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.

Peripheral nerve transfers for dysfunctions in central nervous system injuries: a systematic review.

BACKGROUND: The review highlights recent advancements and innovative uses of nerve transfer surgery in treating dysfunctions caused by central nervous system (CNS) injuries, with a particular focus on spinal cord injury (SCI), stroke, traumatic brain injury, and cerebral palsy. METHODS: A comprehensive literature search was conducted regarding nerve transfer for restoring sensorimotor functions and bladder control following injuries of spinal cord and brain, across PubMed and Web of Science from January 1920 to May 2023. Two independent reviewers undertook article selection, data extraction, and risk of bias assessment with several appraisal tools, including the Cochrane Risk of Bias Tool, the JBI Critical Appraisal Checklist, and SYRCLE's ROB tool. The study protocol has been registered and reported following PRISMA and AMSTAR guidelines. RESULTS: Nine hundred six articles were retrieved, of which 35 studies were included (20 on SCI and 15 on brain injury), with 371 participants included in the surgery group and 192 in the control group. These articles were mostly low-risk, with methodological concerns in study types, highlighting the complexity and diversity. For SCI, the strength of target muscle increased by 3.13 of Medical Research Council grade, and the residual urine volume reduced by more than 100 ml in 15 of 20 patients. For unilateral brain injury, the Fugl-Myer motor assessment (FMA) improved 15.14-26 score in upper extremity compared to 2.35-26 in the control group. The overall reduction in Modified Ashworth score was 0.76-2 compared to 0-1 in the control group. Range of motion (ROM) increased 18.4-80° in elbow, 20.4-110° in wrist and 18.8-130° in forearm, while ROM changed -4.03°-20° in elbow, -2.08°-10° in wrist, -2.26°-20° in forearm in the control group. The improvement of FMA in lower extremity was 9 score compared to the presurgery. CONCLUSION: Nerve transfer generally improves sensorimotor functions in paralyzed limbs and bladder control following CNS injury. The technique effectively creates a 'bypass' for signals and facilitates functional recovery by leveraging neural plasticity. It suggested a future of surgery, neurorehabilitation and robotic-assistants converge to improve outcomes for CNS.

Evaluating Stromal Vascular Fraction As a Treatment for Peripheral Nerve Regeneration: A Scoping Review.

PURPOSE: This study aims to investigate the potential of stromal vascular fraction (SVF) for peripheral nerve regeneration. METHODS: A scoping review of Scopus and PubMed databases was conducted. Inclusion criteria were human or animal studies exploring the use of SVF for peripheral nerve regeneration. Studies were categorized by assessed outcomes: pain assessment, neural integrity, muscle recovery, and functional recovery. Level of evidence and study quality were assessed. RESULTS: Nine studies met the inclusion criteria. SVF injection in humans with trigeminal neuropathic pain reduced pain scores from 7.5 ± 1.58 to 4.3 ± 3.28. SVF injection improved sensation in humans with leprosy neuropathy. Repairing transected rat sciatic nerves with SVF-coated nerve autografts improved wet muscle weight ratios (0.65 ± 0.11 vs 0.55 ± 0.06) and sciatic functional index (SFI) scores (-68.2 ± 9.2 vs -72.5 ± 8.9). Repairing transected rat sciatic nerves with SVF-coated conduits increased the ratio of gastrocnemius muscle weights (RGMW) (7-10% improvement), myelinated fibers (1,605 ± 806.2 vs 543.6 ± 478.66), and myelin thickness (5-20% increase). Repairing transected rat facial nerves with SVF-coated conduits improved whisker motion (9.22° ± 0.65° vs 1.90° ± 0.84°) and myelin thickness (0.57 µm ± 0.17 vs 0.45 µm ± 0.14 µm). Repairing transected rat sciatic nerves with SVF-coated nerve allografts improved RGMW (85 vs 50%), SFI scores (-20 to -10 vs -40 to -30), and Basso, Beatie, and Bresnahan locomotor scores (18 vs 15). All metrics mentioned above were statistically significant. The human studies were level 4 evidence due to being case series, while animal studies were the lowest level of evidence. CONCLUSION: Despite initial promising results, the low-level evidence from the included studies warrants further investigation.

