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Background Traditionally known for bone regeneration, the Ilizarov technique's effectiveness in nerve reconstruction, particularly for extensive nerve damage, has yet to be widely recognized. Case presentation This report presents a case study and proposes the innovative use of the Ilizarov technique for reconstructing extended nerve defects. In this study, we reviewed a 43‐year‐old male diagnosed with an open fracture of the right tibia combined with soft tissue injury resulting in a mangled injury in which a large part of his right tibial bone and nerve were lost. The patient was cured and the sensorimotor function was recovered after distraction osteogenesis by the Ilizarov technique, which is a unique application of this technique to repair a substantial long nerve defect, a rare occurrence in medical literature. It highlights the method of nerve lengthening, which is achieved by attaching the nerve stump to the bone stump. This approach allows for significant nerve regeneration and ensures a stable progression of the nerve, as the bone stump acts as a carrier, overcoming the challenges of direct nerve lengthening. Conclusions The adaptability and effectiveness of the Ilizarov technique in a new area suggests the need to reconsider traditional approaches to complex nerve reconstruction. Placing this case within the context of current medical knowledge underscores the potential of this technique to revolutionize the treatment of extended nerve defects, offering hope for improved outcomes in challenging scenarios.

Purpose: A systematic review to identify treatment approaches for the management of pain following peripheral nerve injury. Methods: A published literature search was performed for the concepts of peripheral nerve injury and pain management with related synonyms. The strategies were created using a combination of controlled vocabulary terms and keywords and were executed in Embase.com, Ovid-Medline All, and Scopus from database inception. Database searches were completed on August 22, 2023. Results: The initial search resulted in a total of 1,793 citations. In total, 724 duplicates were removed, leaving 1,069 unique citations remaining for analysis. This review excluded all papers that were not specific to pain following peripheral nerve injury. Case and cohort studies (n < 5) were also excluded. Thirty-two articles on pain management strategies after peripheral nerve injury remained, with years of publication ranging from 1981 to 2023. An additional four articles were identified by manual search. Of the 36 articles reviewed, 15 articles reported on the approach to the treatment of pain after a peripheral nerve injury, and the other 22 articles consisted of cohort and case series studies. Conclusions: There is a lack of literature describing efficacy of various treatment strategies for pain following peripheral nerve injuries. Few studies provide clear, stepwise clinical guidance for practicing physicians and other health care providers on the treatment of these complicated patients.

Purpose: Vascularized nerve grafts (VNGs) have been proposed as encouraging alternatives to conventional nerve grafting; however, there is ongoing debate regarding the clinical advantages of the approach compared with standard grafting. This review aims to gather and analyze reported cases of upper extremity nerve repair using VNGs documented in the published literature. Methods: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, PubMed/MEDLINE, Embase, and Cochrane were searched. Inclusion criteria for this review included the following: (1) human subjects or cadaveric studies, (2) describing a vascularized nerve grafting procedure or suggesting a nerve and vascular supply for a potential vascularized nerve graft, and (3) upper extremity nerve repair in clinical studies. Results: Data were extracted from 45 clinical studies. Of 535 patients, the most common injury pattern was root avulsion and rupture (88.7%). The most utilized VNG was the ulnar nerve (72.8%), followed by nerve to long head of triceps (8.8%) and sural nerve (8.2%); most common recipients were median (57.6%), axillary (12.5%), and musculocutaneous nerves (11.9%). Between patients who had medical research council scale scores, 69% had functional (M3 and above) motor and 72.7% sensory (S3

Peripheral nerve surgeries are a complex undertaking that require a multifaceted team approach. For optimal outcomes, early involvement of therapy, planning with the surgical team, and communication with the patient are crucial. This facilitates compliance and is an integral component of the recovery process after these large procedures.

Peripheral nerve injuries can be devastating. Although neuropraxic and some axonotmesis injuries will recover spontaneously, nerve repair or reconstruction is required to restore function in high-grade axonotmesis or neurotmesis injuries. The first step of nerve repair or reconstruction is adequate nerve debridement with removal of necrotic and fibrous tissues. Debridement decreases neuroma formation at the repair site and produces an optimal surface for axonal regeneration. This article discusses nerve debridement, including the goals of debridement, debridement techniques, and signs of adequate nerve debridement before repair.

Effective nerve coaptation entails tensionless repair of healthy fascicles with intact fascicular architecture and a well-vascularized environment, supportive of the regenerative cellular behaviors of neurons, immune cells, and Schwann cells. Suture coaptations have historically been used to ensure that these criteria are met for end-to-end repair, nerve transfers, and allograft or autograft reconstructions; however, unfortunately, overall restoration of function remains poor. As optimal coaptation is required for return of sensorimotor function, adjunct biomaterials are increasingly being enlisted attempting to optimize these suture-based coaptations. The purpose of this review was to discuss the biological, preclinical, and clinical data for the use of fibrin glue and nerve wraps made of type 1 collagen, porcine small intestine submucosa, chitosan, and human amniotic membrane. This study provides available data on each material’s ability to optimize the regenerative potential of nerve repair as well as available outcomes data. Although each biomaterial discussed has benefits to nerve regeneration, at large, data remain heterogeneous, and continued investigation is required to fully understand the specific mechanisms involved and the long-term potential clinical impacts each can provide for improvement of sensorimotor outcomes.

Platelet-rich plasma (PRP) has the capability of assisting in the recovery of damaged tissues by releasing a variety of biologically active factors to initiate a hemostatic cascade reaction and promote the synthesis of new connective tissue and revascularization. It is now widely used for tissue engineering repair. In addition, PRP has demonstrated nerve repair and pain relief, and has been studied and applied to the facial nerve, median nerve, sciatic nerve, and central nerve.These suggest that PRP injection therapy has a positive effect on nerve repair. This indicates that PRP has high clinical value and potential application in nerve repair. It is worthwhile for scientists and medical workers to further explore and study PRP to expand its application in nerve repair, and to provide a more reliable scientific basis for the opening of a new approach to nerve repair.

