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PubMed1989

Experimental models of brain injury.

General categories of experimental brain injury models are reviewed regarding their clinical significance, and two new models are presented that use different methodology to produce injury. This report describes and characterizes the pathophysiologic changes produced by a novel fluid percussion (FP) method and a controlled cortical impact (CI) technique, both developed at the General Motors Research Laboratories (GMRL). The new models are compared to prior experimental brain injury techniques in relation to ongoing physical and analytical modeling used in automotive safety research by GMRL. Experimental results from our laboratory indicate that although the FP technique, currently the most widely used method for producing brain injury, is useful for producing graded injury responses systemically and centrally, it is not well-suited for detailed biomechanical analyses. This conclusion is based on high-speed cineradiographic studies where the physiologic saline in the FP cannula was substituted with a radiopaque contrast medium (Conray 1:1 dilution/saline). High speed x-ray movies (1000 fps) were taken of the fluid percussion pulse (1.5-3.4 atm/20 msec) in sagittal, dorsal, and frontal planes of orientation. When viewed together, the cineradiography revealed a complex, dynamic interaction between the injected fluid and the skull/cranial contents. Rapid lateral and anterior/posterior epidural fluid flow suggest that the pathology and dysfunction following FP brain injury reflects diffuse mechanical loading of the brain. Because fluid is used to transfer mechanical energy to brain tissue, and because fluid flow characteristics (i.e., direction, velocity, and displacement) are dependent on the brain geometry and species used, accurate analytical and biomechanical analyses of the resultant injury would be difficult at best. In contrast, the cortical impact model of experimental brain injury uses a known impact interface and a measurable, controllable impact velocity and cortical compression. These controlled variables enable the amount of deformation and the change in deformation over time to be accurately determined. In addition, the CI model produces graded, reproducible cortical contusion, prolonged functional coma, and extensive axonal injury, unlike the FP technique. The quantifiable nature of the single mechanical input used to produce the injury allows correlations to be made between the amount of deformation and the resultant pathology and functional changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury.

Spinal cord injury (SCI) results in rapid and significant oxidative stress. We have previously demonstrated that administration of polyethylene glycol (PEG) inhibits oxidative stress using an in vitro model of SCI. In this study we tested the effects of PEG in vivo, to elucidate the mechanism of PEG-mediated neuroprotection. We show that a compression injury at T10-11 induced diffusive oxidative stress in crude synaptosomal preparations, correlated with synaptosomal dysfunction and increased intrasynaptosomal calcium. Administration of PEG immediately post-injury produced a marked decrease in synaptosomal oxidative stress and calcium, associated with an increase in synaptosomal function. Confocal microscopy using fluorescein conjugated PEG revealed that PEG entered the cells of the injured spinal cord, placing the polymer in a position to directly interact with cellular organelles. PEG attenuates calcium-induced functional compromise of normal spinal cord synaptosomes and mitochondria in vitro. These results indicate that PEG may exert its neuroprotective effect through direct interaction with mitochondria, besides its known ability to rescue neurons and their axons by repairing the plasma membranes. We submit that PEG is likely to interfere with the cascade of secondary injury by several mechanisms of action that in concert reduce oxidative stress.

Animals↗
PubMed1995

Tactile unit properties after human cervical spinal cord injury.

Properties of tactile afferent units innervating the glabrous skin of the hand were examined by microneurography in 11 individuals who had no or impaired touch perception due to chronic (> 1 year post-injury) cervical spinal cord injury (SCI). The results were compared with published control data. The adaptation properties [fast adaptation unit (FA) or slow adaptation unit (SA)], the indentation force threshold, and the size of the receptive field of each unit were assessed using calibrated von Frey hairs. Units were classified as type I (FAI, SAI) or type II (FAII, SAII) if the receptive field was small and well defined or large and diffuse, respectively. Sensitivity to skin stretch was also used to distinguish between the two slowly adapting unit types. In SCI subjects, 66 tactile afferents (and 16 unclassified muscle receptors) were sampled from all the glabrous skin areas typically innervated by the median nerve. Each unit type was represented in similar proportions in the SCI and control data. Similarly, there was an increase in the innervation density from the palm to the finger tips in SCI subjects, as found in control subjects. Afferent axon conduction velocities were not different for the SCI and control data. Indentation force thresholds and receptive field sizes of each unit type were also similar with one exception. The receptive fields for FAII units were larger after SCI. However, when data from all unit types were pooled, receptive fields were larger and indentation force thresholds were higher in SCI subjects. This may be the consequence of the thin, smooth, soft and significantly more compliant glabrous skin of the SCI subjects, factors which may influence the transmission of force from the skin surface to the receptors. Twenty-four units showed sustained responses to passive bending of the fingers and usually an increase in firing rate during finger extension. Eight of these units were slowly adapting tactile units. The others were unclassified units located deep within the forearm. Morphological estimates indicated no loss of myelinated nerve fibres in the median nerve 6 months after SCI. Motor as well as sensory nerve fibres were therefore unaffected below the elbow. Thus, tactile units were largely intact after chronic human cervical SCI despite changes in the mechanical transmission in the skin, and perception deficit.

