Nerve Repair Research Articles

Bioactive MgO/MgCO3/Polycaprolactone Multi-gradient Fibers Facilitate Peripheral Nerve Regeneration by Regulating Schwann Cell Function and Activating Wingless/Integrase-1 Signaling

AbstractPeripheral nerve defects present complex orthopedic challenges with limited efficacy of clinical interventions. The inadequate proliferation and dysfunction of Schwann cells within the nerve scaffold impede the effectiveness of nerve repair. Our previous studies suggested the effectiveness of a magnesium-encapsulated bioactive hydrogel in repairing nerve defects. However, its rapid release of magnesium ions limited its efficacy to long-term nerve regeneration, and its molecular mechanism remains unclear. This study utilized electrospinning technology to fabricate a MgO/MgCO3/polycaprolactone (PCL) multi-gradient nanofiber membrane for peripheral nerve regeneration. Our findings indicated that by carefully adjusting the concentration or proportion of rapidly degradable MgO and slowly degradable MgCO3, as well as the number of electrospun layers, the multi-gradient scaffold effectively sustained the release of Mg2+ over a period of 6 weeks. Additionally, this study provided insight into the mechanism of Mg2+-induced nerve regeneration and confirmed that Mg2+ effectively promoted Schwann cell proliferation, migration, and transition to a repair phenotype. By employing transcriptome sequencing technology, the study identified the Wingless/integrase-1 (Wnt) signaling pathway as a crucial mechanism influencing Schwann cell function during nerve regeneration. After implantation in 10 mm critically sized nerve defects in rats, the MgO/MgCO3/PCL multi-gradient nanofiber combined with a 3D-engineered PCL nerve conduit showed enhanced axonal regeneration, remyelination, and reinnervation of muscle tissue 12 weeks post-surgery. In conclusion, this study successfully developed an innovative multi-gradient long-acting MgO/MgCO3/PCL nanofiber with a tunable Mg2+ release property, which underscored the molecular mechanism of magnesium-encapsulated biomaterials in treating nervous system diseases and established a robust theoretical foundation for future clinical translation. Graphical abstract

Psychology of nerve injury, repair, and recovery: a systematic review

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.

Combining external physical stimuli and nanostructured materials for upregulating pro-regenerative cellular pathways in peripheral nerve repair

Peripheral nerve repair remains a major clinical challenge, particularly in the pursuit of therapeutic approaches that ensure adequate recovery of patient’s activity of daily living. Autografts are the gold standard in clinical practice for restoring lost sensorimotor functions nowadays. However, autografts have notable drawbacks, including dimensional mismatches and the need to sacrifice one function to restore another. Engineered nerve guidance conduits have therefore emerged as promising alternatives. While these conduits show surgical potential, their clinical use is currently limited to the repair of minor injuries, as their ability to reinnervate limiting gap lesions is still unsatisfactory. Therefore, improving patient functional recovery requires a deeper understanding of the cellular mechanisms involved in peripheral nerve regeneration and the development of therapeutic strategies that can precisely modulate these processes. Interest has grown in the use of external energy sources, such as light, ultrasound, electrical, and magnetic fields, to activate cellular pathways related to proliferation, differentiation, and migration. Recent research has explored combining these energy sources with tailored nanostructured materials as nanotransducers to enhance selectivity towards the target cells. This review aims to present the recent findings on this innovative strategy, discussing its potential to support nerve regeneration and its viability as an alternative to autologous transplantation.

A nanofibrous polycaprolactone/collagen neural guidance channel filled with sciatic allogeneic schwann cells and platelet-rich plasma for sciatic nerve repair.

