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JOURNAL/nrgr/04.03/01300535-202501000-00036/figure1/v/2024-05-14T021156Z/r/image-tiff Axonal regeneration following surgical nerve repair is slow and often incomplete, resulting in poor functional recovery which sometimes contributes to lifelong disability. Currently, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery. The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for scalable production and clinical application, aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80% compared with systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

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BACKGROUND: Moebius syndrome (MoS), a rare congenital condition caused by the underdevelopment of the sixth and seventh cranial nerves, presents with uni- or bilateral facial paralysis and lateral gaze palsy. Those with MoS often have incomplete eyelid closure (lagophthalmos). This study aimed to investigate the experiences of individuals living with incomplete eyelid closure due to MoS. METHODS: Participants shared their experiences in semi-structured open-ended focus groups during the 2023 MoS Foundation Conference. Data were analyzed thematically using Nvivo. The Terzis and Bruno scoring system was used to grade participant eyelid closure (range: 1 being no eyelid closure with full scleral show to 5 being complete eyelid closure with no scleral show) and blink (from 1 being no blink to 5 being synchronous and complete blink present). Marginal reflex distances 1 and 2 (MRD1 and MRD2) were measured to grade for ptosis and lid retraction, respectively. RESULTS: Fifteen participants participated in two focus groups, comprising adults (n = 12) and adolescents (n = 3). All participants had lagophthalmos with some scleral show, ptosis, and lid retraction. The median eyelid closure score was 3 (incomplete eye closure with 1/3 scleral showing). Five key themes were identified: social stigma and misunderstanding, daily life impacts, seasonal exacerbations, different attitudes toward surgical intervention between adults and adolescents, and a prevailing sense of self-acceptance regarding their condition. CONCLUSION: Incomplete eyelid closure poses significant social challenges for individuals with MoS, especially around social encounters. Our findings show the importance of developing tailored communication tools to support those living with this facial difference.

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BACKGROUND: Outcomes of pediatric facial reanimation beyond 10 years are not known. This cross-sectional study evaluated long-term surgical and patient-reported outcomes of adults who underwent smile reconstruction as children with either a cross-face nerve graft (CFNG) or masseter nerve transfer at least 10 years previously. METHODS: Commissure excursion was quantified with FACE-Gram software at 3 time points: preoperatively, early postoperatively within 2 years, and at long-term follow-up. Patient-reported outcomes were evaluated with validated questionnaires (Facial Clinimetric Evaluation Scale, FACE-Q 1.0) and thematic analysis of semistructured interviews. Results are reported as median (interquartile range [IQR]). RESULTS: A total of 42 patients were included (26 women and 16 men). Median long-term follow-up was 19.3 years (IQR, 8.8 years) for CFNG and 17.6 years (IQR, 5.8 years) for masseter nerve transfer. For both groups, commissure excursion increased significantly from preoperative to early postoperative time points and remained stable at long-term follow-up (P < 0.0001). Commissure excursion at long-term follow-up between the 2 groups was not significantly different (CFNG, 5.0 mm [IQR, 9.4 mm]; masseter nerve transfer, 8.4 mm [IQR, 4.1 mm]); P > 0.05). For patient-reported outcomes, median Facial Clinimetric Evaluation Scale score was 72 of 100, and 95% of respondents agreed with the statement "I am pleased with the result" on the FACE-Q 1.0. Overall quality of life was rated at 7 of 10 or greater by 97% of participants, and all participants would recommend the surgery to other children. CONCLUSIONS: Pediatric facial reanimation with CFNG or masseter nerve transfer reliably improves commissure excursion with longevity beyond 10 years. Adult patients report overall high satisfaction and social functioning.

