Nerve Allografts: Current Utility and Future Directions.

Processed nerve allograft is a widely accepted tool for reconstructing peripheral nerve defects. Repair parameters that need to be considered include gap length, nerve diameter, nerve type (motor, sensory, or mixed), and the soft tissue envelope. Although the use of processed nerve allograft must be considered based on each unique clinical scenario, a rough algorithm can be formed based on the available animal and clinical literature. This article critically reviews the current surgical algorithm, defines the role of processed nerve allograft compared with nerve autograft, and discusses how this role may change in the future.

Nerve Autograft: Preservation of a Lost Art.

Nerve autografts involve the transplantation of a segment of the patient's own nerve to bridge a nerve gap. Autografts provide biological compatibility, support for axonal regeneration, and the ability to provide an anatomic scaffold for regrowth that other modalities may not match. Disadvantages of the autograft include donor site morbidity and the extra operative time needed to harvest the graft. Nevertheless, nerve autografts such as the sural nerve remain the gold standard in reconstructing nerve gaps, but a multitude of factors need to be favorable in order to garner reliable, consistent outcomes.

Updates in peripheral nerve surgery of the upper extremity: diagnosis and treatment options.

The loss of function resulting from peripheral nerve injuries confers a significant burden to the patient and society. The treatment of peripheral nerve injuries requires an accurate diagnosis and formulation of a functional reconstructive plan. Advances in peripheral nerve imaging complement electrodiagnostic studies, and provide us with detailed information regarding the status of nerve injury, repair, and regeneration in order to prognosticate recovery and determine the need for surgical intervention. When direct nerve repair is not possible, the methods for bridging a nerve gap are the nerve autograft, allograft and conduit. While current research supports the use of conduits and nerve allografts for shorter nerve gaps, the nerve autograft still remains the gold standard for bridging a nerve gap. When direct nerve repair or nerve grafting fails, or is anticipated to be insufficient, nerve transfers are an alternative for reconstruction. Knowledge of axonal counts, upper limb innervation patterns, location and clustering of upper limb peripheral nerves allows for the design of new nerve transfers. The options of nerve transfers for radial, ulnar and median nerve injuries are outlined, as well as their outcomes. Nerve transfers are an attractive option for restoring motor and sensory function while minimizing donor site morbidity. However, one must consider their limitations, and preserve donor sites for secondary tendon transfer options. This article presents the latest information regarding the imaging of peripheral nerves, methods to bridge a nerve gap, and nerve transfers to aid the peripheral nerve surgeon in choosing a reconstructive plan.

Minimally invasive, indirect corneal neurotization using an ipsilateral sural nerve graft for early neurotrophic keratopathy.

Purpose: Neurotrophic keratopathy is a degenerative disease characterized by damage to the corneal nerves leading to corneal hypoesthesia and anaesthesia. The resultant progressive visual deterioration is refractory to existing conventional treatment options. Corneal neurotization is a novel and effective surgical procedure that directly targets the underlying pathology of nerve loss by stimulating new corneal nerve growth. This study reports the outcomes and the pre- and postoperative in vivo confocal microscopy findings of the first published Australian case of indirect, minimally invasive, corneal neurotization using an ipsilateral sural nerve autograft. Observations: An 11-year-old boy developed corneal hypoesthesia in the left eye following surgical debulking of a cerebellopontine angle arachnoid cyst. He was diagnosed with Mackie Stage 1 neurotrophic keratopathy. Due to his hypoesthesia, he had developed recurrent microbial keratitis and corneal ulceration secondary to foreign bodies sustained during contact sports. At presentation, he reported photophobia and dry eye symptoms, corrected-distance visual acuity was 6/18, Cochet-Bonnet aesthesiometer demonstrated reduced corneal sensation (5-15mm), Schirmer's I test was 15mm, and in vivo confocal microscopy showed a complete absence of a subepithelial corneal plexus. He underwent indirect, minimally invasive, corneal neurotization using the ipsilateral supratrochlear nerve and a sural nerve autograft. Subjective improvement in corneal sensation was noticed by the patient at 2 months. Objective improvement, measured on Cochet-Bonnet aesthesiometer, was first observed at 6 months with steady stepwise improvement to 20-35mm at 21 months. Importantly, due to the increase in corneal sensation, the patient did not develop any further corneal complications. At 12 months, dry eye symptoms resolved and Schirmer's I test improved to 30mm. At 15 months, corrected-distance visual acuity improved to 6/5 and in vivo confocal microscopy demonstrated evidence of corneal reinnervation with nerves running through the subepithelial space surrounded by healthy and active keratocytes. Conclusions and importance: Corneal neurotization represents an exciting development in the armamentarium for the treatment of neurotrophic keratopathy and can be considered for younger patients with early-stage disease.