Adult↗
PubMed2000

Effect of long-term vigabatrin administration on the immature rat brain.

PURPOSE: To determine whether the neuropathologic changes produced by vigabatrin (VGB; gamma-vinyl GABA) administration in the developing rat brain are reversible. METHODS: We injected rats daily with VGB (25-40 mg/kg/day, s.c.) from age 12 days for 2 weeks followed by 2 weeks of a drug-free period. Behavioral testing, magnetic resonance (MR) imaging, biochemical assays, and histologic technique were used to assess the adverse effect of VGB in developing brain and its reversibility. RESULTS: At the end of 2 weeks' VGB administration: (a) there was a hyperactivity and a shortened latency to escape out of cool water; (b) white matter appeared hyperintense in T2 and diffusion-weighted MR images with 4-15% increases in T2; (c) microvacuolation, TUNEL-positive nuclei, and swollen axons were observed in the corpus callosum; (d) myelin staining indicated a reduction in myelination, as did the reduction in activities of myelin and oligodendrocyte-associated enzymes and the decrease in myelin basic protein on Western blots. Two weeks after stopping VGB administration: (a) MR images were normal, and microvacuolation was no longer in the white matter; (b) reduction in myelination reversed partially; (c) the T2 relaxation time remained elevated in the hypothalamus; and (d) the behavioral response remained abnormal. CONCLUSIONS: Long-term VGB administration to young rats causes brain injury, which recovers partially on its cessation. The observed cell death, disrupted myelination, and alterations in behavior indicate a need for further safety assessment in infants and children.

Animals↗
PubMed1988

Regeneration of adult dorsal root axons into transplants of embryonic spinal cord.

Transplants of the embryonic rat spinal cord survive and differentiate in the spinal cords of adult and newborn host rats. Very little is known about the extent to which these homotopic transplants can provide an environment for regeneration of adult host axons that normally terminate in the spinal cord. We have used horseradish peroxidase injury filling and transganglionic transport methods to determine whether transected dorsal roots regenerate into fetal spinal cord tissue grafted into the spinal cords of adult rats. Additional transplants were examined for the presence of calcitonin gene-related peptide-like immunoreactivity, which in the normal dorsal horn is derived exclusively from primary afferent axons. Host animals had one side of the L4-5 spinal cord resected and replaced by a transplant of E14 or E15 spinal cord. Adjacent dorsal roots were sectioned and juxtaposed to the graft. The dorsal roots and their projections into the transplants were then labeled 2-9 months later. The tracing methods that used transport or diffusion of horseradish peroxidase demonstrated that severed host dorsal root axons had regenerated and grown into the transplants. In addition, some donor and host neurons had extended their axons into the periphery to at least the midthigh level as indicated by retrograde labeling following application of tracer to the sciatic nerve. Primary afferent axons immunoreactive for calcitonin gene-related peptide were among those that regenerated into transplants, and the projections shown by this immunocytochemical method exceeded those demonstrated by the horseradish peroxidase tracing techniques. Growth of the host dorsal roots into transplants indicates that fetal spinal cord tissue permits regeneration of adult axotomized neurons that would otherwise be aborted at the dorsal root/spinal cord junction. This transplantation model should therefore prove useful in studying the enhancement and specificity of the regrowth of axons that normally terminate in the spinal cord.

Animals↗
PubMed1978

Laminar scars in cerebral white matter: a perinatal injury due to edema.

