Peripheral Nerve Repair Research Articles

Interactions between Schwann cell and extracellular matrix in peripheral nerve regeneration.

Peripheral nerve injuries, caused by various reasons, often lead to severe sensory, motor, and autonomic dysfunction or permanent disability, posing a challenging problem in regenerative medicine. Autologous nerve transplantation has been the gold standard in traditional treatments but faces numerous limitations and risk factors, such as donor area denervation, increased surgical complications, and diameter or nerve bundle mismatches. The extracellular matrix (ECM) is a complex molecular network synthesized and released into the extracellular space by cells residing in tissues or organs. Its main components include collagen, proteoglycans/glycosaminoglycans, elastin, laminin, fibronectin, etc., providing structural and biochemical support to surrounding cells, crucial for cell survival and growth. Schwann cells, as the primary glial cells in the peripheral nervous system, play various important roles. Schwann cell transplantation is considered the gold standard in cell therapy for peripheral nerve injuries, making ECM derived from Schwann cells one of the most suitable biomaterials for peripheral nerve repair. To better understand the mechanisms of Schwann cells and the ECM in peripheral nerve regeneration and their optimal application, this review provides an overview of their roles in peripheral nerve regeneration.

Exploring an innovative decellularization protocol for porcine nerve grafts: a translational approach to peripheral nerve repair.

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

Multichannel Conduits with Fascicular Complementation: Significance in Long Segmental Peripheral Nerve Injury.

Despite the advances in tissue engineering approaches, reconstruction of long segmental peripheral nerve defects remains unsatisfactory. Although autologous grafts with proper fascicular complementation have shown meaningful functional recovery according to the Medical Research Council Classification (MRCC), the lack of donor nerve for such larger defect sizes (>30 mm) has been a serious clinical issue. Further clinical use of hollow nerve conduits is limited to bridging smaller segmental defects of denuded nerve ends (<30 mm). Recently, bioinspired multichannel nerve guidance conduits (NGCs) gained attention as autograft substitutes as they mimic the fascicular connective tissue microarchitecture in promoting aligned axonal outgrowth with desirable innervation for complete sensory and motor function restoration. This review outlines the hierarchical organization of nerve bundles and their significance in the sensory and motor functions of peripheral nerves. This review also emphasizes the major challenges in addressing the longer nerve defects with the role of fascicular arrangement in the multichannel nerve guidance conduits and the need for fascicular matching to accomplish complete functional restoration, especially in treating long segmental nerve defects. Further, currently available fabrication strategies in developing multichannel nerve conduits and their inconsistency in existing preclinical outcomes captured in this review would seed a new process in designing an ideal larger nerve conduit for peripheral nerve repair.

Fas ligand regulate nerve injury and repair by affecting AKT, β-catenin, and NF-κB pathways

ObjectiveTo investigate the regulatory effect of Fas-L on the repair and regeneration of peripheral extension injury in rats. MethodsThis study aimed to explore the effects of Fas-L on apoptosis and axonal regeneration of dorsal root ganglion (DRG) cells in rat peripheral nerve repair and regeneration by using several relevant experimental techniques from the injured nerve animal model, cell biology, and molecular biology. ResultsThe expression level of Fas-L in DRG tissues was significantly down-regulated after sciatic nerve injury. Interference with Fas-L can significantly promote the regeneration of DRG neuronal axons and inhibit apoptosis, while the overexpression of Fas-L is contrary to it. Moreover, Fas-L may play a role in the regulation of DRG function and the repair and regeneration of peripheral nerves in Sprague Dawley (SD) rats by affecting several signaling pathways, such as p-AKT/AKT, β-catenin, and NF-κB. ConclusionFas-L may have a certain effect on the repair and regeneration of peripheral nerve injury in SD rats, which may provide an experimental basis and a new theoretical basis for the functional reconstruction of peripheral nerves. Significance statementThe expression level of Fas-L in DRG tissues was significantly down-regulated after sciatic nerve injury. Fas-L can significantly promote the regeneration of DRG neuronal axons and inhibit apoptosis. Fas-L may play a role in the regulation of DRG function and the repair and regeneration of peripheral nerves in SD rats by affecting several signaling pathways, such as p-AKT/AKT, β-catenin, and NF-κB. Fas-L may have a certain effect on the repair and regeneration of peripheral nerve injury in SD rats, which may provide an experimental basis and a new theoretical basis for the functional reconstruction of peripheral nerves.

