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1.  The Use of Fiber-Reinforced Scaffolds Cocultured with Schwann Cells and Vascular Endothelial Cells to Repair Rabbit Sciatic Nerve Defect with Vascularization 
BioMed Research International  2013;2013:362918.
To explore the feasibility of biodegradable fiber-reinforced 3D scaffolds with satisfactory mechanical properties for the repair of long-distance sciatic nerve defect in rabbits and effects of vascularized graft in early stage on the recovery of neurological function, Schwann cells and vascular endothelial cells were cocultured in the fiber-reinforced 3D scaffolds. Experiment group which used prevascularized nerve complex for the repair of sciatic nerve defect and control group which only cultured with Schwann cells were set. The animals in both groups underwent electromyography to show the status of the neurological function recovery at 4, 8, and 16 weeks after the surgery. Sciatic nerve regeneration and myelination were observed under the light microscope and electron microscope. Myelin sheath thickness, axonal diameter, and number of myelinated nerve fiber were quantitatively analyzed using image analysis system. The recovery of foot ulcer, the velocity of nerve conduction, the number of regenerating nerve fiber, and the recovery of ultrastructure were increased in the experimental group than those in the control group. Prevascularized tissue engineered fiber-reinforced 3D scaffolds for the repair of sciatic nerve defects in rabbits can effectively promote the recovery of neurological function.
doi:10.1155/2013/362918
PMCID: PMC3893804  PMID: 24490158
2.  Conserved Dopamine Neurotrophic Factor-Transduced Mesenchymal Stem Cells Promote Axon Regeneration and Functional Recovery of Injured Sciatic Nerve 
PLoS ONE  2014;9(10):e110993.
Peripheral nerve injury (PNI) is a common disease that often results in axonal degeneration and the loss of neurons, ultimately leading to limited nerve regeneration and severe functional impairment. Currently, there are no effective treatments for PNI. In the present study, we transduced conserved dopamine neurotrophic factor (CDNF) into mesenchymal stem cells (MSCs) in collagen tubes to investigate their regenerative effects on rat peripheral nerves in an in vivo transection model. Scanning electron microscopy of the collagen tubes demonstrated their ability to be resorbed in vivo. We observed notable overexpression of the CDNF protein in the distal sciatic nerve after application of CDNF-MSCs. Quantitative analysis of neurofilament 200 (NF200) and S100 immunohistochemistry showed significant enhancement of axonal and Schwann cell regeneration in the group receiving CDNF-MSCs (CDNF-MSCs group) compared with the control groups. Myelination thickness, axon diameter and the axon-to fiber diameter ratio (G-ratio) were significantly higher in the CDNF-MSCs group at 8 and 12 weeks after nerve transection surgery. After surgery, the sciatic functional index, target muscle weight, wet weight ratio of gastrocnemius muscle and horseradish peroxidase (HRP) tracing demonstrated functional recovery. Light and electron microscopy confirmed successful regeneration of the sciatic nerve. The greater numbers of HRP-labeled neuron cell bodies and increased sciatic nerve index values (SFI) in the CDNF-MSCs group suggest that CDNF exerts neuroprotective effects in vivo. We also observed higher target muscle weights and a significant improvement in muscle atrophism in the CDNF-MSCs group. Collectively, these findings indicate that CDNF gene therapy delivered by MSCs is capable of promoting nerve regeneration and functional recovery, likely because of the significant neuroprotective and neurotrophic effects of CDNF and the superior environment offered by MSCs and collagen tubes.
doi:10.1371/journal.pone.0110993
PMCID: PMC4208796  PMID: 25343619
3.  In Vivo Serial Imaging of Regenerating Corneal Nerves after Surgical Transection in Transgenic Thy1-YFP mice 
After surgical transection, corneal nerves regenerate to achieve normal density but do not readopt the normal arrangement. Myelinated nerve fibers also regenerate along with nociceptive nerve fibers in the central corneal stroma.
Purpose.
To determine the effect of lamellar transection surgery on the nerve fiber density (NFD) and pattern of nerve regeneration in the cornea of thy1-YFP transgenic mice.
Methods.
Wide-field stereo fluorescence microscopy was used to obtain serial images of nerves in live thy1-YFP mice, which express a fluorescent protein in their axons. NFD (mm/mm2) was calculated from maximum intensity projection images as the total length of fibers within the area of the contour in which nerves were traced. Whole-mount confocal microscopy was performed to analyze the arrangement of nerves and the types of regenerating fibers.
Results.
NFD in normal corneas was 35.3 ± 1.8 mm/mm2. Stereo fluorescence microscopy revealed the presence of a subbasal hairpin nerve layer and an intrastromal nerve trunk layer. After surgery, regenerative sprouting was observed from transected distal ends of intrastromal nerve trunks. NFD also increased, with this increase being maximal between 4 and 6 weeks after surgery. NFD approximated baseline values at 6 weeks and did not change any further at 8 weeks. Regenerated nerves did not readopt the normal corneal nerve arrangement. A dense interlacing network of regenerated nerves was present in the corneal bed. Branches from this network traversed the flap to innervate the epithelium. Immunofluorescence staining revealed that regenerating fronds contained peptidergic nociceptive fibers (positive for calcitonin gene-related peptide and substance P) and myelinated non-nociceptive fibers (positive for neurofilament 200).
Conclusions.
Although corneal NFD recovers to normal levels by 8 weeks after nerve transection, the arrangement of regenerated nerves is abnormal.
doi:10.1167/iovs.11-8332
PMCID: PMC3207999  PMID: 21896845
4.  Comparison of Morphometric Aspects of Light and Electron Microscopy of the Hypoglossal Nerve between Young and Aged Male Wistar Rats 
Cell Journal (Yakhteh)  2011;13(4):229-236.
Objective:
Age-related changes occur in many different systems of the body. Many elderly people show dysphagia and dysphonia. This research was conducted to evaluate quantitatively the morphometrical changes of the hypoglossal nerve resulting from the aging process in young and aged rats.
Materials and Methods:
Through an experimental study ten male wistar rats (4 months: 5 rats, 24 months: 5 rats) were selected randomly from a colony of wistars in the UWC. After a fixation process and preparation of samples of the cervical portion of the hypoglossal nerve of these rats, light and electron microscopic imaging were performed. These images were evaluated according to the numbers and size of myelinated nerve fibers, nucleoli of Schwann cells, myelin sheath thickness, axon diameter, and g ratio. All data were analyzed by Mann-Whitney, a non-parametric statistical test.
Results:
In light microscope, numbers of myelinated nerve fibers, the mean entire nerve perimeters, the mean entire nerve areas and the mean entire nerve diameters in young and aged rats' were not significantly different between the two groups.
