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This article presents a personal overview of nerve transfers and emphasizes the various factors that contribute to outcome following these surgeries. There is no "one result" for all nerve transfers. The results will vary depending on factors relating to the donor nerve and the recipient nerve, the degree of the surgical difficulty of the specific procedure, and issues relating to preoperative and postoperative rehabilitation. The general issues that influence all nerve injury and recovery, such as age of the patient, comorbidities, and time since injury, pertain to nerve transfers as well., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Cervical spinal cord injury can result in profound loss of upper extremity function. Recent interest in the use of nerve transfers to restore volitional control is an exciting development in the care of these complex patients. In this article, the authors review preliminary results of nerve transfers in spinal cord injury., Methods: Review of the literature and the authors' cases series of 13 operations in nine spinal cord injury nerve transfer recipients was performed. Representative cases were reviewed to explore critical concepts and preliminary outcomes., Results: The nerve transfers used expendable donors (e.g., teres minor, deltoid, supinator, and brachialis) innervated above the level of the spinal cord injury to restore volitional control of missing function such as elbow extension, wrist extension, and/or hand function (posterior interosseous nerve or anterior interosseous nerve/finger flexors reinnervated). Results from the literature and the authors' patients (after a mean postsurgical follow-up of 12 months) indicate gains in function as assessed by both manual muscle testing and patients' self-reported outcomes measures., Conclusions: Nerve transfers can provide an alternative and consistent means of reestablishing volitional control of upper extremity function in people with cervical level spinal cord injury. Early outcomes provide evidence of substantial improvements in self-reported function despite relatively subtle objective gains in isolated muscle strength. Further work to investigate the optimal timing and combination of nerve transfer operations, the combination of these with traditional treatments (tendon transfer and functional electrical stimulation), and measurement of outcomes is imperative for determining the precise role of these operations., Clinical Question/level of Evidence: Therapeutic, IV.

Following peripheral nerve injury, the distal nerve is primed for regenerating axons by generating a permissive environment replete with glial cells, cytokines, and neurotrophic factors to encourage axonal growth. However, increasing evidence demonstrates that regenerating axons within peripheral nerves still encounter axonal-growth inhibitors, such as chondroitin sulfate proteoglycans. Given the generally poor clinical outcomes following peripheral nerve injury and reconstruction, the use of pharmacological therapies to augment axonal regeneration and overcome inhibitory signals has gained considerable interest. Joshi et al. (2014) have provided evidence for preferential or modality-specific (motor versus sensory) axonal growth and regeneration due to inhibitory signaling from Rho-associated kinase (ROCK) pathway regulation. By providing inhibition to the ROCK signaling pathway through Y-27632, they demonstrate that motor neurons regenerating their axons are impacted to a greater extent compared to sensory neurons. In light of this evidence, we briefly review the literature regarding modality-specific axonal regeneration to provide context to their findings. We also describe potential and novel barriers, such as senescent Schwann cells, which provide additional axonal-growth inhibitory factors for future consideration following peripheral nerve injury., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Complete loss of median nerve motor function is a rare but devastating injury. Loss of median motor hand function and upper-extremity pronation can significantly impact a patient's ability to perform many activities of daily living independently. The authors report the long-term follow-up in a case of median nerve motor fiber transection that occurred during an arthroscopic elbow procedure, which was then treated with multiple nerve transfers. Motor reconstruction used the nerves to the supinator and extensor carpi radialis brevis to transfer to the anterior interosseous nerve and pronator. Sensory sensation was restored using the lateral antebrachial cutaneous (LABC) nerve to transfer to a portion of the sensory component of the median nerve, and a second cable of LABC nerve as a direct median nerve sensory graft. The patient ultimately recovered near normal motor function of the median nerve, but had persistent pain symptoms 4 years postinjury.

