A feasibility study transplanting macrophages to a segmental nerve injury.

INTRODUCTION/AIMS: Promoting regeneration after segmental nerve injury repair is a challenge, but improving angiogenesis could be beneficial. Macrophages facilitate regeneration after injury by promoting angiogenesis. Our aim in this study was to evaluate the feasibility and effects of transplanting exogenous macrophages to a segmental nerve injury. METHODS: Bone marrow-derived cells were harvested from donor mice and differentiated to macrophages (BMDM), then suspended within fibrin hydrogels to facilitate BMDM transplantation. BMDM survival was characterized in vitro. The effect of this BMDM fibrin hydrogel construct at a nerve injury site was assessed using a mouse sciatic nerve gap injury. Mice were equally distributed to "fibrin+Mφ" (fibrin hydrogels containing culture medium and BMDM) or "fibrin" hydrogel control (fibrin hydrogels containing culture medium alone) groups. Flow cytometry (n = 3/group/endpoint) and immunohistochemical analysis (n = 5/group/endpoint) of the nerve gap region were performed at days 3, 5, and 7 after repair. RESULTS: Incorporating macrophage colony-stimulating factor (M-CSF) improved BMDM survival and expansion. Transplanted BMDM survived for at least 7 days in a nerve gap (~40% retained at day 3 and ~15% retained at day 7). From transplantation, macrophage quantities within the nerve gap were elevated when comparing fibrin+Mφ with fibrin control (~25% vs. 3% at day 3 and ~14% vs. 6% at day 7). Endothelial cells increased by about fivefold within the nerve gap, and axonal extension into the nerve gap increased almost twofold for fibrin+Mφ compared with fibrin control. DISCUSSION: BMDM suspended within fibrin hydrogels at a nerve gap do not impair regeneration.

Bioactive Nanofiber-Based Conduits in a Peripheral Nerve Gap Management-An Animal Model Study.

The aim was to examine the efficiency of a scaffold made of poly (L-lactic acid)-co-poly(ϵ-caprolactone), collagen (COL), polyaniline (PANI), and enriched with adipose-derived stem cells (ASCs) as a nerve conduit in a rat model. P(LLA-CL)-COL-PANI scaffold was optimized and electrospun into a tubular-shaped structure. Adipose tissue from 10 Lewis rats was harvested for ASCs culture. A total of 28 inbred male Lewis rats underwent sciatic nerve transection and excision of a 10 mm nerve trunk fragment. In Group A, the nerve gap remained untouched; in Group B, an excised trunk was used as an autograft; in Group C, nerve stumps were secured with P(LLA-CL)-COL-PANI conduit; in Group D, P(LLA-CL)-COL-PANI conduit was enriched with ASCs. After 6 months of observation, rats were sacrificed. Gastrocnemius muscles and sciatic nerves were harvested for weight, histology analysis, and nerve fiber count analyses. Group A showed advanced atrophy of the muscle, and each intervention (B, C, D) prevented muscle mass decrease (p < 0.0001); however, ASCs addition decreased efficiency vs. autograft (p < 0.05). Nerve fiber count revealed a superior effect in the nerve fiber density observed in the groups with the use of conduit (D vs. B p < 0.0001, C vs. B p < 0.001). P(LLA-CL)-COL-PANI conduits with ASCs showed promising results in managing nerve gap by decreasing muscle atrophy.

Advances in the repair of segmental nerve injuries and trends in reconstruction.

Despite advances in surgery, the reconstruction of segmental nerve injuries continues to pose challenges. In this review, current neurobiology regarding regeneration across a nerve defect is discussed in detail. Recent findings include the complex roles of nonneuronal cells in nerve defect regeneration, such as the role of the innate immune system in angiogenesis and how Schwann cells migrate within the defect. Clinically, the repair of nerve defects is still best served by using nerve autografts with the exception of small, noncritical sensory nerve defects, which can be repaired using autograft alternatives, such as processed or acellular nerve allografts. Given current clinical limits for when alternatives can be used, advanced solutions to repair nerve defects demonstrated in animals are highlighted. These highlights include alternatives designed with novel topology and materials, delivery of drugs specifically known to accelerate axon growth, and greater attention to the role of the immune system.