In electron microscope, numbers of myelinated axons, numbers of Schwann cell nucleoli and the mean g ratios of myelinated axon to Schwann cell in young and aged rats were not significantly different. The myelinated fiber diameters, the myelin sheath thicknesses, myelinated axon diameters and the mean g ratio of axon diameter to myelinated fiber diameter in young and aged fibers were significantly different
Conclusion:
The mean g ratio of myelinated nerve fibers of peripheral nerves stabilizes at the level of 0.6 after maturation and persists without major change during adulthood. This ratio of axon diameter to fiber diameter (0.6) is optimum for normal conduction velocity of neural impulses. Our study indicated that the g ratio of myelinated nerve fiber of the hypoglossal nerve decreased prominently in aged rats and can be a cause of impairment in nerve function in old age. Thus, prospective studies concerning electrophysiological and conductive properties of the peripheral nerve could be useful to clarify further the effects of aging on peripheral nerves.
PMCID: PMC3584479  PMID: 23508137
Hypoglossal Nerve; Myelinated Nerve Fiber; Aging; Rat
5.  Beneficial effects of treadmill training in experimental diabetic nerve regeneration 
Clinics  2010;65(12):1329-1337.
OBJECTIVES:
We investigated the effects of treadmill training (10 weeks) on hindlimb motor function and nerve morphometric parameters in diabetic rats submitted to sciatic nerve crush.
MATERIALS AND METHOD:
Wistar rats (n = 64) were divided into the following groups: non-diabetic; trained non-diabetic; non-diabetic with sciatic nerve crush; trained non-diabetic with sciatic nerve crush; diabetic; trained diabetic; diabetic with sciatic nerve crush or trained diabetic with sciatic nerve crush. Diabetes was induced by streptozotocin injection (50 mg/kg, iv). Hindlimb motor function was evaluated weekly by assessing sciatic functional indices, and the proximal and distal portions of the sciatic nerve were used for morphometric analysis.
RESULTS:
At 13 weeks post-injury, the distal nerve portion of all injured groups and the proximal nerve portion of the diabetic with sciatic nerve crush group presented altered morphometric parameters such as decreased myelinated fiber diameter (∼7.4±0.3µm vs ∼4.8±0.2µm), axonal diameter (∼5±0.2µm vs ∼3.5±0.1µm) and myelin sheath thickness (∼1.2±0.07µm vs ∼0.65±0.07µm) and an increase in the percentage of area occupied by endoneurium (∼28±3% vs ∼60±3%). In addition, in the non-diabetic with sciatic nerve crush group the proximal nerve portion showed a decreased myelinated fiber diameter (7.4±0.3µm vs 5.8±0.3µm) and myelin sheath thickness (1.29±0.08µm vs 0.92±0.08µm). The non-diabetic with sciatic nerve crush, trained non-diabetic with sciatic nerve crush, diabetic with sciatic nerve crush and trained diabetic with sciatic nerve crush groups showed normal sciatic functional index from the 4th, 4th, 9th and 7th week post-injury, respectively. Morphometric alterations in the proximal nerve portion of the diabetic with sciatic nerve crush and non-diabetic with sciatic nerve crush groups were either prevented or reverted to values similar to the non-diabetic group by treadmill training.
CONCLUSION:
Diabetic condition promoted delay in sciatic nerve regeneration. Treadmill training is able to accelerate hindlimb motor function recovery in diabetic injured rats and prevent or revert morphometric alterations in proximal nerve portions in non-diabetic and diabetic injured rats.
doi:10.1590/S1807-59322010001200017
PMCID: PMC3020345  PMID: 21340223
Diabetes; Sciatic nerve crush; Motor function; Nerve morphometry; Treadmill training
6.  Effect of Delayed Peripheral Nerve Repair on Nerve Regeneration, Schwann Cell Function and Target Muscle Recovery 
PLoS ONE  2013;8(2):e56484.
Despite advances in surgical techniques for peripheral nerve repair, functional restitution remains incomplete. The timing of surgery is one factor influencing the extent of recovery but it is not yet clearly defined how long a delay may be tolerated before repair becomes futile. In this study, rats underwent sciatic nerve transection before immediate (0) or 1, 3, or 6 months delayed repair with a nerve graft. Regeneration of spinal motoneurons, 13 weeks after nerve repair, was assessed using retrograde labeling. Nerve tissue was also collected from the proximal and distal stumps and from the nerve graft, together with the medial gastrocnemius (MG) muscles. A dramatic decline in the number of regenerating motoneurons and myelinated axons in the distal nerve stump was observed in the 3- and 6-months delayed groups. After 3 months delay, the axonal number in the proximal stump increased 2–3 folds, accompanied by a smaller axonal area. RT-PCR of distal nerve segments revealed a decline in Schwann cells (SC) markers, most notably in the 3 and 6 month delayed repair samples. There was also a progressive increase in fibrosis and proteoglycan scar markers in the distal nerve with increased delayed repair time. The yield of SC isolated from the distal nerve segments progressively fell with increased delay in repair time but cultured SC from all groups proliferated at similar rates. MG muscle at 3- and 6-months delay repair showed a significant decline in weight (61% and 27% compared with contra-lateral side). Muscle fiber atrophy and changes to neuromuscular junctions were observed with increased delayed repair time suggestive of progressively impaired reinnervation. This study demonstrates that one of the main limiting factors for nerve regeneration after delayed repair is the distal stump. The critical time point after which the outcome of regeneration becomes too poor appears to be 3-months.
doi:10.1371/journal.pone.0056484
PMCID: PMC3567071  PMID: 23409189
7.  Tacrolimus reduces scar formation and promotes sciatic nerve regeneration☆ 
Neural Regeneration Research  2012;7(32):2500-2506.