This study uses the saphenous nerve crush model in Thy1-YFP mice and serial transcutaneous imaging to evaluate the rate of nerve regeneration under various FK-506 (tacrolimus) dosing regimens and in the presence of transgenic overexpression of glial cell line-derived neurotrophic factor (GDNF). Thy1-YFP transgenic mice received saphenous nerve crush and were monitored for axonal regeneration via transcutaneous imaging for 7 days. Group A received no FK-506. Groups B and C received FK-506 at 2 or 0.5 mg/kg/day, starting three days before injury (preload). Groups D and E received FK-506 at 2 or 0.5 mg/kg/day, starting on the day of injury. Group F consisted of double transgenic mice with central overexpression of GDNF by CNS astrocytes (GFAP-GDNF/Thy1-YFP). Length and rate of axonal regeneration were measured and calculated over time. Regardless of concentration, FK-506 preload (Groups B and C) improved length and rate of axonal outgrowth compared with controls (Group A) and no preload (Groups D and E). Surprisingly, central overexpression of GDNF (GFAP-GDNF) delayed and stunted axonal outgrowth. Saphenous nerve crush in Thy1-YFP mice represents a viable model for timely evaluation of therapeutic strategies affecting the rate of nerve regeneration. FK-506 administered three days prior to injury accelerates axonal regeneration beyond injury conditioned regeneration alone and may serve as a reliable positive control for the model. GDNF overexpression in the CNS impedes early axonal outgrowth., (Copyright © 2011. Published by Elsevier Inc.)

Purpose: Functional recovery after peripheral nerve injury is predominantly influenced by time to reinnervation and number of regenerated motor axons. For nerve injuries in which incomplete regeneration is anticipated, a reverse end-to-side (RETS) nerve transfer might be useful to augment the regenerating nerve with additional axons and to more quickly reinnervate target muscle. This study evaluates the ability of peripheral nerve axons to regenerate across an RETS nerve transfer. We present a case report demonstrating its potential clinical applicability., Methods: Thirty-six Lewis rats were randomized into 3 groups. In group 1 (negative control), the tibial nerve was transected and prevented from regenerating. In group 2 (positive control), the tibial and peroneal nerves were transected, and an end-to-end (ETE) nerve transfer was performed. In group 3 (experimental model), the tibial nerve and peroneal nerves were transected, and an RETS nerve transfer was performed between the proximal end of the peroneal nerve and the side of the denervated distal tibial stump. Nerve histomorphometry and perfused muscle mass were evaluated. Six Thy1-GFP transgenic Sprague Dawley rats, expressing green fluorescent protein in their neural tissues, also had the RETS procedure for evaluation with confocal microscopy., Results: Nerve histomorphometry showed little to no regeneration in chronic denervation animals but statistically similar regeneration in ETE and RETS animals at 5 and 10 weeks. Muscle mass preservation was similar between ETE and RETS groups by 10 weeks and significantly better than negative controls at both time points. Nerve regeneration was robust across the RETS coaptation of Thy1-GFP rats by 5 weeks., Conclusions: Axonal regeneration occurs across an RETS coaptation. An RETS nerve transfer might augment motor recovery when less-than-optimal recovery is otherwise anticipated., Type of Study/level of Evidence: Therapeutic I., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

In the management of traumatic peripheral nerve injuries, the severity or degree of injury dictates the decision making between surgical management versus conservative management and serial examination. This review explores some of the recent literature, specifically addressing recent basic science advances in end-to-side and reverse end-to-side recovery, Schwann cell migration, and neuropathic pain. The management of nerve gaps, including the use of nerve conduits and acellularized nerve allografts, is examined. Current commonly performed nerve transfers are detailed with focus on both motor and sensory nerve transfers, their indications, and a basic overview of selected surgical techniques., (2011 Elsevier Inc. All rights reserved.)

The effect of sialodacryoadenitis virus (SDAV) infection on axonal regeneration and functional recovery was investigated in male Lewis rats. Animals underwent unilateral tibial nerve transection, immediate repair, and treatment with either FK506 (treated) or control vehicle (untreated). Serial walking track analyses were performed to assess functional recovery. Nerves were harvested for morphometric analysis on postoperative day 18 after an SDAV outbreak occurred that affected the 12 experimental animals. Histomorphometry and walking track data were compared against 36 historical controls. Rats infected with SDAV demonstrated severely impaired axonal regeneration and diminished functional recovery. Total fiber counts, nerve density, and percent neural tissue were all significantly reduced in infected animals (P < 0.05). Active SDAV infection severely impaired nerve regeneration and negated the positive effect of FK506 on nerve regeneration in rats. Immunosuppressive risks must be weighed carefully against the potential neuroregenerative benefits in the treatment of peripheral nerve injuries., (Copyright © 2011 Wiley-Liss, Inc.)

