Physiology of Nerve Regeneration: Key Factors Affecting Clinical Outcomes.

Functional recovery after peripheral nerve injuries is disappointing despite surgical advances in nerve repair. This review summarizes the relatively short window of opportunity for successful nerve regeneration due to the decline in the expression of growth-associated genes and in turn, the decline in regenerative capacity of the injured neurons and the support provided by the denervated Schwann cells, and the atrophy of denervated muscles. Brief, low-frequency electrical stimulation and post-injury exercise regimes ameliorate these deficits in animal models and patients, but the misdirection of regenerating nerve fibers compromises functional recovery and remains an important area of future research.

Alternative Nerve Coaptations: End-To-Side and Beyond.

Modern end-to-side (ETS) nerve transfers have undergone several permutations since the early 1990's. Preclinical data have revealed important mechanisms and patterns of donor axon outgrowth into the recipient nerves and target reinnervation. The versatility of ETS nerve transfers can also potentially address several processes that limit functional recovery after nerve injury by babysitting motor end-plates and/or supporting the regenerative environment within the denervated nerve. Further clinical and basic science work is required to clarify the ideal clinical indications, contraindications, and mechanisms of action for these techniques in order to maximize their potential as reconstructive options.

Polyethylene Glycol-Fusion Repair of Peripheral Nerve Injuries.

Axons successfully repaired with polyethylene glycol (PEG) fusion tecnology restored axonal continuity thereby preventing their Wallerian degeneration and minimizing muscle atrophy. PEG fusion studies in animal models and preliminary clinical trials involving patients with digital nerve repair have shown promise for this therapeutic approach. PEG fusion is safe to perform, and given the enormous potential benefits, there is no reason not to explore its therapeutic potential.

Bioengineered Nerve Conduits and Wraps.

Peripheral nerve injuries are prevalent and their treatments present significant challenges. Among the various reconstructive options, nerve conduits and wraps are popular choices. Advances in bioengineering and regenerative medicine have led to the development of new biocompatible materials and implant designs that offer the potential for enhanced neural recovery. Cost, nerve injury type, and implant size must be considered when deciding on the ideal reconstructive option.

Evaluating Outcomes Following Nerve Repair: Beyond the Medical Research Council.

Peripheral nerve injuries are common and remain a significant health challenge. Outcome measurements are used to evaluate injury, monitor recovery after nerve repair, and compare scientific advances. Clinical judgement is required to determine which available tools are most applicable, which requires a vast understanding of the available outcome measurements. In this article we discuss the highest yield tools available for clinical application.

Therapeutic Electrical Stimulation for Surgeons: How it Works and How to Apply it.

Electrical stimulation (ES) enhances peripheral nerve inherent regeneration capacity by promoting accelerated axonal outgrowth and selectivity toward appropriate motor and sensory targets. These effects lead to significantly improved functional outcomes and shorter recovery time. Electrical stimulation can be applied intra-operatively or immediately post-operatively. Active clinical trials are looking into additional areas of application, length of stimulation, and functional outcomes.

Growth Factors to Enhance Nerve Regeneration: Approaching Clinical Translation.

Following nerve injury, growth factors (GFs) are transiently upregulated in injured neurons, proliferating Schwann cells, and denervated muscle and skin. They act on these same cells and tissues to promote nerve regeneration and end-organ reinnervation. Consequently, much attention has been focused on developing GF-based therapeutics. A major barrier to clinical translation of GFs is their short half-life. To provide sustained GF treatment to the affected nerve, muscle, and skin in a safe and practical manner, engineered drug delivery systems are needed. This review highlights recent advancements in GF-based therapeutics and discusses the remaining hurdles for clinical translation.

Beyond boundaries: The therapeutic potential of exosomes in neural microenvironments in neurological disorders.

Neurological disorders are a diverse group of conditions that can significantly impact individuals' quality of life. The maintenance of neural microenvironment homeostasis is essential for optimal physiological cellular processes. Perturbations in this delicate balance underlie various pathological manifestations observed across various neurological disorders. Current treatments for neurological disorders face substantial challenges, primarily due to the formidable blood-brain barrier and the intricate nature of neural tissue structures. These obstacles have resulted in a paucity of effective therapies and inefficiencies in patient care. Exosomes, nanoscale vesicles that contain a complex repertoire of biomolecules, are identifiable in various bodily fluids. They hold substantial promise in numerous therapeutic interventions due to their unique attributes, including targeted drug delivery mechanisms and the ability to cross the BBB, thereby enhancing their therapeutic potential. In this review, we investigate the therapeutic potential of exosomes across a range of neurological disorders, including neurodegenerative disorders, traumatic brain injury, peripheral nerve injury, brain tumors, and stroke. Through both in vitro and in vivo studies, our findings underscore the beneficial influence of exosomes in enhancing the neural microenvironment following neurological diseases, offering promise for improved neural recovery and management in these conditions.

