Sensory Neuropraxia After Distal Biceps Repair is Not Associated With Patient-Reported Outcomes or Satisfaction: A Retrospective Cohort Study.

BACKGROUND: Cutaneous neuropraxia is the most common complication following distal biceps tendon repair (DBTR). Currently, no patient demographic factors have been implicated in its occurrence, course, or resolution. The purpose of this study is to explore various patient demographics and their association with postoperative neuropraxia. Further it investigates how mental health scores correlate with patient-reported outcomes, and whether occurrence of neuropraxia alters this association. METHODS: This retrospective review evaluates a consecutive series of patients who underwent distal biceps repair with a single-incision cortical button technique. Patients with reported outcome data at a minimum of 1 year (n = 47) were included for analysis. Demographic data including age, sex, body mass index (BMI), diabetes, smoking status, and occurrence of neuropraxia were recorded. Patient-reported outcome measures (PROMs) include the American Shoulder and Elbow Surgeons-Elbow (ASES-E) score, Single Assessment Numeric Evaluation (SANE) score, Visual Analog Scale (VAS) for pain, Disabilities of the Arm, Shoulder, and Hand Score (QuickDASH), and Veterans RAND 12 (VR-12) Mental Component Score (MCS) and Physical Component Score (PCS) quality-of-life assessment. RESULTS: Postoperative neuropraxia of any duration occurred in 45% (21/47) of patients in this cohort following DBTR. Of these, 62% (13/21) reported resolution of symptoms by the latest follow-up. Mean time to resolution of neuropraxia was 148 days. Patient age, BMI, smoking history, time to surgery, tear thickness, and increasing surgeon experience across the study period were not significantly associated with the incidence or time to resolution of postoperative neuropraxia. Scores for patient satisfaction, VAS, ASES, QuickDASH, SANE, VR-12 MCS, VR-12 PCS, and flexion ROM did not differ significantly between patients with and without postoperative neuropraxia. CONCLUSION: Patient satisfaction following DBTR was not significantly associated with postoperative neuropraxia. Patient and surgical characteristics did not influence the occurrence or time to resolution of neuropraxia. The occurrence of postoperative neuropraxia did not result in significant functional limitations.

A tacrolimus-eluting nerve guidance conduit enhances regeneration in a critical-sized peripheral nerve injury rat model.

Critical-sized peripheral nerve injuries pose a significant clinical challenge and lead to functional loss and disability. Current regeneration strategies, including autografts, synthetic nerve conduits, and biologic treatments, encounter challenges such as limited availability, donor site morbidity, suboptimal recovery, potential immune responses, and sustained stability and bioactivity. An obstacle in peripheral nerve regeneration is the immune response that can lead to inflammation and scarring that impede the regenerative process. Addressing both the immunological and regenerative needs is crucial for successful nerve recovery. Here, we introduce a novel biodegradable tacrolimus-eluting nerve guidance conduit engineered from a blend of poly (L-lactide-co-caprolactone) to facilitate peripheral nerve regeneration and report the testing of this conduit in 15-mm critical-sized gaps in the sciatic nerve of rats. The conduit's diffusion holes enable the local release of tacrolimus, a potent immunosuppressant with neuro-regenerative properties, directly into the injury site. A series of in vitro experiments were conducted to assess the ability of the conduit to maintain a controlled tacrolimus release profile that could promote neurite outgrowth. Subsequent in vivo assessments in rat models of sciatic nerve injury revealed significant enhancements in nerve regeneration, as evidenced by improved axonal growth and functional recovery compared to controls using placebo conduits. These findings indicate the synergistic effects of combining a biodegradable conduit with localized, sustained delivery of tacrolimus, suggesting a promising approach for treating peripheral nerve injuries. Further optimization of the design and long-term efficacy studies and clinical trials are needed before the potential for clinical translation in humans can be considered.

Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice.

Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomics analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.

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.

Assessment, management, and rehabilitation of traumatic peripheral nerve injuries for non-surgeons.