Sciatic nerve damage, a common condition affecting approximately 2.8% of the US population, can lead to significant disability due to impaired nerve signal transmission, resulting in loss of sensation and motor function in the lower extremities. In this study, a neural guidance channel was developed by rolling a nanofibrous scaffold produced via electrospinning. The scaffold's microstructure, biocompatibility, biodegradation rate, porosity, mechanical properties, and hemocompatibility were evaluated. Platelet-rich plasma (PRP) activated with 30,000 allogeneic Schwann cells (SCs) was injected into the lumen of the channels following implantation into a rat model of sciatic nerve injury. Recovery of motor function, sensory function, and muscle re-innervation was assessed using the sciatic function index (SFI), hot plate latency time, and gastrocnemius muscle wet weight loss. Results showed mean hot plate latency times of Autograft: 7.03, PCL/collagen scaffolds loaded with PRP and SCs (PCLCOLPRPSCs): 8.34, polymer-only scaffolds (PCLCOL): 10.66, and untreated animals (Negative Control): 12.00. The mean SFI values at week eight were Autograft: -49.30, PCLCOLPRPSCs: -64.29, PCLCOL: -75.62, and Negative Control: -77.14. The PCLCOLPRPSCs group showed a more negative SFI compared to the Autograft group but performed better than both the PCLCOL and Negative Control groups. These findings suggest that the developed strategy enhanced sensory and functional recovery compared to the negative control and polymer-only scaffold groups.

Alginate Use in Orthopedics and Peripheral Nerve Repair: A Systematic Review.

The use of alginate, a derivative of seaweed, has been proposed for multiple orthopedic indications. We aimed to review the current use of alginate in orthopedics and to focus on the future applications of alginate for peripheral nerve repair. A comprehensive literature search was performed to identify biomechanical, laboratory, animal, and human studies where alginate has been utilized for orthopedic or nerve repair indications. A systematic review of orthopedic indications was conducted for safety and efficacy, and a specific focus was placed on alginate for use in peripheral nerve repair and reconstruction. Thirty-two studies were identified. Alginate has a strong history and safety profile for usage in orthopedic surgery. Its primary usage has been for the repair of articular cartilage, although it has also been used for disc regeneration of the lumbar spine and for cushioning joints in osteoarthritis. The primary indication in peripheral nerve repair is to create an environment that encourages Schwann cell migration and repair in nerve injuries while blocking fibrotic scar tissue formation by inhibiting the activity of fibroblasts. Alginate hydrogel may serve as a potential conduit for nerve regeneration in nerve injuries with small to medium-sized gaps.

Nanozyme Hydrogels Promote Nerve Regeneration in Spinal Cord Injury by Reducing Oxidative Stress.

Inhibiting secondary cell death and promoting neuronal regeneration are critical for nerve repair after spinal cord injury (SCI). The excessive accumulation of reactive oxygen species (ROS) after SCI causes cell death and induces apoptosis. These reactions further increase the level of ROS production, leading to a vicious cycle of spinal cord tissue damage. Therefore, intervention targeting ROS is a potential therapeutic approach to improve the recovery of locomotor function after SCI. In this study, we designed and synthesized a nanozyme hydrogel delivery system loaded with multiple drugs, LA/Me/Se NPs-h. LA/Me/Se NPs-h exhibited a satisfactory size distribution and excellent stability, enhancing the bioavailability of therapeutic drugs. Moreover, we explored the antioxidant and protective effects of LA/Me/Se NPs-h against oxidative stress-induced cell damage caused by ROS production after SCI in vitro. In the mice SCI model, the Basso mouse scale and gait analysis showed that LA/Me/Se NPs-h significantly promoted the recovery of locomotor function after SCI. The histological and immunofluorescence results of the injury site revealed that LA/Me/Se NPs-h upregulated the expression of GFAP, NF-200, and superoxide dismutase in spinal cord lesion, reduced caspase-3 expression, improved spinal cord continuity, reduced lesion cavity, and inhibited the axonal demyelination. Consequently, LA/Me/Se NPs-h increased the activity of antioxidant enzymes and reduced neuronal apoptosis by reducing oxidative stress and ultimately promoted nerve regeneration. Taken together, this study demonstrated promising nanozyme hydrogels and provided an effective therapeutic strategy for SCI and other ROS-related diseases.