A sciatic nerve transection and repair model was established in Sprague-Dawley rats by transecting the tendon of obturator internus muscle in the greater sciatic foramen and suturing with nylon sutures. The models were treated with tacrolimus gavage (4 mg/kg per day) for 0, 2, 4 and 6 weeks. Specimens were harvested at 6 weeks of intragastric administration. Masson staining revealed that the collagen fiber content and scar area in the nerve anastomosis of the sciatic nerve injury rats were significantly reduced after tacrolimus administration. Hematoxylin-eosin staining showed that tacrolimus significantly increased myelinated nerve fiber density, average axon diameter and myelin sheath thickness. Intragastric administration of tacrolimus also led to a significant increase in the recovery rate of gastrocnemius muscle wet weight and the sciatic functional index after sciatic nerve injury. The above indices were most significantly improved at 6 weeks after of tacrolimus gavage. The myelinated nerve fiber density in the nerve anastomosis and the sciatic nerve functions had a significant negative correlation with the scar area, as detected by Spearman’s rank correlation analysis. These findings indicate that tacrolimus can promote peripheral nerve regeneration and accelerate the recovery of neurological function through the reduction of scar formation.
doi:10.3969/j.issn.1673-5374.2012.32.003
PMCID: PMC4200705  PMID: 25337101
tacrolimus; scar; myelinated nerve fiber; sciatic nerve; peripheral nerve injury; neural regeneration; neurological function
8.  Impaired Prosaposin Secretion During Nerve Regeneration in Diabetic Rats and Protection of Nerve Regeneration by a Prosaposin-Derived Peptide 
Prosaposin is both a precursor of sphingolipid activator proteins and a secreted neurotrophic and myelinotrophic factor. Because peripheral nerve regeneration is impaired in diabetes mellitus, we measured prosaposin protein levels from control and streptozotocin-diabetic rats by collecting endoneurial fluid secreted into a bridging tube connecting the ends of transected sciatic nerve. Prosaposin protein levels were significantly reduced in endoneurial fluid from diabetic rats and increased in the proximal nerve stump compared to controls. To investigate whether a prosaposin-derived peptide could improve nerve regeneration, rats were treated with prosaptide TX14(A) following sciatic nerve crush. In control rats, TX14(A) was without effect in the uninjured nerve but shortened toe spread recovery time after nerve crush. In diabetic rats, efficacy of prosaptide TX14(A) was confirmed by correction of thermal hypoalgesia, formalin-evoked hyperalgesia and conduction slowing in the uninjured nerve. The peptide also prevented diabetes-induced abnormalities in nerve regeneration distance and mean axonal diameter of regenerated axons, whereas delayed recovery of toe spread was not improved. Muscle denervation atrophy was attenuated by TX14(A) in both control and diabetic rats. These results suggest that reduced prosaposin secretion after nerve injury may contribute to impaired regeneration rates in diabetic rats and that prosaptide TX14(A) can improve aspects of nerve regeneration.
doi:10.1097/NEN.0b013e31817e23f4
PMCID: PMC2748883  PMID: 18596543
Diabetes; Nerve regeneration; Prosaposin; Prosaptide TX14(A)
9.  AVIAN THIAMIN DEFICIENCY  
A correlation of the histopathology and clinical behavior of thiamin deficient pigeons has been undertaken. Opisthotonus in acutely deficient pigeons was frequently attended by no degenerating nerve fibers or neurons in either the central or peripheral nervous systems. When the deficiency was complicated by starvation, it developed more slowly, opisthotonus appeared later, and many degenerating nerve fibers were usually present. In both instances the opisthotonus disappeared in a very short time after thiamin was injected intramuscularly. A more chronic deficiency, characterized by leg weakness (opisthotonus being absent) appeared when the ration was partially deficient in thiamin, or occasionally when the caloric intake was grossly inadequate. In birds of this type degenerating nerve fibers were always found in the peripheral nerves. The number of such fibers in the sciatic nerves corresponded closely with the degree of paralysis, and during repair which occurred when thiamin (irrespective of other factors) was added to the ration, nerve fibers regenerated (increased in number) at a rate which paralleled the clinical improvement closely. The large and long nerve fibers, many of which could be traced directly into the dorsal ganglia, degenerated first, and if the deficiency were prolonged, smaller nerve fibers became affected as well. In many of these pigeons with marked leg weakness, cell bodies in the dorsal ganglia exhibited lysis of chromatin and eccentricity of their nuclei. This was observed nowhere else in the nervous system. During repair and until after the paralysis had been recovered from completely, these phenomena (chromatolysis) persisted. In chronically thiamin deficient pigeons large and long degenerating nerve fibers were found in two regions of the spinal cord at all levels. One group of these in the ventral funiculus was thought to arise in the reticular region of the medulla oblongata, and the other which was situated in the posterior part of the lateral funiculus could be followed to the lateral surface of the medulla oblongata, and from there by way of the inferior cerebellar peduncles into the medullary portion of the cerebellum. In the central as well as the peripheral nervous system the long and large nerve fibers degenerated first. Medium and small sized fibers were affected later and the degeneration became quite generalized. In many of the chronically deficient pigeons with leg weakness, incidental postmortem findings compatible with cardiac failure were encountered. In the hearts from many of these pigeons, microscopic examination revealed many areas of focal necrosis, some of which had become infiltrated with polymorphonuclear leucocytes. In a peripheral neuron of a thiamin deficient pigeon the first consistent morphological alteration appeared in the axis cylinder. No doubt a period of functional impairment of the neuron (such as produced opisthotonus) preceded this. The axis cylinder followed by the myelin sheath degenerated at a point most distal to its trophic cell body. This process of disintegration proceeded toward the trophic cell body for a variable distance, depending upon the severity and duration of the deficiency. The cell body (in a dorsal ganglion) appeared to shrink first and later exhibited chromatolysis. When thiamin was administered the axis cylinder (and myelin sheath) regenerated, and when this was complete, the cell body returned to normal. It has been concluded that the opisthotonus of thiamin deficiency is a manifestation of decerebration due to a functional impairment of the neurons which have an inhibitory influence upon the lower brain stem centers. Leg weakness (when produced by the same deficiency) is due to degeneration of peripheral nerve fibers within the sciatic nerve. Heart failure may be attended by no visible histological changes, but in many instances necrosis of myocardial fibers occurs.
PMCID: PMC2135092  PMID: 19870991
10.  Use new PLGL-RGD-NGF nerve conduits for promoting peripheral nerve regeneration 
Background
Nerve conduits provide a promising strategy for peripheral nerve injury repair. However, the efficiency of nerve conduits to enhance nerve regeneration and functional recovery is often inferior to that of autografts. Nerve conduits require additional factors such as cell adhesion molecules and neurotrophic factors to provide a more conducive microenvironment for nerve regeneration.
Methods
In the present study, poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} (PLGL) was modified by grafting Gly-Arg-Gly-Asp-Gly (RGD peptide) and nerve growth factor (NGF) for fabricating new PLGL-RGD-NGF nerve conduits to promote nerve regeneration and functional recovery. PLGL-RGD-NGF nerve conduits were tested in the rat sciatic nerve transection model. Rat sciatic nerves were cut off to form a 10 mm defect and repaired with the nerve conduits. All of the 32 Wistar rats were randomly divided into 4 groups: group PLGL-RGD-NGF, group PLGL-RGD, group PLGL and group autograft. At 3 months after surgery, the regenerated rat sciatic nerve was evaluated by footprint analysis, electrophysiology, and histologic assessment. Experimental data were processed using the statistical software SPSS 10.0.