Comparison of human amniotic membrane and collagen nerve wraps around sciatic nerve reverse autografts in a rat model.

Human amniotic membrane (hAM) and collagen nerve wraps are biomaterials that have been investigated as therapies for improving outcomes of peripheral nerve regeneration; however, their efficacy has not been compared. The purpose of this study is to compare the efficacy of collagen and human amniotic membrane nerve wraps in a rodent sciatic nerve reverse autograft model. Lewis rats (n = 29) underwent sciatic nerve injury and repair in which a 10-mm gap was bridged with reverse autograft combined with either no nerve wrap (control), collagen nerve wrap or hAM nerve wrap. Behavioral analyses were performed at baseline and 4, 8 and 12 weeks. Electrophysiological studies were conducted at 8, 10 and 12 weeks. Additional outcomes assessed included gastrocnemius muscle weights, nerve adhesions, axonal regeneration and scarring at 12 weeks. Application of both collagen and hAM nerve wraps resulted in improvement of functional and histologic outcomes when compared with controls, with a greater magnitude of improvement for the experimental group treated with hAM nerve wraps. hAM-treated animals had significantly higher numbers of axons compared to control animals (p < 0.05) and significantly less perineural fibrosis than both control and collagen treated nerves (p < 0.05). The ratio of experimental to control gastrocnemius weights was significantly greater in hAM compared to control samples (p < 0.05). We conclude that hAM nerve wraps are a promising biomaterial that is effective for improving outcomes of peripheral nerve regeneration, resulting in superior nerve regeneration and functional recovery compared to collagen nerve wraps and controls.

Long-term sensibility outcomes of secondary digital nerve reconstruction with sural nerve autografts: a retrospective study.

BACKGROUND: Recovery of sensibility after digital nerve injury is crucial for restoring normal hand function. We evaluated long-term outcomes of digital nerve reconstruction with autografts. METHODS: This retrospective study included patients who underwent secondary reconstruction of digital nerves with nerve autografting. Recovery of sensibility was evaluated based on the following: patient self-assessment, two-point discrimination (2PD), and a total sensation score (sum of proprioception, temperature sensation, and sharp/dull discrimination). Mixed models regression was used to study predictors of sensibility outcomes. The predictors analyzed were age, sex, smoking status, number of fingers involved in a patient (as a measure of injury severity), time to reconstruction, and time to follow-up. RESULTS: In 61 patients, 174 digital nerves in 126 fingers were reconstructed after an average of 33.1 weeks from injury. The mean follow-up was 6.4 years from reconstruction. The mean graft length was 3.6 cm. Self-rated sensibility in the affected area was very good in 13% of patients, good in 33%, satisfactory in 40%, and poor in 24%. 2PD at 6 mm was present in 17% of patients, at 10 mm in 12%, and at 15 mm in 18% (mean 2PD was 10.8). Proprioception was preserved in 107 (85%) fingers, sensation of temperature was preserved in 99 (75%) of fingers, and sharp/dull discrimination in 88 (70%) fingers. Time from injury to reconstruction was the only significant predictor of the total sensation score. CONCLUSION: Our data indicate that earlier reconstruction is associated with a favorable outcome.

Comparison of the Effects of Extracorporeal Irradiation and Liquid Nitrogen on Nerve Recovery in a Rat Model.

