised and representative animal models and the application of quantitative methods for assessing functional re-innervation. The ISRT will also sponsor the networking of different disciplines and technologies to apply the most productive skills to spinal repair.

The electrolytic lesion as a model of spinal cord damage and repair in the adult rat

The utility of the electrolytic lesion as a model of spinal cord injury and repair has been studied in adult Wistar rats. Lesions were created using an 0.1 mA current applied for 30 s in the right hand intermediate zone of the cord, at the level of the 10th thoracic vertebra. After three months, secondary pathological changes at these sites resulted in a variable degree of grey matter atrophy, cavitation, macrophage infiltration and loss of white matter in the dorsolateral funiculus. Functionally, lesioned animals exhibited an incomplete spastic paraparesis of the right hind limb, had normal scores on the inclined plane test, but showed subnormal performance of the right hind limb on the Tarlov scale. Spinal cord neurones dissociated from E14 rat embryos survived for at least 3 months if transplanted into a freshly made electrolytic lesion. However, these implants had no ameliorating effect on the motor deficit induced by electrolytic lesions. It was concluded that the electrolytic lesion represents a useful model for qualitative studies on secondary histopathological changes in the injured cord. Electrolytic lesions also support long-term survival of implanted spinal neurones. However, the possible trophic influence of these implants on motor and sensory tracts could probably be better studied using neonatal, rather than adult rats.