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Peripheral nerves convey signals between the spinal cord and the rest of the body. Peripheral nerve injury (PNI) is a challenging problem with a variety of aetiologies and symptoms. Injuries can be classified into three categories: neurapraxia, axonotmesis and neurotmesis. Axonotmesis and neurotmesis result in Wallerian degeneration of the axons distal to the site of injury. After this process is complete, damaged neurons attempt to regenerate the damaged fibre with axonal budding. Successful axonal growth relies on an intact connective tissue tunnel and the requisite signalling molecules to allow the axon to re-grow in the correct direction and re-innervate the target tissue. Without this, the axons may form a painful neuroma. To differentiate between the different grades of nerve injury special tests can be utilized including neurophysiological investigation–nerve conduction studies and electromyography (EMG). Imaging the damaged nerve with ultrasound or MRI may be useful for diagnosis and surgical planning, however investigations should not delay referral to a nerve surgeon. The aim of surgical repair in nerve injury is to re-establish continuity between the connective tissue structures of the nerve; this allows axons to elongate across the site of injury to reach the target tissue. The simplest technique is tensionless end-to-end epineural repair. In injuries where this is impossible other surgical options include nerve grafting, nerve conduits or nerve transfer.

Background: Median and ulnar nerve lacerations at the wrist are often combined with zone 5 tendon injury. The inability to provide early range of motion leads to increased adhesions. Current therapy protocols recommend the wrist be held in 30° of flexion post operatively to protect the nerve repair. However, if tension and elongation across the nerve repair stay under a critical level in less wrist flexion, postoperative splinting in more extension could allow for better tendon excursion and less adhesions. Methods: Six cadaveric specimens were used. After appropriate dissection, the median and ulnar nerves were transected and repaired with a single 10-0 nylon suture. The wrist was ranged from 30° flexion to 45° extension to see if the repair would fail. Next, an epineural repair was accomplished with 9-0 nylon suture. The percent elongation along the nerve repair was measured at set increments from 30° flexion to 45° extension. Results: In all 6 specimens, median and ulnar nerve repairs with a single 10-0 nylon suture did not fail with wrist range of motion from 30° flexion to 45° extension. Mean percent elongation stayed under critical levels in up to 30° of extension. Conclusions: Both median and ulnar nerve repairs stayed under critical levels of tension and elongation in up to 30° of wrist extension. We believe it is possible to be more aggressive with wrist positioning in wrist level median and ulnar nerve repairs.

Functional outcomes following nerve repair remain suboptimal. Scarring at the repair site is a major impediment to regeneration. A biomaterial scaffold applied around the coaptation site that decreases inflammation holds great potential in reducing scarring, enhancing axonal growth, and improving functional recovery. In this study, we evaluated the effect of a macroporous nanofiber wrap, comprised of nonwoven electrospun poly-ε-caprolactone (PCL), in improving axonal regeneration in a rat sciatic nerve cut and direct repair model. Controls consisted of conventional epineurial repair. We also evaluated our wrap against the commercially available AxoGuard wrap. At five weeks following repair, the nanofiber wrap group showed a significantly decreased intraneural macrophage invasion and collagen deposition at the repair site. This was associated with increased expression of the anti-inflammatory cytokine (IL-10), decreased expression of the pro-inflammatory cytokine (TNF-α), and a decrease in the M1:M2 macrophage phenotype ratio. These findings suggest that this nanofiber wrap, with its unique macroporosity, is modulating the inflammatory response at the repair site by polarizing macrophages towards a pro-regenerative M2 phenotype. Concomitantly, a higher number of regenerated axons was noted. At sixteen weeks, the nanofiber wrap resulted in enhanced functional recovery as demonstrated by electrophysiology, neuromuscular re-innervation, and muscle histology. When compared to the AxoGuard wrap, the nanofiber wrap showed similar inflammation at the repair site and similar nerve morphometric findings, but there was a trend towards a lower overall number of macrophages invading the wrap wall. These results demonstrate favorable outcomes of the macroporous nanofiber wrap in promoting neuroregeneration and functional recovery following nerve repair. STATEMENT OF SIGNIFICANCE: Electrospun nanofiber scaffolds, with specific fiber and pore sizes, were shown to modulate the immune response and create a regenerative environment. In this paper, we present a macroporous nanofiber wrap, made of poly-ε-caprolactone, to be applied at the coaptation site in primary nerve repair. We show that it regulates the inflammatory response at the repair site and decreases scarring/fibrosis. This results in enhanced axonal regeneration, allowing a higher number of axons to cross the suture line and reach the target muscle in a timely fashion. Functional outcomes are thus improved.

Segmental nerve loss presents a challenge to the reconstructive surgeon. Collagen nerve conduits are one strategy for reconstruction of segmental defects, but no conduit-based reconstructive strategy has been as successful as autograft reconstruction. We hypothesized that collagen nerve conduits used to bridge segmental sciatic nerve defects may be enhanced by grafting with vomeronasal organ (VNO), owing to this tissue’s capacity for regeneration. Fourteen rats underwent resection of a 1.0 cm segment of sciatic nerve. Seven rats underwent reconstruction of the defect using a commercially available collagen nerve conduit. Seven rats underwent reconstruction using conduit filled with fresh VNO allograft. An additional seven rats underwent transection and direct epineural repair. Fourteen weeks postoperatively, all animals underwent calculation of sciatic functional index (SFI) via walking track analysis. After sacrifice, tissues were processed for histomorphometric analysis, including axon quantification and axon density. All reconstructed nerves were in continuity at sacrifice. At 14 weeks, the mean SFI was significantly higher in the vomeronasal organ-enhanced (VNOE) group and epineural repair (ER) group than the conduit-only (CO) group. `SFI was equivalent between VNOE and ER groups. Axon density was greater in the VNOE and ER groups than the CO group. Axon density was equivalent between VNOE and ER groups. In conclusion, this rat sciatic nerve segmental defect model achieved greater functional recovery and axon density using collagen nerve conduits filled with a pluripotent neuroepithelium relative to reconstruction with an empty conduit. These results suggest a promising strategy for repair of segmental peripheral nerve defects.