Assessing the Efficacy of Allogeneic Nerve Grafts in Trigeminal Nerve Repair: A Systematic Review.

PURPOSE: Our primary objective was to assess the efficacy of allogeneic nerve grafts in inferior alveolar nerve or lingual nerve repair. We hypothesized that using allogeneic nerve grafts would be effective, as evidenced by achieving high rates of functional sensory recovery (FSR). Additionally, we looked if sex, time from injury to repair, etiology of nerve damage, and graft length affected outcomes. METHODS: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. PubMed and Scopus databases were searched using specific search strategies to generate eligible studies. Inclusion criteria encompassed studies reporting use of allogeneic grafts, assessing FSR using either Medical Research Council Scale or Neurosensory Testing, and published within the past 15 years. RESULTS: Across 10 studies conducted between 2011 and 2023, analysis was performed on 149 patients and 151 reconstructed nerves. Allogeneic nerve grafts showed an average FSR rate of 88.0%. Kaplan-Meier analysis of time to FSR postoperatively revealed that of those achieving FSR, 80% achieved it within 6 months and 98% achieved it by 1 year. The mean graft length was 29.92 mm ± 17.94 mm. The most common etiology for nerve damage was third molar extractions (23.3%). Sex distribution among patients revealed that 85 were female (57.0%) and 64 were male (43.0%). CONCLUSION: Our primary hypothesis was supported as nerve allografts achieved high rates of FSR. FSR was achieved in normative timeframes, which is 6 to 12 months postoperatively. Furthermore, allografts reduced the risk of posttraumatic trigeminal neuropathy. Time from injury to repair, graft length, etiology of nerve damage, and sex did not affect FSR. As the assessed variables in our study did not affect outcomes, there needs to be a more nuanced approach to understanding and addressing various factors influencing sensory recovery.

Utilization Trends of Nerve Autograft Alternatives for the Reconstruction of Peripheral Nerve Defects.

BACKGROUND: Autologous nerve grafting is the time-honored reconstruction method for peripheral nerve gaps. However, it is associated with donor-site morbidities. A growing number of studies have demonstrated the effective use of decellularized nerve allograft and synthetic conduits, which are convenient options with no donor deficit. The specific aim of this study was to characterize changes in practice trends for peripheral nerve defect reconstruction. METHODS: The authors queried the 2015 to 2020 Merative MarketScan Databases for patients who underwent nerve autograft, allograft, synthetic conduit, and/or vein graft reconstruction. Patient demographic data (ie, location, indication) and hospital characteristics (ie, facility, provider type) were recorded. Regression analysis identified changes in trends over the study period. RESULTS: A total of 4331 patients underwent one or more nerve gap reconstructive procedures over the study period. Since the introduction of allograft CPT code in 2018, segmented mixed effect longitudinal modeling revealed that allograft utilization significantly increased from 21.5% to 29.6% after 2018 ( P < 0.001), whereas nerve autograft use decreased from 18.6% to 15.8% and conduit use decreased from 60% to 54.7% ( P = 0.09 and P = 0.03, respectively). When stratifying autograft by size, use of autograft less than or equal to 4 cm significantly decreased from 10.6% to 7.7% after 2018 ( P = 0.03), and autograft greater than 4 cm did not. When stratifying by state, there is heterogeneity in utilization rates of each product. CONCLUSION: After creation of a designated allograft CPT code in 2018, there was an increase in allograft use with concomitant decrease in conduit and short length autograft use, suggesting that allograft replaced a portion of procedures used in short nerve gap reconstruction.

A Multicenter Prospective Randomized Comparison of Conduits Versus Decellularized Nerve Allograft for Digital Nerve Repairs.