Engineered PVDF/PLCL/PEDOT Dual Electroactive Nerve Conduit to Mediate Peripheral Nerve Regeneration by Modulating the Immune Microenvironment

AbstractElectroactive materials are increasingly recognized for their efficacy in promoting the repair of peripheral nerve injury. However, the mechanism by which electroactive materials promote peripheral nerve regeneration by modulating the immune microenvironment remains incompletely explored. In this study, a PVDF/PLCL/PEDOT artificial peripheral nerve conduit with dual electroactivity by integrating piezoelectric properties and electrical conductivity is constructed. The electroactive conduit exhibited excellent spontaneous electrical and conductive properties, superior suture resistance and anti‐twisting properties. Detailed in vitro cell experiments and in vivo animal experiments are conducted, revealing that the electroactive nerve conduit can effectively promote rat sciatic nerve regeneration while facilitating reconstruction of both nerve conduction function and motor function. Furthermore, the underlying mechanism in depth is investigated and found that the electroactive material can regulate the immune microenvironment by activating the PI3K/AKT‐Nrf2 signaling pathway, thereby promoting macrophage polarization toward M2 anti‐inflammatory phenotype. This subsequently facilitated Schwann cell recruitment and myelin formation through mediation of the macrophage paracrine system. Importantly, blocking immune signaling pathways diminished the effectiveness of the electroactive nerve conduit in promoting nerve repair. The work elucidated how electroactive materials modulate immune microenvironment to positively impact peripheral nerve repair, highlighting the critical role of immune modulation in peripheral nerve repair.

(061) Xenon Facilitates Schwann Cell Demyelination via Inhibition of SPRY2 in Treating Erectile Function After Cavernous Nerve Injury

Abstract Introduction Cavernous nerve injury induced erectile dysfunction (ED) is the most common complication after radical prostatectomy for prostate cancer. Our previous studies found that xenon (Xe) can partially restore the erectile function and cavernous nerve function of rats with neurogenic ED, but the mechanism is unclear. Schwann cells (SC) play an important role in peripheral nerve repair, and after axonal injury, SC undergo demyelination and transform into repair-type SC to promote repair. Objective The purpose of this study is to verify whether Xe promotes the demyelination of Schwann cells and its molecular mechanism. Methods Human SCs were cultured in vitro and given Echo-lipid particles (ELIPs) carrying Xe. The control group was given empty ELIPs. Ultrasound was performed above the culture dish to break ELIPs and release the gas. After treatment, the expression level of the EGR2 gene, a marker of SC demyelination, was detected, and RNA was extracted for mRNA sequencing. Sequencing results were validated in SC and rat dorsal root ganglion (MRP) tissues through Western blot and qPCR. Results After Xe treatment, the level of EGR2 in SC cultured in vitro decreased, indicating that Xe treatment can promote the demyelination process of SC. RNA-sequencing results showed that after Xe treatment, 88 genes were up-regulated and 231 genes were down-regulated. Top 10 KEGG pathway enrichment analysis suggested an increase in MAPK pathway expression. Meanwhile, among the differentially expressed genes, we found that the expression of SPRY2 (Sprouty RTK Signaling Antagonist 2) decreased, a negative feedback regulator of the MAPK pathway. Using qPCR and Western blot on SC and rat MPG tissues in vitro, we validated the sequencing results and found that after Xe treatment, the expression level of SPRY2 decreased, and the level of pERK increased. Conclusions Xe may promote the demyelination of Schwann cells and the repair of cavernous nerves by inhibiting the SPRY2 level of SC, reducing its inhibition of the MAPK/ERK pathway. Disclosure No.