Abstract Background As a common disabling disease, irreversible neuronal death due to spinal cord injury (SCI) is the root cause of functional impairment; however, the capacity for neuronal regeneration in the developing spinal cord tissue is limited. Therefore, there is an urgent need to investigate how defective neurons can be replenished and functionally integrated by neural regeneration; the reprogramming of intrinsic cells into functional neurons may represent an ideal solution. Methods A mouse model of transection SCI was prepared by forceps clamping, and an adeno-associated virus (AAV) carrying the transcription factors NeuroD1 and Neurogenin-2(Ngn2) was injected in situ into the spinal cord to specifically overexpress these transcription factors in astrocytes close to the injury site. 5-bromo-2´-deoxyuridine (BrdU) was subsequently injected intraperitoneally to continuously track cell regeneration, neuroblasts and immature neurons marker expression, neuronal regeneration, and glial scar regeneration. In addition, immunoprotein blotting was used to measure the levels of transforming growth factor-β (TGF-β) pathway-related protein expression. We also evaluated motor function, sensory function, and the integrity of the blood-spinal cord barrier(BSCB). Results The in situ overexpression of NeuroD1 and Ngn2 in the spinal cord was achieved by specific AAV vectors. This intervention led to a significant increase in cell regeneration and the proportion of cells with neuroblasts and immature neurons cell properties at the injury site(p 0.05), although the treated mice had more sensory sensitivity and greater voluntary motor ability in open field than the non-intervention mice. We observed significant repair of the BSCB at the center of the injury site (p

Abstract Despite recent advancements in peripheral nerve regeneration, the creation of nerve conduits with chemical and physical cues to enhance glial cell function and support axonal growth remains challenging. This study aimed to assess the impact of electrical stimulation (ES) using a conductive nerve conduit on sciatic nerve regeneration in a rat model with transection injury. The study involved the fabrication of conductive nerve conduits using silk fibroin and Au nanoparticles (AuNPs). Collagen hydrogel loaded with green fluorescent protein (GFP)-positive adipose-derived mesenchymal stem cells (ADSCs) served as the filling for the conduit. Both conductive and non-conductive conduits were applied with and without ES in rat models. Locomotor recovery was assessed using walking track analysis. Histological evaluations were performed using H&E, luxol fast blue staining and immunohistochemistry. Moreover, TEM analysis was conducted to distinguish various ultrastructural aspects of sciatic tissue. In the ES + conductive conduit group, higher S100 (p

BackgroundPeripheral nerve injuries (PNIs) are associated with significant physical and psychological challenges, impacting both functional recovery and quality of life. Despite the physical focus of traditional treatments, psychological factors play a crucial role in the outcomes of PNI repair and recovery.ObjectivesThis systematic review aims to evaluate the impact of psychological and social factors on the repair and recovery of peripheral nerve injuries.MethodsA comprehensive literature search was conducted in PubMed/Medline, EMBASE, and Cochrane databases, covering studies from January 1985 to December 2022. A total of 36,190 records were identified, and after screening with Rayyan AI and applying inclusion criteria, 111 articles were selected for review.ResultsThe review highlights that pre-existing psychological conditions, as well as psychological responses to the injury and treatment, significantly influence recovery outcomes in PNI patients. Psychological interventions, when integrated into standard care, may improve functional recovery and quality of life.ConclusionsPsychosocial factors are critical in the management of PNIs and should be incorporated into treatment algorithms to enhance patient outcomes. Future research should focus on developing and integrating psychological support strategies in PNI treatment protocols.

Abstract Successful nerve repair using bioadhesive hydrogels demands minimizing tissue–material interfacial mechanical mismatch to reduce immune responses and scar tissue formation. Furthermore, it is crucial to maintain the bioelectrical stimulation‐mediated cell‐signaling mechanism to overcome communication barriers within injured nerve tissues. Therefore, engineering bioadhesives for neural tissue regeneration necessitates the integration of electroconductive properties with tissue‐like biomechanics. In this study, we propose a stretchable bioadhesive based on a custom‐designed chemically modified elastin‐like polypeptides (ELPs) and a choline‐based bioionic liquid (Bio‐IL), providing an electroconductive microenvironment to reconnect damaged nerve tissue. The stretchability akin to native neural tissue was achieved by incorporating hydrophobic ELP pockets, and a robust tissue adhesion was obtained due to multi‐mode tissue–material interactions through covalent and noncovalent bonding at the tissue interface. Adhesion tests revealed adhesive strength ~10 times higher than commercially available tissue adhesive, Evicel®. Furthermore, the engineered hydrogel supported in vitro viability and proliferation of human glial cells. We also evaluated the biodegradability and biocompatibility of the engineered bioadhesive in vivo using a rat subcutaneous implantation model, which demonstrated facile tissue infiltration and minimal immune response. The outlined functionalities empower the engineered elastic and electroconductive adhesive hydrogel to effectively enable sutureless surgical sealing of neural injuries and promote tissue regeneration.

Background. The use of adipose tissue in reconstructive procedures has become popular in the last decades due to the adipose tissue properties of stem cells and mechanical protection. In acute nerve lesions, there have been experimental reports on the use of non-vascularised adipose tissue as an adjuvant for nerve recovery but to our knowledge there is no published research that describes the effect of the pedicled vascularised adipose tissue (pVAT) on acute nerve injuries. Therefore we decided to study the effect of pVAT on nerve regeneration when wrapped around an epineurial coaptation site and for a 5 mm defect of the sciatic nerve from the rat. Methods. The effect of pedicled vascularized adipose tissue (pVAT) on nerve regeneration was studied on the sciatic nerve injury model in twenty-four Wistar rats divided into four groups: epineurial repair; epineurial repair and pVAT; a 5 mm nerve gap bridged by an autograft; a 5 mm nerve gap bridged by a conduit-pVAT (C-pVAT). Automatization injuries, walking track analysis, postoperative extraneural fibrosis and histological analysis were performed three months after the intervention. Results. Although histological and functional nerve regeneration was present in various degrees in all the studied groups, nerve regeneration was not enhanced by the use of the pVAT or C-pVAT. The harvesting of the pVAT flap caused postoperative fibrosis when used as a conduit. Automutilation was not decreased by the use of the pVAT nor a correlation between automutilation and postoperative fibrosis in the studied groups could be established. The postoperative fibrosis did not influence neural regeneration in the pVAT and autograft group. Conclusion. Vascularized adipose tissue did not enhance neural regeneration when used as an adjunct procedure for primary nerve repair and or even as a novel conduit for 5 mm nerve defects in the rat sciatic nerve.

Objective Common peroneal nerve (CPN) injury is a frequently encountered lower extremity injury. Furthermore, several previous studies have demonstrated that patients who underwent direct suturing of the CPN following rupture experienced unfavorable postoperative prognoses. Therefore, we aimed to present a novel modified surgical approach for CPN rupture and assess the effectiveness of this technique in restoring lower limb functionality. Methods In this retrospective observational study, we included patients with CPN rupture who underwent one‐stage neurorrhaphy and posterior transposition combined with nerve wrapping using a gastrocnemius fascial flap for CPN rupture between January 2016 and December 2020. Lower limb function was evaluated using the lower extremity functional scale (LEFS) and British Medical Research Council (BMRC) grading system. We also assessed the influence of age, sex, duration of symptoms, mechanism of injury, and surgical modality on the postoperative recovery of lower extremity function using subgroup and regression analyses. Results Thirty‐seven patients (mean age = 35.76 ± 13.01 years) with at least 2 years of follow‐up were included in the final analysis. The LEFS scores significantly improved after surgery at the last follow‐up (p