Dual Role of Ibuprofen and Indomethacin in Promoting Peripheral Nerve Regeneration In Vitro.

Peripheral nerve injuries (PNI) can result in significant losses of motor and sensory function. Although peripheral nerves have an innate capacity for regeneration, restoration of function after severe injury remains suboptimal. The gold standard for peripheral nerve regeneration (PNR) is autologous nerve transplantation, but this method is limited by the generation of an additional surgical site, donor-site morbidity, and neuroma formation at the site of harvest. Although targeted drug compounds have the potential to influence axonal growth, there are no drugs currently approved to treat PNI. Therefore, we propose to repurpose commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) to enhance PNR, facilitating easier clinical translation. Additionally, calcium signaling plays a crucial role in neuronal connectivity and regeneration, but how specific drugs modulate this process remains unclear. We developed an in vitro hollow channel collagen gel platform that successfully supports neuronal network formation. This study evaluated the effects of commonly used NSAIDs, namely ibuprofen and indomethacin, in our in vitro model of axonal growth, regeneration, and calcium signaling as potential treatments for PNI. Our results demonstrate enhanced axonal growth and regrowth with both ibuprofen and indomethacin, suggesting a positive influence on PNR. Further, these drugs showed enhanced calcium signaling dynamics, which we posit is a crucial aspect for nerve repair. Taken together, these findings highlight the potential of ibuprofen and indomethacin to be used as treatment options for PNI, given their dual capability to promote axonal growth and enhance calcium signaling.

End to End Sciatic Nerve Repair at Different Angles of Attachment: in Albino Rat Experimental Model

End to End Sciatic Nerve Repair at Different Angles of Attachment: in Albino Rat Experimental Model

Toll-Like Receptor 4 (TLR4) Promotes DRG Regeneration and Repair after Sciatic Nerve Injury via the ERK-NF-kB Pathway.

Previously, we found that the expression of Toll-like receptor 4 (TLR4) is altered after sciatic nerve injury, and its differential expression plays a key role in recovery. However, the mechanisms by which TLR4 affects neuronal function in the dorsal root ganglion (DRG) have not been completely evaluated. The objective is to determine TLR4 expression in DRG tissues after sciatic neural injury and exploring the effects of TLR4 knockdown and overexpression in the DRG on neuronal function and nerve regeneration in rats in vivo and in vitro. We established a model of nerve injury and utilized molecular biology and cell biology experiments to explore the molecular mechanisms by which TLR4 in the DRG affects sciatic nerve restoration and regeneration after injury. Verified the localization of TLR4 in DRG neurons. Investigated pathways that related to apoptosis or nerve regeneration by which TLR4 regulates the function of DRG neurons. TLR4 expression was upregulated in the DRG tissues of rats after sciatic nerve injury. TLR4 overexpression promoted axon regeneration and inhibited apoptosis in DRG neurons. TLR4 promoted the regeneration of axons and the recovery of motor and sensory functions in the sciatic nerve after injury in vivo, and the data showed that TLR4 may regulate the function of DRG neurons and promote nerve repair and regeneration through the ERK and NF-κB signaling pathways in vivo and ex vivo. The study suggests that TLR4 may regulate the function of DRG neurons and promote nerve regeneration by affecting the ERK and NF-κB signaling pathways.

Neural repair function of osteopontin in stroke and stroke‑related diseases (Review).