Artificial intelligence-assisted repair of peripheral nerve injury: a new research hotspot and associated challenges.

Artificial intelligence can be indirectly applied to the repair of peripheral nerve injury. Specifically, it can be used to analyze and process data regarding peripheral nerve injury and repair, while study findings on peripheral nerve injury and repair can provide valuable data to enrich artificial intelligence algorithms. To investigate advances in the use of artificial intelligence in the diagnosis, rehabilitation, and scientific examination of peripheral nerve injury, we used CiteSpace and VOSviewer software to analyze the relevant literature included in the Web of Science from 1994-2023. We identified the following research hotspots in peripheral nerve injury and repair: (1) diagnosis, classification, and prognostic assessment of peripheral nerve injury using neuroimaging and artificial intelligence techniques, such as corneal confocal microscopy and coherent anti-Stokes Raman spectroscopy; (2) motion control and rehabilitation following peripheral nerve injury using artificial neural networks and machine learning algorithms, such as wearable devices and assisted wheelchair systems; (3) improving the accuracy and effectiveness of peripheral nerve electrical stimulation therapy using artificial intelligence techniques combined with deep learning, such as implantable peripheral nerve interfaces; (4) the application of artificial intelligence technology to brain-machine interfaces for disabled patients and those with reduced mobility, enabling them to control devices such as networked hand prostheses; (5) artificial intelligence robots that can replace doctors in certain procedures during surgery or rehabilitation, thereby reducing surgical risk and complications, and facilitating postoperative recovery. Although artificial intelligence has shown many benefits and potential applications in peripheral nerve injury and repair, there are some limitations to this technology, such as the consequences of missing or imbalanced data, low data accuracy and reproducibility, and ethical issues (e.g., privacy, data security, research transparency). Future research should address the issue of data collection, as large-scale, high-quality clinical datasets are required to establish effective artificial intelligence models. Multimodal data processing is also necessary, along with interdisciplinary collaboration, medical-industrial integration, and multicenter, large-sample clinical studies.

G. Carl Huber (1865-1934): A Michigan Pioneer in Peripheral Nerve Injury and Regeneration.

The treatment of peripheral nerve injuries has seen tremendous innovations over the past century. Dr Gotthelf Carl Huber, an American immigrant and early experimental pioneer in the field of peripheral nerve injury, created a foundation of scientific knowledge for these advancements. At the beginning of his career, Huber published novel work in peripheral nerve injury, supporting the concept of Wallerian degeneration and demonstrating the use of nerve grafting for repair. As his scientific career evolved into other research areas at the University of Michigan, Huber's impact extended far beyond just the study of peripheral nerve injury. Because of the external forces of the First World War, Dr Huber's focus returned to translational projects concentrated on the treatment of neuromas and war time peripheral nerve injuries. Huber's scientific impact in the field of peripheral nerve injury and repair came as a result of his incredible work ethic, mentorship, and tremendous leadership qualities; through this, his work still influences clinical practice today, a century later.

Potential of Collagen/PLA-based Nanofibrous Scaffold to Support PC12 Cells and Neural Repair

Objective: This study attempts to modify Polylactic Acid (PLA) with the natural polymer Collagen (Coll), to develop materials such as an electrospun scaffold that have better mechanical stability and biocompatibility. Retinoic acid (RA), a bioactive material that promotes nerve growth, is to be added to the nanofiber scaffolds as part of this project.&#x0D; Methods: One of the most important methods we employed in this work to create nanofibrous scaffolds was electrospinning.&#x0D; Results: The synthesized nanofiber scaffold exhibited a diameter of 255±40 nm and a tensile strength of 175±10.4 N, providing sufficient support for native peripheral nerve repair. The inclusion of Coll enhanced the scaffold's hydrophilic behavior (contact angle: 56±4°), ensuring stability in aqueous solutions. In addition, cell adhesion and proliferation are demonstrated to be improved by PLA composite nanofibers based on Collagen, while PC12 cell adhesion and proliferation are further improved by RA.&#x0D; Conclusion: Based on their biodegradability, robust mechanical properties, and porous structure, these scaffolds are excellent choices for nerve tissue engineering, according to our findings. The significant increase in PC12 cells' adhesion and proliferation upon the addition of RA demonstrates the cells' potential for nerve repair.