Learning Objectives: After reading this article, the participant should be able to: 1. Describe the pathophysiologic bases for nerve injury and how they apply to patient evaluation and management. 2. Recognize the wide variety of injury patterns and associated patient complaints and physical findings associated with peripheral nerve pathology. 3. Evaluate and recommend further tests to aid in defining the diagnosis. 4. Specify treatment options and potential risks and benefits., Summary: Peripheral nerve disorders comprise a gamut of problems, ranging from entrapment neuropathy to direct open traumatic injury and closed brachial plexus injury. The pathophysiology of injury defines the patient's symptoms, examination findings, and treatment options and is critical to accurate diagnosis and treatment. The goals of treatment include management of the often associated pain and improvement of sensory and motor function. Understanding peripheral nerve anatomy is critical to adopting novel nerve transfer procedures, which may provide superior options for a variety of injury patterns.

Peripheral nerve regeneration after injury depends on environmental cues and trophic support. Schwann cells (SCs) secrete trophic factors that promote neuronal survival and help guide axons during regeneration. The addition of SCs to acellular nerve grafts is a promising strategy for enhancing peripheral nerve regeneration; however, inconsistencies in seeding parameters have led to varying results. The current work sought to establish a systematic approach to seeding SCs in cold-preserved acellular nerve grafts. Studies were undertaken to (1) determine the needle gauge for optimal cell survival and minimal epineurial disruption during injection, (2) track the seeded SCs using a commercially available dye, and (3) evaluate the seeding efficiency of SCs in nerve grafts. It was determined that seeding with a 27-gauge needle resulted in the highest viability of SCs with the least damage to the epineurium. In addition, Qtracker(®) dye, a commercially available quantum dot nanocrystal, was used to label SCs prior to transplantation, which allowed visualization of the seeded SCs in nerve grafts. Finally, stereological methods were used to evaluate the seeding efficiency of SCs in nerve grafts immediately after injection and following a 1- or 3-day in vitro incubation in SC growth media. Using a systematic approach, the best needle gauge and a suitable dye for SC visualization in acellular nerve grafts were identified. Seeding efficiency in these grafts was also determined. The findings will lead to improvements ability to assess injection of cells (including SCs) for use with acellular nerve grafts to promote nerve regeneration., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Intraneural administration of local anesthetics has been associated with nerve damage. We undertook the present study to investigate histological changes induced by ropivacaine injection into rat sciatic nerve., Methods: Fifty-four adult male Lewis rats were randomly distributed into 9 groups, 6 animals per group. Fifty microliters of normal saline, 10% phenol, or 0.75% ropivacaine were administered by intrafascicular injection, extrafascicular injection, or extraneural (topical) placement. At 2 weeks, animals were killed and the sciatic nerve at the injection site was evaluated with light microscopy, quantitative histomorphometry, and electron microscopy., Results: On cross-sectional evaluation, extrafascicular ropivacaine injection and extraneural placement of ropivacaine were both associated with damage to the perineurium, with focal demyelination surrounded by edematous endoneurium. Intrafascicular injection of ropivacaine resulted in a wedge-shaped region of demyelination and focal axonal loss with some regeneration, bordered by a region of normally myelinated axons in a background of edematous endoneurium. Extrafascicular injection resulted in more significant damage than extraneural placement of ropivacaine, but less than intrafascicular injection as shown with quantitative histomorphometry. Quantitatively, ropivacaine-injured specimens had significantly lower nerve density than saline-injured specimens. Wallerian degeneration and perineural edema were also demonstrated qualitatively with electron microscopy., Conclusions: This study demonstrates that, in the rat model, ropivacaine is associated with marked histological abnormality, including edema of the perineurium and axonal destruction with wallerian degeneration, when injected into or extraneurally placed onto a nerve. Extrafascicular injection and extraneural placement were associated with similar, although milder, histological damage than intrafascicular injection. Further work is needed to investigate the functional implications, if any, of the histological abnormalities observed in this study.

Object: Peripheral nerve allografts provide a temporary scaffold for host nerve regeneration and allow for the repair of significant segmental nerve injuries. Despite this potential, nerve allograft transplantation requires temporary systemic immunosuppression. Characterization of the immunological mechanisms involved in the induction of immune hyporesponsiveness to prevent nerve allograft rejection will help provide a basis for optimizing immunomodulation regimens or manipulating donor nerve allografts to minimize or eliminate the need for global immunosuppression., Methods: The authors used C57Bl/6 mice and STAT4 and STAT6 gene BALB/c knockout mice. A nonvascularized nerve allograft was used to reconstruct a 1-cm sciatic nerve gap in the murine model. A triple costimulatory blockade of the CD40, CD28/B7, and inducible costimulatory (ICOS) pathways was used. Quantitative assessment was performed at 3 weeks with nerve histomorphometry, walking track analysis, and the enzyme-linked immunospot assay., Results: The STAT6 -/- mice received 3 doses of costimulation-blocking antibodies and had axonal regeneration equivalent to nerve isografts, while treated STAT4 -/- mice demonstrated moderate axonal regeneration but inferior to the T helper cell Type 2-deficient animals. Enzyme-linked immunospot assay analysis demonstrated a minimal immune response in both STAT4 -/- and STAT6 -/- mice treated with a costimulatory blockade., Conclusions: The authors' findings suggest that Type 1 T helper cells may play a more significant role in costimulatory blockade-induced immune hyporesponsiveness in the nerve allograft model, and that Type 2 T helper differentation may represent a potential target for directed immunosuppression.