PURPOSE: While there are advantages and disadvantages to both processed nerve allografts (PNA) and conduits, a large, well-controlled prospective study is needed to compare the efficacy and to delineate how each of these repair tools can be best applied to digital nerve injuries. We hypothesized that PNA digital nerve repairs would achieve superior functional recovery for longer length gaps compared with conduit-based repairs. METHODS: Patients (aged 18-69 years) presenting with suspected acute or subacute (less than 24 weeks old) digital nerve injuries were recruited to prticipate at 20 medical centers across the United States. After stratification to short (5-14 mm) and long (15-25 mm) gap subgroups, the patients were randomized (1:1) to repair with either a commercially available PNA or collagen conduit. Baseline and outcomes assessments were obtained either before or immediately after surgery and planned at 3-, 6-, 9-, and 12-months after surgery. All assessors and patients were blinded to the treatment arm. RESULTS: In total, 220 patients were enrolled, and 183 patients completed an acceptable last evaluable visit (at least 6 months and not more than 15 months postrepair). At last follow-up, for the short gap repair groups, average static two-point discrimination was 7.3 ± 2.8 mm for PNA and 7.5 ± 3.1 mm for conduit repairs. For the long gap group, average static two-point discrimination was significantly lower at 6.1 ± 3.3 mm for PNA compared with 7.5 ± 2.4 mm for conduit repairs. Normal sensation (American Society for Surgery of the Hand scale) was achieved in 40% of PNA long gap repairs, which was significantly more than the 18% observed in long conduit patients. Long gap conduits had more clinical failures (lack of protective sensation) than short gap conduits. CONCLUSIONS: Although supporting similar levels of nerve regeneration for short gap length digital nerve repairs, PNA was clinically superior to conduits for long gap reconstructions. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.

Challenges in Nerve Repair and Reconstruction.

Peripheral nerve injuries may substantially impair a patient's function and quality of life. Despite appropriate treatment, outcomes often remain poor. Direct repair remains the standard of care when repair is possible without excessive tension. For larger nerve defects, nerve autografting is the gold standard. However, a considerable challenge is donor site morbidity. Processed nerve allografts and conduits are other options, but evidence supporting their use is limited to smaller nerves and shorter gaps. Nerve transfer is another technique that has seen increasing popularity. The future of care may include novel biologics and pharmacologic therapy to enhance regeneration.

Loop nerve graft prefabrication for peripheral nerve defect reconstruction.

BACKGROUND: Delayed autologous nerve graft reconstruction is inevitable in devastating injuries. Delayed or prolonged repair time has deleterious effects on nerve grafts. We aimed improving and accelerating nerve graft reconstruction process in a rat long nerve defect model with loop nerve graft prefabrication particularly to utilize for injuries with tissue loss. METHODS: Twenty-four Sprague-Dawley rats were allocated into three groups. 1.5 cm long peroneal nerve segment was excised, reversed in orientation, and used as autologous nerve graft. In conventional interpositional nerve graft group (Group 1), nerve defects were repaired in single-stage. In loop nerve graft prefabrication group (Group 2), grafts were sutured end-to-end (ETE) to the proximal peroneal nerve stumps. Distal ends of the grafts were sutured end-to-side to the peroneal nerve stumps 5 mm proximal to the ETE repair sites in first stage. In second stage, distal ends of the prefabricated grafts were transposed and sutured to distal nerve stumps. In staged conventional interpositional nerve graft group (Group 3), grafts were sutured ETE to proximal peroneal nerve stumps in first stage. Distal ends of the grafts and nerve stumps were tacked to the surrounding muscles until the final repair in second stage. Follow-up period was 4 weeks for each stage in Groups 2 and 3, and 8 weeks for Group 1. Peroneal function index (PFI), electrophysiology, and histological assessments were conducted after 8 weeks. P<0.05 was considered significant for statistical analysis. RESULTS: PFI results of Group 1 (-22.75±5.76) and 2 (-22.08±6) did not show statistical difference (p>0.05). Group 3 (-33.64±6.4) had a statistical difference compared to other groups (p<0.05). Electrophysiology results of Group 1 (16.19±2.15 mV/1.16±0.21 ms) and 2 (15.95±2.82 mV/1.17±0.16 ms) did not present statistical difference (p>0.05), whereas both groups had a statistical difference compared to Group 3 (10.44±1.96 mV/1.51±0.15 ms) (p<0.05). Axon counts of Group 1 (2227±260.4) and 3 (2194±201.1) did not have statistical difference (p>0.05), whereas both groups had significantly poor axon counts compared to Group 2 (2531±91.18) (p<0.05). CONCLUSION: Loop nerve graft prefabrication improved axonal regeneration without delay. Loop prefabrication can accelerate prolonged regeneration time for the injuries indicating a delayed nerve reconstruction. Higher axon counts derived with loop nerve prefabrication may even foster its investigation in immediate long nerve defect reconstructions in further studies.