Introduction: Spinal cord injury (SCI) is associated with microenvironment imbalance, thereby resulting in poor regeneration and recovery of the spinal cord. Gene therapy can be used to balance the inflammatory response, however target genes cannot exist in localized injured areas.Methods: A genetically engineered electrospun scaffold (GEES) to achieve long-term immunoregulation and nerve repair was constructed. By combining the microfluidic and electrospinning techniques, interleukin-10 plasmid (pIL10) was loaded into lipid nanoparticles (LNPs) (pIL10-LNP), which was encapsulated to the nerve growth factor (NGF). Immunofluorescence staining, qRT-PCR, ELISA, flow cytometry, and other tests were employed to comprehensively assess the role of GEES in modulating macrophage polarization and facilitating neural repair.Results: The results showed that the scaffold released >70% of the pIL10-LNP within 10 d and continued slow release within 30 d. In vitro cell experiments have demonstrated that GEES effectively stimulates macrophages to secrete anti-inflammatory cytokines and facilitates the differentiation of neural stem cells into neuronal cells. In rat T9 SCI model, the GEES significantly inhibited the inflammatory response in the acute and chronic phases of SCI by transfecting local tissues with slow-release pIL10-LNP to promote the release of the anti-inflammatory factor IL10, thereby creating a favorable microenvironment. With the addition of NGF, the repair and regeneration of nerve tissues was effectively promoted, and the post-SCI motor function of rats improved.Discussion: GEES can regulate post-SCI immune responses through continuous and effective gene delivery, providing a new strategy for the construction of electrospun scaffolds for nerve repair in gene therapy.

Abstract Background This study aims to assess the recovery patterns and factors influencing outcomes in patients with common peroneal nerve (CPN) injury. Methods This retrospective study included 45 patients with CPN injuries treated between 2009 and 2019 in Jing’an District Central Hospital. The surgical interventions were categorized into three groups: neurolysis (group A; n = 34 patients), nerve repair (group B; n = 5 patients) and tendon transfer (group C; n = 6 patients). Preoperative and postoperative sensorimotor functions were evaluated using the British Medical Research Council grading system. The outcome of measures included the numeric rating scale, walking ability, numbness and satisfaction. Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal time interval between injury and surgery for predicting postoperative foot dorsiflexion function, toe dorsiflexion function, and sensory function. Results Surgical interventions led to improvements in foot dorsiflexion strength in all patient groups, enabling most to regain independent walking ability. Group A (underwent neurolysis) had significant sensory function restoration (P

ObjectiveTo visualize and analyze the literature related to sciatic nerve injury treatment from January 2019 to December 2023, and summarize the current status, hotspots, and development trends of research in this field.MethodsUsing CiteSpace and VOSviewer software, we searched the Web of Science database for literature related to the treatment of sciatic nerve injury. Then we analyzed and plotted visualization maps to show the number of publications, countries, institutions, authors, keywords, references, and journals.ResultsA total of 2,653 articles were included in the English database. The annual number of publications exceeded 230, and the citation frequency increased yearly. The United States and China were identified as high-influence nations in this field. Nantong University was the leading institution in terms of close cooperation among institutions. The authors Wang Yu had the highest number of publications and were highly influential in this field. Keyword analysis and reference Burst revealed a research focus on nerve regeneration and neuropathic pain, which involve regenerative medicine and neural tissue engineering. Chronic pain resulting from sciatic nerve injury often manifests alongside anxiety, depression, cognitive-behavioral disorders, and other issues. Interventions such as stem cells, electrical stimulation, electroacupuncture, total joint replacement, pharmacological interventions, gene therapy, nerve conduits, chitosan scaffolds, and exercise promote nerve repair and alleviate pain. Schwann cells have been the focus of much attention in nerve repair and regeneration. Improving the outcome of sciatic nerve injury is a current research challenge and focus in this field. Based on keyword Burst, nerve conduits and grafts may become a potential research hotspot in the treatment of sciatic nerve injury.ConclusionThis visual analysis summarizes research trends and developments of sciatic nerve injury treatment and predicts potential research frontiers and hot directions.

IntroductionPeripheral nerves are frequently affected by lesions caused by traumatic or iatrogenic damages, resulting in loss of motor and sensory function, crucial in orthopedic outcomes and with a significant impact on patients’ quality of life. Many strategies have been proposed over years to repair nerve injuries with substance loss, to achieve musculoskeletal reinnervation and functional recovery. Allograft have been tested as an alternative to the gold standard, the autograft technique, but nerves from donors frequently cause immunogenic response. For this reason, several studies are focusing to find the best way to decellularize nerves preserving either the extracellular matrix, either the basal lamina, as the key elements used by Schwann cells and axons during the regenerative process.MethodsThis study focuses on a novel decellularization protocol for porcine nerves, aimed at reducing immunogenicity while preserving essential elements like the extracellular matrix and basal lamina, vital for nerve regeneration. To investigate the efficacy of the decellularization protocol to remove immunogenic cellular components of the nerve tissue and to preserve the basal lamina and extracellular matrix, morphological analysis was performed through Masson’s Trichrome staining, immunofluorescence, high resolution light microscopy and transmission electron microscopy. Decellularized porcine nerve graft were then employed in vivo to repair a rat median nerve lesion. Morphological analysis was also used to study the ability of the porcine decellularized graft to support the nerve regeneration.Results and DiscussionThe decellularization method was effective in preparing porcine superficial peroneal nerves for grafting as evidenced by the removal of immunogenic components and preservation of the ECM. Morphological analysis demonstrated that four weeks after injury, regenerating fibers colonized the graft suggesting a promising use to repair severe nerve lesions. The idea of using a porcine nerve graft arises from a translational perspective. This approach offers a promising direction in the orthopedic field for nerve repair, especially in severe cases where conventional methods are limited.

Distinct brain remodeling has been found after different nerve reconstruction strategies, including motor representation of the affected limb. However, differences among reconstruction strategies at the brain network level have not been elucidated. This study aimed to explore intra-network changes related to altered peripheral neural pathways after different nerve reconstruction surgeries, including nerve repair, end-to-end nerve transfer, and end-to-side nerve transfer. Sprague–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight: no nerve repair, grafted nerve repair, phrenic nerve end-to-end transfer, and end-to-side transfer with a graft sutured to the anterior upper trunk. Resting-state brain functional magnetic resonance imaging was obtained 7 months after surgery. The independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the component. Alterations in intra-network resting-state functional connectivity were compared among the groups. Target muscle reinnervation was assessed by behavioral observation (elbow flexion) and electromyography. The results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural pathway. Nerve repair was related to enhanced connectivity within the sensorimotor network, while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor representation. The thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve transfer. Brain areas related to cognition and emotion were enhanced after end-to-side nerve transfer. Our study revealed important brain networks related to different nerve reconstructions. These networks may be potential targets for enhancing motor recovery.

Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague–Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1–2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.

