Nerve regeneration through synthetic biodegradable nerve guides: regulation by the target organ

The successful regeneration of a multifascicular, complete peripheral nerve through a tubular synthetic biodegradable nerve guide across a gap of 10 mm in the rat sciatic nerve is reported. The importance of the distal nerve as a source of target-derived neuronotrophic factors necessary for the successful regeneration of the proximal regenerating nerve is emphasized. A simplified research model for further investigation into and manipulation of the biological processes of nerve regeneration is described. The potential clinical utilization of this model in the management of peripheral nerve injuries and, ultimately, central nervous system lesions is mentioned.     

Muscle-sparing approach to the peroneal nerve of the rabbit.

To study nerve degeneration and regeneration the peroneal nerve of the rabbit is a rewarding experimental model. The access to the nerve should be as atraumatic as possible and no muscular tissue should be incised or transected in order to lower postoperative morbidity and enhance the welfare of the animals. Given such conditions it is not possible to expose the undistributed proximal and central parts of the peroneal nerve from the intervertebral notch to its passage through the lateral head of the gastrocnemius muscle by a single approach, but rather a two-level incision is required. Such an approach to the peroneal nerve was carried out on 24 New Zealand White rabbits. The amount of postoperative pain was estimated by the rabbits social and feeding behaviour. The observed overall impairment was impressively low. This approach has been shown to be beneficial for the animals, and is atraumatic and should be strongly recommended.     

Nerve regeneration through side-to-side neurorrhaphy sites in a rat model: a new concept in peripheral nerve surgery

Despite great improvement and refinements in nerve repair techniques, there were still problems in repair of peripheral nerve injuries for which proximal stumps were not available. In these circumstances for which classic end-to-end neurorrhaphy was impossible, new treatment modalities, benefiting by an adjacent healthy nerve, have been under investigation to overcome this problem. Therefore, end-to-side nerve repair with its modifications came to view and axonal passages through this site were shown. Moreover, the results were unsatisfactory or necessitating sacrifice of another healthy nerve. Three groups, containing 10 rats each, were included in the study. First was the control group, with end-to-end repair of the peroneal nerve. Second was the end-to-side repair group, in which the distal stump of the peroneal nerve trunk was anastomosed to the lateral side of the tibial nerve. The third was the side-to-side repair group. In this technique, 1-mm diameter epineural windows, both from peroneal and tibial nerve trunks facing each other, were removed and side-to-side neurorrhaphy was performed. After 3 weeks, as the second step, the peroneal nerve was sectioned proximally. At 2, 4, 8, 12, 20, and 28 weeks, functional assessment of nerve regeneration was performed by using walking track analysis. The number of myelinated fibers and fiber diameters were measured and an electron microscopic evaluation was carried out. Statistically, both in morphometric and gait analysis, the differences in values between the groups were significant in favor of the control group, followed by the side-to-side group. The study showed that axonal passage was possible with side-to-side technique and the functional results were satisfactory and superior to the end-to-side technique. Continuous supply of neurotrophic factors from their target cells was the probable cause of superior functional return in side-to-side repair, because both joining nerves were intact and healthy during the anastomosis procedure and after 3 weeks. It was concluded that this technique could be indicated in salvage of nerves in cases for which any intermediate segments would be removed, as in tumor ablation surgery, harvesting of nerve grafts, or both.     

A bifid piriformis muscle with dual insertion

A bifid piriformis muscle is described with the aberrant fascicle inserting into the trochanteric fossa along with the obturator internus and gemelli muscles. The sciatic nerve split to enclose the aberrant fascicle between its common peroneal and tibial components.     

Aberrant cutaneous nerve of the thigh arising from the sciatic nerve in the human

An aberrant cutaneous nerve of the thigh arising from the peroneal portion of the human sciatic nerve or common peroneal nerve was observed in 9 cases (4.6% of sides). After giving a branch to the short head of the biceps femoris muscle and a branch to the knee joint, this cutaneous nerve reaches the subcutaneous tissue by passing between the short head of the biceps femoris and the vastus lateralis or by piercing through the biceps femoris. The authors presume that the cutaneous nerve shows the presence of the potential cutaneous nerve routes from the common peroneal nerve to the skin of the lateral aspect of the thigh.     