Comparison of transposition techniques to reduce gap associated with high ulnar nerve lesions.

PURPOSE: To determine in a cadaveric model which of 3 anterior transposition techniques allows for maximum gap reduction for high ulnar nerve lesions. METHODS: Six fresh-frozen human adult upper extremity cadaveric transhumeral specimens were used. We anchored the ulnar nerve to bone 10 cm proximal and distal to the medial epicondyle along its exact course while keeping the elbow in 30° flexion as the baseline measurement. We then used a thick suture to mimic and measure the exact course of the nerve between the pins in varying elbow positions. The nerve was then transposed first subcutaneously, then intramuscularly, and then submuscularly while taking exact measurements of the distance the nerve had to travel in varying degrees of elbow flexion for each transposition method. We performed comparative analysis to analyze gap reduction with respect to transposition method and elbow position. RESULTS: Transposing the ulnar nerve reduced the repair gap required to cross the elbow regardless of transposition technique. When comparing individual techniques, however, the greatest gap reduction was achieved by intramuscular, followed by submuscular and finally subcutaneous transposition. A maximum gap reduction of 25 mm (average, 23 mm) was achieved using intramuscular transposition with the elbow in 90° flexion. Subcutaneous transposition actually increased the repair gap when the elbow was in an extended position. CONCLUSIONS: An intramuscular transposition with the elbow in 90° flexion provided the best gap reduction. However, post-neurorrhaphy mobilization may compromise repair site integrity and vascularity if elbow flexion is required to achieve a primary repair, and these factors should be considered carefully when planning treatment. CLINICAL RELEVANCE: This study provides guidance on techniques to reduce nerve gap for primary repair of the ulnar nerve at the elbow using transposition and elbow flexion.

[Repair of a facial nerve substance loss by interposition of a collagen neurotube]. / Réparation d'une perte de substance du nerf facial par neurotube en collagène.

We are exposing the case of a 22 year-old patient presenting a wound of the right cheek, with a palsy of the right corner of the mouth. He has been sent to us 6 days after the trauma for secondary exploration. A section of the buccal branch of the right facial nerve with a 1cm gap has been brought out. We have bypassed the loss of substance with a collagen absorbable biological conduit. The 6-months clinical and electromyographic follow-up has shown a clear improvement of the function of the orbicularis oris, as well as its reinnervation by the buccal branch of the right facial nerve.

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 regeneration by bioabsorbable nerve conduits filled with platelet-rich fibrin.

PURPOSE: To repair peripheral nerve defects and seek alternatives for autografts, nerve conduits with various growth factors and cells have been invented. Few pieces of literature report the effect of nerve conduits plus platelet-rich fibrin (PRF). This study aimed to investigate the effectiveness of nerve conduits filled with PRF. METHODS: The model of a 10 mm sciatic nerve gap in a rat was used to evaluate peripheral nerve regeneration. The thirty rats were randomly divided into one of the following three groups (n = 10 per group). Autogenous nerve grafts (autograft group), conduits filled with phosphate-buffered saline (PBS) (PBS group), or conduits filled with PRF group (PRF group). We assessed motor and sensory functions for the three groups at 4, 8, and 12 weeks postoperatively. In addition, axon numbers were measured 12 weeks after repair of the peripheral nerve gaps. RESULTS: Significant differences in motor function were observed between the autograft group and the other two groups at 12 weeks postoperatively. In the test to evaluate the recovery of sensory function, there were significant differences between the PBS group and the other two groups at all time points. The most axon number was found in the autograft group. The axon number of the PRF group was significantly more extensive than that of the PBS group. CONCLUSIONS: The nerve conduit filled with PRF promoted the axon regeneration of the sciatic nerve and improved sensory function.

Current perspectives on peripheral nerve repair and management of the nerve gap.