Results
The sciatic function index value of groups PLGL-RGD-NGF and autograft was significantly higher than those of groups PLGL-RGD and PLGL. The nerve conduction velocities of groups PLGL-RGD-NGF and autograft were significantly faster than those of groups PLGL-RGD and PLGL. The regenerated nerves of groups PLGL-RGD-NGF and autograft were more mature than those of groups PLGL-RGD and PLGL. There was no significant difference between groups PLGL-RGD-NGF and autograft.
Conclusions
PLGL-RGD-NGF nerve conduits are more effective in regenerating nerves than both PLGL-RGD nerve conduits and PLGL nerve conduits. The effect is as good as that of an autograft. This work established the platform for further development of the use of PLGL-RGD-NGF nerve conduits for clinical nerve repair.
doi:10.1186/1475-925X-11-36
PMCID: PMC3465232  PMID: 22776032
RGD peptide; Nerve growth factor; Peripheral nerve; Nerve conduits; Nerve regeneration
11.  PROPERTIES OF DORSAL ROOT UNMEDULLATED FIBERS ON THE TWO SIDES OF THE GANGLION 
The Journal of General Physiology  1955;38(5):709-728.
As an aid in the interpretation of the physiological properties of unmedullated nerve fibers, particularly those having their cells of origin in the dorsal root ganglia, more precise information about their morphology has been acquired through employment of the electron microscope. The appearance of the fibers in the skin nerves is described, with special reference to the structure of their sheaths; and a notation is made about the bearing of the axon-sheath relationship on the biophysical mechanism of conduction (p. 714). There is no basic difference between the sheath systems of the d.r.C and the s.C fibers. Attention is called to a point of similarity between the sheaths of unmyelinated and myelinated axons (p. 715). An assessment was made of the likelihood of interaction between the fibers. In action potentials showing temporal dispersion at several distances, the elevations appeared in their calculated positions. A model of a group of Schwann sheaths was constructed from successive electron microscope sections, showing that the lengths of the sheath branches are short in comparison with the wave lengths of the action potentials. Supported by these and other considerations, the argument is strongly in favor of the conclusion that among d.r.C fibers, as in other fibers, there is no cross-excitation between the axons. A new analysis of the size distribution of the fibers in a sural nerve was made from electron microscope pictures; and from the measurements the action potential was constructed. The result confirmed the view, previously expressed, that the velocities of conduction in the fibers can be precisely accounted for by multiplying the diameters by a constant. In the dorsal roots, the striking change that takes place in the appearance of the fibers and their disposition in the Schwann sheaths can be seen in Fig. 11. The axons partake of the special properties of the peripheral branches, which necessitated the creation of the subdivision of d.r.C fibers. But, their diameters are much smaller. At a set of reduced conduction velocities the configuration of the compound action potential in the nerves is repeated in the roots, with the root velocities still conforming to the size-velocity rule derived from nerve axons.
PMCID: PMC2147503  PMID: 14367780
12.  Electrical Stimulation Promotes Regeneration of Defective Peripheral Nerves after Delayed Repair Intervals Lasting under One Month 
PLoS ONE  2014;9(9):e105045.
Background
Electrical stimulation (ES) has been proven to be an effective means of enhancing the speed and accuracy of nerve regeneration. However, these results were recorded when the procedure was performed almost immediately after nerve injury. In clinical settings, most patients cannot be treated immediately. Some patients with serious trauma or contaminated wounds need to wait for nerve repair surgery. Delays in nerve repair have been shown to be associated with poorer results than immediate surgery. It is not clear whether electrical stimulation still has any effect on nerve regeneration after enough time has elapsed.
Methods
A delayed nerve repair model in which the rats received delayed nerve repair after 1 day, 1 week, 1 month, and 2 months was designed. At each point in time, the nerve stumps of half the rats were bridged with an absorbable conduit and the rats were given 1 h of weak electrical stimulation. The other half was not treated. In order to analyze the morphological and molecular differences among these groups, 6 ES rats and 6 sham ES rats per point in time were killed 5 days after surgery. The other rats in each group were allowed to recover for 6 weeks before the final functional test and tissue observation.
Results
The amounts of myelinated fibers in the distal nerve stumps decreased as the delay in repair increased for both ES rats and sham ES rats. In the 1-day-delay and 1-week-delay groups, there were more fibers in ES rats than in sham ES rats. And the compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) results were better for ES rats in these two groups. In order to analyze the mechanisms underlying these differences, Masson staining was performed on the distal nerves and quantitative PCR on the spinal cords. Results showed that, after delays in repair of 1 month and 2 months, there was more collagen tissue hyperplasia in the distal nerve in all rats. The brain-derived neurotrophic factor (BDNF) and trkB expression levels in the spinal cords of ES rats were higher than in sham ES rats. However, these differences decreased as the delay in repair increased.
Conclusions
Electrical stimulation does not continue to promote nerve regeneration after long delays in nerve repair. The effective interval for nerve regeneration after delayed repair was found to be less than 1 month. The mechanism seemed to be related to the expression of nerve growth factors and regeneration environment in the distal nerves.
doi:10.1371/journal.pone.0105045
PMCID: PMC4152131  PMID: 25181499
13.  Immunoelectron microscopic localization of neural cell adhesion molecules (L1, N-CAM, and myelin-associated glycoprotein) in regenerating adult mouse sciatic nerve 
The Journal of Cell Biology  1988;106(5):1735-1746.