Nerve fiber planimetry in acute and chronic nerve lesions and in nerve lesions in continuity

The level of resection of damaged nerve tissue in acute and chronic nerve lesions was determined on the basis of the vascular structure, the consistency of the nerve during palpation, the amount of interfascicular connective tissue, and the mushroom formation of the fascicles. Intraoperative electrophysiologic recordings were performed on the cut nerve ends to determine the function of the axons. Postoperative planimetric analyses of cross sections made through the resected nerve stumps were performed to measure axonal and endoneural tube diameters and to correlate these results with the clinical criteria used through the operating microscope. Axons in the proximal nerve ends of acute and chronic nerve lesions displayed a similar mean diameter. Endoneural tubes in chronic nerve lesions shrunk significantly as nerve repair was delayed. In several nerve lesions in continuity, axons remained present across the injured site despite absence of electrical conduction. When comparing the results of axonal or endoneural tube diameters of chronic nerve lesions to the results of other studies or acute nerve lesions, we demonstrated that careful examination through the operating microscope provided valid information about the proper management and resection level of chronic nerve lesions. Electrophysiologic evaluation aided the surgical management but was not useful for the resection of the distal damaged nerve segment. The presence of an evoked potential in the proximal nerve ends guaranteed a nearly normal nerve fiber diameter distribution, while the absence of such a potential in the distal nerve ends indicated an abnormal, absent, or disturbed endoneural tube diameter histogram.     

Long-term changes in neurotrophic factor expression in distal nerve stump following denervation and reinnervation with motor or sensory nerve

Several factors have been proposed to account for poor motor recovery after prolonged denervation, including motor neuron cell death and incomplete or poor regeneration of motor fibers into the muscle. Both may result from failure of the muscle and the distal motor nerve stump to continue expression of neurotrophic factors following delayed muscle reinnervation. This study investigated whether regenerating motor or sensory axons modulate distal nerve neurotrophic factor expression. We found that transected distal tibial nerve up-regulated brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, down-regulated neurotrophin-3 and ciliary neurotrophic factor mRNA, and that although these levels returned to normal with regeneration, the chronically denervated distal nerve stump continued to express these neurotrophic factors for at least 6 months following injury. A sensory nerve (the cutaneous saphenous nerve) sutured to distal tibial nerve lowered injury-induced BDNF and GDNF mRNA levels in distal stump, but repair with a mixed nerve (peroneal, containing muscle and cutaneous axons) was more effective. Repair with sensory or mixed nerves did not affect nerve growth factor or neurotrophin-3 expression. Thus, distal nerve contributed to a neurotrophic environment for nerve regeneration for at least 6 months, and sensory nerve repair helped normalize distal nerve neurotrophic factor mRNA expression following denervation. Furthermore, as BDNF and GDNF levels in distal stump increased following denervation and returned to control levels following reinnervation, their levels serve as markers for the status of regeneration by either motor or sensory nerve.     

Axotomy induced changes in cholinergic enzymes in rat nerve and muscles.

Abstract— The effect of axotomy on acetylcholinesterase (AChE. EC 3.1.1.7). butyrylcholinesterase (BuChE. EC 3.1.1.8) and choline acetyltransferase (CAT, EC 2.3.1.6) activities in sciatic nerve stumps above (proximal) and below (distal) the site of transection. as well as in soleus (SOL) and extensor digitorum longus (EDL) muscles, has been studied in rat. Within 2 weeks. AChE activity decreased on a per mm basis, in proximal nerve by 65%, in distal nerve by 80% and on a per whole muscle basis, in denervated muscle by 85%. BuChE activity increased in proximal nerve and distal nerve to 150% of control and decreased in muscle to 51% of control. CAT activity in the proximal nerve stump was reduced to 70% of control and in the distal stump to less than 1% within 1 week. CAT activity in muscle decreased to 20 and 30% of control for soleus and EDL respectively during a 14 day period. The reduction in AChE and CAT activity observed in the proximal nerve segment may reflect changes in the synthesis, as well as the transport and local degradation of these enzymes. Previous studies on axotomy induced changes have not examined the simultaneous changes in proximal and distal nerve as well as denervated muscle in a single animal species.     

Somatosensory evoked potentials (SEPs) elicited by magnetic nerve stimulation

Magnetic stimulation of peripheral nerves at distal and proximal sites of the upper and lower extremities and at the midlumbar level were used to elicit cortical somatosensory evoked potentials. Evidence is provided that peripheral nerve trunks, rather than distal receptor afferents, are the anatomical structures stimulated by the electromagnetic fields. Magnetic stimulation of peripheral nerves is considered to be useful for an evaluation of the integrity of proximal nerves, nerve roots and central conduction along sensory pathways. In contrast to electrical nerve stimulation, magnetic stimulation is painless and can be applied to proximal nerves and plexus. By means of proximal nerve stimulation central sensory conduction can be tested even in patients with peripheral nerve lesions or polyneuropathy.     