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The regenerative capacity of the peripheral nervous system is limited, and peripheral nerve injuries often result in incomplete healing and poor outcomes even after repair. Transection injuries that induce a nerve gap necessitate microsurgical intervention; however, even the current gold standard of repair, autologous nerve graft, frequently results in poor functional recovery. Several interventions have been developed to augment the surgical repair of peripheral nerves, and the application of functional biomaterials, local delivery of bioactive substances, electrical stimulation, and allografts are among the most promising approaches to enhance innate healing across a nerve gap. Biocompatible polymers with optimized degradation rates, topographic features, and other functions provided by their composition have been incorporated into novel nerve conduits (NCs). Many of these allow for the delivery of drugs, neurotrophic factors, and whole cells locally to nerve repair sites, mitigating adverse effects that limit their systemic use. The electrical stimulation of repaired nerves in the perioperative period has shown benefits to healing and recovery in human trials, and novel biomaterials to enhance these effects show promise in preclinical models. The use of acellular nerve allografts (ANAs) circumvents the morbidity of donor nerve harvest necessitated by the use of autografts, and improvements in tissue-processing techniques may allow for more readily available and cost-effective options. Each of these interventions aid in neural regeneration after repair when applied independently, and their differing forms, benefits, and methods of application present ample opportunity for synergistic effects when applied in combination.

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Pediatric facial nerve paralysis can present significant challenges based on its various etiologies, unique approach to treatment options, and overall outcomes. It can impact both the child and parent when regarding function, appearance, and psychosocial implications. The etiology of facial nerve palsy can include congenital, traumatic, iatrogenic, and idiopathic causes. In some, the paralysis is transient while others have permanent loss of function. A thorough evaluation and differential diagnosis are essential to guide treatment planning. The purpose of this paper is to review facial paralysis in children with a focus on surgical management.

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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.

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The measurement of corneal sensation allows clinicians to assess the status of corneal innervation and serves as a crucial indicator of corneal disease and eye health. Many devices are available to assess corneal sensation, including the Cochet-Bonnet aesthesiometer, the Belmonte Aesthesiometer, the Swiss Liquid Jet Aesthesiometer, and the newly introduced Corneal Esthesiometer Brill. Increasing the clinical use of in vivo confocal microscopy and optical coherence tomography will allow for greater insight into the diagnosis, classification, and monitoring of ocular surface diseases such as neurotrophic keratopathy; however, formal esthesiometric measurement remains necessary to assess the functional status of corneal nerves. These aesthesiometers vary widely in their mode of corneal stimulus generation and their relative accessibility, precision, and ease of clinical use. The development of future devices to optimize these characteristics, as well as further comparative studies between device types should enable more accurate and precise diagnosis and treatment of corneal innervation deficits. The purpose of this narrative review is to describe the advancements in the use of aesthesiometers since their introduction to clinical practice, compare currently available devices for assessing corneal innervation and their relative limitations, and discuss how the assessment of corneal innervation is crucial to understanding and treating pathologies of the ocular surface.

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Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.

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Background: Sirenomelia is a rare congenital condition characterized by fusion of the lower limbs. Patients with sirenomelia generally do not survive long after birth because the condition is associated with multisystem organ dysfunction due to developmental anomalies. Considering the low incidence and few cases surviving the neonatal period, there is minimal understanding regarding the surgical management of sirenomelia. We present a unique case of an infant born with type 1 sirenomelia, absence of external genitalia, presence of a cloaca, absence of the bladder, and presence of an imperforate and vestigial anus, who not only survived the birth process, but, at the age of 11 months, was determined to be a candidate for surgical separation of the lower extremities. Methods: This case was approached much like a dorsal rectangular flap syndactyly release. Large Z-plasty flaps were designed and raised, and the soft tissue within the skin bridge was meticulously dissected to preserve anatomy and to provide adequate skin flaps without perineal skin grafting. A quadrangular flap was designed to reconstruct the perineum and produce a neo-vulva using de-epithelialization. Results: Successful lower extremity separation was achieved. There were no major postoperative complications. The patient progressed with lower extremity function, and eventually achieved independent ambulation. Conclusions: Management of sirenomelia is incredibly challenging, and data to guide surgical management are limited. This report details our approach to a successful lower extremity separation, repair, and neo-vulvar reconstruction in a case of type I sirenomelia.