Objective: To determine the Sunderland classification of a bipolar electrocautery injury., Methods: Twenty-two rats received crush (a reproducible Sunderland second-degree injury) or bipolar electrocautery injury and were evaluated for functional, histomorphometric, and immunohistochemical recovery at 21 or 42 days. Animal experiments were performed between July 3 and December 12, 2007. Axonal regeneration and end plate reinnervation were evaluated in double transgenic cyan fluorescent protein-conjugated Thy1 and green fluorescent protein-conjugated S100 mice., Results: Compared with crush injury, bipolar electrocautery injury caused greater disruption of myelin and neurofilament architecture at the injury site and decreased nerve fiber counts and percentage of neural tissue distal to the injury (P =.007). Complete functional recovery was seen after crush but not bipolar electrocautery injury. Serial live imaging demonstrated axonal regeneration at week 1 after crush and at week 3 after bipolar electrocautery injury. Qualitative assessment of motor end plate reinnervation at 42 days demonstrated complete neuromuscular end plate reinnervation in the crush group and only limited reinnervation in the bipolar electrocautery group., Conclusion: Bipolar electrocautery injury in a rodent model resulted in a Sunderland third-degree injury, characterized by gradual, incomplete recovery without intervention.

Accurate assessment of peripheral nerve regeneration requires fixation techniques that preserve tissue in a natural state with minimal artifact. While transcardial perfusion fixation is accepted as the gold standard for tissue fixation, the less cumbersome approach of immersion fixation has been criticized for introducing artifacts in brain tissue. We investigated whether immersion fixation increased artifact compared to perfusion fixation in the rat sciatic nerve. Eighteen Lewis rats were randomized into three groups: glutaraldehyde immersion fixation; glutaraldehyde transcardial perfusion; and paraformaldehyde transcardial perfusion. All animals underwent sciatic nerve transection and repair followed by tissue harvest and fixation at three weeks. Qualitative assessment of neural architecture and histological features was followed by quantitative analysis of nerve regeneration parameters. Outcome measures included quantitative histomorphometry, analysis of axon/myelin ratios, assessment of fiber distributions, and ultrastructural analysis. No qualitative or quantitative differences were observed with immersion fixation when compared to the transcardial perfusion fixation methods. Immersion fixation is a valid method for assessment of peripheral nerve regeneration in a rat model.

Autografting is the gold standard in the repair of peripheral nerve injuries that are not amenable to end-to-end coaptation. However, because autografts result in donor-site defects and are a limited resource, an effective substitute would be valuable. In a rat model, we compared isografts with Integra NeuraGen (NG) nerve guides, which are a commercially available type I collagen conduit, with processed rat allografts comparable to AxoGen's Avance human decellularized allograft product. In a 14-mm sciatic nerve gap model, isograft was superior to processed allograft, which was in turn superior to NG conduit at 6 weeks postoperatively (P < 0.05 for number of myelinated fibers both at midgraft and distal to the graft). At 12 weeks, these differences were no longer apparent. In a 28-mm graft model, isografts again performed better than processed allografts at both 6 and 22 weeks; regeneration through the NG conduit was often insufficient for analysis in this long graft model. Functional tests confirmed the superiority of isografts, although processed allografts permitted successful reinnervation of distal targets not seen in the NG conduit groups. Processed allografts were inherently non-immunogenic and maintained some internal laminin structure. We conclude that, particularly in a long gap model, nerve graft alternatives fail to confer the regenerative advantages of an isograft. However, AxoGen processed allografts are superior to a currently available conduit-style nerve guide, the Integra NeuraGen. They provide an alternative for reconstruction of short nerve gaps where a conduit might otherwise be used.