Heterogeneous fascicle behavior within the biceps femoris long head at different muscle activation levels

Magnetic resonance and ultrasound imaging have shown hamstring strain injuries occur most often in the biceps femoris long head (BFLH), and particularly in the proximal vs. distal region of this muscle. Animal research and musculoskeletal modeling (MSK) have detected heterogeneous fascicle behavior within muscle regions, and within fascicles. Understanding architectural behavior differences during muscle contractions may help to discern possible mechanisms behind proximal BFLH injuries. The purpose of our study was to assess the magnitude of shortening of the proximal and distal fascicles of the BFLH under a range of muscle activation levels under isometric conditions using ultrasound imaging (US). Thirteen healthy adults performed targeted sustained isometric contractions while US were taken of the entire BFLH. Measurements of fascicle lengths in both muscle regions were compared at 20%, 30%, 50%, and 67% MVIC. The results showed that while both regions shortened significantly with activation, the proximal fascicles were significantly longer, regardless of activation level (~38%), and shortened significantly more than the distal fascicles overall (~40%), and cumulatively at higher activation levels (30% and above). No significant strain differences were found between the two regions. These data suggest heterogeneous fascicle behavior exists in an absolute sense; however, differences in behavior are eliminated when normalized (strain). Coupled with MSK literature, the absence of regional fascicle strain differences in this study may indicate strain heterogeneity is not detectable at the whole fascicle level. Further knowledge of this commonly strained muscle?s regional behavior during dynamic movements could provide evidence of proximal hamstring strain predisposition.     

The harvest and clinical application of the superficial peroneal sensory nerve for grafting motor and sensory nerve defects.

Potential donor nerves for autografting are finite and usually limited to cutaneous nerves of the extremities. The superficial peroneal nerve is the major lateral branch of the common peroneal nerve that innervates the peroneus longus and brevis muscles and provides sensation to the lateral aspect of the lower leg and the dorsal foot. It has generally been overlooked as a potential donor of nerve autografts. Cadaver dissections were performed on 10 fresh lower extremity specimens to investigate the anatomic characteristics of the superficial peroneal nerve and to refine a harvesting technique for the nerve. Thirty-one patients underwent nerve grafting of 39 upper and lower extremity nerves using the superficial peroneal donor. There were nine median nerves, four ulnar nerves, two radial nerves, two brachial plexus lesions, 16 digital nerves, and six lower extremity nerves grafted. The superficial peroneal nerve provided a consistently long donor, comparable in length to the sural nerve. The anatomic pattern is consistent, the patient positioning is simple, the surgical harvesting technique is straightforward, and the donor defect is acceptable. The superficial peroneal nerve provides a safe and valuable donor nerve, particularly in cases where multiple or very long nerve grafts are required.     

Electron-microscopic analysis of the mouse facial nerve near the geniculate ganglion

An electron-microscopic analysis of the mouse facial nerve near the geniculate ganglion shows that there are, on the everage, 603 more nerve fibers in the portion of the nerve distal to the geniculate ganglion than there are in the part proximal to the ganglion. The average distal increase in the number of unmyelinated fibers is 444 and that in the myelinated fibers is 165. The somatic motor nerve fibers and the parasympathetic fibers in the mouse facial nerve may not contribute to the distal excess. It is possible that the increase in the number of unmyelinated fibers distal to the geniculate ganglion is mainly due to the presence of postganglionic sympathetic fibers in the facial trunk distal to the geniculate ganglion and the greater petrosal nerve. The distal increase in the number of myelinated fibers may be mainly contributed by the sensory fibers.     