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Background: The use of sensory nerve transfers to the anesthetic cornea has transformed the treatment of neurotrophic keratopathy by restoring ocular surface sensation and activating dysfunctional epithelial repair mechanisms. However, despite numerous reports on surgical techniques, there is a scarcity of information on the interdisciplinary management, preoperative assessment, and surgical decision-making, which are equally critical to treatment success. Methods: This Special Topic presents a standardized, interdisciplinary preoperative workup based on our 10-year experience with corneal neurotization in 32 eyes of patients with neurotrophic keratopathy. Results: Our assessment includes a medical history review, ophthalmic evaluation, and systematic facial sensory donor nerve mapping for light touch and pain modalities. This approach enables evidence-based patient selection, optimal surgery timing, and suitable donor nerve identification, including backup options. Conclusions: Based on a decade-long experience, this special topic highlights the importance of interdisciplinary collaboration and provides a practical roadmap for optimizing patient selection and surgical decision-making in patients undergoing corneal neurotization.

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The cornea is the window through which we see the world. Corneal clarity is required for vision, and blindness occurs when the cornea becomes opaque. The cornea is covered by unique transparent epithelial cells that serve as an outermost cellular barrier bordering between the cornea and the external environment. Corneal sensory nerves protect the cornea from injury by triggering tearing and blink reflexes, and are also thought to regulate corneal epithelial renewal via unknown mechanism(s). When protective corneal sensory innervation is absent due to infection, trauma, intracranial tumors, surgery, or congenital causes, permanent blindness results from repetitive epithelial microtraumas and failure to heal. The condition is termed neurotrophic keratopathy (NK), with an incidence of 5:10,000 people worldwide. In this report, we review the currently available therapeutic solutions for NK and discuss the progress in our understanding of how the sensory nerves induce corneal epithelial renewal.

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Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.

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BACKGROUND: Pediatric brachial plexus injuries (BPI) can have a devastating impact on upper extremity function. With localized lesions, nerve grafting and transfers are well-described. However, reconstruction of pan-plexus (C5-T1) injuries (PPI) requires donor nerves outside of the brachial plexus. The cross C7 (CC7) nerve transfer extended with sural nerve grafts to the contralateral recipient nerve offers the advantage of supplying robust donor axons. Though controversial in the West, CC7 transfer is routine in many Asian centers. We present a case series of pediatric patients who underwent CC7 transfer for BPI. Our objective was to catalog donor site morbidity incurred by transferring the C7 nerve root. METHODS: This retrospective study was approved by the Institutional Review Board of our university. INCLUSION CRITERIA: patients under 18 years old that underwent CC7 nerve transfer for BPI at our health system between 2021 and 2022. A chart review was completed to collect demographic and outcomes data. RESULTS: Three patients underwent a complete CC7 transfer between 2021 and 2022 for BPI reconstruction. All patients underwent concomitant additional nerve transfers. Post-operative donor site sensory deficits were minimal and transient in all but one patient, who reported mild but persistent paresthesia of the donor side hand with movement of recipient side digits; however, no patients suffered donor site motor deficits (Table 1). CONCLUSIONS: We conclude that CC7 nerve transfer is a safe surgical option to provide additional donor motor axons for PPI in pediatric patients.

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Purpose: Corneal sensory nerves protect the cornea from injury. They are also thought to stimulate limbal stem cells (LSCs) to produce transparent epithelial cells constantly, enabling vision. In other organs, Schwann cells (SCs) associated with tissue-innervating axon terminals mediate tissue regeneration. This study defines the critical role of the corneal axon-ensheathing SCs in homeostatic and regenerative corneal epithelial cell renewal. Methods: SC localization in the cornea was determined by in situ hybridization and immunohistochemistry with SC markers. In vivo SC visualization and/or ablation were performed in mice with inducible corneal SC-specific expression of tdTomato and/or Diphtheria toxin, respectively. The relative locations of SCs and LSCs were observed with immunohistochemical analysis of harvested genetically SC-prelabeled mouse corneas with LSC-specific antibodies. The correlation between cornea-innervating axons and the appearance of SCs was ascertained using corneal denervation in rats. To determine the limbal niche cellular composition and gene expression changes associated with innervation-dependent epithelial renewal, single-cell RNA sequencing (scRNA-seq) of dissociated healthy, de-epithelized, and denervated cornea limbi was performed. Results: We observed limbal enrichment of corneal axon-associated myelinating and non-myelinating SCs. Induced local genetic ablation of SCs, although leaving corneal sensory innervation intact, markedly inhibited corneal epithelial renewal. scRNA-seq analysis (1) highlighted the transcriptional heterogenicity of cells populating the limbal niche, and (2) identified transcriptional changes associated with corneal innervation and during wound healing that model potential regulatory paracrine interactions between SCs and LSCs. Conclusions: Limbal SCs are required for innervation-dependent corneal epithelial renewal.