The localization of the neural cell adhesion molecules L1, N-CAM, and the myelin-associated glycoprotein was studied by pre- and postembedding staining procedures at the light and electron microscopic levels in transected and crushed adult mouse sciatic nerve. During the first 2-6 d after transection, myelinated and nonmyelinated axons degenerated in the distal part of the proximal stump close to the transection site and over the entire length of the distal part of the transected nerve. During this time, regrowing axons were seen only in the proximal, but not in the distal nerve stump. In most cases L1 and N- CAM remained detectable at cell contacts between nonmyelinating Schwann cells and degenerating axons as long as these were still morphologically intact. Similarly, myelin-associated glycoprotein remained detectable in the periaxonal area of the degenerating myelinated axons. During and after degeneration of axons, nonmyelinating Schwann cells formed slender processes which were L1 and N-CAM positive. They resembled small-diameter axons but could be unequivocally identified as Schwann cells by chronical denervation. Unlike the nonmyelinating Schwann cells, only few myelinating ones expressed L1 and N-CAM. At the cut ends of the nerve stumps a cap developed (more at the proximal than at the distal stump) that contained S-100-negative and fibronectin-positive fibroblast-like cells. Most of these cells were N-CAM positive but always L1 negative. Growth cones and regrowing axons expressed N-CAM and L1 at contact sites with these cells. Regrowing axons of small diameter were L1 and N- CAM positive where they made contact with each other or with Schwann cells, while large-diameter axons were only poorly antigen positive or completely negative. 14 d after transection, when regrowing axons were seen in the distal part of the transected nerve, regrowing axons made L1- and N-CAM-positive contacts with Schwann cells. When contacting basement membrane, axons were rarely found to express L1 and N-CAM. Most, if not all, Schwann cells associated with degenerating myelin expressed L1 and N-CAM. In crushed nerves, the immunostaining pattern was essentially the same as in the cut nerve. During formation of myelin, the sequence of adhesion molecule expression was the same as during development: L1 disappeared and N-CAM was reduced on myelinating Schwann cells and axons after the Schwann cell process had turned approximately 1.5 loops around the axon. Myelin-associated glycoprotein then appeared both periaxonally and on the turning loops of Schwann cells in the uncompacted myelin.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC2115039  PMID: 2453520
14.  Effect of Modified Formula Radix Hedysari on the Amplification Effect during Peripheral Nerve Regeneration 
Many studies have demonstrated a compensatory amplification phenomenon during nerve regeneration. When a relatively fine nerve is used as a donor to connect to a distal nerve after transection, the donor nerve regenerates more collaterals than its own fibers, which extend to the distal stump, grow into distal endoneurial tubes, and finally reach and dominate the target organs. This is known as the amplification phenomenon. In this study, we investigated the amplification phenomenon in rats treated with Modified Formula Radix Hedysari (MFRH) as adjuvant therapy for 12 weeks. The rats were divided into three groups at random (six animals in each group). In the model group and the treatment group, the proximal common peroneal nerve was used as a donor nerve to connect to the distal tibial nerve. Rats in the normal group did not undergo surgery. After surgery, the treatment group was administered MFRH as systemic therapy, while the model group and the normal group were not given treatment. The results demonstrated that the nerve conduction velocity, the fiber diameter, the axon diameter, the number of regenerating nerve fibers, and the amplification ratio were better in the treatment group than in the model group, suggesting that MFRH promoted the nerve amplification effect.
doi:10.1155/2013/647982
PMCID: PMC3595679  PMID: 23533510
15.  High-Frequency Electrical Stimulation Can Be a Complementary Therapy to Promote Nerve Regeneration in Diabetic Rats 
PLoS ONE  2013;8(11):e79078.
The purpose of this study was to evaluate whether 1 mA of percutaneous electrical stimulation (ES) at 0, 2, 20, or 200 Hz augments regeneration between the proximal and distal nerve stumps in streptozotocin diabetic rats. A10-mm gap was made in the diabetic rat sciatic nerve by suturing the stumps into silicone rubber tubes. Normal animals were used as the controls. Starting 1 week after transection, ES was applied between the cathode placed at the distal stump and the anode at the proximal stump every other day for 3 weeks. At 4 weeks after surgery, the normal controls and the groups receiving ES at 20, and 200 Hz had a higher success percentage of regeneration compared to the ES groups at 0 and 2 Hz. In addition, quantitative histology of the successfully regenerated nerves revealed that the groups receiving ES at a higher frequency, especially at 200 Hz, had a more mature structure with more myelinated fibers compared to those in the lower-frequency ES groups. Similarly, electrophysiology in the ES group at 200 Hz showed significantly shorter latency, larger amplitude, larger area of evoked muscle action potentials and faster conduction velocity compared to other groups. Immunohistochemical staining showed that ES at a higher frequency could significantly promote calcitonin gene-related peptide expression in lamina I-II regions in the dorsal horn and recruit a higher number of macrophages in the diabetic distal sciatic nerve. The macrophages were found that they could stimulate the secretion of nerve growth factor, platelet-derived growth factor, and transforming growth factor-β in dissected sciatic nerve segments. The ES at a higher frequency could also increase cutaneous blood flow in the ipsilateral hindpaw to the injury. These results indicated that a high-frequency ES could be necessary to heal severed diabetic peripheral nerve with a long gap to be repaired.
doi:10.1371/journal.pone.0079078
PMCID: PMC3827114  PMID: 24265744
16.  Use of Natural Neural Scaffolds Consisting of Engineered Vascular Endothelial Growth Factor Immobilized on Ordered Collagen Fibers Filled in a Collagen Tube for Peripheral Nerve Regeneration in Rats 
The search for effective strategies for peripheral nerve regeneration has attracted much attention in recent years. In this study, ordered collagen fibers were used as intraluminal fibers after nerve injury in rats. Vascular endothelial growth factor (VEGF) plays an important role in nerve regeneration, but its very fast initial burst of activity within a short time has largely limited its clinical use. For the stable binding of VEGF to ordered collagen fibers, we fused a collagen-binding domain (CBD) to VEGF through recombinant DNA technology. Then, we filled the ordered collagen fibers-CBD-VEGF targeting delivery system in a collagen tube to construct natural neural scaffolds, which were then used to bridge transected nerve stumps in a rat sciatic nerve transection model. After transplantation, the natural neural scaffolds showed minimal foreign body reactions and good integration into the host tissue. Oriented collagen fibers in the collagen tube could guide regenerating axons in an oriented manner to the distal, degenerating nerve segment, maximizing the chance of target reinnervation. Functional and histological analyses indicated that the recovery of nerve function in the natural neural scaffolds-treated group was superior to the other grafted groups. The guiding of oriented axonal regeneration and effective delivery systems surmounting the otherwise rapid and short-lived diffusion of growth factors in body fluids are two important strategies in promoting peripheral nerve regeneration. The natural neural scaffolds described take advantage of these two aspects and may produce synergistic effects. These properties qualified the artificial nerve conduits as a putative candidate system for the fabrication of peripheral nerve reconstruction devices.
doi:10.3390/ijms151018593
PMCID: PMC4227234  PMID: 25322152
engineered vascular endothelial growth factor (VEGF); natural neural scaffolds; biodebradable materials; peripheral nerve regeneration
17.  A simple model of radial nerve injury in the rhesus monkey to evaluate peripheral nerve repair 
Neural Regeneration Research  2014;9(10):1041-1046.