Sensory nerves belong to the afferent nerve part of the peripheral nervous system. Their role is to accept the stimuli inside and outside the body and transmit them to the center nerve system to form sensations or reflexes. Sensory nerve damage can be caused by trauma, tumor invasion, surgical injury, etc. Sensory nerve injury may cause decline or loss of some sensory organs function in patients. Damage of important sensory nerves such as optic nerves and auditory nerves can bring profound troubles to patients' lives. So far, the main clinical method to repair sensory nerves is autologous nerve transplantation. However, its application is limited by various factors, and the recovery effect of nerve function is often limited. Stem cells have the potential of multi-directional differentiation, which can differentiate into Schwann cells, and then secrete neurotrophic factors to promote axonal growth and myelin regeneration. Schwann cells directionally proliferate and form Büngner zones which guide nerve regeneration. Stem cells can also differentiate into neurons and construct nerve defect repair materials, which is an ideal choice for nerve repair. At present, the tissue engineering technology based on stem cells, combined with several key biotechnology, such as the use of biopolymerized or artificial surface micro-patterning nerve conduit to bridge nerve defects, and the use of microspheres to achieve the controlled release of extracellular matrix proteins and neurotrophic factors, is being widely studied and has achieved certain research results. This article reviews the research progress of stem cells in the repair of several major sensory nerves, such as optic nerves, olfactory nerves, cochlear nerves and sensory nerve fibers of sciatic nerve, expecting to provide a new perspective for neural repair of stem cells, broaden the preclinical research in nerve repair, and provide reference for follow-up clinical application.

Introduction: Peripheral nerve injury (PNI) is increasingly prevalent and challenging to treat despite advances in microsurgical techniques. In this context, adipose tissue derivatives, such as adipose-derived stem cells, nanofat, and stromal vascular fraction have been gaining attention as potential allies in peripheral nerve regeneration. Objectives: This study aims to explore the use of adipose tissue derivatives in nerve regeneration following peripheral nerve transection in murine models. Thus, we assess and synthesize the key techniques and methods used for evaluating the obtained nerve regeneration to guide future experimental research and clinical interventions. Methodology: A systematic review was conducted in February 2024, adhering to the Cochrane and PRISMA 2020 guidelines, using the PubMed, SciELO, and LILACS databases. The focus was on experimental studies involving adipose tissue derivatives in nerve regeneration in animal models post-transection. Only experimental trials reporting nerve regeneration outcomes were included; studies lacking a comparator group or evaluation methods were excluded. Results: Out of 273 studies initially identified from MEDLINE, 19 were selected for detailed analysis. The average study included 32.5 subjects, with about 10.2 subjects per intervention subgroup. The predominant model was the sciatic nerve injury with a 10 mm gap. The most common intervention involved unprocessed adipose-derived stem cells, utilized in 14 articles. Conclusions: This review underscores the significant potential of current methodologies in peripheral nerve regeneration, particularly highlighting the use of murine models and thorough evaluation techniques.

Abstract Peripheral nerve injury (PNI) is a common and severe clinical disease worldwide, which leads to a poor prognosis because of the complicated treatments and high morbidity. Autologous nerve grafting as the gold standard still cannot meet the needs of clinical nerve transplantation because of its low availability and limited size. The development of artificial nerve conduits was led to a novel direction for PNI treatment, while most of the currently developed artificial nerve conduits was lack biochemical cues to promote nerve regeneration. In this study, we designed a novel composite neural conduit by inserting decellularized the rat sciatic nerve or kidney in a poly (lactic-co-glycolic acid) (PLGA) grooved conduit. The nerve regeneration effect of all samples was analyzed using rat sciatic nerve defect model, where decellularized tissues and grooved PLGA conduit alone were used as controls. The degree of nerve regeneration was evaluated using the motor function, gastrocnemius recovery, and morphological and histological assessments suggested that the combination of a grooved conduit with decellularized tissues significantly promoted nerve regeneration compared with decellularized tissues and PLGA conduit alone. It is worth to note that the grooved conduits containing decellularized nerves have a promotive effect similar to that of autologous nerve grafting, suggesting that it could be an artificial nerve conduit used for clinical practice in the future. Graphical Abstract

Summary: Background: The incidence of incisional self-harm of the upper limbs is increasing, and recurrence rates are high. It is not known whether different wound treatment strategies (dressings only vs. surgery) or the operative setting (main theatre vs. non-main theatre) affect wound or mental health-related outcomes. Methods: Four electronic databases (Ovid MEDLINE, OVID EMBASE, PsycINFO and CENTRAL) were searched from inception to 14/09/2021 for studies which describe the management of incisional self-harm wounds of the upper limb(s) in adults and children. Dual-author screening and data extraction were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: In total, 19 studies (1477 patients) were included. Overall, the evidence was limited by a paucity of comparative data on wound management strategy and setting, and poor-quality outcome reporting. Only four studies clearly identified the operative setting for definitive wound management (two in main operating theatres, one in the emergency department and one using both settings, depending on injury severity). Few studies inconsistently reported surgical outcomes (n=9) or mental health outcomes (n=4), hindering evidence synthesis. Conclusion: Further investigation is needed to determine the most cost-effective management strategies and settings for these injuries.

BackgroundPeripheral nerve injuries (PNIs) of the upper limb are very common events within the pediatric population, especially following soft tissue trauma and bone fractures. Symptoms of brachial plexus nerve injuries can differ considerably depending on the site and severity of injury. Compared to median and radial nerves, the ulnar nerve (UN) is the most frequently and severely injured nerve of the upper extremity. Indeed, due to its peculiar anatomical path, the UN is known to be particularly vulnerable to traumatic injuries, which result in pain and substantial motor and sensory disabilities of the forearm and hand. Therefore, timely and appropriate postoperative management of UN lesions is crucial to avoid permanent sensorymotor deficits and claw hand deformities leading to lifelong impairments. Nevertheless, the literature regarding the rehabilitation following PNIs is limited and lacks clear evidence regarding a solid treatment algorithm for the management of UN lesions that ensures full functional recovery.Case presentationThe patient is a 11-year-old child who experienced left-hand pain, stiffness, and disability secondary to a domestic accident. The traumatic UN lesion occurred about 8 cm proximal to Guyon’s canal and it was surgically treated with termino-terminal (end-to-end) neurorrhaphy. One month after surgery, the patient underwent multimodal rehabilitative protocol and both subjective and functional measurements were recorded at baseline (T0) and at 3- (T1) and 5-month (T2) follow-up. At the end of the rehabilitation protocol, the patient achieved substantial reduction in pain and improvement in quality of life. Of considerable interest, the patient regained a complete functional recovery with satisfactory handgrip and pinch functions in addition with a decrease of disability in activities of daily living.ConclusionA timely and intensive rehabilitative intervention done by qualified hand therapist with previous training in the rehabilitation of upper limb neuromuscular disorders is pivotal to achieve a stable and optimal functional recovery of the hand, while preventing the onset of deformities, in patients with peripheral nerve injuries of the upper limb.

Abstract Iron accumulates in the neural tissue during peripheral nerve degeneration. Some studies have already been suggested that iron facilitates Wallerian degeneration (WD) events such as Schwann cell de‐differentiation. On the other hand, intracellular iron levels remain elevated during nerve regeneration and gradually decrease. Iron enhances Schwann cell differentiation and axonal outgrowth. Therefore, there seems to be a paradox in the role of iron during nerve degeneration and regeneration. We explain this contradiction by suggesting that the increase in intracellular iron concentration during peripheral nerve degeneration is likely to prepare neural cells for the initiation of regeneration. Changes in iron levels are the result of changes in the expression of iron homeostasis proteins. In this review, we will first discuss the changes in the iron/iron homeostasis protein levels during peripheral nerve degeneration and regeneration and then explain how iron is related to nerve regeneration. This data may help better understand the mechanisms of peripheral nerve repair and find a solution to prevent or slow the progression of peripheral neuropathies.