Peripheral nerve injuries can result in devastating numbness and paralysis. Surgical repair strategies have historically focused on restoring the original anatomy with interposition grafts. Distal nerve transfers are becoming a more common strategy in the repair of nerve deficits as these interventions can restore function in months as opposed to more than a year with nerve grafts. The changes that take place over time in the cell body, distal nerve, and target organ after axotomy can compromise the results of traditional graft placement and may at times be better addressed with the use of distal nerve transfers. A carefully devised nerve transfer offers restoration of function with minimal (if any) detectable deficits at the donor site. A new understanding of cortical plasticity along with patient reeducation allow for good return of strength and function after nerve transfer.

Modern nerve-to-nerve transfers represent one of the greatest advances in peripheral nerve surgery. Lessons of tendon transfers have taught that nerves to specific musculotendinous units are expendable, and greater understanding of peripheral nerve topography has revealed redundant fascicles in peripheral nerves. Transfer of these redundant or expendable nerves to recipient nerves close to the end organ allows for earlier reinnervation and preservation of those musculotendinous units. Such nerve transfers provide significantly better treatment options in many cases of nerve injury where previous outcomes were expected to be poor, such as with proximal injuries, long nerve gaps, or unavailability of the proximal injured segment. This article will review current nerve transfers in the hand and upper extremity.

Quantitative histomorphometry is the current gold standard for objective measurement of nerve architecture and its components. Many methods still in use rely heavily upon manual techniques that are prohibitively time consuming, predisposing to operator fatigue, sampling error, and overall limited reproducibility. More recently, investigators have attempted to combine the speed of automated morphometry with the accuracy of manual and semi-automated methods. Systematic refinements in binary imaging analysis techniques combined with an algorithmic approach allow for more exhaustive characterization of nerve parameters in the surgically relevant injury paradigms of regeneration following crush, transection, and nerve gap injuries. The binary imaging method introduced here uses multiple bitplanes to achieve reproducible, high throughput quantitative assessment of peripheral nerve. Number of myelinated axons, myelinated fiber diameter, myelin thickness, fiber distributions, myelinated fiber density, and neural debris can be quantitatively evaluated with stratification of raw data by nerve component. Results of this semi-automated method are validated by comparing values against those obtained with manual techniques. The use of this approach results in more rapid, accurate, and complete assessment of myelinated axons than manual techniques.

Retrograde labeling has become an important method of evaluation for peripheral nerve regeneration after injury. We review the features of the commonly used retrograde tracers Fast Blue, Fluoro-Gold, and Fluoro Ruby in addition to the various application methods (conduit reservoir, intramuscular injection, and crystal powder application) and the techniques used to count stained neurons. Upon application of the staining techniques and dyes in a rat and mouse nerve injury model, Fluoro-Gold was found to stain the greatest number of neurons with all application methods. However, due to variability of staining intensity, neuron size, and background staining, it is difficult to count the stained neurons accurately. Fast Blue stains consistently using intramuscular injection in the mouse but fails to provide adequate staining using the muscle injection method in the rat model and shows high failure rates using the conduit reservoir technique. However, crystal dye application with Fast Blue to the cut nerve end provides excellent results. We believe that it is imperative to use the various tracers and application methods prior to their experimental use to develop a consistent standardized approach to retrograde labeling.

Advances in the field of microsurgery have improved the results after peripheral nerve surgery and have extended the types of nerve repair that can be accomplished. Innovative techniques using microsurgical dissection, such as nerve transfers and end-to-side repairs are direct consequences of these advances.

Background: Limitations in autogenous tissue have inspired the study of alternative materials for repair of complex peripheral nerve injuries. Cadaveric allografts are one potential reconstructive material, but their use requires systemic immunosuppression. Cold preservation (> or =7 weeks) renders allografts devoid of antigens, but these acellular substrates generally fail in supporting regeneration beyond 3 cm. In this study, the authors evaluated the reconstruction of extensive nonhuman primate peripheral nerve defects using 7-week cold-preserved allografts repopulated with cultured autologous Schwann cells., Methods: Ten outbred Macaca fascicularis primates were paired based on maximal genetic disparity as measured by similarity index assay. A total of 14 ulnar nerve defects measuring 6 cm were successfully reconstructed using autografts (n = 5), fresh allografts (n = 2), cold-preserved allografts (n = 3), or cold-preserved allografts seeded with autogenous Schwann cells (n = 4). Recipient immunoreactivity was evaluated by means of enzyme-linked immunosorbent spot assay, and nerves were harvested at 6 months for histologic and histomorphometric analysis., Results: Cytokine production in response to cold-preserved allografts and cold-preserved allografts seeded with autologous Schwann cells was similar to that observed for autografts. Schwann cell-repopulated cold-preserved grafts demonstrated significantly enhanced fiber counts, nerve density, and percentage nerve (p < 0.05) compared with unseeded cold-preserved grafts at 6 months after reconstruction., Conclusions: Cold-preserved allografts seeded with autologous Schwann cells were well-tolerated in unrelated recipients and supported significant regeneration across 6-cm peripheral nerve defects. Use of cold-preserved allogeneic nerve tissue supplemented with autogenous Schwann cells poses a potentially safe and effective alternative to the use of autologous tissue in the reconstruction of extensive nerve injuries.