AIM OF THE STUDY: Biologic reconstruction using tumor-bearing bone autografts devitalized by liquid nitrogen or extracorporeal irradiation (oncological sterilization) is a safe and effective method in musculoskeletal surgery. The purpose of this study was to examine the effects of these two oncological sterilization methods on nerve recovery. METHODS: A total of 48 rats were randomly divided into 3 groups as autograft, irradiation and liquid nitrogen groups. A nerve defect created in the right sciatic nerve was reconstructed with an autograft obtained from the nerve itself. Group I underwent reconstruction with standard nerve autograft. Group II and Group III underwent reconstruction with devitalized nerve autograft treated through extracorporeal irradiation and liquid nitrogen, respectively. The left sciatic nerves of the rats served as control. Electromyography, motor function test and histomorphological analysis were performed to assess the nerve recovery on the 3rd (early stage) and 4th months (late stage). RESULTS: Electrophysiological assessment revealed better results in irradiation group compared with liquid nitrogen group in terms of myelinization and axonal regeneration. Motor performance of the autograft group was slightly better than the other groups. Histologically, autograft group demonstrated better results compared with other groups. Late-stage assessments revealed high rates of myelinization in the graft segment in liquid nitrogen group and in the segment distal to the graft in irradiation group. CONCLUSIONS: This study has demonstrated that nerve autografts treated by oncological sterilization methods may be used for nerve reconstruction in limb salvage surgery. However, further studies are needed to clarify the applicability of these methods.

Enhanced nerve autograft using stromal vascular fraction.

PURPOSE: While many studies have been conducted on peripheral nerve regeneration, few have focused on strengthening the nerve autografts. This study hypothesized that adding autologous stromal vascular fraction (SVF) to a nerve autograft will improve nerve regeneration. The purpose of this study was to compare the results of nerve autograft with and without SVF. METHODS: An adipose tissue sample was excised from the right inguinal region of female Wistar rats, and SVF was separated by centrifugation. The left sciatic nerve was resected at a length of 15 mm and the defect was bridged by a resected nerve autograft. We added SVF with collagen gel around the nerve autograft in the SVF group and added saline in the control group. At 12 weeks after surgery, the wet muscle weight, distal latency, and amplitude of the compound muscle action potential of the tibialis anterior were evaluated by the ratio of left and right sides. Sciatic functional index (SFI) was also evaluated. RESULTS: The wet muscle weight was significantly better in the SVF group than in the control group. The results of distal latency, amplitude, and SFI were not significantly different between the two groups; however, these results tended to be better in the SVF group than in the control group. CONCLUSION: SVF added to artificial nerve grafts has been reported to promote axonal regeneration through secretion of angiogenic, neurotrophic, and anti-apoptotic factors. This study indicates that SVF may also be effective for nerve autografts and improve the clinical result of nerve autograft.

A Multicenter Matched Cohort Study of Processed Nerve Allograft and Conduit in Digital Nerve Reconstruction.

PURPOSE: Biomaterials used to restore digital nerve continuity after injury associated with a defect may influence ultimate outcomes. An evaluation of matched cohorts undergoing digital nerve gap reconstruction was conducted to compare processed nerve allograft (PNA) and conduits. Based on scientific evidence and historical controls, we hypothesized that outcomes of PNA would be better than for conduit reconstruction. METHODS: We identified matched cohorts based on patient characteristics, medical history, mechanism of injury, and time to repair for digital nerve injuries with gaps up to 25 mm. Data were stratified into 2 gap length groups: short gaps of 14 mm or less and long gaps of 15 to 25 mm. Meaningful sensory recovery was defined as a Medical Research Council scale of S3 or greater. Comparisons of meaningful recovery were made by repair method between and across the gap length groups. RESULTS: Eight institutions contributed matched data sets for 110 subjects with 162 injuries. Outcomes data were available in 113 PNA and 49 conduit repairs. Meaningful recovery was reported in 61% of the conduit group, compared with 88% in the PNA group. In the group with a 14-mm or less gap, conduit and PNA outcomes were 67% and 92% meaningful recovery, respectively. In the 15- to 25-mm gap length group, conduit and PNA outcomes were 45% and 85% meaningful recovery, respectively. There were no reported adverse events in either treatment group. CONCLUSIONS: Outcomes of digital nerve reconstruction in this study using PNA were consistent and significantly better than those of conduits across all groups. As gap lengths increased, the proportion of patients in the conduit group with meaningful recovery decreased. This study supports the use of PNA for nerve gap reconstruction in digital nerve reconstructions up to 25 mm. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Silicone tubes with thyroid hormone (Τ3) and BDNF as an alternative to autografts for bridging neural defects.