Branched plate-like demyelinated lesions were present in the gyral and central white matter of two individuals, 3 and 54 years of age. The degenerated areas contained very few axons and were densely gliotic, and in the older case, contained connective tissue fibers and were continuous with a large parenchymal cyst. The lesions were covered on both sides by normally myelinated white matter, often representing only the subcortical arcuate white matter, occasionally being considerably broader. In some of the latter zones, there was a central area of less severe degeneration which, however, spared the arcuate zone which remained normal. It is suggested that these lesions represent the effects of edema induced by birth injury, under circumstances which permitted the continued formation and maturation of white matter after the edema had subsided. The edema is thought due for the most part to diffuse hypoxia and acidosis, but other mechanisms, such as infection, venous stasis and trauma, may have contributed to the pathogenesis of the edema, and to the lesions directly.

Birth Injuries↗
PubMed2000

Time course of trace of diffusion tensor [Trace(D)] and histology in brain edema.

We examined the correlation between changes in the trace of diffusion tensor [Trace(D)], regional water content and tissue ultrastructure relating to cellular (cytotoxic) and vasogenic brain edema. Cellular edema was induced by left middle cerebral artery occlusion in cats (Kuroiwa T et al., 1998). Vasogenic edema was induced in the white matter of cats by a cold lesion (Kuroiwa T et al., 1999). In cellular edema, the water content increase correlated linearly with the Trace(D) decrease in both the gray and white matter. However, both the slopes and intercepts of the correlation lines were significantly different. Hydropic astrocytic swelling was seen in both structures, and in the white matter, oligodendrocytic and myelinated axonal swelling were observed. In vasogenic edema, the increase in Trace(D) showed a significant linear correlation with the increase in tissue water content. Histologically, nerve fibers were dissociated and the extracellular space was markedly enlarged with protein-rich fluid. These result showed that the different slopes and intercepts of the water content--Trace(D) correlation lines for different subtype of brain edema, which reflect different ultrastructural localization of water, should be taken into account when evaluating brain edema using Trace(D) mapping.

Animals↗
PubMedDate not supplied

Integrated evaluation of central nervous system lesions: stains for neurons, astrocytes, and microglia reveal the spatial and temporal features of MK-801-induced neuronal necrosis in the rat cerebral cortex.

Routinely processed, hematoxylin and eosin (H&E)-stained slides are typically used to assess the morphologic integrity of the central nervous system in neurotoxicity safety studies. However, the value of special stains for improving neuropathologic evaluations during the assessment of neurotoxicity has been emphasized in the neuroscience literature and by regulatory agencies. The primary objective of the present study was to characterize the spatial and temporal changes in neurons, astrocytes, and microglia after dizocilpine maleate (MK-801)-induced focal neuronal necrosis in the posterior cingulate/retrosplenial (PC/RS) cortex of the rat. A secondary objective was to evaluate the application of special stains and a novel sectioning procedure for detecting neurotoxicity. Sixty adult male Sprague-Dawley rats were treated with sterile water vehicle or 10 mg/kg MK-801 and perfused through the left ventricle (pumped at 65 mm Hg pressure) with 10% neutral buffered formalin or 4% paraformaldehyde at 4 hr and on days 1, 3, 7, 14, and 28 after treatment. For light microscopic evaluation, brain sections were stained with H&E, a special cupric-silver (CS) stain that selectively impregnates degenerating neurons and makes them readily evident, glial fibrillary acidic protein (GFAP) immunohistochemistry for astrocytes, and Griffonia simplicifolia isolectin B4(GSA) histochemistry for microglia. Brains perfusion-fixed with 4% paraformaldehyde were prepared for CS staining with a novel frozen-sectioning procedure for multiple embedding in a composite gelatin block. In H&E sections from treated rats, necrotic nerve cell bodies were observed in PC/RS cortical layers 3 and 4 on days 1, 3, 7, and 14, but not on day 28. These necrotic neurons required high magnification for detection (x20 objective, x10 ocular). In contrast, degenerating neurons selectively stained with CS were observed in the same location as necrotic neurons seen with H&E but at low magnification (x2 objective, x10 ocular). Cupric-silver staining showed details not seen with H&E, including dendritic and axonal degeneration with progressive fragmentation. Beginning on day 3, GFAP immunohistochemistry revealed hypertrophic astrocytes in a diffuse pattern throughout the region of cell body necrosis, a change that persisted throughout the study. However, GSA lectin histochemistry identified a few reactive microglia on day 1 in a multifocal pattern throughout the region of cell body necrosis. Reactive microglia were observed on days 3, 7, and 14, but not on day 28. Glial changes observed with H&E staining were limited to an increase in the cellularity of glial cell nuclei in the area of neuronal necrosis. This study provides a comprehensive and integrated view of the temporal changes occurring in neurons, astrocytes, and microglia during acute neurotoxic injury. Moreover, advantages for using new staining and sectioning methodologies to enhance the toxicologic evaluation of the central nervous system are demonstrated.