There is an urgent need for a peripheral nerve repair product that can match or exceed the abilities of the current "gold-standard", nerve autografts. Using a sectioning-based fabrication technique, decellularized tendon sections formed into tubular conduits that maintain the native structure of the collagen. Our previous studies have demonstrated that these collagen structures provide nanotopographical growth guidance cues for regenerating neurons and support glia. Here, the regenerative abilities of the tendon-derived nerve guidance conduits to repair a critically sized defect (15 mm) are evaluated in a rat sciatic nerve model. Using the conduits, functional recovery occurs at a similar rate to isografts, when evaluated with a sciatic function index test. However, muscular recovery, as measured by gastrocnemius weight, was not as great in the conduit-treated group. Both conduit and isograft repairs are histologically evaluated using Masson's trichrome stain and immunofluorescent staining for neurofilament-160 and S100 (markers for neurons and Schwann cells, respectively). This evaluation shows that by week 14, conduits promote regrowth of both neuronal tissue and some physiological support structures, such as blood vessels and epi/perineurium-like structures. Lastly, positive staining for these two markers at week 14 is calculated as a quantitative means of assessment, and shows greater total content of neurofilament-160 and S100 in conduits than in isografts, but a smaller percent area, which may be a result of the greater cross-sectional area of the conduit.

The sciatic nerve is a mixed nerve. It is the largest nerve in the human body. Its path is posterior to the root of the lower body, under the buttock, until the popliteal fossa, at which point it splits into two terminal branches: the tibial nerve and the common fibular nerve. The sciatic nerve trunk innervates the muscles of the posterior compartment of the thigh.

Objective: To determine the effects of chicken embryo brain extract (BE) on transects sciatic nerve in male rats. Methods: Thirty adult male Sprague-Dawley rats weighing 200 to 250 g, were randomized into three groups treated with (1) sham surgery, (2) normal saline (NS), and (3) brain extract (BE). The BE was taken from incubating chick embryos at day 8. The sciatic nerve was exposed and sharply transected at the mid thigh level. Immediate epineurial repair was then performed. The BE treated animals were given 400 µl/kg of the chick embryo BE intraperitoneal, once daily, for 2 weeks. All animals were evaluated by sciatic functional index (SFI), electrophysiology, histology, and immunohistochemistry at days 28, 90 after surgery. Results: The mean SFI difference between BE and NS groups at days 28, 60 and 90 after surgery was statistically significant ( p =0.086). The mean number of myelinated fibers in the BE group was significantly greater than that of the NS group on days 28 and 90 after surgery ( p =0.034). At days 28 and 90 after surgery, the mean nerve conduction velocity (NCV) in the BE group was significantly faster than that of the NS group ( p =0.041). Conclusion: These results indicate for the first time that chick embryo brain extract can enhance peripheral nerve regeneration in rat.

Purpose Outcomes after end-to-end epineural suture repair remain poor. Nerve wraps have been advocated to improve regeneration across repair sites by potentially reducing axonal escape and scar ingrowth; however, limited evidence currently exists to support their use. Methods Forty Lewis rats underwent median nerve division and immediate repair. Half were repaired with epineural suturing alone, and the others underwent epineural suture repair with the addition of a nerve wrap. Motor recovery was measured using weekly grip strength and nerve conduction testing for 15 weeks. Histomorphometric analyses were performed to assess intraneural collagen deposition, cellular infiltration, and axonal organization at the repair site, as well as axonal regeneration and neuromuscular junction reinnervation distal to the repair site. Results The wrapped group demonstrated significantly less intraneural collagen deposition at 5 weeks. Axonal histomorphometry, cellular infiltration, neuromuscular junction reinnervation, and functional recovery did not differ between groups. Conclusions Nerve wraps reduced collagen deposition within the coaptation; however, no differences were observed in axonal regeneration, neuromuscular junction reinnervation, or functional recovery. Clinical relevance These findings suggest that extracellular matrix nerve wraps can attenuate scar deposition at the repair site. Any benefits that may exist with regards to axonal regeneration and functional recovery were not detected in our model.

The research on artificial nerve conduits has become a focus of study in peripheral nerve reconstruction so as a possible replacement for the treatment of autologous nerve grafts in clinics. In this study, we used longitudinally oriented collagen conduit (LOCC) combined with nerve growth factor (NGF) to reconstruct long distance of sciatic nerve defects (35 mm) in adult dog model. The long term follow-up evaluation demonstrated that the LOCC/NGF conduit allowed functional and morphological nerve regeneration at the transection site of the injured sciatic nerve. Furthermore, the functional study confirmed that when NGF was loaded onto LOCC it promoted a better recovery of regenerated axons than LOCC alone. The gastrocnemius muscle mass in the LOCC/NGF group was significantly greater than in the LOCC alone group. The results indicated that when LOCC conduit combined with NGF it would provide a preferential environment for sciatic nerve regeneration. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2131-2139, 2018.

Low-dose radiation has been used in clinical and experimental models for the prevention of scarring and for fracture healing. There is evidence that low-dose radiation improves the hormesis of various cell types but little is known about its effects on peripheral nerve tissue. In this study, we investigated the beneficial effects of low-dose radiation on the regeneration of transectional peripheral nerve injury in an experimental rat model. Seventy-two male Sprague-Dawley rats received transection injury to the left sciatic nerves, and the nerves were subsequently sutured by epineurium end-to-end anastomosis to restore continuity. Animals were randomly assigned to one of two treatment groups (n = 36/group): 1 Gy X-ray irradiation or control (sham irradiation). Gait analysis, electrophysiological examination and morphological investigations were performed. In addition, Western blot and qRT-PCR were performed to determine the level of vascular endothelial growth factor (VEGF) and growth-associated protein-43 (GAP-43). Content of VEGF and GAP-43 in the regenerated sciatic nerve of the irradiated group was higher than the control group. At 4 to 12 weeks after surgery, the irradiated animals exhibited a significantly improved functional recovery relative to controls. At 12 weeks after surgery, amplitude and conduction velocity of the irradiated group were higher than the control group (P < 0.05). The number of nerve fibers, diameter of axons and morphological structure of the myelin sheath in the irradiated group were superior to those of the control group. These results suggest that low-dose radiation contributed to regeneration and functional recovery after transverse peripheral nerve injury by inducing increased production of VEGF and GAP-43, which promote the axonal regeneration and myelination.