In this study, the authors evaluated whether the pretransplant portal venous administration of UV-B irradiated donor alloantigen would induce tolerance to long peripheral nerve allografts in a swine model. They completed nerve allograft transplantation between four swine of separate lineages. Regeneration across the nerve allografts was followed for 10 months postoperatively. Sequential IN VITRO assays demonstrated the successful and prolonged suppression of the recipient immune response to donor antigen following antigen inoculation. Histomorphometric analysis demonstrated successful regeneration across the long nerve allografts in the pretreated recipients, but not across allografts in unimmunosuppressed recipients. A single pretransplant antigen delivery protocol has the potential to replace chronic medicinal immunosuppressant therapy and its associated morbidities. Furthermore, tolerance to long nerve allografts has immediate applicability to clinical requirements for bridging multiple, complex, long nerve gaps.

A major limitation to overall success in peripheral nerve surgery is time for regeneration. Although one can help speed up the regenerative process to some extent, success is hindered by issues such as number of coaptation sites, supply of donor nerves, and the limitations of nerve substitutes. In the case of a large gap, a nerve graft is often used to fill in the deficit. Autogenous nerve grafts are in limited supply, with sural nerve grafts being the primary source. Alternatives to the standard treatment include vein grafts, synthetic nerve conduits, nerve transfers, and nerve transplantation. Schwann cell-lined nerve conduits and tissue-engineered substitutions are still in their infancy and have some limited clinical application.

Investigators have theorized that tortuosity in nerve grafts may adversely affect nerve regeneration. This study investigated the effect of graft configuration and redundancy on regeneration across 2.5-cm rat sciatic nerve isografts. Thirty-two Lewis rats were randomized to four nerve grafting groups defined by gap distance and isograft conformation. In Group 1, grafts were interposed into a 2-cm gap, resulting in mild graft redundancy. In Groups 2 and 3, grafts were tacked in sinusoidal or omega-shaped configurations, respectively, to bridge a 0.5-cm gap. In Group 4, grafts were interposed after 1 cm of native sciatic nerve was resected, resulting in no graft redundancy and an interstump distance of 2.5 cm. At 6 weeks, nerve tissue was harvested; subsequent histomorphometric analysis revealed no significant differences in regeneration between groups. These data suggest that regeneration through isografts is independent of the graft geometry and redundancy.

Numerous small-animal studies have demonstrated that FK506 enhances nerve regeneration and accelerates functional recovery after nerve injury. However, no experimental study has corroborated these neuroregenerative effects in larger animals. This study investigated the effects of FK506 on nerve regeneration in inbred miniature swine. Eight animals received 8-cm ulnar nerve autografts and allografts. Treated animals received 0.1 to 0.4 mg/kg FK506 injections twice weekly to maintain immunosuppressive serum FK506 levels. At 24 weeks posttransplant, nerve grafts were harvested for histomorphometric analysis. Mixed lymphocyte cultures demonstrated alloreactivity in 1 treated animal and all untreated animals. In autografts, mean fiber count, nerve density, and percent neural tissue were doubled with FK506 therapy. In allografts, significant neuroregeneration was observed in animals treated with FK506, whereas untreated animals had no regeneration. Treatment with FK506 resulted in a trend toward enhanced axonal regeneration through nerve autografts and allografts in a large-animal model with defined histocompatibility barriers.