Animals↗
PubMed2005

A microcapsule technique for long-term conduction block of the sciatic nerve by tetrodotoxin.

Tetrodotoxin (TTX) is a selective blocker of voltage-gated Na+ channels that is used to block action potentials in vitro and in vivo. Maintaining a sufficiently high local concentration of TTX in vivo to block conduction in a peripheral nerve is technically demanding and carries a risk of systemic toxicity. We report that slow diffusion of TTX out of a microcapsule (glass capillary) inserted beneath the epineurium of the sciatic nerve, with a loose cuff around the nerve, combines high blocking efficacy with low systemic toxicity in rats and mice. The local anaesthesia and motor paralysis was stable for at least 4-6 weeks. The conduction block was reversible and did not cause any obvious nerve injury. Low cost and simple surgical implementation make this new system an interesting alternative to existing long-term drug delivery methods.

Animals↗
PubMed2006

Neurobehavioral functional deficits following closed head injury in the neonatal pig.

Neurobehavioral deficits in higher cortical systems have not been described previously in a large animal model of diffuse brain injury. Anesthetized 3-5 day old piglets were subjected to either mild (142 rad/s) or moderate (188 rad/s) rapid non-impact axial rotations of the head. Multiple domains of cortical function were evaluated 5 times during the 12 day post-injury period using tests of neurobehavioral function devised for piglets. There were no observed differences in neurobehavioral outcomes between mild injury pigs (N=8) and instrumented shams (N=4). Moderately injured piglets (N=7) had significantly lower interest in exploring their environment and had higher failure rates in visual-based problem solving compared to instrumented shams (N=5) on days 1 and 4 after injury. Neurobehavioral functional deficits correlated with neuropathologic damage in the neonatal pigs after inertial head injury. Injured axons detected by immunohistochemistry (beta-APP) were absent in mild injury and sham piglets, but were observed in moderately injured piglet brains. In summary, we have developed a quantitative battery of neurobehavioral functional assessments for large animals that correlate with neuropathologic axonal damage and may have wide applications in the fields of cardiac resuscitation, stroke, and hypoxic-ischemic brain injury.

Amyloid beta-Protein Precursor↗
PubMed2004

Synthesis, localization and externalization of galectin-1 in mature dorsal root ganglion neurons and Schwann cells.

We recently confirmed that oxidized galectin-1 is a novel factor enhancing axonal growth in peripheral nerves after axotomy, but the process of extracellular release and oxidization of endogenous galectin-1 in the injured nervous tissue remains unknown. In the present study, we examined the distribution of galectin-1 in adult rat dorsal root ganglia (DRG) in vivo and in vitro. By RT-PCR analysis and in situ hybridization histochemistry, galectin-1 mRNA was detected in both DRG neurons and non-neuronal cells. Immunohistochemical analyses revealed that galectin-1 was distributed diffusely throughout the cytoplasm in smaller diameter neurons and Schwann cells in DRG sections. In contrast, the immunoreactivity for galectin-1 was detected in almost all DRG neurons from an early stage in culture (3 h after seeding) and was restricted to the surface and/or extracellular region of neurons and Schwann cells at later stages in culture. In a manner similar to the primary cultured cells, we also observed the surface and extracellular expression of this molecule in immortalized adult mouse Schwann cells (IMS32). Western blot analysis has revealed that both reduced and oxidized forms of galectin-1 were detected in culture media of DRG neurons and IMS32. These findings suggest that galectin-1 is externalized from DRG neurons and Schwann cells upon axonal injury. Some of the molecules in the extracellular milieu may be converted to the oxidized form, which lacks lectin activity but could act on neural tissue as a cytokine.

Animals↗
PubMed2005

Magnetic resonance imaging monitoring of multiple sclerosis lesion evolution.