Aging influences peripheral nerve regeneration. Nevertheless, most basic research of bioabsorbable nerve conduits including commercial products have been performed in very young animals. Results from these studies may not provide information about axonal regeneration in aged tissue, because young nerve tissue holds sufficient endogenous potential for axonal regeneration. The clinical target age for nerve conduit application is most likely going to increase with a rapidly growing elderly population. In the present study, we examined axonal regeneration after sciatic nerve defects in aged and young mice. 5-mm sciatic nerve defects in young (6 weeks old) and aged (92 weeks old) mice were reconstructed using nerve conduits (composed of a poly lactide and caprolactone) or autografts. In addition, in aged mice, sciatic nerve defects were reconstructed using nerve conduits coated with mouse induced pluripotent stem cell (iPSc)-derived neurospheres. Using electrophysiological and histological techniques, we demonstrated axonal regeneration was significantly less effective in aged than in young mice both for nerve conduits and for nerve autografts. However, despite the low regenerative capacity of the peripheral nerve in aged mice, axonal regeneration significantly increased when nerve conduits coated with iPSc-derived neurospheres, rather than nerve conduits alone, were used. The present study shows that aging negatively affects peripheral nerve regeneration based on nerve conduits in mice. However, axonal regeneration using nerve conduits was improved when supportive iPSc-derived neurospheres were added in the aged mice. We propose that tissue-engineered bioabsorbable nerve conduits in combination with iPSc-derived neurospheres hold therapeutic potential both in young and elderly patients. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1752-1758, 2018.

The outcome of peripheral nerve repair following transection is influenced by a number of factors but almost all approaches require anastomosis of the nerve using technically demanding microsurgical procedures. However, the use of sutures presents a number of unavoidable challenges including additional nerve trauma, stimulation of an inflammatory response, and endoneural fibrosis. The objective of the present study was to determine the efficacy of a sutureless approach to nerve repair. A rat sciatic nerve transection model was used with a laser-activated, chitosan-based adhesive (SurgiLux), combined with different forms of extracellular matrix (ECM), known to promote Schwann cell proliferation and nerve growth both in peripheral nerve applications. Following a 5 mm transection of the sciatic nerve, nerve guide wraps were prepared using: (1) laser-activated adhesive (SurgiLux) alone, (2) SurgiLux incorporating ECM (SurgiLux ECM), (3) ECM secured using SurgiLux, and (4) ECM secured using 8-0 Prolene sutures. A no treatment groups was used as a negative control. Evaluation of tissue remodeling was conducted with histolomorphometric assessment of neuroma, integrity of repair, nerve immunolabeling, ratio of myelinated to non-myelinated fibers, and amount of connective tissue. Quantitative and semi-quantitative analysis of the repaired nerve transections at 6 and 12 weeks showed that that SurgiLux incorporating powdered ECM (SurgiLux ECM), SurgiLux alone and ECM alone all improved the healing response compared to no-treatment controls, with less fibrotic tissue and more nerve staining. Histologic scoring showed that the SurgiLux ECM group showed the greatest increase in histologic score between the two time points tested. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1698-1711, 2018.

Investigating the effect of four types of artificial nerve graft (ANG) structures on rat sciatic nerve defect repair will aid future ANG designs. In this study, fibroin fibers and polylactic acid were used to prepare four ANGs with differing structures: nerve conduit with micron-sized pores (Conduit with pore group), nerve conduit without micron-sized pores (Conduit group), nerve scaffold comprising Conduit with pore group material plus silk fibers (Scaffold with pore group), and nerve scaffold comprising Conduit group material plus silk fibers (Scaffold group). ANGs or autologous nerves (Autologous group) were implanted into 10 mm rat sciatic nerve defects (n = 50 per group). Twenty weeks after nerve grafting, the time required to retract the surgical limb from the hot water was ranked as follows: Conduit with pore group > Scaffold with pore group > Conduit group > Scaffold group > Autologous group. The static sciatic index was ranked in descending order: Autologous group > Scaffold group > Conduit group > Scaffold with pore group > Conduit with pore group. Immunofluorescence staining identified significant differences in the distribution and number of axons, Schwann cells, and fibroblasts. These findings indicate that ANGs with micron-sized pores had a negative impact on the repair of peripheral nerve defects, while internal microchannels were beneficial. © 2017 The Authors. Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3077-3085, 2017.

Many surgical techniques are available for the repair of peripheral nerve defects. Autologous nerve grafts are the gold standard for most clinical conditions. In selected cases, alternative types of reconstructions are performed to fill the nerve gap. Non-nervous autologous tissue-based conduits or synthetic ones are alternatives to nerve autografts. Allografts represent another new field of interest. Decision making in the treatment of nerve defects is based on timing of referral, level of the injury, type of lesion, and size of any gap. This review focuses on current clinical practice, influenced by the numerous new experimental researches.

Background Tissue processing to create immunotolerant nerve allograft removes neurosupportive cells. Few strategies have been described for implanting new cells into the graft to support axonal regeneration. New method Micropuncture of the nerve allograft surface combined with immersion into a pressurized cell-rich solution to potentiate the introduction of viable Schwann cells (SC) into processed nerve allograft. Allografts were used to repair rodent sciatic nerve defects. At 3, 7, and 21 days, grafts were harvested, stained for SCs, and analyzed using total cross sectional area (CSA) occupied by SCs to quantify SC presence. Results At days 3 and 7, SC CSA was significantly greater for the injection group compared to all other groups. At day 21, SC CSA for the injection group (0.2252% ± 0.2730) was significantly greater compared to following groups: pressurized-punctured (0.0653% ± 0.0934), nonpressurized-nonpunctured (0.0607% ± 0.0709), punctured-control (0.0246% ± 0.0398), and nonpunctured-control (0.0126% ± 0.0151). A significant decrease in percent CSA occupied by SCs from day 3 to day 21 was noted in nonpressurized-punctured group (p = 0.0106), pressurized-nonpunctured group (p = 0.0477), and injection group (p = 0.0010). Comparison with existing method(s) Most studies have used small caliber hypodermic needles to inject the cells into grafts. Conclusions Despite a presumed decrease in cell viability over the three weeks of the study, the large initial inoculum achieved by injection technique results in higher levels of final SC seeding in acellular nerve allograft compared with bathing techniques with or without micropuncture or pressurization.