Evaluation of anatomical and histological characteristics of human peripheral nerves: as an effort to develop an efficient allogeneic nerve graft.

Management of peripheral nerve defects is a complicated problem in clinical contexts. Autologous nerve grafting, a gold standard for surgical treatment, has been well known to have several limitations, such as donor site morbidity, a limited amount of available donor tissue, and size mismatches. Acellular nerve allografts (ANAs) have been developed as an alternative and have been applied clinically with favorable outcomes. However, because of the limited availability of commercialized ANAs due to supplier-related issues and high costs, efforts continue to produce alternative sources for ANAs. The present study evaluated the anatomical and histological characteristics of human peripheral nerves using 25 donated human cadavers. The length, diameter, and branching points of various peripheral nerves (median, ulnar, tibial, lateral femoral cutaneous, saphenous, and sural nerves) in both the upper and lower extremities were evaluated. The cross-sectional area (CSA), ratio of fascicular area, and numbers of fascicles were also evaluated via histologic analysis. CSA, the ratio of fascicular area, and the number of fascicles were analyzed statistically in correlation with demographic data (age, sex, height, weight, BMI). The mean length of all evaluated nerves ranged from 17.1 to 41.4 cm, and the mean diameter of all evaluated nerves ranged from 1.2 to 4.9 mm. Multiple regression analysis revealed correlations between the ratio of fascicular area and sex (p = 0.005) and BMI (p = 0.024) (R2 = 0.051). The results of the present study will be helpful in selecting necessary nerve allograft sources while considering the characteristics of each nerve in the upper and lower extremities during ANAs production.

[Use of acellular allogeneic nerve transplants for nerve defects of the hand : Experience from a German hand surgery center]. / Einsatz von azellulären allogenen Nerventransplantaten bei Nervendefekten an der Hand : Erfahrung aus einem deutschen handchirurgischen Zentrum.

Peripheral nerve injuries are often encountered in traumatological care. The aim of this manuscript is to provide initial data, experiences and performance reports from Germany in the implantation of acellular human nerve transplants in peripheral sensory nerve defects of the hand and to put these data in the context of a comprehensive review of the literature. Of the patients 4 (7 digital nerves) were examined 6 months postoperatively and 5 patients (6 digital nerves) were examined 1 year after the operation (3 were also at the 6­month examination). All patients had a clinical improvement after nerve reconstruction (≥ S3 according to the classification of sensory recovery of the Medical Research Council modified by Mackinnon and Dellon). Disadvantages of our clinical study are the small number of patients, the inhomogeneity (primary and secondary nerve reconstruction) and the lack of comparison with other nerve reconstruction methods.

Three-Dimensional Engineered Peripheral Nerve: Toward a New Era of Patient-Specific Nerve Repair Solutions.

Reconstruction of peripheral nerve injuries (PNIs) with substance loss remains challenging because of limited treatment solutions and unsatisfactory patient outcomes. Currently, nerve autografting is the first-line management choice for bridging critical-sized nerve defects. The procedure, however, is often complicated by donor site morbidity and paucity of nerve tissue, raising a quest for better alternatives. The application of other treatment surrogates, such as nerve guides, remains questionable, and it is inefficient in irreducible nerve gaps. More importantly, these strategies lack customization for personalized patient therapy, which is a significant drawback of these nerve repair options. This negatively impacts the fascicle-to-fascicle regeneration process, critical to restoring the physiological axonal pathway of the disrupted nerve. Recently, the use of additive manufacturing (AM) technologies has offered major advancements to the bioengineering solutions for PNI therapy. These techniques aim at reinstating the native nerve fascicle pathway using biomimetic approaches, thereby augmenting end-organ innervation. AM-based approaches, such as three-dimensional (3D) bioprinting, are capable of biofabricating 3D-engineered nerve graft scaffolds in a patient-specific manner with high precision. Moreover, realistic in vitro models of peripheral nerve tissues that represent the physiologically and functionally relevant environment of human organs could also be developed. However, the technology is still nascent and faces major translational hurdles. In this review, we spotlighted the clinical burden of PNIs and most up-to-date treatment to address nerve gaps. Next, a summarized illustration of the nerve ultrastructure that guides research solutions is discussed. This is followed by a contrast of the existing bioengineering strategies used to repair peripheral nerve discontinuities. In addition, we elaborated on the most recent advances in 3D printing and biofabrication applications in peripheral nerve modeling and engineering. Finally, the major challenges that limit the evolution of the field along with their possible solutions are also critically analyzed. Impact statement Complex nerve injuries, including critical-sized gaps (>3 cm loss of substance), gaps involving nerve bifurcations, and those associated with ischemic environments, are difficult to manage. A biomimetic, personalized peripheral nerve tissue surrogate to address these injuries is lacking. The peripheral nerve repair market currently represents a multi-billion-dollar industry that is projected to expand. Given the clinical and economical dilemmas posed by this medical condition, it is crucial to devise novel and effective nerve substitutes. In this review article, we discuss progress in three-dimensional printing technologies, including biofabrication and nerve computer-aided design modeling, toward achieving a patient-specific and biomimetic nerve repair solution.