Spinal cord injury (SCI) is a critical neurological condition that may impair motor, sensory, and autonomous functions. At the cellular level, inflammation, impairment of axonal regeneration, and neuronal death are responsible for SCI-related complications. Regarding the high mortality and morbidity rates associated with SCI, there is a need for effective treatment. Despite advances in SCI repair, an optimal treatment for complete recovery after SCI has not been found so far. Therefore, an effective strategy is needed to promote neuronal regeneration and repair after SCI. In recent years, regenerative treatments have become a potential option for achieving improved functional recovery after SCI by promoting the growth of new neurons, protecting surviving neurons, and preventing additional damage to the spinal cord. Transplantation of cells and cells-derived extracellular vesicles (EVs) can be effective for SCI recovery. However, there are some limitations and challenges related to cell-based strategies. Ethical concerns and limited efficacy due to the low survival rate, immune rejection, and tumor formation are limitations of cell-based therapies. Using EVs is a helpful strategy to overcome these limitations. It should be considered that short half-life, poor accumulation, rapid clearance, and difficulty in targeting specific tissues are limitations of EVs-based therapies. Hydrogel-encapsulated exosomes have overcome these limitations by enhancing the efficacy of exosomes through maintaining their bioactivity, protecting EVs from rapid clearance, and facilitating the sustained release of EVs at the target site. These hydrogel-encapsulated EVs can promote neuroregeneration through improving functional recovery, reducing inflammation, and enhancing neuronal regeneration after SCI. This review aims to provide an overview of the current research status, challenges, and future clinical opportunities of hydrogel-encapsulated EVs in the treatment of SCI.

The field of peripheral nerve regeneration is a dynamic and rapidly evolving area of research that continues to captivate the attention of neuroscientists worldwide. The quest for effective treatments and therapies to enhance the healing of peripheral nerves has gained significant momentum in recent years, as evidenced by the substantial increase in publications dedicated to this field. This surge in interest reflects the growing recognition of the importance of peripheral nerve recovery and the urgent need to develop innovative strategies to address nerve injuries. In this context, this article aims to contribute to the existing knowledge by providing a comprehensive review that encompasses both biomaterial and clinical perspectives. By exploring the utilization of nerve guidance conduits and pharmacotherapy, this article seeks to shed light on the remarkable advancements made in the field of peripheral nerve regeneration. Nerve guidance conduits, which act as artificial channels to guide regenerating nerves, have shown promising results in facilitating nerve regrowth and functional recovery. Additionally, pharmacotherapy approaches have emerged as potential avenues for promoting nerve regeneration, with various therapeutic agents being investigated for their neuroprotective and regenerative properties. The pursuit of advancing the field of peripheral nerve regeneration necessitates persistent investment in research and development. Continued exploration of innovative treatments, coupled with a deeper understanding of the intricate processes involved in nerve regeneration, holds the promise of unlocking the complete potential of these groundbreaking interventions. By fostering collaboration among scientists, clinicians, and industry partners, we can accelerate progress in this field, bringing us closer to the realization of transformative therapies that restore function and quality of life for individuals affected by peripheral nerve injuries.

Traumatic nerve injuries are common lesions that affect several hundred thousand humans, as well as dogs and cats. The assessment of nerve regeneration through animal models may provide information for translational research and future therapeutic options that can be applied mutually in veterinary and human medicine, from a One Health perspective. This review offers a hands-on vision of the non-invasive and conservative approaches to peripheral nerve injury, focusing on the role of neurorehabilitation in nerve repair and regeneration. The peripheral nerve injury may lead to hypersensitivity, allodynia and hyperalgesia, with the possibility of joint contractures, decreasing functionality and impairing the quality of life. The question remains regarding how to improve nerve repair with surgical possibilities, but also considering electrical stimulation modalities by modulating sensory feedback, upregulation of BDNF, GFNF, TrKB and adenosine monophosphate, maintaining muscle mass and modulating fatigue. This could be improved by the positive synergetic effect of exercises and physical activity with locomotor training, and other physical modalities (low-level laser therapy, ultrasounds, pulsed electromagnetic fields, electroacupuncture and others). In addition, the use of cell-based therapies is an innovative treatment tool in this field. These strategies may help avoid situations of permanent monoplegic limbs that could lead to amputation.

Peripheral nerve injury (PNI) is a structural event with harmful consequences worldwide. Due to the limited intrinsic regenerative capacity of the peripheral nerve in adults, neural restoration after PNI is difficult. Neurological remodeling has a crucial effect on the repair of the form and function during the regeneration of the peripheral nerve after the peripheral nerve is injured. Several studies have demonstrated that acupuncture is effective for PNI-induced neurologic deficits, and the potential mechanisms responsible for its effects involve the nervous system remodeling in the process of nerve repair. Moreover, acupuncture promotes neural regeneration and axon sprouting by activating related neurotrophins retrograde transport, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), N-cadherin, and MicroRNAs. Peripheral nerve injury enhances the perceptual response of the central nervous system to pain, causing central sensitization and accelerating neuronal cell apoptosis. Together with this, the remodeling of synaptic transmission function would worsen pain discomfort. Neuroimaging studies have shown remodeling changes in both gray and white matter after peripheral nerve injury. Acupuncture not only reverses the poor remodeling of the nervous system but also stimulates the release of neurotrophic substances such as nerve growth factors in the nervous system to ameliorate pain and promote the regeneration and repair of nerve fibers. In conclusion, the neurological remodeling at the peripheral and central levels in the process of acupuncture treatment accelerates nerve regeneration and repair. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of PNI.

Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair; however, results are still not comparable with the current gold standard technique “autografts”. Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair. Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance. In this study, we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model. Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks. Nevertheless, the molecular assessment in the early regeneration phase (7, 14, and 28 days) has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones. Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1, a growth factor that plays an important role in Schwann cell transdifferentiation. The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2, VEGF-A, BDNF, c-Jun, and ATF3.

Studies have shown that human hair keratin (HHK) has no antigenicity and excellent mechanical properties. Schwann cells, as unique glial cells in the peripheral nervous system, can be induced by interleukin-1β to secrete nerve growth factor, which promotes neural regeneration. Therefore, HHK with Schwann cells may be a more effective approach to repair nerve defects than HHK without Schwann cells. In this study, we established an artificial nerve graft by loading an HHK skeleton with activated Schwann cells. We found that the longitudinal HHK microfilament structure provided adhesion medium, space and direction for Schwann cells, and promoted Schwann cell growth and nerve fiber regeneration. In addition, interleukin-1β not only activates Schwann cells, but also strengthens their activity and increases the expression of nerve growth factors. Activated Schwann cells activate macrophages, and activated macrophages secrete interleukin-1β, which maintains the activity of Schwann cells. Thus, a beneficial cycle forms and promotes nerve repair. Furthermore, our studies have found that the newly constructed artificial nerve graft promotes the improvements in nerve conduction function and motor function in rats with sciatic nerve injury, and increases the expression of nerve injury repair factors fibroblast growth factor 2 and human transforming growth factor B receptor 2. These findings suggest that this artificial nerve graft effectively repairs peripheral nerve injury.