Employment of regenerative properties of cells at the service of nerve repair has been initiated during recent decades. Effects of local transplantation of bone marrow-derived mast cells on peripheral nerve regeneration were studied using a rat sciatic nerve transection model.A 10-mm sciatic nerve defect was bridged using a conduit chitosan-based hybrid conduit filled with BMMCs in BMMC group. In positive control group (Pos), the conduit was filled with phosphate-buffered saline alone. The regenerated nerve fibers were studied within 12 weeks after surgery. In sham-operated group, the sciatic nerve was only exposed and manipulated. In negative control (Neg) a 10-mm sciatic nerve defect was created and the nerve stumps were sutured to the adjacent muscles. The regenerated nerve fibers were studied functionally, biomechanically, histologically and immunohiscochemically.Functional and biomechanical studies confirmed faster recovery of regenerated axons in BMMCs transplanted animals compared to Pos group (p0.05). Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in BMMCs transplanted animals than in Pos group (p0.05). In immunohistochemistry, location of reactions to S-100 in BMMCs transplanted animals was clearly more positive than that in Pos group.BMMCs transplantation could be considered as a readily accessible source of cells that could improve functional recovery of transected sciatic nerve.

In recent years, bone marrow-derived cells have been found to be crucial for peripheral nerve regeneration. After traumatic peripheral nerve injury, bone marrow-derived macrophages quickly infiltrate into the distal regions of nerves. To explore the changes caused by bone marrow-derived cells within the proximal regions of the nerves, sciatic nerves of chimeric mice carrying bone marrow cells expressing green fluorescent protein were crushed to observe the infiltration of invading bone marrow-derived cells. Seven days after surgery, abundant bone marrow-derived cells had infiltrated into the damaged proximal nerve segments. The numbers of these cells increased to a peak at 2 weeks and then gradually returned to normal levels within 30 weeks. Through immunofluorescence staining, many of these cells were identified as macrophages, and they showed a similar infiltration tendency toward distal nerve segments. However, fewer cells infiltrated proximal segments than distal nerve segments. In conclusion, these findings suggest that bone marrow-derived cells response not only occurs within the distal nerve segments but may also take place within the proximal segments of nerve tissues after nerve injury.

Alternatives to nerve autograft have been invented and approved for clinical use. The reported outcomes of these alternatives in mixed motor nerve repair in humans are scarce and marked by wide variabilities. The purpose of our Current Concepts review is to provide an evidence-based overview of the effectiveness of nerve conduits and allografts in motor and mixed sensory/motor nerve reconstruction. Nerve graft substitutes have good outcomes in mixed/motor nerves in gaps less than 6 mm and internal diameters between 3 and 7 mm. There is insufficient evidence for their use in larger-gap and -diameter nerves; the evidence remains that major segmental motor or mixed nerve injury is optimally treated with a cabled nerve autograft.

Formation, distribution and possible communication of the median nerve are essential to know in treatment and surgeries of various conditions of injuries e.g. repair or reconstruction of the median nerve post traumatic accident. In the present study, 44 upper limbs were dissected. Root forming the median nerve, the median nerve in relation with the axillary artery and communication of the median nerve with other nerves were noted.

Surgical repair of larger peripheral nerve lesions requires the use of autologous nerve grafts. At present, clinical alternatives to avoid nerve transplantation consist of empty tubes, which are only suitable for the repair over short distances and have limited success. We developed a cell-free, three-dimensional scaffold for axonal guidance in long-distance nerve repair. Sub-micron scale fibres of biodegradable poly-e-caprolactone (PCL) and collagen/PCL (c/PCL) blends were incorporated in a gelatin matrix and inserted in collagen tubes. The conduits were tested by replacing 15-mm-long segments of rat sciatic nerves in vivo. Biocompatibility of the implants and nerve regeneration were assessed histologically, with electromyography and with behavioural tests for motor functions. Functional repair was achieved in all animals with autologous transplants, in 12 of 13 rats that received artificial implants with an internal structure and in half of the animals with empty nerve conduits. In rats with implants containing c/PCL fibres, the extent of recovery (compound muscle action potentials, motor functions of the hind limbs) was superior to animals that had received empty implants, but not as good as with autologous nerve transplantation. Schwann cell migration and axonal regeneration were observed in all artificial implants, and muscular atrophy was reduced in comparison with animals that had received no implants. The present design represents a significant step towards cell-free, artificial nerve bridges that can replace autologous nerve transplants in the clinic. Copyright © 2017 John Wiley & Sons, Ltd.

End-to-side neurorrhaphy is an option in the treatment of the long segment defects of a nerve. It involves suturing the distal stump of the disconnected nerve (recipient nerve) to the side of the intimate adjacent nerve (donor nerve). However, the motor-sensory specificity after end-to-side neurorrhaphy remains unclear. This study sought to evaluate whether cutaneous sensory nerve regeneration induces motor nerves after end-to-side neurorrhaphy. Thirty rats were randomized into three groups: (1) end-to-side neurorrhaphy using the ulnar nerve (mixed sensory and motor) as the donor nerve and the cutaneous antebrachii medialis nerve as the recipient nerve; (2) the sham group: ulnar nerve and cutaneous antebrachii medialis nerve were just exposed; and (3) the transected nerve group: cutaneous antebrachii medialis nerve was transected and the stumps were turned over and tied. At 5 months, acetylcholinesterase staining results showed that 34% ± 16% of the myelinated axons were stained in the end-to-side group, and none of the myelinated axons were stained in either the sham or transected nerve groups. Retrograde fluorescent tracing of spinal motor neurons and dorsal root ganglion showed the proportion of motor neurons from the cutaneous antebrachii medialis nerve of the end-to-side group was 21% ± 5%. In contrast, no motor neurons from the cutaneous antebrachii medialis nerve of the sham group and transected nerve group were found in the spinal cord segment. These results confirmed that motor neuron regeneration occurred after cutaneous nerve end-to-side neurorrhaphy.