Etiologies of iatrogenic occipital nerve injury: And outcomes following treatment with nerve decompression surgery.

INTRODUCTION: This study analyzed the etiologies and treatment of iatrogenic occipital nerve injuries. METHODS: Patients with occipital neuralgia (ON) who were screened for occipital nerve decompression surgery were prospectively enrolled. Patients with iatrogenic occipital nerve injuries who underwent nerve decompression surgery were identified. Data included surgical history, pain characteristics, and surgical technique. Outcomes included pain frequency (days/month), duration (h/day), intensity (0-10), migraine headache index (MHI), and patient-reported percent-resolution of pain. RESULTS: Among the 416 patients with ON, who were screened for occipital nerve decompression surgery, 12 (2.9%) cases of iatrogenic occipital nerve injury were identified and underwent surgical treatment. Preoperative headache frequency was 30 (±0.0) days/month, duration was 19.4 (±6.9) h, and intensity was 9.2 (±0.9). Neuroma excision was performed in 5 cases followed by targeted muscle reinnervation in 3, nerve cap in 1, and muscle burial in 1. In patients without neuromas, greater occipital nerve decompression and/or lesser occipital nerve neurectomy were performed. At the median follow-up of 12 months (IQR 12-12 months), mean pain frequency was 4.0 (±6.6) pain days/month (p < 0.0001), duration was 6.3 (±8.9) h (p < 0.01), and intensity was 4.4 (±2.8) (p < 0.001). Median patient-reported resolution of pain was 85% (56.3%-97.5%) and success rate was (≥50% MHI improvement) 91.7%. CONCLUSIONS: Iatrogenic occipital nerve injuries can be caused by various surgical interventions, including craniotomies, cervical spine interventions, and scalp tumor resections. The associated pain can be severe and chronic. Iatrogenic ON should be considered in the differential diagnosis of post-operative headaches and can be treated with nerve decompression surgery or neuroma excision with reconstruction of the free nerve end.

Exosomes From Muscle-Derived Stem Cells Repair Peripheral Nerve Injury by Inhibiting Ferroptosis via the Keap1-Nrf2-Ho-1 Axis.

Currently, the clinical outcomes of peripheral nerve injuries are suboptimal, highlighting the urgent need to understand the mechanisms of nerve injury to enhance treatment strategies. Muscle-derived stem cells (MDSCs) are a diverse group of multipotent cells that hold promise for peripheral nerve regeneration due to their strong antioxidant and regenerative properties. Our research has revealed that severe ferroptosis occurs in the sciatic nerve and ipsilateral dorsal root ganglion following sciatic nerve injury. Interestingly, we have observed that MDSC-derived exosomes effectively suppress cell ferroptosis and enhance cell viability in Schwann cells and dorsal root ganglion cells. Treatment with exosomes led to increased expression of BDNF and P62 in Schwann cells, decreased expression of Keap1, Nrf2, and HO-1 in Schwann cells, and upregulated dorsal root ganglion cells. Rats treated with exosomes exhibited improvements in sciatic nerve function, sensitivity to stimuli, and reduced muscle atrophy, indicating a positive impact on post-injury recovery. In conclusion, our findings demonstrate the occurrence of ferroptosis in the sciatic nerve and dorsal root ganglion post-injury, with MDSC exosomes offering a potential therapeutic strategy by inhibiting ferroptosis, activating the Keap1-Nrf2-HO-1 pathway, and optimizing the post-injury repair environment.

Myelinated peripheral axons are more vulnerable to mechanical trauma in a model of enlarged axonal diameters.