Stroke, including hemorrhagic stroke and ischemic stroke, is a common disease of the central nervous system. It is characterized by a high mortality and disability rate and is closely associated with atherosclerosis, hypertension hyperglycemia, atrial fibrillation and unhealthy living habits. The continuous development of surgery and medications has decreased the mortality rate of patients with stroke and has greatly improved the disease prognosis. At present, the direction of clinical treatment and research has gradually shifted to the repair of nerve function after stroke. Osteopontin (OPN) is a widely distributed extracellular matrix protein. Due to its structural characteristics, OPN can be cut and modified into terminal fragments with different functions, which play different roles in various pathophysiological processes, such as formation of tumors, inflammation and autoimmune diseases. It has also become a potential diagnostic and therapeutic marker. In order to comprehensively analyze the specific role of OPN in nerve repair and its relationship with stroke and stroke-related diseases, the following key words were used: 'Osteopontin, stroke, atherosis, neuroplasticity, neural repair'. PubMed, Web of Science and Cochrane articles related to OPN were searched and summarized. The present review describes the OPN structure, isoforms, functions and its neural repair mechanism, and its association with the occurrence and development of stroke and related diseases was explored.

Enhanced Understanding of Facial Nerve Anatomy and Arborization in the Indian Population: Implications for Surgical Procedures.

The anatomy and arborization patterns of the extraparotid facial nerve show considerable variation among different populations, impacting surgical approaches in plastic, head and neck, and ENT surgeries. This study focuses on the Indian population to provide a detailed understanding of these variations, specifically highlighting the Davis type IV arborization pattern's prevalence and its clinical relevance. We conducted a comprehensive dissection of 16 formalin-preserved Indian cadaveric hemifaces. The study meticulously mapped the facial nerve trunk (FNT), its furcation points, and branches. Key anatomical landmarks for locating these nerve structures were identified, including the tip of the mastoid process, the angle of the mandible, and a novel line between the lateral palpebral fissure and otobasion superioris. The most common arborization pattern observed was Davis type IV (31.3%). The study provided precise measurements for locating the FNT and its branches, using identifiable landmarks. These findings facilitate more accurate surgical planning, crucial for procedures involving nerve repair or grafting. This research offers vital insights into the facial nerve anatomy specific to the Indian population, with significant implications for surgical precision and patient outcomes. By establishing reliable anatomical landmarks and elucidating the predominant arborization pattern, the study enhances the understanding of facial nerve behavior during surgical interventions, particularly in the context of facial paralysis treatment and reconstructive surgeries. Due to the small sample size, however, this study only acts as a pilot for further research.

The Effectiveness of High Intensity Laser in Improving Motor Deficits in Patients with Lumbar Disc Herniation.

High-Intensity Laser (HIL) therapy, known for its biostimulatory effects on nerve cell growth and repair, shows promise for improving motor deficits caused by morphopathological changes. This research study aimed to comprehensively assess muscle strength changes through muscle testing, complemented by functional tests evaluating factors contributing to disability in patients with Lumbar Disc Herniation (LDH) and associated motor impairment, following a complex rehabilitation protocol incorporating HIL therapy. A total of 133 individuals with LDH and motor deficits were divided into two groups. Group 1 (n = 66) received HIL therapy followed by standard rehabilitation, while Group 2 (n = 67) underwent only the standard rehabilitation program. Functional parameters, including muscle strength, the ability to walk on tiptoes or heels, and self-assessed fall risk, were monitored. Both groups showed statistically significant improvements in all monitored parameters. A comparative analysis revealed a significant result for the HIL therapy regimen across all indicators. The group undergoing a rehabilitation program with integrated HIL therapy displayed significantly greater improvement in motor deficits, affirming the positive impact of HIL therapy on functional parameters among LDH patients.

Long-term subjective and objective outcomes after digital nerve repair: a cohort study.

Digital nerve injuries are common, but few studies report long-term effects for the individual. The primary aim of this matched-pairs study comparing digital nerve injuries in border digits or central fingers was to investigate hand function 3-10 years after digital nerve repair, assessed using the Mini Sollerman test in 86 patients. Secondary outcomes were sensory function, range of motion, grip strength and patient-reported measures. No significant difference was seen in hand function between the groups, except for lower grip strength in patients with central finger injury. Tactile discrimination was achieved in 87%, with best results among participants aged less than 44 years. Touch perception was measurable in 99%. No statistically significant differences in sensory function were found between the groups. Patient-reported disability was low, with median Quick Disabilities of the Arm, Shoulder and Hand score of 5, but half of the patients reported neuropathic pain. Numbness and cold sensitivity were the symptoms graded worst after digital nerve injury.Level of evidence: III.