Rat models of complete and partial injuries are the most frequently used models for analysis of the cellular and molecular processes of nerve regeneration and axon sprouting. Studies of nerve regeneration and axon sprouting after complete and partial nerve injuries, respectively, are reviewed. Special consideration is made of the peripheral nerves chosen for the studies and the outcome measures that were utilized in the studies. The studies have made important contributions to our knowledge of the degenerative and regenerative processes that occur after the peripheral nerve injuries, why functional recovery is frequently compromised after delayed surgery, the positive effects of neurotrophic factors on nerve regeneration after delayed nerve repair or after insertion of autografts between transected nerve, and how axon regeneration may be accelerated by brief periods of electrical stimulation and/or by administration of androgens.

Background The gold standard in the primary and secondary treatment for a nerve gap reconstruction is still autologous nerve grafting. Over short distances, application of nerve conduits can effectively solve the problems of limited availability of donor tissue, sacrifice of a functional nerve, and possible neuroma formation of autologous nerve grafting. There are a variety of non-absorbable and absorbable nerve conduits. Method and Results The 21-years old patient was a war victim in Syria and suffered a shooting trauma of the left thigh two years ago. Nerve reconstruction of the sciatic nerve with a giant nerve tube was performed 9 months after the trauma. Due to the young age of the patient we decide to conduct an exploration and possibly autologous nerve transplantation 2 years after primary surgery. Intraoperatively we found an intubation tube used as a non-bioabsorbable nerve tube including no nerval tissue. Conclusion This case describes probably the largest nerve tube ever but it also reflects the improvisation of war surgeons under limited circumstances in order to provide a satisfactory medical care during war times.

Progress in material development has enabled the production of nerve guides that increasingly resemble the characteristics of an autologous nerve graft. In the present study, 20 mm adult rat sciatic nerve defects were bridged with the collagen-based, two-component nerve guide 'Neuromaix', the commercially available NeuraGen® nerve tube or an autologous nerve graft. Neuromaix was able to support structural as well as functional regeneration across this gap. The majority of the axons grew across the scaffold into the distal nerve segment and retrograde tracing confirmed that these axons were of somatosensory and motor origin. Histomorphology revealed that axons regenerating through Neuromaix exhibited reduced myelin sheath thickness, whereas axon diameter and axon density were comparable to those of the autograft. Neuromaix implantation resulted in reinnervation of the gastrocnemius muscle to a level that was not significantly different from that supported by the autograft, as demonstrated by electrophysiology. Our findings show that the use of the Neuromaix scaffold not only allowed axonal regeneration across large nerve gaps, but that the regenerating axons were also able to functionally reinnervate the muscles. These data provide a promising perspective for the first in human application of the materials. Copyright © 2016 John Wiley & Sons, Ltd.

We report a nerve graft procedure bridging the thenar branch of the median nerve to the ulnar nerve in three patients with ulnar nerve transection and defect at the mid-forearm. Ulnar nerve function was evaluated with electroneurography and quantitative sensory-motor testing before and after surgery, and at a 6-year follow-up. After surgery all patients showed electroneurographic evidence of median nerve innervation of the intrinsic muscles normally innervated by the ulnar nerve. The average strength was Grade 4 in the intrinsic muscles originally supplied by the ulnar nerve at the final follow-up. Our results indicate that the thenar branch of the median nerve may support ulnar nerve regeneration and so help prevent intrinsic muscles from irreversible atrophy, but our report is preliminary. This procedure should be validated by future clinical data, especially those with complete ulnar nerve transection at or above the elbow. Level of evidence: IV

Patients suffering from nerve injury with sensory disturbances or orofacial pain have greatly reduced quality of life, and it is a big cost for the society. Abnormal sensations caused by trigeminal nerve injury often become chronic, severely debilitating, and extremely difficult to treat. In general, non-invasive treatment such as drug treatment has been insufficient, and there are currently few available effective treatments. Surgical interventions such as end-to-end connection or nerve grafting have disadvantages such as donor site morbidity or formation of neuroma. There is need for optimizing the technique for nerve repair, especially for the trigeminal nerve system, which has so far not yet been well explored. Recently, tissue engineering using biodegradable synthetic material and cell-based therapies represents a promising approach to nerve repair and it has been reported that mesenchymal stem cell (MSC) has an anti-inflammatory effect and seems to play an important role in nerve healing and regeneration. publishedVersion

Although the gold standard for the surgical treatment of peripheral nerve injury, the autograft is associated with many drawbacks, including a second surgical procedure, donor site morbidity, mismatch of donor nerve size, and limited donor nerve length. As an alternative to the autograft, nerve guidance conduits may be used to promote neuronal growth and guide axonal extension after nerve injury. Using a blend of RGD-conjugated polyurea and polycaprolactone, a nerve guidance conduit was designed consisting of intraluminal microchannels with aligned nanofibers. A 10 mm sciatic nerve transection rat model was used to evaluate the efficacy of the conduit up to 8 weeks after nerve transection and conduit implantation. Restoration of electrophysiological activity from the nerve guidance conduit was significantly improved compared to the autograft. Functional and histological assessments indicated that the nerve guidance conduit is comparable to autograft in functional recovery and target muscle reinnervation, respectively.

Background: The repair of a segmental peripheral nerve injury is a clinical challenge. Several studies have been performed to determine superior methods for overcoming nerve gaps. The purpose of this study was to investigate if the inside-out slided epineurium of the distal segment of an injured nerve can serve as a conduit to bridge a short nerve defect (10 mm). Methods: Nineteen sciatic nerves in Sprague–Dawley rats were transected, and a 10-mm gap was left between the ends. A section of distal epineurium was pulled inside out to bridge the gap. Walking track analysis was performed, and the sciatic function index (SFI) was calculated. Wet muscle mass and withdrawal reflex were measured. The density of axon fibers at different levels of repaired nerves was determined, and histological analysis was performed at 16 weeks. Results: The mean SFI improved from −81.0 at 4 weeks to 36.3 at 16 weeks. The axon densities showed regeneration through the epineural tube, and 5 of the rats demonstrated a withdrawal reflex. The weight of the tibialis anterior muscle of the injured limb at 16 weeks was 59% that of the uninjured side. Conclusions: The distal epineural sheath tube provided a size-matched conduit between the nerve stumps, with no histological donor-site morbidity. Histologically, regeneration occurred through the epineural tube without neuroma formation, and functional recovery was comparable to that of previous studies of nerve repair techniques. Technique may be an addition to the armamentarium of tools used to treat segmental nerve defects.