Astrocytes as gate-keepers in optic nerve regeneration--a mini-review

Animals that develop without extra-embryonic membranes (anamniotes--fish, amphibians) have impressive regenerative capacity, even to the extent of replacing entire limbs. In contrast, animals that develop within extra-embryonic membranes (amniotes--reptiles, birds, mammals) have limited capacity for regeneration as adults, particularly in the central nervous system (CNS). Much is known about the process of nerve development in fish and mammals and about regeneration after lesions in the CNS in fish and mammals. Because the retina of the eye and optic nerve are functionally part of the brain and are accessible in fish, frogs, and mice, optic nerve lesion and regeneration (ONR) has been extensively used as a model system for study of CNS nerve regeneration. When the optic nerve of a mouse is severed, the axons leading into the brain degenerate. Initially, the cut end of the axons on the proximal, eye-side of the injury sprout neurites which begin to grow into the lesion. Simultaneously, astrocytes of the optic nerve become activated to initiate wound repair as a first step in reestablishing the structural integrity of the optic nerve. This activation appears to initiate a cascade of molecular signals resulting in apoptotic cell death of the retinal ganglion cells axons of which make up the neural component of the optic nerve; regeneration fails and the injury is permanent. Evidence specifically implicating astrocytes comes from studies showing selective poisoning of astrocytes at the optic nerve lesion, along with activation of a gene whose product blocks apoptosis in retinal ganglion cells, creates conditions favorable to neurites sprouting from the cut proximal stump, growing through the lesion and into the distal portion of the injured nerve, eventually reaching appropriate targets in the brain. In anamniotes, astrocytes ostensibly present no such obstacle since optic nerve regeneration occurs without intervention; however, no systematic study of glial involvement has been done. In fish, vigorously growing neurites sprout from the cut axons and within a few days begin to re-enervate the brain. This review offers a new perspective on the role of glia, particularly astrocytes, as "gate-keepers;" i.e., as being permissive or inhibitory, by comparison between fish and mammals of glial function during ONR.     

Responses in muscle sympathetic nerve activity to sustained hand-grips of different tensions in humans

To clarify whether sympathetic nerve activity increases in relation to the tension of a sustained muscle contraction, muscle sympathetic nerve activity (MSA) was recorded directly from the peroneal nerve fascicle at the popliteal fossa by means of tungsten microelectrodes in five healthy male subjects. A sustained muscle contraction was performed by handgrip for two minutes in a supine position at tensions of 10, 30 and 45% of maximal grip strength (MGS). MSA, electrocardiogram (ECG) using bipolar electrodes from the chest and surface electromyogram (EMG) from the extensor pollicis longus were recorded simultaneously before and during the sustained handgrip. Arterial blood pressure was measured at the resting upper arm by auscultation. During handgrip with tensions of 10, 30 and 45% MGS, average MSA burst rate (bursts X min-1) increased to 122, 152 and 230% of the resting value, respectively. During the same experimental procedures with tensions of 10, 30 and 45% MGS, average heart rate increased to 105, 110 and 111% of the resting value. These results confirm that sympathetic outflow to a resting muscle is increased with elevation of tension in an active muscle. This process would promote perfusion pressure in the active muscle.     

Spinal cord dorsum potentials recorded in vivo after cold injury to the sural nerve in the rabbit

Evoked potentials were recorded in the spinal cord dorsum of rabbits during and after local cooling or freezing of the sural nerve. The potentials were elicited by stimulation through implanted bipolar electrodes distal and proximal to the site of cooling. Recordings were made with a unipolar electrode implanted dorsally into the epidural space.The first two negative deflections of the evoked field potentials (s- and n-potentials) decreased or disappeared during cooling to temperatures between 12 and 2 °C. Immediately following cooling the potentials were depressed by as much as 40% below that of controls. Gradual recovery of the nerve conduction velocity and of both potentials occurred between postoperative Days 20 and 60. Cooling of the nerve to between +2 and ?2 °C caused a 70–80% decrease in amplitude and the precooling values were not obtained within 90 days' follow-up. Local freezing of the sural nerve to ?45 °C resulted in disappearance of the cord dorsum potentials previously obtained by stimulation of the sural nerve with electrode distal to the site frozen. About 40% decrease occurred when stimulated proximal to the site frozen. A fast amplitude increase took place between days 50 and 100 and a slower increase between days 150 and 450 to values more than twice the preoperative amplitudes. A similar amplitude increase was obtained by stimulation of the nerve proximal to the site frozen.     

A surgical approach to the motor branch of the ulnar nerve

Isolated injury to the motor branch of the ulnar nerve is a relatively rare injury, often initially misdiagnosed. If repair is attempted through the original laceration without complete motor branch exposure, results can be less than satisfactory. A recent case illustrates this injury and provides us with an opportunity to review the surgical anatomy of the motor branch of the ulnar nerve. The surgical approach to the motor branch has been detailed and specifically emphasizes complete motor branch exposure from the main ulnar nerve trunk to the most distal motor branch entry into the adductor pollicis muscle. This approach permits definition of the exact level of the nerve injury, preservation of any intact proximal fine motor branches, and facilitates the mechanics of nerve repair.     