A number of potential approaches aim to optimize functional recovery after spinal cord injury. They include minimizing the progression of secondary injury, manipulating the neuroinhibitory environment of the spinal cord, replacing lost tissue with transplanted cells or peripheral nerve grafts, remyelinating denuded axons, and maximizing the intrinsic regenerative potential of endogenous progenitor cells. We review the application of stem cell transplantation to the spinal cord, emphasizing the use of embryonic stem cells for remyelinating damaged axons. We speculate that harnessing the potential of endogenously born stem cells already present in the spinal cord represents an important therapeutic target. We also discuss the potential application of peripheral nervous system reconstruction to recovery from spinal cord injury. The principles of peripheral nerve regeneration and concepts of nerve grafting are reviewed. Particular attention is given to peripheral nerve allotransplantation for repairing extensively injured tissue when autologous donor nerve material is scarce. The potential role of nerve transfers for reconstructing the injured spinal cord, particularly the cauda equina and lumbosacral plexus, are also described., (Copyright 2004 Elsevier B.V.)

This manuscript reviews studies relating to peripheral nerve allografts, neuroregenerative agents and end-to-side neurorrhaphy. With respect to peripheral nerve allografts, animal studies with the agents cyclosporin A, FK506 and rapamycin are reviewed and related to recent clinical experience. FK506 distinguishes itself as an agent capable of reversing acute rejection of a peripheral nerve allograft and an agent with some neuroregenerative properties. In addition to systemic immunosuppression, experience with agents purported to initiate a state of donor specific tolerance are discussed. Specifically, experimental studies with administration of ultraviolet B treated donor splenocytes, antibodies to cellular adhesion molecules and antibodies to components of the costimulatory pathway of immunosuppression are reviewed. The neuroregenerative properties of FK506 and related compounds are examined in animal models. Finally, the experimental finding that reinnervation following end-to-side neurorrhaphy is mostly sensory and related to the degree of axonal damage at the level of an epineurotomy or perineurotomy is discussed.

The purpose of this study was to characterize the mechanism of unresponsiveness produced by the intraportal administration of ultraviolet-B (UV-B)-irradiated donor antigen. Pretreated Buffalo rats accepted Lewis nerve allografts, had decreased in vitro T-cell reactivity, and demonstrated nerve regeneration and recovery of limb function, while rejecting third-party nerve allografts. Regenerated nerve grafts were then retransplanted into a second naïve recipient. Rejection of the retransplanted allograft by naïve donor-strain, but not recipient-strain, animals suggests that the allografts were completely replaced by host tissue. Pretreated Buffalo rats were also given a second Lewis allograft after the first had regenerated. The second allograft was rejected and in vitro immune reactivity was comparable to naïve animals. Because the unresponsiveness state was extinguished with loss of exposure to donor antigen, these findings suggest that the intraportal administration of UV-B-irradiated donor antigen works by anergic or suppressive regulatory, rather than deletional, mechanisms.

Monoclonal antibody directed against CD40 ligand prevents acute allograft rejection in several models of solid-organ transplantation. This study describes the use of CD40 ligand as antirejection therapy in a mouse peripheral nerve allograft model. C3H mice received 8-mm nerve isografts (n = 2) or nerve allografts from C57BL donors. Treated animals (n = 11) received anti-CD40 ligand antibody applied to the graft and by intraperitoneal injections postoperatively. At 3 weeks, nerve histology from treated animals was comparable to isografts, whereas untreated allografts demonstrated virtually no signs of regeneration. Walking-track analysis demonstrated a trend toward improved functional recovery in treated animals. In conclusion, blockade of the CD40 pathway suppresses nerve allograft rejection in mice, and facilitates regeneration comparable to isografts., (Copyright 2004 Wiley-Liss, Inc.)

The response to nerve injury is a complex and often poorly understood mechanism. An in-depth and current command of the relevant neuroanatomy, classifications systems, and responses to injury and regeneration are critical to current clinical success. Continued progress must be made in our current understanding of these varied physiologic mechanisms of neuro-regeneration if any significant progress in clinical treatments or outcome is to be expected in the future. Reconstructive surgeons have in many ways maximized the technical aspects of peripheral nerve repair. However, advances in functional recovery may be seen with improvements in sensory and motor rehabilitation after peripheral nerve surgery and with a combined understanding of the neurobiology and neurophysiology of nerve injury and regeneration.

Advances in the field of peripheral nerve surgery have increased our understanding of the complex cellular and molecular events involved in nerve injury and repair. Application of these important discoveries has led to important developments in the techniques of nerve repair, nerve grafting, nerve allografts, end-to-side repairs, and nerve-to-nerve transfers. As our understanding of this dynamic field increases, further improvement in functional outcomes after nerve injury and repair can be expected.