Differentiated mesenchymal stem cells-derived exosomes immobilized in decellularized sciatic nerve hydrogels for peripheral nerve repair

Peripheral nerve injury (PNI) and the limitations of current treatments often result in incomplete sensory and motor function recovery, which significantly impact the patient's quality of life. While exosomes (Exo) derived from stem cells and Schwann cells have shown promise on promoting PNI repair following systemic administration or intraneural injection, achieving effective local and sustained Exo delivery holds promise to treat local PNI and remains challenging. In this study, we developed Exo-loaded decellularized porcine nerve hydrogels (DNH) for PNI repair. We successfully isolated Exo from differentiated human adipose-derived mesenchymal stem cells (hADMSC) with a Schwann cell-like phenotype (denoted as dExo). These dExo were further combined with polyethylenimine (PEI), and DNH to create polyplex hydrogels (dExo-loaded pDNH). At a PEI content of 0.1%, pDNH showed cytocompatibility for hADMSCs and supported neurite outgrowth of dorsal root ganglions. The sustained release of dExos from dExo-loaded pDNH persisted for at least 21 days both in vitro and in vivo. When applied around injured nerves in a mouse sciatic nerve crush injury model, the dExo-loaded pDNH group significantly improved sensory and motor function recovery and enhanced remyelination compared to dExo and pDNH only groups, highlighting the synergistic regenerative effects. Interestingly, we observed a negative correlation between the number of colony-stimulating factor-1 receptor (CSF-1R) positive cells and the extent of PNI regeneration at the 21-day post-surgery stage. Subsequent in vitro experiments demonstrated the potential involvement of the CSF-1/CSF-1R axis in Schwann cells and macrophage interaction, with dExo effectively downregulating CSF-1/CSF-1R signaling.

An Adaptable Drug Delivery System Facilitates Peripheral Nerve Repair by Remodeling the Microenvironment.

The multifaceted process of nerve regeneration following damage remains a significant clinical issue, due to the lack of a favorable regenerative microenvironment and insufficient endogenous biochemical signaling. However, the current nerve grafts have limitations in functionality, as they require a greater capacity to effectively regulate the intricate microenvironment associated with nerve regeneration. In this regard, we proposed the construction of a functional artificial scaffold based on a "two-pronged" approach. The whole system was developed by encapsulating Tazarotene within nanomicelles formed through self-assembly of reactive oxygen species (ROS)-responsive amphiphilic triblock copolymer, all of which were further loaded into a thermosensitive injectable hydrogel. Notably, the hydrogel exhibits obvious temperature sensitivity at a concentration of 6 wt %, and the nanoparticles possess concentration-dependent H2O2-response capability with a controlled release profile in 48 h. The combined strategy promoted the repair of injured peripheral nerves, attributed to the dual role of the materials, which mainly involved providing structural support, modulating the immune microenvironment, and enhancing angiogenesis. Overall, this study opens up intriguing prospects in tissue engineering.

Leveraging Oriented Lateral Walls of Nerve Guidance Conduit with Core-Shell MWCNTs Fibers for Peripheral Nerve Regeneration.