The characteristic feature of multiple sclerosis (MS) pathology is the demyelinated plaque distributed throughout the central nervous system. Although MS is a primary demyelinating disease, acute axonal injury is common in actively demyelinating MS lesions and it is considered one of the major determinants of neurological deficit. Magnetic resonance imaging (MRI) has had a dramatic impact on MS in both the clinical practice and basic science settings. Techniques such as T2-weighted and gadolinium-enhanced T1-weighted MRI are very sensitive in detecting lesions and, thus, increase the level of certainty of MS diagnosis. Conventional MRI has also improved our understanding of the pathogenesis of the disease and has provided objective and reliable measures to monitor the effect of experimental treatments in clinical trials. However, conventional MRI does not provide specific information on the heterogeneous pathologic substrate of MS lesions. Advanced MRI techniques, such as magnetization transfer imaging, diffusion tensor imaging, and proton MR spectroscopy, offer the unprecedented ability to observe and quantify pathological changes in lesions and normal-appearing brain tissue over time. The present review will discuss the major contributions of conventional MRI and quantitative MRI techniques to understand how individual MS lesions evolve.

Atrophy↗
PubMedDate not supplied

Atypical diffuse Lewy body disease with neuritic abnormalities.

Dementia associated with cortical and subcortical Lewy bodies (LB's) is a distinct entity with variable clinico-pathological presentation. We present the case of a 49-year-old male with progressive dementia. At autopsy, the brain showed diffuse cortical atrophy and ubiquitin-positive LB's in the dentate gyrus, deep layers of the neocortex, basal ganglia, nucleus basalis and substantia nigra. Thioflavine S stains of the neocortex and hippocampus were negative for the presence of plaques and tangles. Anti-ubiquitin immunostaining revealed abundant dystrophic neurites, torpedo-like axons and abnormal neuritic processes in the molecular layer of the dentate gyrus, pyramidal cell layer in CA1, subiculum, deep layers of the neocortex, claustrum, caudate, putamen and globus pallidus. Relatively mild neuritic alterations were observed in the nucleus basalis of Meynert (NbM) and locus ceruleus. The presence of this unique type of axonal damage associated with Lewy body disease, in the absence of plaques and tangles, might suggest a divergent mechanism of neuritic injury in the wide spectrum of this disorder.

Brain↗
PubMed2005

Distribution of sodium channels during nerve elongation in rat peripheral nerve.

A number of studies have investigated electrophysiological and morphological changes of peripheral nerves during gradual elongation. There has been, however, no report on the distribution of sodium channels at Ranvier's nodes during peripheral nerve elongation. We investigated peripheral nerve injury after the gradual elongation of rat sciatic nerves. Indirect nerve elongation was induced by leg lengthening at a rate of 3 mm/day by 15 or 30 mm. At 7 days after the leg lengthening, the electrophysiological properties of sciatic nerves, the ultrastructures of the Ranvier's nodes and axons, and the distribution of voltage-dependent sodium channels were examined. In the control nerves, most sodium channels were localized at Ranvier's nodes in myelinated axons, providing the physiological basis of saltatory conduction. In the elongated nerves, both the amplitude and conduction velocity of compound nerve action potential decreased following leg lengthening. The elongated nerves also showed paranodal demyelination in Ranvier's nodes longer than those in the control group. In addition, the distribution of sodium channels became diffuse or disappeared at Ranvier's nodes of elongated nerves. The diffuse distribution and/or disappearance of sodium channels may underlie the electrophysiological changes in compound nerve action potential induced by nerve elongation.

Animals↗
PubMed1996

Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat.

Recent reports suggest a relationship between traumatic brain injury and the precocious development of neurodegenerative cascades, including diffuse deposits of beta-amyloid peptides (A beta) in the injured brain. Because the lateral fluid-percussion (FP) model of experimental brain injury produces clinically relevant neuropathological sequelae in the rat brain, we used this model together with a series of antibodies specific for amyloid precursor proteins (APPs), APP-like proteins (APLPs), or A beta to identify acute neurodegenerative changes after brain trauma. Male Sprague-Dawley rats were anesthetized and subjected to lateral FP brain injury of moderate to high severity. At 1 hr, 2 hr, 48 hr, 1 week, or 2 weeks after injury, animals were killed and their brains were removed for immunohistochemical analysis. APP/APLP immunoreactivity increased in specific brain regions as early as 1 hr after injury and persisted for at least 2 weeks. Axons in the thalamus and subcortical white matter showed the greatest APP/APLP accumulation. Injured cortex, striatum, cingulum, and hippocampus also demonstrated significant axonal accumulations of APP/APLP. Accumulation of APP/APLPs occurred primarily ipsilateral to the injury, although bilateral changes were observed in some brain regions. No deposition of A beta was observed in any brain region at any time point examined. These results demonstrate a pattern of widespread axonal pathology after lateral FP brain injury in the rat, characterized by intra-axonal accumulations of APP/APLP immunoreactivity in the absence of plaque-like deposits of A beta in the traumatized brain.