BACKGROUND Conduits preseeded with either Schwann cells or stem cells differentiated into Schwann cells demonstrated promising results for the outcome of nerve regeneration in nerve defects. METHODS The concept of this trial combines nerve repair by means of a commercially available nerve guidance conduit and preseeding with autologous, undifferentiated, adipose tissue-derived stem cells. Adipose tissue-derived stem cells were harvested from rats and subsequently seeded onto a U.S. Food and Drug Administration-approved type I collagen conduit. Sciatic nerve gaps 10 mm in length were created, and nerve repair was performed by the transplantation of either conduits preseeded with autologous adipose tissue-derived stem cells or acellular (control group) conduits. After 6 months, the motor and sensory nerve conduction velocity were assessed. Nerves were removed and examined by hematoxylin and eosin, van Gieson, and immunohistochemistry (S100 protein) staining for the quality of axonal regeneration. RESULTS Nerve gaps treated with adipose tissue-derived stem cells showed superior nerve regeneration, reflected by higher motor and sensory nerve conduction velocity values. The motor and sensory nerve conduction velocity were significantly greater in nerves treated with conduits preseeded with adipose tissue-derived stem cells than in nerves treated with conduits alone (p < 0.05). Increased S100 immunoreactivity was detected for the adipose tissue-derived stem cell group. In this group, axon arrangement inside the conduits was more organized. CONCLUSIONS Transplantation of adipose tissue-derived stem cells significantly improves motor and sensory nerve conduction velocity in peripheral nerve gaps. Preseeded conduits showed a more organized axon arrangement inside the conduit in comparison with nerve conduits alone. The approach used here could readily be translated into a clinical therapy. CLINCAL QUESTION/LEVEL OF EVIDENCE Therapeutic, V.

Background The authors evaluated the long-term efficacy of the "babysitter" procedure in improving nerve regeneration and denervated muscle atrophy for peripheral nerve repair. Methods Eighty Lewis rats were allocated equally into four groups. The peroneal nerves of all animals were divided. In group A, the peroneal nerve stumps were anchored into adjacent muscles. Rats in group B underwent end-to-end neurorrhaphy. Rats in group C underwent end-to-side neurorrhaphy of the distal peroneal nerve stump to an epineurial window on the tibial nerve. Rats in group D underwent end-to-side neurorrhaphy of the distal stump to the tibial nerve with 40 percent neurectomy. After 8 weeks, end-to-end neurorrhaphy of the peroneal nerve stumps was performed in group A, C, and D during a second-stage procedure. Electrophysiology, myelinated fiber counts, muscle force and weight, and muscle histomorphometry were analyzed at 4, 8, 12, and 24 weeks postoperatively. Results At 4 weeks, the end-to-end group showed predominant advantages in nerve regeneration and muscle preservation. No differences were observed in the latency delaying rate, tetanic tension, myelinated fiber number, or muscle weight between groups B and D by 24 weeks (p > 0.05). At 24 weeks, the results revealed superior latency delaying rate, myelinated axon regeneration, and size of muscle fibers in group D as compared with group C. Conclusions Peripheral nerve repair with an initial motor nerve babysitter with 40 percent neurectomy of the donor nerve can achieve high efficacy in functional and structural recovery of the recipient system. Nerve babysitter by motor nerve with an epineural window was less effective.

Peripheral nerve injuries are challenging problems. Nerve transfers are one of many options available to surgeons caring for these patients, although they do not replace tendon transfers, nerve graft, or primary repair in all patients. Distal nerve transfers for the treatment of high ulnar nerve injuries allow for a shorter reinnervation period and improved ulnar intrinsic recovery, which are critical to function of the hand.

Poor functional outcomes are frequent after peripheral nerve injuries despite the regenerative support of Schwann cells. Motoneurons and, to a lesser extent, sensory neurons survive the injuries but outgrowth of axons across the injury site is slow. The neuronal regenerative capacity and the support of regenerating axons by the chronically denervated Schwann cells progressively declines with time and distance of the injury from the denervated targets. Strategies, including brief low-frequency electrical stimulation that accelerates target reinnervation and functional recovery, and the insertion of cross-bridges between a donor nerve and a recipient denervated nerve stump, are effective in promoting functional outcomes after complete and incomplete injuries.

BACKGROUND Lower-limb function is severely impaired after sacral plexus nerve injury. Nerve transfer is a useful reconstructive technique for proximal nerve injuries. OBJECTIVE To investigate the clinical effectiveness and safety of transferring the ipsilateral obturator nerve to the branch of the tibial nerve innervating the medial head of the gastrocnemius muscle to recover knee and ankle flexion. METHODS From 2007 to 2011, 5 patients with sacral plexus nerve injury underwent ipsilateral obturator nerve transfer as part of a strategy for surgical reconstruction of their plexuses. The mean patient age was 31.4 years (range, 19-45 years), and the mean interval from injury to surgery was 5.8 months (range, 3-8 months). The anterior branch of the obturator nerve was coapted to the branch of the tibial nerve innervating the medial head of the gastrocnemius muscle by autogenous nerve grafting. RESULTS Patient follow-up ranged from 24 to 38 months. There were no complications related to the surgery. Three patients recovered to Medical Research Council grade 3 or better in the medial head of the gastrocnemius muscle. Thigh adduction function was not affected in any patient. CONCLUSION Knee and ankle flexion can be achieved by transferring the anterior branch of the obturator nerve to the branch of the tibial nerve innervating the medial head of the gastrocnemius muscle, which is useful for balance. This procedure can be used as a new method for treating sacral plexus nerve injury. ABBREVIATION MRC, Medical Research Council.

