Nerve Repair Research Articles

GFRα1 Promotes Axon Regeneration after Peripheral Nerve Injury by Functioning as a Ligand.

The neurotrophic factor, Glial cell line derived neurotrophi factor (GDNF), exerts a variety of biological effects through binding to its receptors, GDNF family receptor alpha-1 (GFRα1), and RET. However, the existence of cells expressing GFRα1 but not RET raises the possibility that GFRα1 can function independently from RET. Here, it is shown that GFRα1 released from repair Schwann cells (RSCs) functions as a ligand in a GDNF-RET-independent manner to promote axon regeneration after peripheral nerve injury (PNI). Local administration of GFRα1 into injured nerve promoted axon regeneration, even more when combined with GDNF blockade. GFRα1 bound to a receptor complex consisting of NCAM and integrin α7β1 of dorsal root ganglion neurons in a GDNF-RET independent manner. This is further confirmed by the Ret Y1062F knock-in mice, which cannot transmit most of GDNF-RET signaling. Finally, local administration of GFRα1 into injured sciatic nerve promoted functional recovery. These findings reveal a novel role of GFRα1 as a ligand, the molecular mechanism supporting axon regeneration by RSCs, and a novel therapy for peripheral nerve repair.

End-to-Side Cross-face Nerve Graft for Mental Nerve Reconstruction after Segmental Mandibulectomy.

The traditional technique for mental never reconstruction after segmental mandibulectomy is to bridge the gap between the proximal end of the inferior alveolar nerve (IAN) and the mental nerve stump. However, it often presents significant challenges. In cases of proximal IAN stump is close to skull base or kept inside the remaining mandible body and ramus, approaching the proximal end of the IAN can be very challenging.To overcome the limitation, a novel technique of cross-face mental nerve re-innervation with end-to-side coaptation to the contralateral mental nerve has been developed. This procedure involves preparing the recipient site before mandibulectomy, harvesting a donor nerve, preparing the contralateral mental nerve for end-to-side neurorrhaphy, and performing cross-face reinnervation after flap inset. The technique utilizes end-to-side coaptation to connect the nerve graft to the contralateral mental nerve.This new technique overcomes challenges posed by traditional methods, offering advantages such as shorter nerve grafts, easier coaptation due to superficial nerve position, and reduced risk of interference with second-stage dental surgeries. Initial outcomes have been promising, with all patients showing sensation recovery above S3 and no significant interference with contralateral mental nerve function.This innovative approach provides a solution for patients undergoing segmental mandibulectomy and has potential applications in restoring sensation lost due to various causes. It opens new possibilities for nerve rehabilitation and warrants further investigation through larger clinical trials to validate its efficacy and explore its potential in other nerve repair scenarios.

Dysregulated Treg repair responses lead to chronic rejection after heart transplantation.

Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.

Mechanism and Application of Chinese Herb Medicine in Treatment of Peripheral Nerve Injury.

Peripheral nerve injury (PNI) encompasses damage to nerves located outside the central nervous system, adversely affecting both motor and sensory functions. Although peripheral nerves possess an intrinsic capacity for self-repair, severe injuries frequently result in significant tissue loss and erroneous axonal junctions, thereby impeding complete recovery and potentially causing neuropathic pain. Various therapeutic strategies, including surgical interventions, biomaterials, and pharmacological agents, have been developed to enhance nerve repair processes. While preclinical studies in animal models have demonstrated the efficacy of certain pharmacological agents in promoting nerve regeneration and mitigating inflammation, only a limited number of these agents have been translated into clinical practice to expedite nerve regeneration. Chinese herb medicine (CHM) possesses a longstanding history in the treatment of various ailments and demonstrates potential efficacy in addressing PNI through its distinctive, cost-effective, and multifaceted methodologies. This review critically examines the advancements in the application of CHM for PNI treatment and nerve regeneration. In particular, we have summarized the most commonly employed and rigorously investigated CHM prescriptions, individual herbs, and natural products, elucidating their respective functions and underlying mechanisms in the context of PNI treatment. Furthermore, we have deliberated on the prospective development of CHM in both clinical practice and fundamental research.

PKN2 Promotes Peripheral Nerve Repair by Regulating Autophagy via Activation of the AKT-mTOR Pathway: An In Vitro Study.