The way thyroid hormone works in peripheral nerve regeneration has not been fully elucidated, although studies have shown that it has a strong positive effect on nerve regeneration. It is argued that its action is probably stronger than the neurotrophic factors that have been used for some time. It is hypothesized that the use of thyroid hormone in the nerve tubes has a beneficial effect on nerve regeneration to the extent that the results of its use are comparable to those of the autograft technique in bridging small nerve deficits. In this experimental study, we examined the effect of thyroid hormone and BDNF (Brain Derived Neurotrophic Factor) on the repair of 10 mm nerve defects when administered within silicone nerve tubes and compared the results with the autograft method. Thyroid hormone promotes nerve regeneration mainly by increasing its speed and its effect on the maturation of nerve fibers compared to the other groups where the nerve deficit was bridged by entubulation. Also, better organization and the absence of intraneural fibrosis, compared to the other groups, may argue for the action of thyroid hormone in regulating the inflammatory response. Functionally, the AG group showed better results compared to the other groups by the end of the study (16 weeks).

A single session of brief electrical stimulation enhances axon regeneration through nerve autografts.

Nerve graft reconstruction of gap defects may result in poor clinical outcomes, particularly with long regeneration distances. Electrical stimulation (ES) of nerves may improve outcomes in such patients. A single session of ES at 20 Hz for 1 h significantly enhances axon regeneration in animals and human subjects after nerve crush or nerve transection and repair. The objectives of this study were to evaluate if ES enhances axon regeneration through nerve grafts and if there is added benefit of a second, delayed session of ES (serial ES) on axon regeneration as compared to a single session only of ES. In female rats, a gap defect was created in the hindlimb common peroneal (CP) nerve and immediately reconstructed with a 10 mm nerve autograft (Experiment 1) or a 20 mm nerve autograft (Experiment 2). In Experiment 1, rats were randomized to 1 h of CP nerve ES or sham stimulation. In Experiment 2, rats were randomized to control (sham ES + sham ES), single ES (ES + sham ES), or serial ES (ES + ES), which consisted of an initial 1 h session of either ES or sham stimulation of the CP nerve, followed by a second 1 h session of ES or sham stimulation of the CP nerve 4 weeks later. In both experiments, after a 6 week period of nerve regeneration, CP neurons that had regenerated axons distal to the autograft were retrograde labelled for enumeration, and the CP nerve distal to the autograft was harvested for histomorphometry. In Experiment 1, rats that received CP nerve ES had statistically significantly more motor (p < .05) and sensory (p < .05) neurons that regenerated axons distal to the 10 mm nerve autograft, with more myelinated axons on histomorphometry (p < .001). Similarly, in Experiment 2, significantly more motor (p < .01) and sensory (p < .05) neurons regenerated axons distal to the 20 mm nerve autograft after a single session or two sessions of CP nerve ES. There was no significant difference in the number of regenerated motor or sensory neurons between rats with 20 mm CP nerve autografts receiving either one or two sessions of CP nerve ES (p > .05). In conclusion, a single session of ES enhances axon regeneration following nerve autografting with no added effect of a second, delayed session of ES. These findings support previous studies in animals and humans of the robust effect of a single session of ES in promoting nerve regeneration following injury and repair.

Current concepts in peripheral nerve surgery.

The injuries of the peripheral nerves are relatively frequent. Some of them may lead to defects which cannot be repaired with direct end-to-end repair without tension. These injuries may cause function loss to the patient, and they consist a challenge for the treating microsurgeon. Autologous nerve grafts remain the gold standard for bridging the peripheral nerve defects. Nevertheless, there are selected cases where alternative types of nerve reconstruction can be performed in order to cover the peripheral nerve defects. In all these types of reconstruction, the basic principles of microsurgery are necessary and the surgeon should be aware of them in order to achieve a successful reconstruction. The purpose of the present review was to present the most current data concerning the surgical options available for bridging such defects.

An Experimental Study on the Optimal Timing for the Repair of Incomplete Facial Paralysis by Hypoglossal-facial 'Side'-to-side Neurorrhaphy in Rats.