Comparative study of decellularization techniques to obtain natural extracellular matrix scaffolds of human peripheral-nerve allografts.

BACKGROUND: We hypothesize that adding sonication cycles to the process of decellularization of cadaveric human peripheral nerves will increase the removal of cell debris and myelin sheath, increasing their utility as allografts. METHODS: Our aim of this study was to develop a decellularization protocol that allows the removal of cells and myelin sheath without detrimental effects on nerve architecture. Segments of ulnar and median nerves from human donors, isolated both before and after cardiac arrest, were subjected to two methods of decellularization: two-detergent-based (M1) and the same method with sonication added (M2). We evaluated the histology of unprocessed and decellularized nerves (n = 24 per group) for general morphology, presence of cell nuclei, nuclear remnants, collagen fibers, and myelin. We performed immunohistochemistry to verify the removal of Schwann cells associated with histomorphometry. We used scanning electron microscopy (EM) to evaluate the ultrastructure of both native and decellularized nerves. The efficacy of decellularization was assessed by analysis of genomic DNA. RESULTS: Histology confirmed that both decellularization protocols were adequate and maintained natural nerve architecture. Scanning EM showed that 3D ultrastructural architecture also was maintained. Histomorphometric parameters showed a more complete removal of the myelin with the M2 protocol than with M1 (p = 0.009). Fiber diameter and density were not modified by decellularization methods. CONCLUSIONS: Sonication can be a complementary method to decellularization of peripheral nerve allografts with sonication increasing the effectiveness of detergent-based protocols for the removal of unwanted cellular components from peripheral nerve allografts.

Flow-Through Arterialized Posterior Interosseous Nerve Grafts for Digital Neurovascular Bundle Defects: Anatomical Study.

BACKGROUND: Digital neurovascular bundle defects are often encountered during crush or avulsion injuries and require complex reconstruction. Use of an arterialized nerve graft (neurovascular graft) serving both as an interpositional arterial conduit and as a nerve graft could be a reconstructive option in these cases. In this anatomical study, the authors aimed to describe a neurovascular graft of the posterior interosseous nerve and a branch of the anterior interosseous artery for neurovascular bundle reconstruction of the fingers. METHODS: Eighteen forearms were injected with red latex in order to collect the anatomical characteristics of the posterior interosseous nerve and the artery running near it. RESULTS: In all cases, the posterior interosseous nerve was followed by a branch of the anterior interosseous artery: the distal dorsal branch of the anterior interosseous nerve. The origin of this artery was proximal to the radiocarpal joint, at an average of 56.5 ± 11.1 mm. The proximal and distal diameters of the branch of the anterior interosseous artery were 1.6 ± 0.2 and 1.1 ± 0.2 mm, respectively. The proximal and distal diameters of the posterior interosseous nerve were 1.2 ± 0.3 mm and 1.1 ± 0.3 mm, respectively. CONCLUSIONS: These results show that a potential free neurovascular graft using the posterior interosseous nerve as nerve graft and the anterior interosseous artery as an arterial bypass to reconstruct both the nerve and arterial tree of the finger could be a useful approach. The authors speculate that this graft could be used to reconstruct the neurovascular bundle of amputated or devascularized digits.

Failed Acellular Nerve Allografts: A Critical Review.