Peripheral nerve regeneration and functional recovery rely on the chemical, physical, and structural properties of nerve guidance conduits (NGCs). However, the limited support for long-distance nerve regeneration and axonal guidance has hindered the widespread use of NGCs. This study introduces a novel nerve guidance conduit with oriented lateral walls, incorporating multi-walled carbon nanotubes (MWCNTs) within core-shell fibers prepared in a single step using a modified electrohydrodynamic (EHD) printing technique to promote peripheral nerve regeneration. The structured conduit demonstrated exceptional stability, mechanical properties, and biocompatibility, significantly enhancing the functionality of NGCs. In vitro cell studies revealed that RSC96 cells adhered and proliferated effectively along the oriented fibers, demonstrating a favorable response to the distinctive architectures and properties. Subsequently, a rat sciatic nerve injury model demonstrated effective efficacy in promoting peripheral nerve regeneration and functional recovery. Tissue analysis and functional testing highlighted the significant impact of MWCNT concentration in enhancing peripheral nerve regeneration and confirming well-matured aligned axonal growth, muscle recovery, and higher densities of myelinated axons. These findings demonstrate the potential of oriented lateral architectures with coaxial MWCNT fibers as a promising approach to support long-distance regeneration and encourage directional nerve growth for peripheral nerve repair in clinical applications.

Polyethylene Glycol-Mediated Axonal Fusion Promotes Early Sensory Recovery After Digital Nerve Injury: A Randomized Clinical Trial

Background. Peripheral nerve repair is limited by Wallerian degeneration coupled with the slow and inconsistent rates of nerve regrowth. In more proximal injuries, delayed nerve regeneration can cause debilitating muscle atrophy. Topical application of polyethylene glycol (PEG) during neurorrhaphy facilitates the fusion of severed axonal membranes, immediately restoring action potentials across the coaptation site. In preclinical animal models, PEG-fusion resulted in remarkable early functional recovery. Methods. This is the first randomized clinical trial comparing functional outcomes between PEG-fusion and standard neurorrhaphy. Participants with digital nerve transections were followed up at 2 weeks, 1 month, and 3 months postoperatively. The primary outcome was assessed using the Medical Research Council Classification (MRCC) rating for sensory recovery at each timepoint. Semmes-Weinstein monofilaments and static two-point discrimination determined MRCC ratings. Postoperative quality of life was measured using the Michigan Hand Questionnaire (MHQ). Results. Forty-eight transected digital nerves (25 control, 23 PEG) across twenty-two patients were analyzed. PEG-fused nerves demonstrated significantly higher MRCC scores at 2 weeks (OR 16.95, 95% CI: 1.79 – 160.38, p = 0.008) and 1 month (OR 13.40, 95% CI: 1.64 – 109.77, p = 0.009). Participants in the PEG cohort also had significantly higher average MHQ scores at 2 weeks (Hodge’s g 1.28, 95% CI: 0.23 – 2.30, p = 0.0163) and 1 month (Hodge’s g 1.02, 95% CI: 0.04 – 1.99, p = 0.049). No participants had adverse events related to the study drug. Conclusion. PEG-fusion promotes early sensory recovery and improved patient well-being following peripheral nerve repair of digital nerves.

Role of Oxygen and Its Radicals in Peripheral Nerve Regeneration: From Hypoxia to Physoxia to Hyperoxia.

Oxygen is compulsory for mitochondrial function and energy supply, but it has numerous more nuanced roles. The different roles of oxygen in peripheral nerve regeneration range from energy supply, inflammation, phagocytosis, and oxidative cell destruction in the context of reperfusion injury to crucial redox signaling cascades that are necessary for effective axonal outgrowth. A fine balance between reactive oxygen species production and antioxidant activity draws the line between physiological and pathological nerve regeneration. There is compelling evidence that redox signaling mediated by the Nox family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases plays an important role in peripheral nerve regeneration. Further research is needed to better characterize the role of Nox in physiological and pathological circumstances, but the available data suggest that the modulation of Nox activity fosters great therapeutic potential. One of the promising approaches to enhance nerve regeneration by modulating the redox environment is hyperbaric oxygen therapy. In this review, we highlight the influence of various oxygenation states, i.e., hypoxia, physoxia, and hyperoxia, on peripheral nerve repair and regeneration. We summarize the currently available data and knowledge on the effectiveness of using hyperbaric oxygen therapy to treat nerve injuries and discuss future directions.