From the first surgical repair of a nerve in the 6th century, progress in the field of peripheral nerve surgery has marched on; at first slowly but today at great pace. Whether performing primary neurorrhaphy or managing multiple large nerve defects, the modern nerve surgeon has an extensive range of tools, techniques and choices available to them. Continuous innovation in surgical equipment and technique has enabled the maturation of autografting as a gold standard for reconstruction and welcomed the era of nerve transfer techniques all while bioengineers have continued to add to our armamentarium with implantable devices, such as conduits and acellular allografts. We provide the reader a concise and up-to-date summary of the techniques available to them, and the evidence base for their use when managing nerve transection including current use and applicability of nerve transfer procedures.

Loss of Gata1 decreased eosinophils, macrophages, and type 2 cytokines in regenerating nerve and delayed axon regeneration after a segmental nerve injury.

The immune system has garnered attention for its role in peripheral nerve regeneration, particularly as it pertains to regeneration across segmental injuries. Previous work demonstrated that eosinophils are recruited to regenerating nerve and express interleukin-4, amongst potential cytokines. These results suggest a direct role for eosinophils in promoting nerve regeneration. Therefore, we further considered eosinophils roles in nerve regeneration using a segmental nerve injury and Gata1 knockout (KO) mice, which are severely eosinophil deficient, compared to wild-type BALB/c mice (WT). Mice receiving a sciatic nerve gap injury demonstrated distinct cytokine expression and leukocytes within regenerating nerve. Compared to controls, Gata1 KO regenerated nerves contained decreased expression of type 2 cytokines, including Il-5 and Il-13, and decreased recruitment of eosinophils and macrophages. At this early time point during ongoing regeneration, the macrophages within Gata1 KO nerves also demonstrated significantly less M2 polarization compared to controls. Subsequently, motor and sensory axon regeneration across the gap injury was decreased in Gata1 KO compared to WT during ongoing nerve regeneration. Over longer observation to allow for more complete nerve regeneration, behavioral recovery measured by grid-walk assessment was not different comparing groups but modestly delayed in Gata1 KO compared to WT. The extent of final axon regeneration was not different amongst groups. Our data provide additional evidence suggesting eosinophils contribute to nerve regeneration across a nerve gap injury, but are not essential to regeneration in this context. Our evidence also suggests eosinophils may regulate cytokines that promote distinct macrophage phenotypes and axon regeneration.

Techniques and graft materials for repairing peripheral nerve defects.

Peripheral nerve defects refer to damage or destruction occurring in the peripheral nervous system, typically affecting the limbs and face. The current primary approaches to address peripheral nerve defects involve the utilization of autologous nerve transplants or the transplantation of artificial material. Nevertheless, these methods possess certain limitations, such as inadequate availability of donor nerve or unsatisfactory regenerative outcomes post-transplantation. Biomaterials have been extensively studied as an alternative approach to promote the repair of peripheral neve defects. These biomaterials include both natural and synthetic materials. Natural materials consist of collagen, chitosan, and silk, while synthetic materials consist of polyurethane, polylactic acid, and polycaprolactone. Recently, several new neural repair technologies have also been developed, such as nerve regeneration bridging technology, electrical stimulation technology, and stem cell therapy technology. Overall, biomaterials and new neural repair technologies provide new methods and opportunities for repairing peripheral nerve defects. However, these methods still require further research and development to enhance their effectiveness and feasibility.

Treatment options for digital nerve injury: a systematic review and meta-analysis.