BACKGROUND: Acellular nerve allograft (ANA) occupies an increasingly prominent role in the treatment of peripheral nerve reconstruction. There is demonstrable efficacy; however, some grafts fail to support axonal regrowth and the reasons for this are unclear. This study examines the ANA experience in a specialized peripheral nerve surgery department to discuss the clinical and histological findings in failed cases. METHOD: Failed ANA grafts were identified from a prospective database using Medical Research Council Classification (MRCC) S3 and M3 as thresholds for success. Cases in which ANA grafting was indicated for nerve related pain and dysesthesia but where no subjective improvement in symptoms occurred were also included. Patients requiring revision surgery after ANA grafting were also considered failures. Cases were then examined in conjunction with a literature review to identify possible mechanisms of failure, including detailed histological analysis in 2 cases. RESULTS: Eight failed procedures were identified from a database of 99 separate allograft records on 74 patients. This included procedures for 2 tibial nerves, 2 superficial radial nerves, 2 median nerves, 1 digital nerve and a lateral cord brachial plexus injury (male/female, 5:3; age range, 24-54 years). Allograft length range 25 to 120 mm. One postoperative infection was identified. Histological findings in 2 cases included adequate vascularization of allograft material without subsequent axonal regeneration, a reduction of large myelinated fibers proximal to a tibial nerve allograft in the setting of a chronic injury, and a preference for small rather than large fiber regeneration. CONCLUSIONS: This article reports instances of ANA graft failure in a variety of contexts, for which the primary reasons for failure remain unclear. The etiology is likely to be multifactorial with both patient, graft and surgeon factors contributing to failure. Further clinical and histological analysis of ANA failures will improve our understanding of the mechanisms of graft failure.

Comparison of nerve conduits and nerve graft in digital nerve regeneration: A systematic review and meta-analysis.

The goal of this systematic review and meta-analysis was to compare nerve conduits and nerve graft for peripheral nerve regeneration. This type of lesion frequently causes disability due to pain, paresthesia and motor deficit. On the PICO process, "P" corresponded to patients with peripheral digital nerve lesions of any age, gender or ethnicity, "I" to interventions with nerve conduits or nerve graft, "C" to the control group with no treatment, placebo or receiving other treatment, and "O" to outcome assessment of nerve regeneration. Initial search found in 3859 studies, including 2001 duplicates. The remaining 1858 studies were selected by title and/or abstract; 1798 articles were excluded, leaving 60 articles for full-text review. Thirty-nine of these 60 reports were excluded as not meeting our inclusion criteria, and 21 articles were ultimately included in the systematic review. For patients older than 40 years, there was a greater mean improvement on S2PD and M2PD tests with grafting, which seemed to be the better surgical technique, positively impacting prognosis. On the M2PD test, there was significantly greater improvement in 11-17.99 mm defects with grafting (P < 0.001); this finding should guide surgical strategy in peripheral nerve regeneration, to ensure better outcomes.

Bone marrow-derived mesenchymal stem cells transplanted into a vascularized biodegradable tube containing decellularized allogenic nerve basal laminae promoted peripheral nerve regeneration; can it be an alternative of autologous nerve graft?

Previously, we showed silicone nerve conduits containing a vascular bundle and decellularized allogenic basal laminae (DABLs) seeded with bone marrow-derived mesenchymal stem cells (BMSCs) demonstrated successful nerve regeneration. Nerve conduits should be flexible and biodegradable for clinical use. In the current study, we used nerve conduits made of polyglycoric acid (PGA) fiber mesh, which is flexible, biodegradable and capillary-permeable. DABLs were created using chemical surfactants to remove almost all cell debris. In part 1, capillary infiltration capability of the PGA tube was examined. Capillary infiltration into regenerated neural tissue was compared between the PGA tube with blood vessels attached extratubularly (extratubularly vascularized tube) and that containing blood vessels intratubularly (intratubularly vascularized tube). No significant difference was found in capillary formation or nerve regeneration between these two tubes. In part 2, a 20 mm gap created in a rat sciatic nerve model was bridged using the extratubularly vascularized PGA tube containing the DABLs with implantation of isogenic cultured BMSCs (TubeC+ group), that containing the DABLs without implantation of the BMSCs (TubeC- group), and 20 mm-long fresh autologous nerve graft (Auto group). Nerve regeneration in these three groups was assessed electrophysiologically and histomorphometrically. At 24 weeks, there was no significant difference in any electrophysiological parameters between TubeC+ and Auto groups, although all histological parameters in Auto group were significantly greater than those in TubeC+ and TubeC- groups, and TubeC+ group demonstrated significant better nerve regeneration than TubeC- group. The transplanted DABLs showed no signs of immunological rejection and some transplanted BMSCs were differentiated into cells with Schwann cell-like phenotype, which might have promoted nerve regeneration within the conduit. This study indicated that the TubeC+ nerve conduit may become an alternative to nerve autograft.