The immunosuppressive agent FK-506 has a well-described neuroregenerative effect that is mediated by a mechanism independent of calcineurin inhibition. FK-506 levels that fall below the threshold for immunosuppression could therefore potentially enhance nerve regeneration while minimizing toxicity. The purpose of this study was to characterize the dose-dependent effects of FK506 on T-cell proliferation, and establish a subimmunosuppressive dosing regimen for FK-506 in mice. Forty BALB/cJ mice were randomized to four groups corresponding to 0, 0.25, 0.5, or 1.0 mg/kg/day doses of FK-506. Ten days postoperatively, animals were sacrificed, and mixed lymphocyte reaction assays were performed to quantify the immune response to nerve allografts. Mice receiving 0.25 and 0.5 mg/kg/day of FK-506 exhibited a robust T-cell proliferation response, with stimulation indices approaching those of untreated animals. Mice treated with 1.0 mg/kg/day of FK-506 demonstrated significantly decreased T-cell proliferation. These results establish 0.5 mg/kg/day as an upper limit for subimmunosuppressive FK-506 administration., (Copyright 2003 Wiley-Liss, Inc.)

The purpose of this study was to identify the optimal murine model for the study of peripheral nerve injury and nerve and limb transplantation. The degree of self-mutilation (autotomy) following sciatic and saphenous nerve injury was assessed in four mouse strains, Balb/C, C57BL/6J, C57BL/10J, and C3HEB, commonly used in surgical research. Experimental groups included sciatic and saphenous nerve transection with repair (n = 9) or without repair (n = 9), as well as housing arrangements favoring social interaction vs. isolation. Autotomy was most prevalent in the Balb/c and C3H strains at 56% and 89% overall, respectively, and was much less frequently seen in the C57Bl/10 and C57Bl/6 strains (22% and 11%, respectively). Autotomy was found to correlate most strongly with mouse strain, and with social contact as well. Two strains, C57BL/6J and C57BL/10J, were found to be highly resistant to self-mutilation, and are thus ideal animal models for peripheral-nerve and whole-limb transplant studies., (Copyright 2003 Wiley-Liss, Inc. MICROSURGERY 23:363-368 2003)

Prevention and control of graft rejection remain essential in the investigation of peripheral nerve allotransplantation. Although use of cyclosporin A (CsA) has been shown to suppress successfully the rejection of nerve allografts, limited information exists concerning use of this drug to arrest rejection in progress, and thereby effect salvage of these grafts. The aim of this study was to determine the efficacy of CsA in the treatment of ongoing acute rejection of peripheral nerve allografts. Buffalo rats received posterior tibial nerve grafts from either Lewis or Buffalo donor animals and were divided into five groups: group 1 received isografts and no CsA treatment (n = 8), group 2 received allografts with continuous CsA therapy (n = 10), group 3 received allografts with no treatment (n = 7), group 4 received allografts with initiation of CsA therapy delayed until 3 weeks after the procedure (n = 11), and group 5 received allografts with an interrupted course of CsA (n = 15). All grafts were harvested at 10 weeks. Histomorphometric analysis demonstrated comparable nerve regeneration in groups 1 and 2 and good regeneration in group 3 animals, despite cellular infiltrate suggestive of rejection. At 3 weeks after surgery, group 4 animals showed early rejection and significantly less neuroregeneration than positive controls at 10 weeks after delayed initiation of CsA therapy. Finally, group 5 animals showed early regeneration at 3 weeks but significantly lesser regeneration by 10 weeks after interruption of therapy. In this experimental protocol, CsA was ineffective in rescuing histologically proven rejection in progress.

Peripheral nerve allotransplantation allows the reconstruction of injuries with long nerve gaps that are otherwise unsalvageable. In this study, the efficacy of anti-CD4 monoclonal antibody (mAb) combined with donor antigen pretreatment in prolonging the survival of short peripheral nerve allografts was investigated in a rodent model. Such an approach could potentially avoid the need for systemic immunosuppression and its concomitant morbidities. Buffalo rats received either nerve isografts or nerve allografts from Lewis rats. Untreated isograft and allograft groups were used as controls. Allograft recipients received either a single dose of RIB 5/2, a nondepleting anti-CD4 mAb, a single dose of Lewis splenocytes, or both antigen and RIB 5/2, 7 days prior to transplantation. Flow cytometric analysis verified that the T-lymphocyte population was maintained, while CD4 expression was downregulated by RIB 5/2. Histologic evaluation demonstrated better regeneration in the allograft recipients receiving both donor antigen and antibody, compared to recipients of untreated allografts or treatment with antigen or antibody alone., (Copyright 2002 Wiley-Liss, Inc. MICROSURGERY 22:329-334 2002)