The superficial peroneal nerve is now known as the superficial fibular nerve (SFN). Identification and treatment of entrapment of the SFN are important topics of discussion for foot and ankle surgeons, because overlooking the diagnosis can lead to permanent nerve damage. With the proper tools and skills, surgeons are able to help patients with symptomatic SFN entrapment, patients who often present in some degree of desperation, with the peripheral nerve surgeon as a last resort.

Neurotrophic factors and peripheral nerves are known to be good substrates for bridging CNS trauma. The involvement of fibroblast growth factor-2 (FGF-2) activation in the dorsal root ganglion (DRG) was examined following spinal cord injury in the rat. We evaluated whether FGF-2 increases the ability of a sciatic nerve graft to enhance neuronal plasticity, in a gap promoted by complete transection of the spinal cord. The rats were subjected to a 4 mm-long gap at low thoracic level and were repaired with saline (Saline or control group, n = 10), or fragment of the sciatic nerve (Nerve group, n = 10), or fragment of the sciatic nerve to which FGF-2 (Nerve + FGF-2 group, n = 10) had been added immediately after lesion. The effects of the FGF-2 and fragment of the sciatic nerve grafts on neuronal plasticity were investigated using choline acetyl transferase (ChAT)-immunoreactivity of neurons in the dorsal root ganglion after 8 weeks. Preservation of the area and diameter of neuronal cell bodies in dorsal root ganglion (DRG) was seen in animals treated with the sciatic nerve, an effect enhanced by the addition of FGF-2. Thus, the addition of exogenous FGF-2 to a sciatic nerve fragment grafted in a gap of the rat spinal cord submitted to complete transection was able to improve neuroprotection in the DRG. The results emphasized that the manipulation of the microenvironment in the wound might amplify the regenerative capacity of peripheral neurons

A nerve block is an effective tool for diagnostic and therapeutic methods. If a diagnostic nerve block is successful for pain relief and the subsequent therapeutic nerve block is effective for only a limited duration, the next step that should be considered is a nerve ablation or modulation. The nerve ablation causes iatrogenic neural degeneration aiming only for sensory or sympathetic denervation without motor deficits. Nerve ablation produces the interruption of axonal continuity, degeneration of nerve fibers distal to the lesion (Wallerian degeneration), and the eventual death of axotomized neurons. The nerve ablation methods currently available for resection/removal of innervation are performed by either chemical or thermal ablation. Meanwhile, the nerve modulation method for interruption of innervation is performed using an electromagnetic field of pulsed radiofrequency. According to Sunderland's classification, it is first and foremost suggested that current neural ablations produce third degree peripheral nerve injury (PNI) to the myelin, axon, and endoneurium without any disruption of the fascicular arrangement, perineurium, and epineurium. The merit of Sunderland's third degree PNI is to produce a reversible injury. However, its shortcoming is the recurrence of pain and the necessity of repeated ablative procedures. The molecular mechanisms related to axonal regeneration after injury include cross-talk between axons and glial cells, neurotrophic factors, extracellular matrix molecules, and their receptors. It is essential to establish a safe, long-standing denervation method without any complications in future practices based on the mechanisms of nerve degeneration as well as following regeneration.

The present study investigated the effects of transforming growth factor (TGF)-β3 on the regeneration of facial nerves in rabbits. A total of 20 adult rabbits were randomly divided into three equal groups: Normal control (n=10), surgical control (n=10) and TGF-β3 treatment (n=10). The total number and diameter of the regenerated nerve fibers was significantly increased in the TGF-β3 treatment group, as compared with in the surgical control group (P

An increasing number of biomaterial nerve guides has been developed that await direct comparative testing with the 'gold-standard' autologous nerve graft in functional repair of peripheral nerve defects. In the present study, 20 mm rat sciatic nerve defects were bridged with either a collagen-based micro-structured nerve guide (Perimaix) or an autologous nerve graft. Axons regenerated well into the Perimaix scaffold and, the majority of these axons grew across the 20 mm defect into the distal nerve segment. In fact, both the total axon number and the number of retrogradely traced somatosensory and motor neurons extending their axons across the implant was similar between Perimaix and autologous nerve graft groups. Implantation of Schwann cell-seeded Perimaix scaffolds provided only a beneficial effect on myelination within the scaffold. Functional recovery supported by the implanted, non-seeded Perimaix scaffold was as good as that observed after the autologous nerve graft, despite the presence of thinner myelin sheaths in the Perimaix implanted nerves. These findings support the potential of the Perimaix collagen scaffold as a future off-the-shelf device for clinical applications in selected cases of traumatic peripheral nerve injury.

The use of a nerve conduit provides an opportunity to regulate cytokines, growth factors and neurotrophins in peripheral nerve regeneration and avoid autograft defects. We constructed a poly-D-L-lactide (PDLLA)-based nerve conduit that was modified using poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} and β-tricalcium phosphate. The effectiveness of this bioactive PDLLA-based nerve conduit was compared to that of PDLLA-only conduit in the nerve regeneration following a 10-mm sciatic nerve injury in rats. We observed the nerve morphology in the early period of regeneration, 35 days post injury, using hematoxylin-eosin and methylene blue staining. Compared with the PDLLA conduit, the nerve fibers in the PDLLA-based bioactive nerve conduit were thicker and more regular in size. Muscle fibers in the soleus muscle had greater diameters in the PDLLA bioactive group than in the PDLLA only group. The PDLLA-based bioactive nerve conduit is a promising strategy for repair after sciatic nerve injury.

Acellular nerve allografts can help preserve normal nerve structure and extracellular matrix composition. These allografts have low immunogenicity and are more readily available than autologous nerves for the repair of long-segment peripheral nerve defects. In this study, we repaired a 40-mm ulnar nerve defect in rhesus monkeys with tissue-engineered peripheral nerve, and compared the outcome with that of autograft. The graft was prepared using a chemical extract from adult rhesus monkeys and seeded with allogeneic Schwann cells. Pathomorphology, electromyogram and immunohistochemistry findings revealed the absence of palmar erosion or ulcers, and that the morphology and elasticity of the hypothenar eminence were normal 5 months postoperatively. There were no significant differences in the mean peak compound muscle action potential, the mean nerve conduction velocity, or the number of neurofilaments between the experimental and control groups. However, outcome was significantly better in the experimental group than in the blank group. These findings suggest that chemically extracted allogeneic nerve seeded with autologous Schwann cells can repair 40-mm ulnar nerve defects in the rhesus monkey. The outcomes are similar to those obtained with autologous nerve graft.