BACKGROUND: Surgical treatment of finger nerve injury is common for hand trauma. However, there are various surgical options with different functional outcomes. The aims of this study are to compare the outcomes of various finger nerve surgeries and to identify factors associated with the postsurgical outcomes via a systematic review and meta-analysis. METHODS: The literature related to digital nerve repairs were retrieved comprehensively by searching the online databases of PubMed from January 1, 1965, to August 31, 2021. Data extraction, assessment of bias risk and the quality evaluation were then performed. Meta-analysis was performed using the postoperative static 2-point discrimination (S2PD) value, moving 2-point discrimination (M2PD) value, and Semmes-Weinstein monofilament testing (SWMF) good rate, modified Highet classification of nerve recovery good rate. Statistical analysis was performed using the R (V.3.6.3) software. The random effects model was used for the analysis. A systematic review was also performed on the other influencing factors especially the type of injury and postoperative complications of digital nerve repair. RESULTS: Sixty-six studies with 2446 cases were included in this study. The polyglycolic acid conduit group has the best S2PD value (6.71 mm), while the neurorrhaphy group has the best M2PD value (4.91 mm). End-to-side coaptation has the highest modified Highet's scoring (98%), and autologous nerve graft has the highest SWMF (91%). Age, the size of the gap, and the type of injury were factors that may affect recovery. The type of injury has an impact on the postoperative outcome of neurorrhaphy. Complications reported in the studies were mainly neuroma, cold sensitivity, paresthesia, postoperative infection, and pain. CONCLUSION: Our study demonstrated that the results of surgical treatment of digital nerve injury are generally satisfactory; however, no nerve repair method has absolute advantages. When choosing a surgical approach to repair finger nerve injury, we must comprehensively consider various factors, especially the gap size of the nerve defect, and postoperative complications. Type of study/level of evidence Therapeutic IV.

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice: effects of 4-aminopyridine.

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine (4-AP), a potassium channel blocker, on functional recovery and muscle atrophy after sciatic nerve crush injury in rodents. However, this effect of 4-AP is unknown in nerve transection, gap, and grafting models. To evaluate and compare the functional recovery, nerve morphology, and muscle atrophy, we used a novel stepwise nerve transection with gluing (STG), as well as 7-mm irreparable nerve gap (G-7/0) and 7-mm isografting in 5-mm gap (G-5/7) models in the absence and presence of 4-AP treatment. Following surgery, sciatic functional index was determined weekly to evaluate the direct in vivo global motor functional recovery. After 12 weeks, nerves were processed for whole-mount immunofluorescence imaging, and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber cross-sectional area and minimal Feret's diameter. Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model. 4-AP did not affect the sciatic functional index recovery in any model. Compared to STG, nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting. While muscle weight, cross-sectional area, and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7, 4-AP treatment significantly increased right TA muscle mass, cross-sectional area, and minimal Feret's diameter in G-7/0 model. These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap, and 4-AP exerts differential effects on functional recovery and muscle atrophy.

Approach to management of nerve gaps in peripheral nerve injuries.

Peripheral nerve injuries (PNI) are a major clinical problem. In general, PNI results from motor vehicle accidents, lacerations with sharp objects, penetrating trauma (gunshot wounds) and stretching or crushing trauma and fractures. They can result in significant morbidity, including motor and/or sensory loss, which can affect significantly the life of the patient. Currently, the standard surgical technique for complete nerve transection is end-to-end neurorrhaphy. Unfortunately, there is segmental loss of the nerve trunk in some cases where nerve mobilization may permit end-to-end neurorrhaphy if the gap is less than 1 cm. When the nerve gap exceeds 1 cm, autologous nerve grafting is the gold standard of treatment. But in light of limited availability and concerned donor site morbidity, other techniques have been used: vascularized nerve grafts, cellular and acellular allografts, nerve conduits, nerve transfers and end-to-side neurorrhaphy. This review intends to present an overview of the literature on the applications of these techniques in repair of peripheral nerve injuries. This article also focuses on preoperative assessment, surgical timing, available options and future perspectives.

Closing the Gap: Bridging Peripheral Sensory Nerve Defects with a Chitosan-Based Conduit a Randomized Prospective Clinical Trial.