Spinal cord injury causes varying degrees of motor and sensory function loss. However, there are no effective treatments for spinal cord repair following an injury. Moreover, significant preclinical advances in bioengineering and regenerative medicine have not yet been translated into effective clinical therapies. The spinal cord’s poor regenerative capacity makes repairing damaged and lost neurons a critical treatment step. Reprogramming-based neuronal transdifferentiation has recently shown great potential in repair and plasticity, as it can convert mature somatic cells into functional neurons for spinal cord injury repair in vitro and in vivo, effectively halting the progression of spinal cord injury and promoting functional improvement. However, the mechanisms of the neuronal transdifferentiation and the induced neuronal subtypes are not yet well understood. This review analyzes the mechanisms of resident cellular transdifferentiation based on a review of the relevant recent literature, describes different molecular approaches to obtain different neuronal subtypes, discusses the current challenges and improvement methods, and provides new ideas for exploring therapeutic approaches for spinal cord injury.

Background: Olfactory ensheathing cells (OECs) serve as a bridge by migrating at the site of spinal cord injury (SCI) to facilitate the repair of the neural structure and neural function. However, OEC migration at the injury site not only faces the complex and disordered internal environment but also is closely associated with the migration ability of OECs. Methods: We extracted OECs from the olfactory bulb of SD rats aged

Abstract Background Repairing all nerves is challenging in cases of upper arm avulsion combined with defects in multiple nerves because the donor area for autogenous nerve transplantation is limited and the outcomes of long-segment allogeneic nerve transplantation are poor. Based on the principle of magnified nerve regeneration, we present a method called nerve merging repair, the feasibility of which needs to be confirmed in clinical practice. Methods The nerve merging repair method relies on the use of fewer proximal nerves to innervate more distal nerves and depends mainly on whether the radial nerve (RN) can repair itself. In the case of defects in multiple nerves precluding RN self-repair, median-(median + radial) (M-(M + R)) repair is performed. If the RN can undergo self-repair, median-(median + ulnar) (M-(M + U)) or ulnar-(ulnar + median) (U-(U + M)) is used to repair the three nerves. Five cases were included in the study and involved the analysis of joint motor function, muscle strength and sensory recovery of the affected limb. Results The replanted limb survived in all 5 cases. Follow-up visits were conducted with the patients for 51–80 months, during which they experienced satisfactory recovery of skin sensation, elbow flexion and extension and partial recovery of hand muscle strength. Conclusions To a certain extent, treatment with the nerve merging repair method improved the sensory and motor function of the affected limb and limited the loss of function of the donor nerve area. This intervention provides a new approach for repairing long-segment defects in multiple nerves caused by avulsion amputation of the upper limb.

Spinal cord injury (SCI) is a disease of the central nervous system often caused by accidents, and its prognosis is unsatisfactory, with long-term adverse effects on patients’ lives. The key to its treatment lies in the improvement of the microenvironment at the injury and the reconstruction of axons, and tissue repair is a promising therapeutic strategy. Hydrogel is a three-dimensional mesh structure with high water content, which has the advantages of biocompatibility, degradability, and adjustability, and can be used to fill pathological defects by injectable flowing hydrophilic material in situ to accurately adapt to the size and shape of the injury. Hydrogels mimic the natural extracellular matrix for cell colonization, guide axon extension, and act as a biological scaffold, which can be used as an excellent carrier to participate in the treatment of SCI. The addition of different materials to make composite hydrogel scaffolds can further enhance their performance in all aspects. In this paper, we introduce several typical composite hydrogels and review the research progress of hydrogel for SCI to provide a reference for the clinical application of hydrogel therapy for SCI.

[INLINE:1] The introduction of neurotrophic factors into injured peripheral nerve sites is beneficial to peripheral nerve regeneration. However, neurotrophic factors are rapidly degraded in vivo and obstruct axonal regeneration when used at a supraphysiological dose, which limits their clinical benefits. Bioactive mimetic peptides have been developed to be used in place of neurotrophic factors because they have a similar mode of action to the original growth factors and can activate the equivalent receptors but have simplified sequences and structures. In this study, we created polydopamine-modified chitin conduits loaded with brain-derived neurotrophic factor mimetic peptides and vascular endothelial growth factor mimetic peptides (Chi/PDA-Ps). We found that the Chi/PDA-Ps conduits were less cytotoxic in vitro than chitin conduits alone and provided sustained release of functional peptides. In this study, we evaluated the biocompatibility of the Chi/PDA-Ps conduits. Brain-derived neurotrophic factor mimetic peptide and vascular endothelial growth factor mimetic peptide synergistically promoted proliferation of Schwann cells and secretion of neurotrophic factors by Schwann cells and attachment and migration of endothelial cells in vitro. The Chi/PDA-Ps conduits were used to bridge a 2 mm gap between the nerve stumps in rat models of sciatic nerve injury. We found that the application of Chi/PDA-Ps conduits could improve the motor function of rats and reduce gastrocnemius atrophy. The electrophysiological results and the microstructure of regenerative nerves showed that the nerve conduction function and remyelination was further restored. These findings suggest that the Chi/PDA-Ps conduits have great potential in peripheral nerve injury repair.

Our previous RNA sequencing study showed that the long non-coding RNA ischemia-related factor Vof-16 (lncRNA Vof-16) was upregulated after spinal cord injury, but its precise role in spinal cord injury remains unclear. Bioinformatics predictions have indicated that lncRNA Vof-16 may participate in the pathophysiological processes of inflammation and apoptosis. PC12 cells were transfected with a pHBLV-U6-MCS-CMV-ZsGreen-PGK-PURO vector to express an lncRNA Vof-16 knockdown lentivirus and a pHLV-CMVIE-ZsGree-Puro vector to express an lncRNA Vof-16 overexpression lentivirus. The overexpression of lncRNA Vof-16 inhibited PC12 cell survival, proliferation, migration, and neurite extension, whereas lncRNA Vof-16 knockdown lentiviral vector resulted in the opposite effects in PC12 cells. Western blot assay results showed that the overexpression of lncRNA Vof-16 increased the protein expression levels of interleukin 6, tumor necrosis factor-α, and Caspase-3 and decreased Bcl-2 expression levels in PC12 cells. Furthermore, we established rat models of spinal cord injury using the complete transection at T10. Spinal cord injury model rats were injected with the lncRNA Vof-16 knockdown or overexpression lentiviral vectors immediately after injury. At 7 days after spinal cord injury, rats treated with lncRNA Vof-16 knockdown displayed increased neuronal survival and enhanced axonal extension. At 8 weeks after spinal cord injury, rats treated with the lncRNA Vof-16 knockdown lentiviral vector displayed improved neurological function in the hind limb. Notably, lncRNA Vof-16 knockdown injection increased Bcl-2 expression and decreased tumor necrosis factor-α and Caspase-3 expression in treated animals. Rats treated with the lncRNA Vof-16 overexpression lentiviral vector displayed opposite trends. These findings suggested that lncRNA Vof-16 is associated with the regulation of inflammation and apoptosis. The inhibition of lncRNA Vof-16 may be useful for promoting nerve regeneration and functional recovery after spinal cord injury. The experiments were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.