The velocity of axonal impulse propagation is facilitated by myelination and axonal diameters. Both parameters are frequently impaired in peripheral nerve disorders, but it is not known if the diameters of myelinated axons affect the liability to injury or the efficiency of functional recovery. Mice lacking the adaxonal myelin protein chemokine-like factor-like MARVEL-transmembrane domain-containing family member-6 (CMTM6) specifically from Schwann cells (SCs) display appropriate myelination but increased diameters of peripheral axons. Here we subjected Cmtm6-cKo mice as a model of enlarged axonal diameters to a mild sciatic nerve compression injury that causes temporarily reduced axonal diameters but otherwise comparatively moderate pathology of the axon/myelin-unit. Notably, both of these pathological features were worsened in Cmtm6-cKo compared to genotype-control mice early post-injury. The increase of axonal diameters caused by CMTM6-deficiency thus does not override their injury-dependent decrease. Accordingly, we did not detect signs of improved regeneration or functional recovery after nerve compression in Cmtm6-cKo mice; depleting CMTM6 in SCs is thus not a promising strategy toward enhanced recovery after nerve injury. Conversely, the exacerbated axonal damage in Cmtm6-cKo nerves early post-injury coincided with both enhanced immune response including foamy macrophages and SCs and transiently reduced grip strength. Our observations support the concept that larger peripheral axons are particularly susceptible toward mechanical trauma.

Effect of repeated sciatic nerve crush on the conditioning lesion response: Generating an experimental animal model to prolong the denervation period while maintaining peripheral nerve continuity.

Peripheral nerves exhibit long-term residual motor dysfunction following injury. The length of the denervation period before nerve and muscle reconnection is an important factor in motor function recovery. We aimed to investigate whether repeated nerve crush injuries to the same site every 7 days would preserve the conditioning lesion (CL) response and to determine the number of nerve crush injuries required to create an experimental animal model that would prolong the denervation period while maintaining peripheral nerve continuity. Rats were grouped according to the number of sciatic nerve crushes. A significant decrease in the soleus muscle fiber cross-sectional area was observed with increased crushes. After a single crush, macrophage accumulation and macrophage chemotaxis factor CCL2 expression in dorsal root ganglia were markedly increased, which aligned with the gene expression of Ccl2 and its receptor Ccr2. Macrophage numbers, histological CCL2 expression, and Ccl2 and Ccr2 gene expression levels decreased, depending on the number of repeated crushes. Histological analysis and gene expression analysis in the group with four repeated crushes did not differ significantly when compared with uninjured animals. Our findings indicated that repeated nerve crushes at the same site every 7 days sustained innervation loss and caused a loss of the CL response. The experimental model did not require nerve stump suturing and is useful for exploring factors causing prolonged denervation-induced motor dysfunction. SIGNIFICANCE STATEMENT: This study elucidates the effects of repeated nerve crush injury to the same site on innervation and conditioning lesion responses and demonstrates the utility of an experimental animal model that recapitulates the persistent residual motor deficits owing to prolonged denervation without requiring nerve transection and transection suturing.

Chiral MoS2@BC fibrous membranes selectively promote peripheral nerve regeneration.

BACKGROUND: Molybdenum disulfide (MoS2) has excellent physical and chemical properties. Further, chiral MoS2 (CMS) exhibits excellent chiroptical and enantioselective effects, and the enantioselective properties of CMS have been studied for the treatment of neurodegenerative diseases. Intriguingly, left- and right-handed materials have different effects on promoting the differentiation of neural stem cells into neurons. However, the effect of the enantioselectivity of chiral materials on peripheral nerve regeneration remains unclear. METHODS: In this study, CMS@bacterial cellulose (BC) scaffolds were fabricated using a hydrothermal approach. The CMS@BC films synthesized with L-2-amino-3-phenyl-1-propanol was defined as L-CMS. The CMS@BC films synthesized with D-2-amino-3-phenyl-1-propanol was defined as D-CMS. The biocompatibility of CMS@BC scaffolds and their effect on Schwann cells (SCs) were validated by cellular experiments. In addition, these scaffolds were implanted in rat sciatic nerve defect sites for three months. RESULTS: These chiral scaffolds displayed high hydrophilicity, good mechanical properties, and low cytotoxicity. Further, we found that the L-CMS scaffolds were superior to the D-CMS scaffolds in promoting SCs proliferation. After three months, the scaffolds showed good biocompatibility in vivo, and the nerve conducting velocities of the L-CMS and D-CMS scaffolds were 51.2 m/s and 26.8 m/s, respectively. The L-CMS scaffolds showed a better regenerative effect than the D-CMS scaffolds. Similarly, the sciatic nerve function index and effects on the motor and electrophysiological functions were higher for the L-CMS scaffolds than the D-CMS scaffolds. Finally, the axon diameter and myelin sheath thickness of the regenerated nerves were improved in the L-CMS group. CONCLUSION: We found that the CMS@BC can promote peripheral nerve regeneration, and in general, the L-CMS group exhibited superior repair performance. Overall, the findings of this study reveal that CMS@BC can be used as a chiral nanomaterial nerve scaffold for peripheral nerve repair.