Amyloid beta-Peptides↗
PubMed1992

Immunotactoid-like endoneurial deposits in a patient with monoclonal gammopathy of undetermined significance and neuropathy.

An 85-year-old man with a 2-year history of progressive lower limb weakness and paresthesia was found to have an IgG kappa monoclonal gammopathy of undetermined significance (mgus). Clinical and electrophysiological studies revealed a severe distal bilateral symmetrical polyneuropathy. A sural nerve biopsy showed extensive nerve fibre loss with the deposition of large amounts of amorphous material throughout the endoneurium. Electron microscopy showed the deposits to be composed of microtubular structures which were located diffusely throughout the endoneurium. The deposits were also located within the lumina of the vasa nervorum, some of which were undergoing disintegration and rupture with release of the proteinaceous material into the endoneurium. The regions of the nerve in which they appeared most numerous showed more severe nerve fibre damage than other areas. These microtubular structures were also observed in disintegrating vessels and adjacent endoneurium. On immunohistochemistry they stained with antibody to IgG. Identical deposits were found in the dermis in which there was a leucocytoclastic vasculitis. Located in linear arrays within the axons of myelinated and unmyelinated fibres were highly organised tubular structures resembling immunotactoids. Identification of immunotactoid-like structures within the nerve is unique and may be another mechanism by which monoclonal proteins can induce nerve fibre injury.

Aged↗
PubMed2001

Glial cell and macrophage reactions in rat spinal ganglion after peripheral nerve lesions: an immunocytochemical and morphometric study.

Following peripheral nerve injury perineuronal satellite cell reaction in the corresponding spinal ganglion is observed. The mechanisms underlying the glial responses to axon injury remain unknown. In an immunocytochemical and morphometric study we investigated satellite cell and macrophage responses in the rat L4 and L5 dorsal root ganglia (DRG) during the seven days immediately after unilateral sciatic nerve crush or transection. Nerve lesion induced a significant increase of glial fibrillary acidic protein-immunoreactive (GFAP-IR) cells in the ipsilateral L4-L5 DRGs. The number of ED1-positive macrophages significantly increased as well. We found no significant differences between the increases provoked by the two types of nerve lesion, but the macrophage activation was detected earlier after nerve transection than after crush. No correlation was detected between satellite cells and macrophages reactions over the 7 day period we examined. These findings support the idea that intercellular neuron-glial diffusible signals play a major role in DRG glial cell response to peripheral nerve lesion.

Animals↗
PubMed2001

Grafting of encapsulated BDNF-producing fibroblasts into the injured spinal cord without immune suppression in adult rats.

Grafting of genetically modified cells that express therapeutic products is a promising strategy in spinal cord repair. We have previously grafted BDNF-producing fibroblasts (FB/BDNF) into injured spinal cord of adult rats, but survival of these cells requires a strict protocol of immune suppression with cyclosporin A (CsA). To develop a transplantation strategy without the detrimental effects of CsA, we studied the properties of FB/BDNF that were encapsulated in alginate-poly-L-ornithine, which possesses a semipermeable membrane that allows production and diffusion of a therapeutic product while protecting the cells from the host immune system. Our results show that encapsulated FB/BDNF, placed in culture, can survive, secrete bioactive BDNF and continue to grow for at least one month. Furthermore, encapsulated cells that have been stored in liquid nitrogen retain the ability to grow and express the transgene. Encapsulated FB/BDNF survive for at least one month after grafting into an adult rat cervical spinal cord injury site in the absence of immune suppression. Transgene expression decreased within two weeks after grafting but resumed when the cells were harvested and re-cultured, suggesting that soluble factors originating from the host immune response may contribute to the downregulation. In the presence of capsules that contained FB/BDNF, but not cell-free control capsules, there were many axons and dendrites at the grafting site. We conclude that alginate encapsulation of genetically modified cells may be an effective strategy for delivery of therapeutic products to the injured spinal cord and may provide a permissive environment for host axon growth in the absence of immune suppression.

Alginates↗