Sticky and Strain-Gradient Artificial Epineurium for Sutureless Nerve Repair in Rodents and Nonhuman Primates.

The need for the development of soft materials capable of stably adhering to nerve tissues without any suturing followed by additional damages is at the fore at a time when success in postoperative recovery depends largely on the surgical experience and/or specialized microsuturing skills of the surgeon. Despite fully recognizing such prerequisite conditions, designing the materials with robust adhesion to wet nerves as well as acute/chronic anti-inflammation remains to be resolved. Herein, a sticky and strain-gradient artificial epineurium (SSGAE) that overcomes the most critically challenging aspect for realizing sutureless repair of severely injured nerves is presented. In this regard, the SSGAE with a skin-inspired hierarchical structure entailing strain-gradient layers, anisotropic Janus layers including hydrophobic top and hydrophilic bottom surfaces, and synergistic self-healing capabilities enables immediate and stable neurorrhaphy in both rodent and nonhuman primate models, indicating that the bioinspired materials strategy significantly contributes to translational medicine for effective peripheral nerve repair.

Brief Electrical Stimulation Promotes Recovery after Surgical Repair of Injured Peripheral Nerves.

Injured peripheral nerves regenerate their axons in contrast to those in the central nervous system. Yet, functional recovery after surgical repair is often disappointing. The basis for poor recovery is progressive deterioration with time and distance of the growth capacity of the neurons that lose their contact with targets (chronic axotomy) and the growth support of the chronically denervated Schwann cells (SC) in the distal nerve stumps. Nonetheless, chronically denervated atrophic muscle retains the capacity for reinnervation. Declining electrical activity of motoneurons accompanies the progressive fall in axotomized neuronal and denervated SC expression of regeneration-associated-genes and declining regenerative success. Reduced motoneuronal activity is due to the withdrawal of synaptic contacts from the soma. Exogenous neurotrophic factors that promote nerve regeneration can replace the endogenous factors whose expression declines with time. But the profuse axonal outgrowth they provoke and the difficulties in their delivery hinder their efficacy. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) proximal to the injury site promotes the expression of endogenous growth factors and, in turn, dramatically accelerates axon outgrowth and target reinnervation. The latter ES effect has been demonstrated in both rats and humans. A conditioning ES of intact nerve days prior to nerve injury increases axonal outgrowth and regeneration rate. Thereby, this form of ES is amenable for nerve transfer surgeries and end-to-side neurorrhaphies. However, additional surgery for applying the required electrodes may be a hurdle. ES is applicable in all surgeries with excellent outcomes.

Comparison of Functionality Level, Disability and Quality of Life in Subjects with Peripheral Nerve Repair in the Upper Extremity.

Peripheral nerve damage is a very important factor in patients' quality of life and functionality for various reasons. We aimed to compare the functionality level, disability and quality of life in subjects with peripheral nerve repair in the upper extremity. This cross-sectional study was conducted on patients with nerve injuries in 2019. Among those patients, Eighty-five were selected as the sample. The instruments used in this study included the health-related quality of life standard questionnaire (SF-36), and the disability of the arm, shoulder and hand questionnaire (DASH-38). Data were analyzed by SPSS software version 22 and one-way ANOVA and Kruskal-Wallis statistical tests. Results of the Kruskal-Wallis test showed that the disability score in the groups of patients was not significant. In addition, according to the results of the one-way ANOVA test, the quality of life score was not significant among the patient groups. Considering that peripheral nerve damage has a significant impact on patients' quality of life and functionality, apart from more research on the subject, it is necessary to provide support for patients to improve their quality of life.

Isoflurane conditioning improves functional outcomes after peripheral nerve injury in a sciatic cut repair murine model.