[Progress on application of hydrogels in the field of peripheral nerve injury repair].

As one of the common traumatic diseases in clinical practice, peripheral nerve injury (PIN) often causes nerve pain, abnormal reflexes, autonomic disorders, and even sensorimotor disorders due to the slow regeneration rate after injury, which seriously affects body function. Even as the gold standard of treatment, autologous nerve transplantation has limitations such as limited donor area and donor injury, which greatly limits its clinical application effect. Therefore, the preparation of artificial nerve grafts suitable for clinical practice has become the future development trend of peripheral nerve injury treatment, and the repair of injury defects and the promotion of nerve regeneration have also become research hotspots in tissue engineering and regenerative medicine. In recent years, extensive research has been carried out on nerve guidance conduits (NGCs) in the field of nerve regeneration and repair, in which scaffold materials and internal fillers have also become the focus of research as the core elements of neural catheters, and a series of achievements have been made in the application of new materials, embedding stem cells/precursor cells, and developing trophic factors and drug-loaded sustained-release systems. Therefore, this paper focuses on the application progress of hydrogel and its related derivative materials in the field of peripheral nerve injury repair, and provides new ideas for promoting the related research of tissue engineering and clinical medicine.

The Role of Macrophages in Nerve Regeneration: Polarization and Combination with Tissue Engineering.

Peripheral nerve regeneration after trauma poses a substantial clinical challenge that has already been investigated for many years. Infiltration of immune cells is a critical step in the response to nerve damage that creates a supportive microenvironment for regeneration. In this work, we focus on a special type of immune cell, macrophage, in addressing the problem of neuronal regeneration. We discuss the complex endogenous mechanisms of peripheral nerve injury and regrowth vis-à-vis macrophages, including their recruitment, polarization, and interplay with Schwann cells post-trauma. Furthermore, we elucidate the underlying mechanisms by which exogenous stimuli govern the above events. Finally, we summarize the necessary roles of macrophages in peripheral nerve lesions and reconstruction. There are many challenges in controlling macrophage functions to achieve complete neuronal regeneration, even though considerable progress has been made in understanding the connection between these cells and peripheral nerve damage.

Combat-related peripheral nerve injuries.

Active-duty service members (ADSM) and military Veterans represent a population with increased occupational risk for nerve injuries sustained both during training operations and wartime. Mechanisms of war-related nerve injuries have evolved over time, from the musket ball-related traumas described by S.W. Mitchell to complex blast injuries and toxic exposures sustained during Middle East conflicts in the 21st century. Commonly encountered nerve injury etiologies in this population currently include compression, direct trauma, nutritional deficits, traumatic limb amputation, toxic chemical exposures, or blast-related injuries. Expeditious identification and comprehensive, interdisciplinary treatment of combat-associated neuropathies, as well as prevention of these injuries whenever possible is critical to reduce chronic morbidity and disability for service members and to maintain a well-prepared military. However, diagnosis of a combat-associated nerve injury may be particularly challenging due to comorbid battlefield injuries or delayed presentation of neuropathy from military toxic exposures. Advances in imaging for nerve injury, including MRI and ultrasound, provide useful tools to compliment EMG in establishing a diagnosis of combat-associated nerve injury, particularly in the setting of anatomic disruption or edema. Surgical techniques can improve pain control or restoration of function. In all cases, comprehensive interdisciplinary rehabilitation provides the best framework for optimization of recovery. Further work is needed to prevent combat-associated nerve injuries and promote nerve recovery following injury.

Types of Short-Duration Electrical Stimulation-Induced Efficiency in the Axonal Regeneration and Recovery: Comparative in Vivo Study in Rat Model of Repaired Sciatic Nerve and its Tibial Branch after Transection Injury.