Current research on bone marrow stem cell transplantation and autologous or xenogenic nerve transplantation for peripheral nerve regeneration has mainly focused on the repair of peripheral nerve defects in rodents. In this study, we established a standardized experimental model of radial nerve defects in primates and evaluated the effect of repair on peripheral nerve injury. We repaired 2.5-cm lesions in the radial nerve of rhesus monkeys by transplantation of autografts, acellular allografts, or acellular allografts seeded with autologous bone marrow stem cells. Five months after surgery, regenerated nerve tissue was assessed for function, electrophysiology, and histomorphometry. Postoperative functional recovery was evaluated by the wrist-extension test. Compared with the simple autografts, the acellular allografts and allografts seeded with bone marrow stem cells facilitated remarkable recovery of the wrist-extension functions in the rhesus monkeys. This functional improvement was coupled with radial nerve distal axon growth, a higher percentage of neuron survival, increased nerve fiber density and diameter, increased myelin sheath thickness, and increased nerve conduction velocities and peak amplitudes of compound motor action potentials. Furthermore, the quality of nerve regeneration in the bone marrow stem cells-laden allografts group was comparable to that achieved with autografts. The wrist-extension test is a simple behavioral method for objective quantification of peripheral nerve regeneration.
doi:10.4103/1673-5374.133166
PMCID: PMC4146303  PMID: 25206757
nerve regeneration; peripheral nerve injury; rhesus monkeys; bone marrow stem cells; allogeneic nerve; transplantation; wrist-extension test; electrophysiology; neurological function; NSFC grant; neural regeneration
18.  Combination of Acellular Nerve Graft and Schwann Cells-Like Cells for Rat Sciatic Nerve Regeneration 
Neural Plasticity  2014;2014:139085.
Objective. To investigate the effect of tissue engineering nerve on repair of rat sciatic nerve defect. Methods. Forty-five rats with defective sciatic nerve were randomly divided into three groups. Rats in group A were repaired by acellular nerve grafts only. Rats in group B were repaired by tissue engineering nerve. In group C, rats were repaired by autogenous nerve grafts. After six and twelve weeks, sciatic nerve functional index (SFI), neural electrophysiology (NEP), histological and transmission electron microscope observation, recovery ratio of wet weight of gastrocnemius muscle, regenerated myelinated nerve fibers number, nerve fiber diameter, and thickness of the myelin sheath were measured to assess the effect. Results. After six and twelve weeks, the recovery ratio of SFI and wet weight of gastrocnemius muscle, NEP, and the result of regenerated myelinated nerve fibers in groups B and C were superior to that of group A (P < 0.05), and the difference between groups B and C was not statistically significant (P > 0.05). Conclusion. The tissue engineering nerve composed of acellular allogenic nerve scaffold and Schwann cells-like cells can effectively repair the nerve defect in rats and its effect was similar to that of the autogenous nerve grafts.
doi:10.1155/2014/139085
PMCID: PMC4120921  PMID: 25114806
19.  Effect of limb lengthening on internodal length and conduction velocity of peripheral nerve 
The influences of axon diameter, myelin thickness and internodal length on the velocity of conduction of peripheral nerve action potentials are unclear. Previous studies have demonstrated a strong dependence of conduction velocity on internodal length. However, a theoretical analysis has suggested that this relationship may be lost above a nodal separation of about 0.6 mm. Here we measured nerve conduction velocities in a rabbit model of limb lengthening that produced compensatory increases in peripheral nerve growth. Divided tibial bones in one hind limb were gradually lengthened at 0.7 mm per day using an external frame attached to the bone. This was associated with a significant increase (33%) of internodal length (0.95 to 1.3 mm) in axons of the tibial nerve that varied in proportion to the mechanical strain in the nerve of the lengthened limb. Axonal diameter, myelin thickness and g-ratios were not significantly altered by limb-lengthening. Despite the substantial increase in internodal length, no significant change was detected in conduction velocity (about 43 ms-1) measured either in vivo or in isolated tibial nerves. The results demonstrate that the internode remains plastic in the adult but that increases in internodal length of myelinated adult nerve axons do not result in either deficiency or proportionate increases in their conduction velocity and supports the view that the internodal lengths of nerves reach a plateau beyond which their conduction velocities are no longer sensitive to increases in internodal length.
doi:10.1523/JNEUROSCI.4176-12.2013
PMCID: PMC4335134  PMID: 23467369
20.  “Supercharge Nerve Transfer to Enhance Motor Recovery, a Laboratory Study” 
The Journal of hand surgery  2013;38(3):466-477.
Purpose
To investigate the ability of a supercharge end-to-side (SETS) nerve transfer to augment the effect of regenerating native axons in an incomplete rodent sciatic nerve injury model.
Methods
Fifty-four Lewis rats were randomized to 3 groups. The first group was an incomplete recovery model (IRM) of the tibial nerve complemented with a SETS transfer from the peroneal nerve (SETS-IRM). The IRM consisted of tibial nerve transection and immediate repair using a 10mm fresh tibial isograft to provide some, but incomplete, nerve recovery. The 2 control groups were IRM alone and SETS alone.
Nerve histomorphometry, electron microscopy, retrograde labeling, and muscle force testing were performed.
Results
Histomorphometry of the distal tibial nerve showed significantly increased myelinated axonal counts in the SETS-IRM group compared to the IRM and SETS groups at 5 and 8 weeks. Retrograde labeling at 8 weeks confirmed increased motoneuron counts in the SETS-IRM group. Functional recovery at 8 weeks showed a significant increase in muscle specific force in the SETS-IRM group compared to the IRM group.
Conclusions
A SETS transfer enhanced recovery from an incomplete nerve injury as determined by histomorphometry, motoneuron labeling within the spinal cord, and muscle force measurements.
Clinical Relevance
A SETS distal nerve transfer may be useful in nerve injuries with incomplete regeneration such as proximal Sunderland II or III degree injuries, where long regeneration distance yields prolonged time to muscle reinnervation and suboptimal functional recovery.
doi:10.1016/j.jhsa.2012.12.020
PMCID: PMC3583195  PMID: 23391355
Nerve regeneration; nerve transfer; neurorrhaphy; peripheral nerve; supercharge end-to-side
21.  EQUILIBRIA OF FROG NERVE WITH DIFFERENT EXTERNAL CONCENTRATIONS OF SODIUM IONS 
The Journal of General Physiology  1951;35(1):145-182.