Anesthetic conditioning has been shown to provide neuroprotection in several neurological disorders. Whether anesthetic conditioning provides protection against peripheral nerve injuries remains unknown. The aim of our current study is to investigate the impact of isoflurane conditioning on the functional outcomes after peripheral nerve injury (PNI) in a rodent sciatic nerve injury model. Adult male Lewis rats underwent sciatic nerve cut and repair and exposed to none (Group 1, sham), single isoflurane exposure (Group 2), three-time isoflurane exposure (Group 3), and six-time isoflurane exposure (Group 4). Isoflurane conditioning was established by administration of 2% isoflurane for 1 hour, beginning 1-hour post sciatic nerve cut and repair. Groups 3 and 4 were exposed to isoflurane for 1 hour, 3 and 6 consecutive days respectively. Functional outcomes assessed included compound muscle action potential (CMAP), evoked muscle force (tetanic and specific tetanic force), wet muscle mass, and axonal counting. We observed an increase in axons, myelin width and a decrease in G-ratio in the isoflurane conditioning groups (3- and 6-days). This correlated with a significant improvement in tetanic and specific tetanic forces, observed in both groups 3 and 4. Isoflurane conditioning (3- and 6-day groups) resulted in improvement in functional outcomes at 12 weeks post peripheral nerve injury and repair in a murine model. Future experiments should be focused on identifying the therapeutic window of isoflurane conditioning and exploring the underlying molecular mechanisms responsible for isoflurane conditioning induced neuroprotection in PNI.

Strain-induced bands of Büngner formation promotes axon growth in 3D tissue-engineered constructs

Treatment of peripheral nerve lesions remains a major challenge due to poor functional recovery; hence, ongoing research efforts strive to enhance peripheral nerve repair. In this study, we aimed to establish three-dimensional tissue-engineered bands of Büngner constructs by subjecting Schwann cells (SCs) embedded in fibrin hydrogels to mechanical stimulation. We show for the first time that the application of strain induces (i) longitudinal alignment of SCs resembling bands of Büngner, and (ii) the expression of a pronounced repair SC phenotype as evidenced by upregulation of BDNF, NGF, and p75NTR. Furthermore, we show that mechanically aligned SCs provide physical guidance for migrating axons over several millimeters in vitro in a co-culture model with rat dorsal root ganglion explants. Consequently, these constructs hold great therapeutic potential for transplantation into patients and might also provide a physiologically relevant in vitro peripheral nerve model for drug screening or investigation of pathologic or regenerative processes.

Heterologous fibrin biopolymer as an emerging approach to peripheral nerve repair: a scoping review.

Nerve injuries present a substantial challenge within the medical domain due to their prevalent occurrence and significant impact. In nerve injuries, a range of physiopathological and metabolic responses come into play to stabilize and repair the resulting damage. A critical concern arises from the disruption of connections at neuromuscular junctions, leading to profound degeneration and substantial loss of muscle function, thereby hampering motor tasks. While end-to-end neurorrhaphy serves as the established technique for treating peripheral nerve injuries, achieving comprehensive morphofunctional recovery remains a formidable challenge. In pursuit of enhancing the repair process, alternative and supportive methods are being explored. A promising candidate is the utilization of heterologous fibrin biopolymer, a sealant devoid of human blood components. Notably, this biopolymer has showcased its prowess in establishing a stable and protective microenvironment at the site of use in multiple scenarios of regenerative medicine. Hence, this scoping review is directed towards assessing the effects of associating heterologous fibrin biopolymer with neurorrhaphy to treat nerve injuries, drawing upon findings from prior studies disseminated through PubMed/MEDLINE, Scopus, and Web of Science databases. Further discourse delves into the intricacies of the biology of neuromuscular junctions, nerve injury pathophysiology, and the broader utilization of fibrin sealants in conjunction with sutures for nerve reconstruction procedures. The association of the heterologous fibrin biopolymer with neurorrhaphy emerges as a potential avenue for surmounting the limitations associated with traditional sealants while also mitigating degeneration in nerves, muscles, and NMJs post-injury, thereby fostering a more conducive environment for subsequent regeneration. Indeed, queries arise regarding the long-term regenerative potential of this approach and its applicability in reconstructive surgeries for human nerve injuries.