The restoration of adequate function and sensation in nerves following an injury is often insufficient. Electrical stimulation (ES) applied during nerve repair can promote axon regeneration, which may enhance the likelihood of successful functional recovery. However, increasing operation time and complexity are associated with limited clinical use of ES. This study aims to better assess whether short-duration ES types (voltage mode vs. current mode) are able to produce enhanced regenerative activity following peripheral nerve repair in rat models. Wistar rats were randomly divided into 3 groups: no ES (control), 30-minute ES with a current pulse, and 30-minute ES with a voltage pulse. All groups underwent sciatic nerve transection and repair using a silicone tube to bridge the 6-mm gap between the stumps. In the 2 groups other than the control, ES was applied after the surgical repair. Outcomes were evaluated using electrophysiology, histology, and serial walking track analysis. Biweekly walking tracks test over 12 weeks revealed that subjects that underwent ES experienced more rapid functional improvement than subjects that underwent repair alone. Electrophysiological analysis of the newly intratubular sciatic nerve at week 12 revealed strong motor function recovery in rats that underwent 30-minute ES. Histologic analysis of the sciatic nerve and its tibial branch at 12 weeks demonstrated robust axon regrowth in all groups. Both types of short-duration ES applied during nerve repair can promote axon regrowth and enhance the chances of successful functional recovery.

Advances in novel biomaterials combined with traditional Chinese medicine rehabilitation technology in treatment of peripheral nerve injury.

Peripheral nerve injuries (PNI) represent one of the primary neuropathies leading to lifelong disability. Nerve regeneration and targeted muscle atrophy stand as the two most crucial factors influencing functional rehabilitation post peripheral nerve injury. Over time, traditional Chinese medicine (TCM) rehabilitation approaches such as acupuncture, Tuina, and microneedles serve as pivot means to activate the regeneration of injured nerve Schwann cells. By promoting axon regeneration, these approaches can accomplish nerve repair, reconstruction, and functional rehabilitation. Although TCM rehabilitation approaches have clinically demonstrated effectiveness in promoting the repair and regeneration of PNI, the related molecular mechanisms remain unclear. This significantly hampers the application and promotion of TCM rehabilitation in PNI recovery. Therefore, deeply delving into the cellular and molecular mechanisms of TCM rehabilitation technologies to foster nerve regeneration stands as the most pressing issue. On the other hand, in recent years, novel biomaterials represented by hydrogels, microfluidic platforms, and new chitosan scaffolds have showed their unique roles in treating various degrees of nerve injury. These methods exhibit immense potential in conducting high-throughput cell and organoid culture in vitro and synthesizing diverse tissue engineering scaffolds and drug carriers. We believe that the combination of TCM rehabilitation technology and novel biomaterials can more effectively address precise treatment issues such as identification of treatment target and dosage control. Therefore, this paper not only summarizes the molecular mechanisms of TCM rehabilitation technology and novel biomaterials in treating peripheral nerve injury individually, but also explores the research direction of precise treatment by integrating the two at both macro and micro levels. Such integration may facilitate the exploration of cellular and molecular mechanisms related to neurodegeneration and regeneration, providing a scientific and theoretical foundation for the precise functional rehabilitation of PNI in the future.

Ficus carica L. (Fig) promotes nerve regeneration in a mouse model of sciatic nerve crush.

Peripheral nerve injuries result in significant loss of motor and sensory function, and the slow rate of nerve regeneration can prolong recovery time. Thus, approaches that promote axonal regeneration are critical to improve the outcomes for patients with peripheral nerve injuries. In this study, we investigated the effects of Ficus carica L. (fig) and Vaccinium macrocarpon Ait. (cranberry), which are rich in phytochemicals with demonstrable and diverse medicinal properties, on nerve regeneration in a mouse model of sciatic nerve crush. Our investigation revealed that fig extract, but not cranberry extract, prevented the decline in muscle weight and nerve conduction velocity induced by nerve crush. The fig extract also mitigated motor function impairment, myelin thinning, and axon diameter reduction, indicating its potential to promote nerve regeneration. Furthermore, the fig extract enhanced macrophage infiltration into the nerve tissue, suggesting that it could ameliorate nerve injury by promoting tissue repair via increased macrophage infiltration. The study provides valuable insights into the potential of the fig extract as a novel agent promoting nerve regeneration. Further investigation into the mechanisms underlying the action of fig extracts is needed to translate these findings into clinical applications for patients with peripheral nerve injuries.