Electrodiagnostic evaluation is often requested for persons with peripheral nerve injuries and plays an important role in their diagnosis, prognosis, and management. Peripheral nerve injuries are common and can have devastating effects on patients' physical, psychological, and socioeconomic well-being; alongside surgeons, electrodiagnostic medicine specialists serve a central function in ensuring patients receive optimal treatment for these injuries. Surgical intervention-nerve grafting, nerve transfers, and tendon transfers-often plays a critical role in the management of these injuries and the restoration of patients' function. Increasingly, nerve transfers are becoming the standard of care for some types of peripheral nerve injury due to two significant advantages: first, they shorten the time to reinnervation of denervated muscles; and second, they confer greater specificity in directing motor and sensory axons toward their respective targets. As the indications for, and use of, nerve transfers expand, so too does the role of the electrodiagnostic medicine specialist in establishing or confirming the diagnosis, determining the injury's prognosis, recommending treatment, aiding in surgical planning, and supporting rehabilitation. Having a working knowledge of nerve and/or tendon transfer options allows the electrodiagnostic medicine specialist to not only arrive at the diagnosis and prognosticate, but also to clarify which nerves and/or muscles might be suitable donors, such as confirming whether the branch to supinator could be a nerve transfer donor to restore distal posterior interosseous nerve function. Moreover, post-operative testing can determine if nerve transfer reinnervation is occurring and progress patients' rehabilitation and/or direct surgeons to consider tendon transfers.

Biological characteristics of tissue engineered-nerve grafts enhancing peripheral nerve regeneration.

BACKGROUND: A favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA). METHODS: In order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein-protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively. RESULTS: The results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1ß and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-ß, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences. CONCLUSIONS: This study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation.

Quantitative mass spectrometry analysis of the injured proximal and distal human digital nerve ends.

Introduction: Proteomic analysis of injured human peripheral nerves, particularly focusing on events occurring in the proximal and distal nerve ends, remains relatively underexplored. This study aimed to investigate the molecular patterns underlying a digital nerve injury, focusing on differences in protein expression between the proximal and distal nerve ends. Methods: A total of 26 human injured digital nerve samples (24 men; 2 women; median age 47 [30-66] years), harvested during primary nerve repair within 48 h post-injury from proximal and distal nerve ends, were analyzed using mass spectrometry. Results: A total of 3,914 proteins were identified, with 127 proteins showing significant differences in abundance between the proximal and the distal nerve ends. The downregulation of proteins in the distal nerve end was associated with synaptic transmission, autophagy, neurotransmitter regulation, cell adhesion and migration. Conversely, proteins upregulated in the distal nerve end were implicated in cellular stress response, neuromuscular junction stability and muscle contraction, neuronal excitability and neurotransmitter release, synaptic vesicle recycling and axon guidance and angiogenesis. Discussion: Investigation of proteins, with functional annotations analysis, in proximal and the distal ends of human injured digital nerves, revealed dynamic cellular responses aimed at promoting tissue degeneration and restoration, while suppressing non-essential processes.

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes as Nanomedicine for Peripheral Nerve Injury.

Peripheral nerve injury (PNI) is a complex and protracted process, and existing therapeutic approaches struggle to achieve effective nerve regeneration. Recent studies have shown that mesenchymal stem cells (MSCs) may be a pivotal choice for treating peripheral nerve injury. MSCs possess robust paracrine capabilities, and exosomes, as the primary secretome of MSCs, are considered crucial regulatory mediators involved in peripheral nerve regeneration. Exosomes, as nanocarriers, can transport various endogenous or exogenous bioactive substances to recipient cells, thereby promoting vascular and axonal regeneration while suppressing inflammation and pain. In this review, we summarize the mechanistic roles of exosomes derived from MSCs in peripheral nerve regeneration, discuss the engineering strategies for MSC-derived exosomes to improve therapeutic potential, and explore the combined effects of MSC-derived exosomes with biomaterials (nerve conduits, hydrogels) in peripheral nerve regeneration.

Roles of SMAD and SMAD-Associated Signaling Pathways in Nerve Regeneration Following Peripheral Nerve Injury: A Narrative Literature Review.

Although several methods are being applied to treat peripheral nerve injury, a perfect treatment that leads to full functional recovery has not yet been developed. SMAD (Suppressor of Mothers Against Decapentaplegic Homolog) plays a crucial role in nerve regeneration by facilitating the survival and growth of nerve cells following peripheral nerve injury. We conducted a systematic literature review on the role of SMAD in this context. Following peripheral nerve injury, there was an increase in the expression of SMAD1, -2, -4, -5, and -8, while SMAD5, -6, and -7 showed no significant changes; SMAD8 expression was decreased. Specifically, SMAD1 and SMAD4 were found to promote nerve regeneration, whereas SMAD2 and SMAD6 inhibited it. SMAD exerts its effects by promoting neuronal survival and growth through BMP/SMAD1, BMP/SMAD4, and BMP/SMAD7 signaling pathways. Furthermore, it activates nerve regeneration programs via the PI3K/GSK3/SMAD1 pathway, facilitating active regeneration of nerve cells and subsequent functional recovery after peripheral nerve damage. By leveraging these mechanisms of SMAD, novel strategies for treating peripheral nerve damage could potentially be developed. We aim to further elucidate the precise mechanisms of nerve regeneration mediated by SMAD and explore the potential for developing targeted nerve treatments based on these findings.