OBJECTIVE: To investigate the optimal timing for the repair of persistent incomplete facial paralysis by hypoglossal-facial 'side'-to-side neurorrhaphy in rats. METHODS: A total of 30 adult rats with crushed and bulldog-clamped facial nerve injury were randomly divided into 5 groups (n = 6 each) that were subjected to injury without nerve repair or with immediate repair, 2-week-delayed repair, 4-week-delayed repair, or 8-week-delayed repair. Three months later, the effects of repair in each rat were evaluated by facial symmetry assessment, electrophysiological examination, retrograde labeling, and axon regeneration measurement. RESULTS: At 3 months after injury, the alpha angle significantly increased in the group of rats with 4-week-delayed repair compared with the other four groups. Upon stimulation of the facial nerve or Pre degenerated nerve, the muscle action potentials MAPs were recorded in the whisker pad muscle, and the MAP amplitude and area under the curve in the 4-week-delayed repair group were significantly augmented at 3 months post-injury. Similarly, the number of retrograde-labeled motor neurons in the facial and hypoglossal nuclei was quantified to be significantly greater in the 4-week-delayed repair group than in the other groups, and a large number of regenerated axons was also observed. CONCLUSION: The results of this study demonstrated that hemiHN-FN neurorrhaphy performed 4 weeks after facial nerve injury was most effective in terms of the functional recovery of axonal regeneration and activation of facial muscles.

An Experimental Study on the Optimal Timing for the Repair of Incomplete Facial Paralysis by Hypoglossal-facial 'Side'-to-side Neurorrhaphy in Rats / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate the optimal timing for the repair of persistent incomplete facial paralysis by hypoglossal-facial 'side'-to-side neurorrhaphy in rats.</p><p><b>METHODS</b>A total of 30 adult rats with crushed and bulldog-clamped facial nerve injury were randomly divided into 5 groups (n = 6 each) that were subjected to injury without nerve repair or with immediate repair, 2-week-delayed repair, 4-week-delayed repair, or 8-week-delayed repair. Three months later, the effects of repair in each rat were evaluated by facial symmetry assessment, electrophysiological examination, retrograde labeling, and axon regeneration measurement.</p><p><b>RESULTS</b>At 3 months after injury, the alpha angle significantly increased in the group of rats with 4-week-delayed repair compared with the other four groups. Upon stimulation of the facial nerve or Pre degenerated nerve, the muscle action potentials MAPs were recorded in the whisker pad muscle, and the MAP amplitude and area under the curve in the 4-week-delayed repair group were significantly augmented at 3 months post-injury. Similarly, the number of retrograde-labeled motor neurons in the facial and hypoglossal nuclei was quantified to be significantly greater in the 4-week-delayed repair group than in the other groups, and a large number of regenerated axons was also observed.</p><p><b>CONCLUSION</b>The results of this study demonstrated that hemiHN-FN neurorrhaphy performed 4 weeks after facial nerve injury was most effective in terms of the functional recovery of axonal regeneration and activation of facial muscles.</p>

Nerve Repair and Nerve Grafting.

Direct repair and nerve autografting are primary options in the treatment of upper extremity peripheral nerve injuries. Deciding between these surgical options depends on the mechanism of injury, time since injury, and length of repair defect. Principles of direct repair and nerve autografting are reviewed. Finally, a literature-based review of the outcomes of upper extremity peripheral nerve repair and autografting is provided. Taken together, this article provides relevant and recent data for surgeons regarding patient selection, technique selection, surgical technique, surgical outcomes, and prognostic factors that will aid surgeons treating patients with upper extremity peripheral nerve injuries.

A chronically-denervated versus a freshly-harvested autograft for nerve repair in rats.

OBJECTIVES: Autologous nerve grafting remains the gold standard for repair of peripheral nerve injuries. Its use, however, is limited by donor nerve availability and donor site morbidity. This is especially problematic after failure of an initial autograft that requires a repeat nerve graft, resulting in a second surgical site with associated morbidity. Based on the molecular differences in nerve degeneration in the proximal and distal segments after transection, we hypothesized that a chronically-denervated proximal stump may be viable for autologous nerve repair. METHODS: 20 Sprague-Dawley rats underwent right sciatic nerve excision and sural nerve transection. After 8 weeks, nerve repair was performed by harvesting the proximal segment of the sural nerve (n=10) or a fresh sural nerve (n=10) from the contralateral hind limb. Electrophysiological changes were analyzed to compare the fresh and denervated grafts. RESULTS: Electrophysiological testing demonstrated higher compound motor action potential in the denervated group compared to the fresh autograft group, however this difference was not statistically significant (p=0.117). CONCLUSION: The proximal segment of a chronically-denervated sural nerve can be as effective as a fresh sural nerve for autologous repair of peripheral nerve injuries in a rodent model.