Iatrogenic nerve injuries are always a matter for concern. This article will address the common causes, diagnosis and management of iatrogenic peripheral nerve injuries. The most widely used classification of peripheral nerve injury is that described by Seddon in 1943.1 He divided nerve injuries into three types: neurapraxia, axonotmesis and neurotmesis. Neurapraxia (inactivity of the nerve) is a non-degenerative lesion of a nerve characterised by a complete or partial failure to propagate an action, potentially resulting in motor and/or sensory loss. It is usually caused by compression or ischaemia, resulting in ischaemia of the myelin sheath. The nerve remains intact and Wallerian degeneration does not occur. It is reversible if the injurious agent is removed. If the distal segment of the nerve is stimulated, there is a motor response. The lesion recovers by remyelination of the distal segment and takes between two and 12 weeks, depending on the age of the patient and the site of the injury. In practice, it is unwise to assume that a lesion is a neurapraxia rather than a more severe injury because this will lead to delay in diagnosis and a poorer outcome. The presence of persistent pain suggests that the injurious agent is continuing to act. The diagnosis should not be made in the presence of a strong Tinel test which indicates that axons have been ruptured. An axonotmesis (cutting of the axon) is the result of disruption of the axon and its myelin sheath. The supporting structures, Schwann cells, endoneurium, perineurium and epineurium remain intact. It is usually the result of severe compression or a crush injury. Wallerian degeneration occurs distally, and proximally to the closest node of Ranvier. Repair is by a combination of collateral sprouting in lesser injuries and axonal regeneration in more severe injuries. The latter occurs at …

Cable nerve grafting is the recommended surgical treatment for large peripheral nerve defects. Traditionally, this is performed by bridging a gap in the nerve with multiple autologous nerve cables, repairing the epineurium of each cable to the perineurium of a fascicle of the injured nerve that is similar in size to the graft. The authors present a new technique in which they used nerve-cutting guides to aid in the placement of fibrin glue to secure the sides of the cabled nerve graft together to facilitate handling of the cabled nerve graft and to expedite repair. Freshening the graft nerve ends after the application of fibrin glue using appropriately sized nerve-cutting guides allows for donor-recipient size match and epineurium-to-epineurium repair of the cabled graft to injured nerve. Though further follow-up is needed to determine long-term outcomes following this technique, early results are promising with clinical improvement seen in a similar timeframe to traditional grafting.

We evaluated the strength of conduit-assisted primary digital nerve repairs, with varying suture location and number, in 56 digital nerves from cadavers. Maximum load to failure was tested for the following seven repairs, designated by the number of epineurial sutures followed by the number of sutures at each end of the conduit: 4 (epineurial sutures)/0 (sutures at each end of conduit), 4/4, 4/2, 2/2, 0/4, 0/2, 0/1. The 4/4 repair (3.0 N) was significantly stronger than 4/0 (1.5 N), 2/2 (1.6 N), 0/4 (2.0 N), 0/2 (1.4 N) and 0/1 (1.1 N). Considering all repair types, there was a significant correlation between suture number and failure load, with the strongest repair having a total of 12 sutures, which is impractical. Reasonable repair options, which have two sutures at each end of the conduit and either two or no epineurial sutures, are as strong as a four-suture epineurial repair but have less sutures at the coaptation site.

In peripheral nerve (PN) injuries requiring surgical repair, as in PN transection, cellular and ECM remodeling at PN epineurial repair sites is hypothesized to reduce PN functional outcomes by slowing, misdirecting, or preventing axons from regrowing appropriately across the repair site. Herein this study reports on deriving and analyzing fetal porcine urinary bladder extracellular matrix (fUB-ECM) by vacuum assisted decellularization, fabricating fUBM-ECM nerve wraps, and testing fUB-ECM nerve wrap biocompatibility and bioactivity in a trigeminal, infraorbital nerve (ION) branch transection and direct end-to-end repair model in rat. FUB-ECM nerve wraps significantly improved epi- and endoneurial organization and increased both neovascularization and growth associated protein-43 (GAP-43) expression at PN repair sites, 28-days post surgery. However, the number of neurofilament positive axons, remyelination, and whisker-evoked response properties of ION axons were unaltered, indicating improved tissue remodeling per se does not predict axon regrowth, remyelination, and the return of mechanoreceptor cortical signaling. This study shows fUB-ECM nerve wraps are biocompatible, bioactive, and good experimental and potentially clinical devices for treating epineurial repairs. Moreover, this study highlights the value provided by precise, analytic models, like the ION repair model, in understanding how PN tissue remodeling relates to axonal regrowth, remyelination, and axonal response properties.

PURPOSE The aim of this study was to define a sutureless peripheral nerve repair technique with a vein graft and bone marrow-derived stem cells (BMSC) and compare it to epineural repair. MATERIALS AND METHODS Thirty Wistar Albino rats were divided into five groups evenly. In the control group (C), epineural repair was performed. In the SV (suture + vein) and MSV (BMSC + suture + vein) groups, epineural repair was wrapped with a vein graft. In the V (vein) and MV (vein + BMSC) groups, sutureless repair using a vein graft was performed by taking sutures away from the regeneration site. Rats were evaluated with pinprick, toe spread tests and sciatic nerve index (SFI) at 4th, 8th, and 12th weeks. They were sacrificed at 12th week, repair sites were harvested and evaluated immunohistochemically. RESULTS There was no difference in pinprick and toe spread tests between the groups at 12th week. The mean SFI was -76.5 ± 3.7, -65.2 ± 11.7, -46.2 ± 19.4, -68.8 ± 9.8, -56 ± 8.8 in the C, SV, MSV, V, MV groups, respectively. The MSV group showed significantly the best SFI results (P