Shining a Light on Venom-Peptide Receptors: Venom Peptides as Targeted Agents for In Vivo Molecular Imaging.

Molecular imaging has revolutionised the field of biomedical research by providing a non-invasive means to visualise and understand biochemical processes within living organisms. Optical fluorescent imaging in particular allows researchers to gain valuable insights into the dynamic behaviour of a target of interest in real time. Ion channels play a fundamental role in cellular signalling, and they are implicated in diverse pathological conditions, making them an attractive target in the field of molecular imaging. Many venom peptides exhibit exquisite selectivity and potency towards ion channels, rendering them ideal agents for molecular imaging applications. In this review, we illustrate the use of fluorescently-labelled venom peptides for disease diagnostics and intraoperative imaging of brain tumours and peripheral nerves. Finally, we address challenges for the development and clinical translation of venom peptides as nerve-targeted imaging agents.

Supercharged end-to-side anterior interosseous nerve transfer to restore intrinsic function in high ulnar nerve injury: a prospective cohort study.

BACKGROUND: High ulnar nerve injuries is known to have unfavorable motor outcomes compared to other peripheral nerve injuries in the upper extremity. Functional muscle recovery after peripheral nerve injury depends on the time to motor end plate reinnervation and the number of motor axons that successfully reach the target muscle. The purpose of this study is to assess the functional recovery, and complications following performing supercharge end-to-side (SETS) anastomosis for proximal ulnar nerve injuries. Our study focuses on the role of SETS in the recovery process of high ulnar nerve injury. PATIENT AND METHODS: This study is a prospective, single-arm, open-label, case series. The original proximal nerve pathology was dealt with according to the cause of injury, then SETS was performed distally. The follow-up period was 18 months. We compared the neurological findings before and after the procedure. A new test was used to show the effect of SETS on recovery by performing a Lidocaine proximal ulnar nerve block test. RESULTS: Recovery of the motor function of the ulnar nerve was evident in 33 (86.8%) patients. The mean time to intrinsic muscle recovery was 6.85 months ± 1.3, only 11.14% of patients restored protective sensation to the palm and finger and 86.8% showed sensory level at the wrist level at the end of the follow-up period. Lidocaine block test was performed on 35 recovered patients and showed no change in intrinsic hand function in 31 patients. CONCLUSION: SETS exhibit a remarkable role in the treatment of high ulnar nerve damage. SETS transfer can act as a nerve transfer that can supply intrinsic muscles by its fibers and allows for proximal nerve regeneration. We believe that this technique improves recovery of hand motor function and allows recovery of sensory fibers when combined with treating the proximal lesion. TRIAL REGISTRATION: Approved by Research Ethics Committee of Faculty of Medicine- Cairo University on 01/09/2021 with code number: MD-215-2021.

BDNF-loaded chitosan-based mimetic mussel polymer conduits for repair of peripheral nerve injury.

Care for patients with peripheral nerve injury is multifaceted, as traditional methods are not devoid of limitations. Although the utilization of neural conduits shows promise as a therapeutic modality for peripheral nerve injury, its efficacy as a standalone intervention is limited. Hence, there is a pressing need to investigate a composite multifunctional neural conduit as an alternative treatment for peripheral nerve injury. In this study, a BDNF-loaded chitosan-based mimetic mussel polymer conduit was prepared. Its unique adhesion characteristics allow it to be suture-free, improve the microenvironment of the injury site, and have good antibacterial properties. Researchers utilized a rat sciatic nerve injury model to evaluate the progression of nerve regeneration at the 12-week postoperative stage. The findings of this study indicate that the chitosan-based mimetic mussel polymer conduit loaded with BDNF had a substantial positive effect on myelination and axon outgrowth. The observed impact demonstrated a favorable outcome in terms of sciatic nerve regeneration and subsequent functional restoration in rats with a 15-mm gap. Hence, this approach is promising for nerve tissue regeneration during peripheral nerve injury.

Aetiologies 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.