Introduction: If tensionless nerve coaptation is not possible, bridging the resulting peripheral nerve defect with an autologous nerve graft is still the current gold standard. The concept of conduits as an alternative with different materials and architectures, such as autologous vein conduits or bioartificial nerve conduits, could not replace the nerve graft until today. Chitosan, as a relatively new biomaterial, has recently demonstrated exceptional biocompatibility and material stability with neural lineage cells. The purpose of this prospective randomized clinical experiment was to determine the efficacy of chitosan-based nerve conduits in regenerating sensory nerves in the hand. Materials and methods: Forty-seven patients with peripheral nerve defects up to 26 mm distal to the carpal tunnel were randomized to receive either a chitosan conduit or an autologous nerve graft with the latter serving as the control group. Fifteen patients from the conduit group and seven patients from the control group were available for a 12-month follow-up examination. The primary outcome parameter was tactile gnosis measured with two-point discrimination. The secondary outcome parameters were Semmens Weinstein Monofilament Testing, self-assessed pain, and patient satisfaction. Results: Significant improvement (in static two-point discrimination) was observed six months after trauma (10.7 ± 1.2 mm; p < 0.05) for chitosan-based nerve conduits, but no further improvement was observed after 12 months of regeneration (10.9 ± 1.3 mm). After six months and twelve months, the autologous nerve graft demonstrated comparable results to the nerve conduit, with a static two-point discrimination of 11.0 ± 2.0 mm and 7.9 ± 1.1 mm. Semmes Weinstein Filament Testing in the nerve conduit group showed a continuous improvement over the regeneration period by reaching from 3.1 ± 0.3 after three months up to 3.7 ± 0.4 after twelve months. Autologous nerve grafts presented similar results: 3.3 ± 0.4 after three months and 3.7 ± 0.5 after twelve months. Patient satisfaction and self-reported pain levels were similar between the chitosan nerve conduit and nerve graft groups. One patient required revision surgery due to complications associated with the chitosan nerve tube. Conclusion: Chitosan-based nerve conduits are safe and suitable for bridging nerve lesions up to 26 mm in the hand. Tactile gnosis improved significantly during the early regeneration period, and functional outcomes were similar to those obtained with an autologous nerve graft. Thus, chitosan appears to be a sufficient substitute for autologous nerve grafts in the treatment of small nerve defects in the hand.

Digital Nerve Reconstruction.

Tension-free primary digital nerve repair may be unachievable in the presence of a nerve defect and require digital nerve reconstruction. Multiple techniques are available for reconstruction of a digital nerve defect using conduits, autograft, and allograft. Multiple comparison studies exist in the literature, suggesting similar results with autograft and allograft reconstruction, with several comparison studies suggesting inferior outcomes with conduit repair.

Transgenic Schwann cells overexpressing POU6F1 promote sciatic nerve regeneration within acellular nerve allografts.

Objective.Acellular nerve allograft (ANA) is an effective surgical approach used to bridge the sciatic nerve gap. The molecular regulators of post-surgical recovery are not well-known. Here, we explored the effect of transgenic Schwann cells (SCs) overexpressing POU domain class 6, transcription factor 1 (POU6F1) on sciatic nerve regeneration within ANAs. We explored the functions of POU6F1 in nerve regeneration by using a cell model of H2O2-induced SCs injury and transplanting SCs overexpressing POU6F1 into ANA to repair sciatic nerve gaps.Approach.Using RNA-seq, Protein-Protein Interaction network analysis, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway analysis, we identified a highly and differentially expressed transcription factor, POU6F1, following ANA treatment of sciatic nerve gap. Expressing a high degree of connectivity, POU6F1 was predicted to play a role in peripheral nervous system myelination.Main results.To test the role of POU6F1 in nerve regeneration after ANA, we infected SCs with adeno-associated virus-POU6F1, demonstrating that POU6F1 overexpression promotes proliferation, anti-apoptosis, and migration of SCsin vitro. We also found that POU6F1 significantly upregulated JNK1/2 and c-Jun phosphorylation and that selective JNK1/2 inhibition attenuated the effects of POU6F1 on proliferation, survival, migration, and JNK1/2 and c-Jun phosphorylation. The direct interaction of POU6F1 and activated JNK1/2 was subsequently confirmed by co-immunoprecipitation. In rat sciatic nerve injury model with a 10 mm gap, we confirmed the pattern of POU6F1 upregulation and co-localization with transplanted SCs. ANAs loaded with POU6F1-overexpressing SCs demonstrated the enhanced survival of transplanted SCs, axonal regeneration, myelination, and functional motor recovery compared to the ANA group loaded by SCs-only in line within vitrofindings.Significance.This study identifies POU6F1 as a novel regulator of post-injury sciatic nerve repair, acting through JNK/c-Jun signaling in SCs to optimize therapeutic outcomes in the ANA surgical approach.