Using the ability of the nerve fibers to conduct impulses as indicator of changes in the concentration of sodium ions in the interstitial spaces of nerve an evaluation has been made of the diffusion constant of sodium ions. The calculated minimal value (0.62 x 10–4 cm.2/min.) undoubtedly is much too low; nevertheless, it is still so high that as a rule the diffusion of sodium ions is far more rapid than the establishment of excitability changes; therefore, diffusion times need not be taken into account in the interpretation of ordinary experiments. By measurements of the changes in the longitudinal conductivity of nerve which result from changes in the external concentration of sodium chloride an evaluation has been made of the diffusion constant of sodium chloride in the interstitial spaces of nerve. A minimal value for this constant is 1.4 x 10–4 cm.2/min. The evidence presented would be compatible with the assumption that the permeability of the connective tissue sheath for sodium ions decreases slightly after the concentration of sodium ions in the interstitial spaces of the nerve has become negligible; the evidence, however, shows that changes in the permeability of the sheath cannot play a significant role in determining the temporal courses of the development of inexcitability in a sodium-free medium and of the restoration of excitability by added sodium ions. If a decrease in the permeability of the sheath should take place in a sodium-free medium, the change would be small and would occur after the nerve fibers have become inexcitable; on the other hand the action of a moderate concentration of sodium ions would be sufficient to restore the permeability of the sheath. As measured by the recovery by A fibers of the ability to conduct impulses the restoration by 0.1 N sodium ions of nerve that has been deprived of sodium for 15 to 20 hours, i.e. for several hours after the nerve fibers have become inexcitable, begins after a significant delay, since no A fiber begins to conduct impulses in less than 8 or 10 minutes. The delay is referable to the fact that, before the A fibers can regain the ability to conduct impulses, those changes in their properties have to be reversed, which have taken place in the absence of sodium ions. Usually within 1 minute after sodium ions are made available to the nerve the polarizability of the membrane by the anodal current begins to increase; the A fibers soon begin to produce unconducted impulses in response to the break of the anodal current; then, they produce unconducted impulses in response to the closure of the cathodal current, and finally they become able to conduct impulses, although at a markedly reduced speed. The C fibers, that become inexcitable in a sodium-free medium later than the A fibers, begin to conduct impulses within 1 minute or 2 after 0.1 N sodium ions are made available to the nerve. Treatment of a nerve, that has been kept in a sodium-free medium, for 15 to 20 hours, with a moderate concentration of sodium ions (0.015, 0.02 N), acting for 1 hour or 2, is not sufficient to restore the ability to conduct impulses to more than a few A fibers, but it produces in a relatively large number of fibers a partial restoration, so that when the concentration of sodium ions outside the epineurium is increased by 0.005 or 0.01 N a significant number of A fibers begin to conduct impulses within less than 5 seconds. Initially the recovery progresses with great rapidity, but after a small number of minutes the height of the conducted spike remains practically stationary. Increase of the external concentration of sodium ions by a small amount again causes a rapid enhancement of the recovery, but once more, after a few minutes the height of the spike remains practically stationary, etc. A subnormal concentration of sodium ions may restore to all the A fibers the ability to conduct impulses, but only 0.1 N sodium ions are able to produce a complete restoration of the speed of conduction, and only after they have been allowed to act for a considerable period of time. The ability of all the C fibers to conduct impulses may be restored by relatively small concentrations of sodium ions, 0.02 to 0.025 N. Nerve fibers that have become inexcitable in a sodium-free medium and have been restored by sodium ions are far more sensitive to the effect of the lack of sodium than the fibers of untreated nerve. Repeated removal and addition of sodium ions may bring the nerve fibers, especially those of spinal roots, to a state in which the sensitivity to the lack of sodium is exceedingly great; spinal root fibers may then begin to become inexcitable in a sodium-free medium within a few seconds. Treatment of the nerve with 0.1 N sodium ions for 1 hour or 2 is sufficient to bring about a marked increase in the resistance to the lack of sodium. On the other hand keeping a nerve in Ringer's solution or in the presence of 0.04 N sodium ions does not produce a readily detectable increase in the sensitivity to the lack of sodium. Even the resistance of nerve kept in the presence of 0.025 N sodium ions for 23 hours is very high, since after 2 hours in a sodium-free medium more than two-thirds of the initially conducting fibers will be able to conduct impulses. Frog nerve reaches different states of equilibrium with different external concentrations of sodium ions. The states are characterized by the degree of effectiveness of the nerve reaction, the speed of conduction of impulses, and the number of conducting fibers. Approximately the same equilibrium state may be reached by (a) leaving the nerve for 20 to 24 hours in the presence of a subnormal concentration of sodium ions and (b) by leaving the nerve in a sodium-free medium for 15 to 20 hours, restoring it with 0.1 N sodium ions acting for a short period of time, rendering it inexcitable again in a sodium-free medium, and finally restoring it with a moderate concentration of sodium ions. If, however, the nerve that has been kept in a sodium-free medium for 15 to 20 hours is restored directly by a moderate concentration of sodium ions the state will not be reached, at least not for several hours, which corresponds to equilibrium with that concentration. The role of sodium in nerve physiology is discussed. Sodium participates in at least four processes, (a) The regulation of the concentration of water outside the nerve fibers; (b) the regulation of the total value of the membrane potential; (c) the production of the nerve impulse, and (d) the establishment of the nerve reaction. In so far as processes (c) and (d) are concerned only the sodium present inside the nerve fibers plays a role; the presence of sodium ions outside the nerve fibers is important only because in the absence of interstitial sodium ions the nerve fibers lose a part of their internal sodium content. The nerve impulse and the nerve reaction may be produced for long periods of time after the concentration of sodium ions outside the nerve fibers has become negligible. A working hypothesis is put forward according to which the internal sodium content and the interstitial concentration of sodium ions are in equilibrium in so far as a different internal sodium content corresponds to each interstitial concentration. The properties of the nerve fibers are determined by the internal sodium content. The change in properties, i.e. in the state of the nerve fibers, results from processes that take place inside the nerve fibers after the interstitial concentration of sodium ions and consequently also the internal sodium content have been changed.
PMCID: PMC2147304  PMID: 14873926
22.  Chemical and structural changes of neurofilaments in transected rat sciatic nerve 
The Journal of Cell Biology  1978;78(2):369-378.