Local FK506 drug delivery enhances nerve regeneration through fresh, unprocessed peripheral nerve allografts.

OBJECTIVE: Nerve allografts offer many advantages in the reconstruction of peripheral nerve gaps: they retain their native microstructure, contain pro-regenerative Schwann cells, are widely available, and avoid donor site morbidity. Unfortunately, clinical use of nerve allografts is limited by the need for systemic immunosuppression and its adverse effects. To eliminate the toxicity of the systemic immunosuppressant FK506, we developed a local FK506 drug delivery system (DDS) to provide drug release over 28 days. The study objective was to investigate if the local FK506 DDS enhances nerve regeneration in a rodent model of nerve gap defect reconstruction with immunologically-disparate nerve allografts. METHODS: In male Lewis rats, a common peroneal nerve gap defect was reconstructed with either a 20 mm nerve isograft from a donor Lewis rat or a 20 mm fresh, unprocessed nerve allograft from an immunologically incompatible donor ACI rat. After 4 weeks of survival, nerve regeneration was evaluated using retrograde neuronal labelling, quantitative histomorphometry, and serum cytokine profile. RESULTS: Treatment with both systemic FK506 and the local FK506 DDS significantly improved motor and sensory neuronal regeneration, as well as histomorphometric indices including myelinated axon number. Rats with nerve allografts treated with either systemic or local FK506 had significantly reduced serum concentrations of the pro-inflammatory cytokine IL-12 compared to untreated vehicle control rats with nerve allografts. Serum FK506 levels were undetectable in rats with local FK506 DDS. INTERPRETATION: The local FK506 DDS improved motor and sensory nerve regeneration through fresh nerve allografts to a level equal to that of either systemic FK506 or nerve isografting. This treatment may be clinically translatable in peripheral nerve reconstruction or vascularized composite allotransplantation.

Targeted Muscle Reinnervation as a Solution for Nerve Pain.

LEARNING OBJECTIVES: After reading this article, the participants should be able to: 1. List current nonsurgical and surgical strategies for addressing postamputation neuroma pain and discuss their limitations. 2. Summarize the indications and rationale for targeted muscle reinnervation. 3. Develop an operative plan for targeted muscle reinnervation in an acute or delayed fashion for upper and lower extremity amputations. 4. Propose a management algorithm for treatment of symptomatic neuromas in an intact limb. 5. Discuss the risk of neuroma development after primary revision digital amputation or secondary surgery for a digital neuroma. 6. Compare and contrast targeted muscle reinnervation to the historical gold standard neuroma treatment of excision and burying the involved nerve in muscle, bone, or vein graft. 7. Interpret and discuss the evidence that targeted muscle reinnervation improves postamputation neuroma and phantom pain when performed either acutely or in a delayed fashion to treat existing pain. SUMMARY: Symptomatic injured nerves resulting from amputations, extremity trauma, or prior surgery are common and can decrease patient quality of life, thus necessitating an effective strategy for management. Targeted muscle reinnervation is a modern surgical strategy for prevention and treatment of neuroma pain that promotes nerve regeneration and healing rather than neuroma formation. Targeted muscle reinnervation involves the transfer of cut peripheral nerves to small motor nerves of adjacent, newly denervated segments of muscle and can be easily performed without specialized equipment. Targeted muscle reinnervation strategies exist for both upper and lower extremity amputations and for symptomatic neuromas of intact limbs. Targeted muscle reinnervation has been shown in a prospective, randomized, controlled trial to result in lower neuroma and phantom pain when compared to the historical gold standard of burying cut nerves in muscle.