Influence of 50 Hz-1 mT magnetic field on human median nerve

In this study, human median nerve was exposed to power frequency magnetic fields in order to provide clarification for possibly changeable nerve conduction mechanism. The nerve was exposed to 50 Hz magnetic field by utilizing a special Helmholtz applicator. The experiments were carried out with six healthy human-volunteers. Median motor distal amplitude/proximal amplitude ratios were recorded from adult human median nerve pre-exposure, during, and post-exposure to a 50 Hz, 1 mT magnetic field. The result of 18 measurements shows that median motor distal amplitude/proximal amplitude ratio significantly decreases in pre-exposure state as compare to post exposure of which. The results of this study may be useful for some nerve rehabilitation, excitation, and stimulation in more effective/safe physical therapy. Additionally, 50 Hz, 1 mT sinusoidal magnetic field should not be recognizing as safe for conduction mechanism on a nerve. These mechanisms would be cleared by new advanced engineering models in other future works.     

Functional Recovery of Denervated Skeletal Muscle with Sensory or Mixed Nerve Protection: A Pilot Study

Functional recovery is usually poor following peripheral nerve injury when reinnervation is delayed. Early innervation by sensory nerve has been indicated to prevent atrophy of the denervated muscle. It is hypothesized that early protection with sensory axons is adequate to improve functional recovery of skeletal muscle following prolonged denervation of mixed nerve injury. In this study, four groups of rats received surgical denervation of the tibial nerve. The proximal and distal stumps of the tibial nerve were ligated in all animals except for those in the immediate repair group. The experimental groups underwent denervation with nerve protection of peroneal nerve (mixed protection) or sural nerve (sensory protection). The experimental and unprotected groups had a stage II surgery in which the trimmed proximal and distal tibial nerve stumps were sutured together. After 3 months of recovery, electrophysiological, histological and morphometric parameters were assessed. It was detected that the significant muscle atrophy and a good preserved structure of the muscle were observed in the unprotected and protective experimental groups, respectively. Significantly fewer numbers of regenerated myelinated axons were observed in the sensory-protected group. Enhanced recovery in the mixed protection group was indicated by the results of the muscle contraction force tests, regenerated myelinated fiber, and the results of the histological analysis. Our results suggest that early axons protection by mixed nerve may complement sensory axons which are required for promoting functional recovery of the denervated muscle natively innervated by mixed nerve.     

A new surgical technique for the treatment of high common peroneal nerve palsy

In this article, the authors introduce a new procedure for the treatment of high common peroneal nerve palsy. The principle of this technique consists of the neurotization of the anterior tibial nerve (deep peroneal nerve) with the bundle composed of the nerves to the soleus and lateral head of gastrocnemius muscles. The authors used this procedure for eight children who had permanent common peroneal nerve palsy caused by the injection of diclofenac in the gluteal region and for a 25-year-old male patient whose common peroneal nerve was transected near the gluteal region by a stab wound. For the cases in which paralysis was less than 8 months in duration, the results are satisfactory.     

Diabetes affects retrograde but not anterograde transport of sciatic nerve phosphofructokinase in Sprague-Dawley rats.

Phosphofructokinase activity was measured in the sciatic nerve of streptozotocin-induced diabetic and nondiabetic rats. Average steady-state phosphofructokinase activity was obtained from three consecutive segments of the mid-femoral region in the left sciatic nerve in both diabetic (4 and 24 weeks) and nondiabetic, age-matched animals. Over time, phosphofructokinase activity significantly decreased (p less than 0.05) with diabetes, with no effect demonstrated within similar age-groups. The accumulation of phosphofructokinase activity was accomplished by ligating the mid-femoral region of the right sciatic nerve for 24 h. Anterograde and retrograde axonal transport of phosphofructokinase was measured in the 3-mm segment proximal and distal to the ligature, respectively. There was a trend (p = 0.0627) towards a decline in net proximal accumulation (mean proximal minus mean background) with age. Net distal (mean distal minus mean background) activity declined by 80% (p less than 0.05) in the control group between 4 and 24 weeks of the diabetic state. However, diabetic animals did not experience the same age-related decline in retrograde transport. The findings suggest that diabetes affects the age-associated evolution of retrograde transport, presumably a reflection of the neuropathy occurring in the distal axon branches, without altering anterograde transport to any appreciable extent.