The clinical “gold standard” technique for attempting to restore function to nerves with a gap is to bridge the gap with sensory autografts. However, autografts induce good to excellent recovery only across short nerve gaps, in young patients, and when repairs are performed a short time post nerve trauma. Even under the best of conditions, < 50% of patients recover good recovery. Although many alternative techniques have been tested, none is as effective as autografts. Therefore, alternative techniques are required that increase the percentage of patients who recover function and the extent of their recovery. This paper examines the actions of lithium, and how it appears to trigger all the cellular and molecular events required to promote axon regeneration, and how both in animal models and clinically, lithium administration enhances both the extent of axon regeneration and neurological recovery. The paper proposes more extensive clinical testing of lithium for its ability and reliability to increase the extent of axon regeneration and functional recovery.

Background Multiple nerve transfer techniques are used to treat patients with nerve injuries when a primary repair is not possible. These techniques are categorized to end-to-end, end-to-side, and side-to-side neurorrhaphy. Our study aims to explore the utility of the cross-bridge ladder technique (H-shaped), which has shown promising results in animal models and probably underutilized clinically. Methods Four patients with significant loss of ankle dorsiflexion were seen in the clinic and underwent evaluation, including electrodiagnostic studies. A cross-bridge ladder repair technique was used between the tibial nerve as the donor and the common peroneal nerve as the recipient via one or two nerve grafts coapted in parallel with end-to-side neurorrhaphies. Dorsiflexion strength was measured preoperatively using the Medical Research Council (MRC) grading system and at each postoperative follow-up appointment. Results All four patients had suffered persistent and severe foot drop (MRC of 0) following trauma that had occurred between 6 and 15 months preoperatively. Three of the four patients improved to an MRC of 2 several months postoperatively. The last patient had an immediate improvement to an MRC of 2 by his first month and had a complete recovery of ankle dorsiflexion within 4 months from surgery. Conclusion We demonstrate the utility and clinical outcomes of the cross-bridge ladder technique in patients with persistent and prolonged foot drop following trauma. Both early and late recovery were seen while all patients regained motor function, with some patients continuing to improve up to the most recent follow-up. IRB Approval: Obtained 2013–1411-CP005

Background The extent of functional recovery induced in healthy patients by sensory nerve grafts, the clinical “gold standard” technique for repairing peripheral nerves with a gap, is significantly limited by increasing gap length, time between trauma and repair, and patient age. When the values of any two, or all three, variables increase simultaneously, there is little to no recovery. For diabetic patients, even under the best of conditions and without any large variables, the extent of axon regeneration and functional recovery is significantly less, but generally none. Therefore, novel techniques are required that enhance recovery in diabetic patients. Methods A 12-cm long median nerve gap in the wrist/palm of a 71-year-old male long-term diabetic patient was bridged 1.3 years post nerve injury with a sural nerve graft within a platelet-rich plasma-filled collagen tube. Results By 2 months post-repair, the patient's level 6 chronic neuropathic pain was permanently eliminated. By 6.75 months, the palm had recovered good sensitivity to stimuli of all sensory modalities, including 4.56 g pressure and less than 15 mm two-point discrimination. Each finger had good motor function of M3–5, with partial to complete sensitivity to stimuli of all sensory modalities and an overall recovery of S3. Conclusion This technique permanently eliminates severe chronic neuropathic pain while simultaneously inducing good motor and sensory recovery in a long-term diabetic patient, under conditions where recovery is rarely, if ever, seen, even in non-diabetic patients. This technique holds great promise of restoring function to diabetic patients, for whom it is otherwise not possible.

Background Recurrent laryngeal nerve (RLN) injury carries significant morbidity. Microsurgical repair of the RLN has proven promising for enhancing patient recovery of vocal function; however, data remains limited. Methods This retrospective cohort study included patients who underwent RLN repair from 2007 to 2022. Demographics and medical history were collected. The location and etiology of RLN injury, as well as the repair technique, were collected. Follow-up data were collected at the initial postoperative visit, at 6 months and at 1 year. Hoarseness was classified as mild, moderate, or severe. Of patients who underwent nasopharyngolaryngoscopy (NPL) following repair, the glottic gap was measured. Vocal interventions performed were also recorded. This study utilized descriptive statistical methods. Results Eleven patients underwent RLN repair. All patients underwent immediate repair. Fifty-four percent (n = 6) of RLN injuries resulted from tumor inflammation or nerve encasement. Eighty-two percent (n = 9) underwent direct RLN coaptation, 9% (n = 1) underwent vagus-RLN anastomosis, and 9% (n = 1) underwent an interposition nerve graft. Technical success was 100%. Seventy-three percent (n = 8) required otolaryngology referral, and of those, 50% (n = 4) required intervention. At initial evaluation, 91% (n = 10) suffered from mild to severe hoarseness, and of patients who underwent NPL, all had a glottic gap. At 1 year, 82% of patients (n = 9) improved to having mild to no appreciable hoarseness. Of the patients who underwent NPL, 62% (n = 5) had closure of the glottic gap. Conclusion Patients undergoing repair of the RLN following injury showed excellent recovery of vocal function and resolution of glottic gap at 1 year.

Peripheral nervous system (PNS) injuries are an ongoing health care concern. While autografts and allografts are regarded as the current clinical standard for traumatic injury, there are inherent limitations that suggest alternative remedies should be considered for therapeutic purposes. In recent years, nerve guidance conduits (NGCs) have become increasingly popular as surgical repair devices, with a multitude of various natural and synthetic biomaterials offering potential to enhance the design of conduits or supplant existing technologies entirely. From a cellular perspective, it has become increasingly evident that Schwann cells (SCs), the primary glia of the PNS, are a predominant factor mediating nerve regeneration. Thus, the development of severe nerve trauma therapies requires a deep understanding of how SCs interact with their environment, and how SC microenvironmental cues may be engineered to enhance regeneration. Here we review the most recent advancements in biomaterials development and cell stimulation strategies, with a specific focus on how the microenvironment influences the behavior of SCs and can potentially lead to functional repair. We focus on microenvironmental cues that modulate SC morphology, proliferation, migration, and differentiation to alternative phenotypes. Promotion of regenerative phenotypic responses in SCs and other non-neuronal cells that can augment the regenerative capacity of multiple biomaterials is considered along with innovations and technologies for traumatic injury.