Tissue-Adaptive BSA Hydrogel with Dual Release of PTX and bFGF Promotes Spinal Cord Injury Repair via Glial Scar Inhibition and Axon Regeneration.

Spinal cord injury (SCI) is a severe clinical disease usually accompanied by activated glial scar, neuronal axon rupture, and disabled motor function. To mimic the microenvironment of the SCI injury site, a hydrogel system with a comparable mechanical property to the spinal cord is desirable. Therefore, a novel elastic bovine serum albumin (BSA) hydrogel is fabricated with excellent adhesive, injectable, and biocompatible properties. The hydrogel is used to deliver paclitaxel (PTX) together with basic fibroblast growth factor (bFGF) to inhibit glial scar formation as well as promote axon regeneration and motor function for SCI repair. Due to the specific interaction of BSA with both drugs, bFGF, and PTX can be controllably released from the hydrogel system to achieve an effective concentration at the wound site during the SCI regeneration process. Moreover, benefiting from the combination of PTX and bFGF, this bFGF/PTX@BSA system significantly aided axon repair by promoting the elongation of axons across the glial scar with reduced reactive astrocyte secretion. In addition, remarkable anti-apoptosis of nerve cells is evident with the bFGF/PTX@BSA system. Subsequently, this multi-functionalized drug system significantly improved the motor function of the rats after SCI. These results reveal that bFGF/PTX@BSA is an ideal functionalized material for nerve repair in SCI.

Peripheral nerve grafting

Peripheral nerve lesions often lead to significant and permanent loss of motor and sensory function. The aim of peripheral nerve grafting is to bridge nerve defects. When tension-free nerve repair is not possible, peripheral nerve grafting is indicated. Local infection, insufficient soft tissue coverage, significant muscle atrophy or joint contraction in case of "motor" nerve grafting, lack of microsurgical instruments or experience, life-threatening injuries. Exposure and preparation of the nerve stumps. Choosing and preparation of the donor nerve. Approximation. Nerve repair. Nerve reconstruction must always be tension-free as nerve repair with tension frequently leads to disruption of nerve healing and poor functional outcome. Autologous nerve grafting from various donor sites leads to excellent functional results with little sensory deficits at the donor regions. Limited immobilization, physiotherapy, ergotherapy, regular clinical and neurological assessments. Outcome of peripheral nerve grafting may, for example, depend on defect length, caliber and quality of the injured nerve, quality of the donor nerve, microsurgical expertise of the surgeon, time of reconstruction, and age of the patient.

Current Strategies for Optic Nerve Protection and Repair

Damage to the optic nerve and its functioning is referred to as optic neuropathy, unlike the peripheral nervous system (PNS), the optic nerve is part of the central nervous system (CNS), which presents limitations in its regenerative abilities. Both intrinsic and extrinsic factors contribute to these limitations. Strategies for neuroprotection and neuroregeneration have been studied and implemented to address these challenges. While there is no definite treatment in the past two decades there have been many advances in the modulation of inflammation, apoptosis, neurotrophic factors and stem cell replacement strategies. The advances in these areas could transform our approach to optic nerve impairment in the future.

Single-cell profiling of cellular changes in the somatic peripheral nerves following nerve injury.