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BACKGROUND: Nerve transection is the most common form of peripheral nerve injury. Treatment of peripheral nerve injury has primarily focused on stabilization and mechanical cues to guide extension of the regenerating growth cone across the site of transection. The authors investigated the effects of a peripheral nerve matrix (PNM) hydrogel on recovery after nerve transection. METHODS: The authors used rodent models to determine the effect of PNM on axon extension, electrophysiologic nerve conduction, force generation, and neuromuscular junction formation after nerve transection and repair. The authors complemented this work with in vivo and in vitro fluorescence-activated cell sorting and immunohistochemistry approaches to determine the effects of PNM on critical cell populations early after repair. RESULTS: Extension of axons from the proximal stump and overall green fluorescent protein-positive axon volume within the regenerative bridge were increased in the presence of PNM compared with an empty conduit ( P < 0.005) 21 days after repair. PNM increased electrophysiologic conduction (compound muscle action potential amplitude) across the repair site ( P < 0.05) and neuromuscular junction formation ( P = 0.04) 56 days after repair. PNM produced a shift in macrophage phenotype in vitro and in vivo ( P < 0.05) and promoted regeneration in a murine model used to characterize the early immune response to PNM ( P < 0.05). CONCLUSION: PNM, delivered by subepineural injection, promoted recovery after nerve transection with immediate repair, supporting a beneficial macrophage response, axon extension, and downstream remodeling using a range of clinically relevant outcome measures. CLINICAL RELEVANCE STATEMENT: This article describes an approach for subepineural injection at the site of nerve coaptation to modulate the response to injury and improve outcomes.

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Effective regeneration after peripheral nerve injury requires macrophage recruitment. We investigated the activation of remodeling pathways within the macrophage population when repair is delayed and identified alteration of key upstream regulators of the inflammatory response. We then targeted one of these regulators, using exogenous IL10 to manipulate the response to injury at the repair site. We demonstrate that this approach alters macrophage polarization, promotes macrophage recruitment, axon extension, neuromuscular junction formation, and increases the number of regenerating motor units reaching their target. We also demonstrate that this approach can rescue the effects of delayed nerve graft.

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CASE: We present the case of a 14-year-old adolescent boy with a distal femoral osteosarcoma partially encasing the tibial nerve. He underwent rotationplasty with resection and coaptation (end-to-end repair) of the tibial nerve. By 1 year postoperatively, he had recovered sensation on the plantar aspect of his foot and Medical Research Council scale 4+/5 gastro-soleus contraction that powered extension of the new knee. CONCLUSION: Tibial nerve resection is not an absolute contraindication for rotationplasty, even in an adolescent. Nerve coaptation allows for well-functioning rotationplasty as an alternative to endoprosthetic reconstruction or above-knee amputation.

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The brachial plexus consists of an intricate array of nerves originating from the C5-T1 ventral rami of the spinal cord. Their course is complex and can be substantially distorted after injury. Thus, dissection of the brachial plexus can be difficult. Here, we present a practical approach to the supraclavicular dissection of the brachial plexus, with emphasis on relevant anatomy and surgical landmarks. Methods: This anatomical review was prepared using intraoperative surgical imaging. In addition, illustrations are used to display the images in schematic form. We present a stepwise surgical approach to the supraclavicular dissection of the brachial plexus. We highlight the differences between pre- and postganglionic nerve root injuries, and also relevant anatomical variants of the brachial plexus. Results: Eleven steps are recommended to facilitate the supraclavicular approach to the brachial plexus. Conclusion: The supraclavicular dissection of the brachial plexus is reliable with consistent landmarks and can be carried out in a stepwise fashion.