The maintenance of appropriate endoplasmic reticulum (ER) homeostasis is critical to effective spinal cord injury (SCI) repair. In previous reports, protein disulfide isomerase A6 (PDIA6) demonstrated to serve as a reversible functional modulator of ER stress responses, while spastin can coordinate ER organization through the modulation of the dynamic microtubule network surrounding this organelle. While both PDIA6 and spastin are thus important regulators of the ER, whether they interact with one another for SCI repair still needs to be determined. Here a proteomics analysis identified PDIA6 as being related to SCI repair, and protein interaction mass spectrometry further confirmed the ability of PDIA6 and spastin to interact with one another. Pull-down and co-immunoprecipitation assays were further performed to validate and characterize the interactions between these two proteins. The RNAi-based knockdown of PDIA6 in COS-7 cells inhibited the activity of spastin-dependent microtubule severing. PDIA6 was also found to promote injured neuron repair, while spastin knockdown reversed this reparative activity. Together, these results thus confirm that PDIA6 and spastin function together as critical mediators of nerve repair, highlighting their potential value as validated targets for efforts to promote SCI repair.

ObjectiveTo systematically evaluate the literature on the therapeutic use of Schwann cells (SC) in the repair of peripheral nerve injuries.MethodsThe Cochrane Library and PubMed databases were searched using terms [(“peripheral nerve injury” AND “Schwann cell” AND “regeneration”) OR (“peripheral nerve injuries”)]. Studies published from 2008 to 2022 were eligible for inclusion in the present study. Only studies presenting data from in-vivo investigations utilizing SCs in the repair of peripheral nerve injuries qualified for review. Studies attempting repair of a gap of ≥10 mm were included. Lastly, studies needed to have some measure of quantifiable regenerative outcome data such as histomorphometry, immunohistochemical, electrophysiology, or other functional outcomes.ResultsA search of the PubMed and Cochrane databases revealed 328 studies. After screening using the abstracts and methods, 17 studies were found to meet our inclusion criteria. Good SC adherence and survival in conduit tubes across various studies was observed. Improvement in morphological and functional outcomes with the use of SCs in long gap peripheral nerve injuries was observed in nearly all studies.ConclusionBased on contemporary literature, SCs have demonstrated clear potential in the repair of peripheral nerve injury in animal studies. It has yet to be determined which nerve conduit or graft will prove superior for delivery and retention of SCs for nerve regeneration. Recent developments in isolation and culturing techniques will enable further translational utilization of SCs in future clinical trials.

Abstract Background Silicone tube (ST) conduits have been accepted as a therapeutic alternative to direct nerve suturing in the treatment of nerve injuries; however, the search for optimal adjuncts to maximize the outcomes is still ongoing. Frankincense (Fr) and graphene oxide (GO) have both been cited as neuroregenerative compounds in the literature. This study assesses the efficacy of these materials using a ST conduit in a rat facial nerve motor neuron axotomy model, distal to the stylomastoid foramen. Methods Ammonia-functionalized graphene oxide (NH2-GO) and/or Fr extract were embedded in a collagen-chitosan hydrogel and were injected inside a ST. The ST was inserted in the gap between the axotomized nerve stumps. Return of function in eye closure, blinking reflex, and vibrissae movements were assessed and compared to control groups through 30 days following axotomy. To assess the histological properties of regenerated nerves, biopsies were harvested distal to the axotomy site and were visualized through light and fluorescence microscopy using LFB and anti-MBP marker, respectively. Results There was no significant difference in behavioral test results between groups. Histological analysis of the nerve sections revealed increased number of regenerating axons and mean axon diameter in NH2-GO group and decreased myelin surface area in Fr group. Using both NH2-GO and Fr resulted in increased number of regenerated axons and myelin thickness compared to the hydrogel group. Conclusions The findings suggest a synergistic effect of the substances above in axon regrowth, notably in myelin regeneration, where Fr supposedly decreases myelin synthesis.

A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane (n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping (n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes–Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes–Weinstein monofilament examination. The ratio (percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00% and 94.44%, respectively, with no significant difference between the two groups. There were no significant differences in the results of routine blood tests, liver and renal function tests, coagulation function tests, or immunoglobulin tests at 14 and 180 days postoperatively between the two groups. These findings suggest that the novel nerve matrix membrane is similar in efficacy to the commercially-available bovine-derived collagen membrane in the repair of peripheral nerve injury, and it may therefore serve as an alternative in the clinical setting. The clinical trial was approved by the Institutional Ethics Committee of Beijing Jishuitan Hospital, China (approval No. 20160902) on October 8, 2016, the Institutional Ethics Committee of the First Bethune Hospital of Jilin University, China (approval No. 160518-088) on December 14, 2016, and the Institutional Ethics Committee of Yantai Yuhuangding Hospital, China (approval No. 2016-10-01) on December 9, 2016. The clinical trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000033324) on May 28, 2020.

Complete transection of peripheral mixed nerves immediately produces loss of sensory perception, muscle contractions and voluntary behavior mediated by the severed distal axons. In contrast to natural regeneration (~1 mm/d) of proximal axons that may eventually reinnervate denervated targets, re-innervation is restored within minutes by PEG-fusion that consists of neurorrhaphy and a sequence of well specified hypo- and isotonic calcium-free or calcium-containing solutions, the anti-oxidant methylene blue (MB) and the membrane fusogen polyethylene glycol (PEG). In this study, we examined the relative efficacy of PEG-fusion with no MB (0%), 0.5% MB, or 1% MB on the recovery of voluntary behaviors by female Sprague-Dawley rats with a complete mid-thigh severance of their sciatic nerve bathed in extracellular fluid or calcium-containing isotonic saline. The recovery of voluntary behaviors is the most relevant measure of success of any technique to repair peripheral nerve injuries. We assessed recovery by the sciatic functional index, a commonly used measure of voluntary hindlimb behaviors following complete sciatic transections. We reported that both 1% MB and 0.5% MB in sterile distilled water in our PEG-fusion protocol with neurorrhaphy significantly increased the rate and extent of behavioral recovery compared to PEG plus neurorrhaphy alone. Furthermore, 0.5% MB was as effective as 1% MB in voluntary behavioral recovery as assessed by the sciatic functional index. Since sterile 1% MB is no longer clinically available, we therefore recommend that 0.5% MB be included in upcoming human clinical trials to evaluate the safety and efficacy of PEG-fusion. All animal procedures were approved by the University of Texas Institutional Animal Care and Use Committee (AUP-2019-00225) on September 9, 2020.

Peripheral nerve injury (PNI) is common and, unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury. Peripheral myelinating glia, Schwann cells (SCs), interact with various cells in and around the injury site and are important for debris elimination, repair, and nerve regeneration. Following PNI, Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages. Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair. The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve. In particular, SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers. This mobility increases SC interactions with other cells in the nerve and the exogenous environment, which influence SC behavior post-injury. Following PNI, SCs directly and indirectly interact with other SCs, fibroblasts, and macrophages. In addition, the inter- and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve. This review provides a basic assessment of SC function post-PNI, as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and, ultimately, repair of the injured nerve.