The sequence of changes occurring in transected rat sciatic nerve was examined by electron microscopy and by sodium dodecyl sulfate (SDS) polyacrylamide disc gel electrophoresis. Representative segments of transected nerves were processed for ultrastructural examinations between 0 and 34 days after the transection of sciatic nerves immediately below the sacro-sciatic notch. The remainder of the transected nerves and the intact portions of sciatic nerves were desheathed and immediately homogenized in 1 percent SDS containing 8 M urea and 50 mM dithioerythritol. Solubilized proteins were analyzed on 12 percent gels at pH 8.3 in a discontinuous electrophoretic system. Initial changes were limited to the axons of transected nerve fibers and were characterized by the loss of microtubules and neurofilaments and their replacement by an amorphous floccular material. These changes became widespread between 24 and 48 h after transection. The disruption of neurofilaments during this interval occurred in parallel with a selective loss of 69,000, 150,000 and 200,000 mol wt proteins from nerve homogenates, thus corroborating the view that these proteins represent component subunits of mammalian neurofilaments. Furthermore, the selective changes of neurofilament proteins in transected nerves indicate their inherent lability and suggest their susceptibility to calcium-mediated alterations. Electrophoretic profiles of nerve proteins during the 4-34-day interval after nerve transection reflected the breakdown and removal of myelin, the proliferation of Schwann cells and the deposition of endoneurial collagen. A marked increase of intermediate-sized filaments within proliferating Schwann cell processes was not accompanied by the appearance of neurofilamentlike proteins in gels of nerve homogenates.
PMCID: PMC2110124  PMID: 690171
23.  Altered expression of neuronal cell adhesion molecules induced by nerve injury and repair 
The Journal of Cell Biology  1986;103(3):929-945.
Peripheral nerve injury results in short-term and long-term changes in both neurons and glia. In the present study, immunohistological and immunoblot analyses were used to examine the expression of the neural cell adhesion molecule (N-CAM) and the neuron-glia cell adhesion molecule (Ng-CAM) within different parts of a functionally linked neuromuscular system extending from skeletal muscle to the spinal cord after peripheral nerve injury. Histological samples were taken from 3 to 150 d after crushing or transecting the sciatic nerve in adult chickens and mice. In unperturbed tissues, both N-CAM and Ng-CAM were found on nonmyelinated axons, and to a lesser extent on Schwann cells and myelinated axons. Only N-CAM was found on muscles. After denervation, the following changes were observed: The amount of N-CAM in muscle fibers increased transiently on the surface and in the cytoplasm, and in interstitial spaces between fibers. Restoration of normal N-CAM levels in muscle was dependent on reinnervation; in a chronically denervated state, N-CAM levels remained high. After crushing or cutting the nerve, the amount of both CAMs increased in the area surrounding the lesion, and the predominant form of N-CAM changed from a discrete Mr 140,000 component to the polydisperse high molecular weight embryonic form. Anti-N-CAM antibodies stained neurites, Schwann cells, and the perineurium of the regenerating sciatic nerve. Anti-Ng- CAM antibodies labeled neurites, Schwann cells and the endoneurial tubes in the distal stump. Changes in CAM distribution were observed in dorsal root ganglia and in the spinal cord only after the nerve was cut. The fibers within affected dorsal root ganglia were more intensely labeled for both CAMs, and the motor neurons in the ventral horn of the spinal cord of the affected segments were stained more intensely in a ring pattern by anti-N-CAM and anti-Ng-CAM than their counterparts on the side contralateral to the lesion. Taken together with the previous studies (Rieger, F., M. Grumet, and G. M. Edelman, J. Cell Biol. 101:285-293), these data suggest that local signals between neurons and glia may regulate CAM expression in the spinal cord and nerve during regeneration, and that activity may regulate N-CAM expression in muscle. Correlations of the present observations are made here with established events of nerve degeneration and suggest a number of roles for the CAMs in regenerative events.(ABSTRACT TRUNCATED AT 400 WORDS)
PMCID: PMC2114294  PMID: 2427528
24.  Chemoattractive capacity of different lengths of nerve fragments bridging regeneration chambers for the repair of sciatic nerve defects 
Neural Regeneration Research  2012;7(29):2293-2298.
A preliminary study by our research group showed that 6-mm-long regeneration chamber bridging is equivalent to autologous nerve transplantation for the repair of 12-mm nerve defects. In this study, we compared the efficacy of different lengths (6, 8, 10 mm) of nerve fragments bridging 6-mm regeneration chambers for the repair of 12-mm-long nerve defects. At 16 weeks after the regeneration chamber was implanted, the number, diameter and myelin sheath thickness of the regenerated nerve fibers, as well as the conduction velocity of the sciatic nerve and gastrocnemius muscle wet weight ratio, were similar to that observed with autologous nerve transplantation. Our results demonstrate that 6-, 8- and 10-mm-long nerve fragments bridging 6-mm regeneration chambers effectively repair 12-mm-long nerve defects. Because the chemoattractive capacity is not affected by the length of the nerve fragment, we suggest adopting 6-mm-long nerve fragments for the repair of peripheral nerve defects.
doi:10.3969/j.issn.1673-5374.2012.29.008
PMCID: PMC4268731  PMID: 25538752
nerve fragment length; nerve regeneration chamber; bridging; long nerve defect; chemotactic ability; neural regeneration
25.  OLFACTORY NERVE FIBERS 
The Journal of General Physiology  1956;39(4):473-496.
Cross sections of olfactory nerves present a unique appearance. They indicate the presence of large numbers of very small nerve fibers, with a modal diameter of about 0.2 µ and a narrow range for their size variation. From one side of the nasal septum of a pig the yield of fibers was estimated at 6,000,000; the number arising from the turbinates would be considerably larger. The fibers are attached to the membranes of the Schwann sheaths in large bundles through mesaxons longer and more branched than those that have been seen in other nerves. Continuity of the axons between the nerves and the bipolar cells was traced in an examination of the olfactory mucous membrane; and the indication of a one-to-one relationship between cells and axons was reinforced by a comparative count. After the axons leave the bipolar cells they become incased in the central projections of the sustentacular cells. Where the latter come into contact with the basal cells the axons emerge to push back the plasma membranes of the basal cells in the first step in acquiring their nerve sheaths. Later steps are described. When the axons are delivered by the basal cells to the collecting Schwann tubes, they are already aggregated into small bundles with sheaths fundamentally the same as those they will possess until they are delivered to the glia in the olfactory bulb. Some of the aspects of the cytology of the bipolar cells and adjoining sustentacular cells are described. A survey of the physiological properties of olfactory nerve fibers was made in some experiments on the olfactory nerve of the pike. Almost all of the action potential is encompassed within a single elevation, manifesting at its front a conduction velocity of 0.2 m./sec. For a comparison, the last elevation in the C action potential in the sciatic nerve of the frog is cited as an example of conduction at the same velocity. Though expressed through long time constants, the properties of the pike olfactory fibers conform to the generalized schema for properties of vertebrate nerve fibers. This conformity signalizes that they differ from the exceptional properties of the unmedullated fibers of dorsal root origin. An afferent function for unmedullated nerve fibers does not imply that the fibers concerned are alike in their physiological properties.
PMCID: PMC2147553  PMID: 13295549

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