Injury to the peripheral nervous system disconnects targets to the central nervous system, disrupts signal transmission, and results in functional disability. Although surgical and therapeutic treatments improve nerve regeneration, it is generally hard to achieve fully functional recovery after severe peripheral nerve injury. A better understanding of pathological changes after peripheral nerve injury helps the development of promising treatments for nerve regeneration. Single-cell analyses of the peripheral nervous system under physiological and injury conditions define the diversity of cells in peripheral nerves and reveal cell-specific injury responses. Herein, we review recent findings on the single-cell transcriptome status in the dorsal root ganglia and peripheral nerves following peripheral nerve injury, identify the cell heterogeneity of peripheral nerves, and delineate changes in injured peripheral nerves, especially molecular changes in neurons, glial cells, and immune cells. Cell-cell interactions in peripheral nerves are also characterized based on ligand-receptor pairs from coordinated gene expressions. The understanding of cellular changes following peripheral nerve injury at a single-cell resolution offers a comprehensive and insightful view for the peripheral nerve repair process, provides an important basis for the exploration of the key regulators of neuronal growth and microenvironment reconstruction, and benefits the development of novel therapeutic drugs for the treatment of peripheral nerve injury.

The current status and development of nerve repair techniques for bilateral vocal cord paralysis

The related research of nerve repair for bilateral vocal cord paralysis（BVCP） can be traced back to a century ago. There is still no standardized surgical therapeutic schedule and the evaluation of curative effect, due to the variability and complexity of laryngeal nerve innervation. Otolaryngologists have been constantly weighing and improving the surgical plan in relieving airway obstruction, maintaining vocal function and reducing cough to protect the normal physiological function of the larynx. Different medical institutions have great differences in the treatment methods. Many studies and literatures were published on the treatment of BVCP, yet have few related works on the application of it's nerve repair technology presently. The research progress of nerve repair technology for BVCP were described, along with its developing trend, aiming to lay the foundation for the future technical exploration and development.

An injectable thermosensitive pluronic F127 loaded-nanohydroxyapatite / Polydopamine for promoting sciatic nerve repair after crush injury

Peripheral nerve injury (PNI) remains an urgent issue due to its huge financial burden and high rate of disability. Here, an injectable HAP/PDA thermosensitive Pluronic F127 hydrogel is proposed for peripheral nerve repair. We investigated the surface characteristics of HAP/PDA and evaluated biocompatibility, cellular proliferation, and apoptosis in vitro. After injecting the hydrogel into the injured site of rats, we recorded the recovery of motor function and judged the dregree of nerves through electrophysiological and morphological changes. The hydrogel was found to accelerate the nerve regeneration. Collectively, the HAP/PDA thermosensitive Pluronic F127 hydrogel has potential in promoting sciatic nerve repair.

Effect of Yiqi Huoxue Decoction on Neurological Function for Cervical Spinal Cord Injury

Cervical spinal cord injury (CSCI) can lead to neurological dysfunction, such as limb numbness, muscle stiffness, and motor disorders. Although early decompression surgery has demonstrated efficacy in alleviating symptoms for patients with CSCI, there are still some limitations in the recovery of motor function. It has been reported that traditional Chinese medicine (TCM) has advantages in the treatment of CSCI due to its safety and efficacy and its ability to modulate the immune system and promote neuroregeneration. In this study, we investigate the clinical efficacy of combining Yiqi Huoxue Decoction with acupoint massage therapy in patients with CSCI after decompression and fixation surgery. A total of 140 patients who were first diagnosed with CSCI at our hospital and underwent early decompression and internal fixation surgery from October 2022 to June 2023 were included in this study. They were divided into two groups: Group A (n = 70) received conventional Western medicine treatment, and Group B (n = 70) received Yiqi Huoxue Decoction and acupoint massage therapy. We observed significant improvements in the American Spinal Injury Association scores after the combined treatment. Moreover, the levels of neuron-specific enolase decreased, while the levels of nerve growth factor and insulin-like growth factor-1 increased. Additionally, the levels of CD3+, CD4+, and CD8+ T cells exhibited a notable decrease. Furthermore, acupoint massage was found to stimulate nerve endings, thereby promoting nerve regeneration and repair. In summary, this combined treatment effectively improves the neurological function of patients with CSCI.