Nerve autografts and tissue-engineered materials for the repair of peripheral nerve injuries: a 5-year bibliometric analysis.

With advances in biomedical methods, tissue-engineered materials have developed rapidly as an alternative to nerve autografts for the repair of peripheral nerve injuries. However, the materials selected for use in the repair of peripheral nerve injuries, in particular multiple injuries and large-gap defects, must be chosen carefully. Various methods and materials for protecting the healthy tissue and repairing peripheral nerve injuries have been described, and each method or material has advantages and disadvantages. Recently, a large amount of research has been focused on tissue-engineered materials for the repair of peripheral nerve injuries. Using the keywords "pe-ripheral nerve injury", "autotransplant", "nerve graft", and "biomaterial", we retrieved publications using tissue-engineered materials for the repair of peripheral nerve injuries appearing in the Web of Science from 2010 to 2014. The country with the most total publications was the USA. The institutions that were the most productive in this field include Hannover Medical School (Germany), Washington University (USA), and Nantong University (China). The total number of publications using tissue-engineered materials for the repair of peripheral nerve injuries grad-ually increased over time, as did the number of Chinese publications, suggesting that China has made many scientific contributions to this field of research.

Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence.

Repair of large nerve defects with acellular nerve allografts (ANAs) is an appealing alternative to autografting and allotransplantation. ANAs have been shown to be similar to autografts in supporting axonal regeneration across short gaps, but fail in larger defects due to a poorly-understood mechanism. ANAs depend on proliferating Schwann cells (SCs) from host tissue to support axonal regeneration. Populating longer ANAs places a greater proliferative demand on host SCs that may stress host SCs, resulting in senescence. In this study, we investigated axonal regeneration across increasing isograft and ANA lengths. We also evaluated the presence of senescent SCs within both graft types. A sciatic nerve graft model in rats was used to evaluate regeneration across increasing isograft (~autograft) and ANA lengths (20, 40, and 60 mm). Axonal regeneration and functional recovery decreased with increased graft length and the performance of the isograft was superior to ANAs at all lengths. Transgenic Thy1-GFP rats and qRT-PCR demonstrated that failure of the regenerating axonal front in ANAs was associated with increased levels of senescence related markers in the graft (senescence associated ß-galactosidase, p16(INK4A), and IL6). Lastly, electron microscopy (EM) was used to qualitatively assess senescence-associated changes in chromatin of SCs in each graft type. EM demonstrated an increase in the presence of SCs with abnormal chromatin in isografts and ANAs of increasing graft length. These results are the first to suggest that SC senescence plays a role in limited axonal regeneration across nerve grafts of increasing gap lengths.

Viscoelasticity of repaired sciatic nerve by poly(lactic-co-glycolic acid) tubes.

Medical-grade synthetic poly(lactic-co-glycolic acid) polymer can be used as a biomaterial for nerve repair because of its good biocompatibility, biodegradability and adjustable degradation rate. The stress relaxation and creep properties of peripheral nerve can be greatly improved by repair with poly(lactic-co-glycolic acid) tubes. Ten sciatic nerve specimens were harvested from fresh corpses within 24 hours of death, and were prepared into sciatic nerve injury models by creating a 10 mm defect in each specimen. Defects were repaired by anastomosis with nerve autografts and poly(lactic-co-glycolic acid) tubes. Stress relaxation and creep testing showed that at 7 200 seconds, the sciatic nerve anastomosed by poly(lactic-co-glycolic acid) tubes exhibited a greater decrease in stress and increase in strain than those anastomosed by nerve autografts. These findings suggest that poly(lactic-co-glycolic acid) exhibits good viscoelasticity to meet the biomechanical require-ments for a biomaterial used to repair sciatic nerve injury.