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.

GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries.

Peripheral nerve injuries commonly occur due to trauma, like a traffic accident. Peripheral nerves get severed, causing motor neuron death and potential muscle atrophy. The current golden standard to treat peripheral nerve lesions, especially lesions with large (≥ 3 cm) nerve gaps, is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur. If not tended early, degeneration of motor neurons and loss of axon regeneration can occur, leading to loss of function. Although surgical procedures exist, patients often do not fully recover, and quality of life deteriorates. Peripheral nerves have limited regeneration, and it is usually mediated by Schwann cells and neurotrophic factors, like glial cell line-derived neurotrophic factor, as seen in Wallerian degeneration. Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth. Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy, sciatic nerve crush, and compression, thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries. Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries. In this review, we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor, the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries, delivery systems, and complementary treatments (electrical muscle stimulation and exercise). Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients' quality of life.

Better nerve regeneration with distally based fascicular turnover flap than with conventional autologous nerve graft in a rat sciatic nerve defect model.

The authors hypothesize that a fascicular turnover flap will achieve better nerve regeneration in nerve gap repair than a conventional nerve graft in a rat sciatic nerve defect model. Seven-millimeter-long sciatic nerve defects were repaired with an autologous nerve graft, a proximal fascicular turnover flap, or a distal fascicular turnover flap. Following walking footprint analysis 8 weeks after the surgery, the gastrocnemius-soleus muscles of the hind limbs, nerve graft, and flaps were harvested for wet muscle weight assessment, immunohistochemistry, and transmission electron microscopy. The distal fascicular turnover flap exhibited improvement in the sciatic function index similar as that observed for the autologous nerve graft. Histologically, cross sections showed a higher staining intensity for S-100 in the distal fascicular turnover flap group than for S-100 in the nerve graft group (p = 0.01). In the longitudinal sections, the staining intensity for NF-200 was higher in the distal fascicular turnover flap group than in the nerve graft (p = 0.009) and proximal fascicular turnover flap (p = 0.004) groups. More mature capillaries were observed in the proximal (p < 0.001) and distal (p = 0.029) fascicular turnover flap groups than in the nerve graft group. Transmission electron microscopy results showed a compact, regular myelin sheath around the myelinated nerve fibers in the distal fascicular turnover flap group, unlike observations in the nerve graft and proximal fascicular turnover flap groups. This study demonstrates better nerve regeneration in nerve gap repair with the distal fascicular turnover flap than with the conventional nerve graft.

Adipose-Derived Neural Stem Cells Combined with Acellular Dermal Matrix as a Neural Conduit Enhances Peripheral Nerve Repair.

Reconstruction to close a peripheral nerve gap continues to be a challenge for clinical medicine, and much effort is being made to develop nerve conduits facilitate nerve gap closure. Acellular dermal matrix (ADM) is mainly used to aid wound healing, but its malleability and plasticity potentially enable it to be used in the treatment of nerve gaps. Adipose-derived stem cells (ADSCs) can be differentiated into three germ layer cells, including neurospheres. We tested the ability of ADSC-derived neural stem cells (NSCs) in combination with ADM or acellular sciatic nerve (ASN) to repair a transected sciatic nerve. We found that NSCs form neurospheres that express Nestin and Sox2, and could be co-cultured with ADM in vitro, where they express the survival marker Ki67. Following sciatic nerve transection in rats, treatment with ADM+NSC or ASN+NSC led to increases in relative gastrocnemius weight, cross-sectional muscle fiber area, and sciatic functional index as compared with untreated rats or rats treated with ADM or ASN alone. These findings suggest that ADM combined with NSCs can improve peripheral nerve gap repair after nerve transection and may also be useful for treating other types of neurological gaps.