This study aims to explore the role of Protein Kinase N2 (PKN2) in peripheral nerve injury (PNI) and evaluate its potential as a therapeutic target. The study employed a PC12 cell model to assess the effects of PKN2 overexpression on cell proliferation, migration, synaptic growth, and autophagic activity, with a focus on the regulatory role of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. The results demonstrated that PKN2 overexpression significantly promoted PC12 cell proliferation and cell migration, while also enhancing synaptic growth. Additionally, a significant suppression of autophagy was observed. Mechanistic analysis revealed that PKN2 inhibited autophagic activity through the activation of the AKT/mTOR pathway. In summary, PKN2 plays a significant role in peripheral nerve repair by promoting cell proliferation, migration, and synaptic growth, while inhibiting autophagy through the AKT/mTOR pathway. These findings suggest that targeting PKN2 may represent an effective therapeutic strategy for the treatment of PNI.

Evolution of natural polymer nerve conduit technology in peripheral nerve repair: a narrative review

Peripheral nerve injury is a worldwide challenge in the clinic. Although autologous nerve is considered the gold standard for bridging large nerve defects (> 5 mm), donor-site morbidity, limited sources of donor nerves and other potential side effects restrict its application in nerve regeneration. Nerve guidance conduits have become increasingly popular as a promising alternative to autologous nerve repair and regeneration. The evolution of nerve guidance conduits from nondegradable materials to various biodegradable materials subsequently results in enhanced properties, such as superior biodegradability, a mimetic extracellular matrix and an optimal structure. This review describes current therapies for nerve repair and the mechanism and evolution of nerve guidance conduits with advantages and limitations; proposes the detailed requirements of ideal nerve guidance conduits; and emphasizes the applications of natural polymers, including collagen, chitosan, alginate, gelatin, silk fibroin and hyaluronic acid, in nerve regeneration with the incorporation of various functional materials, chemical modifications and feasible techniques to promote cell proliferation and axon regeneration. Compared with natural polymers, advanced nerve guidance conduits have considerable potential for nerve regeneration in the clinic.

Quality, Reliability, and Readability of Peripheral Nerve Intervention Websites for Patients.

This study aims to evaluate the readability, quality, and reliability of online resources about peripheral nerve surgeries to determine if they meet recommended literacy standards. We analyzed a total of 137 peripheral nerve surgery website by performing a Google search using the search terms "nerve transfer," "nerve repair," "nerve graft," "nerve decompression," "neurolysis," "targeted muscle reinnervation," "regenerative peripheral nerve interface," and "vascularized denervated muscle target." The reading level of the website text was assessed using Simple Measures of Gobbledygook, Flesch-Kincaid, and Gunning Fog. Quality was evaluated using the DISCERN Instrument. Reliability was determined using the Journal of American Medical Association Benchmark Criteria. All the websites exceeded the sixth-grade reading level, with median readability scores corresponding to a high school reading level or above. Conceptually harder peripheral nerve surgeries such as targeted muscle reinnervation and regenerative peripheral nerve interface websites were generally written at a significantly higher reading level than conceptually easier surgeries such as nerve repair and nerve graft. The median quality of the websites was rated as poor, and the median reliability of the websites was rated as low. The findings indicate that the current peripheral nerve surgery websites texts do not adhere to recommended reading levels and are constructed with poor quality and low reliability. This potentially hinders patients understanding and utilization of peripheral nerve surgeries, suggesting a need for standardized guidelines to enhance the accessibility of medical information online.

Advanced Thermoactive Nanomaterials for Thermomedical Tissue Regeneration: Opportunities and Challenges.

Nanomaterials usually possess remarkable properties, including excellent biocompatibility, unique physical and chemical characteristics, and bionic attributes, which make them highly promising for applications in tissue regeneration. Thermal therapy has emerged as a versatile approach for wound healing, nerve repair, bone regeneration, tumor therapy, and antibacterial tissue regeneration. By combining nanomaterials with thermal therapy, multifunctional nanomaterials with thermogenic effects and tissue regeneration capabilities can be engineered to achieve enhanced therapeutic outcomes. This study provides a comprehensive review of the effects of thermal stimulation on cellular and tissue regeneration. Furthermore, it highlights the applications of photothermal, magnetothermal, and electrothermal nanomaterials, and thermally responsive drug delivery systems in tissue engineering. In Addition, the bioactivities and biocompatibilities of several representative thermal nanomaterials are discussed. Finally, the challenges facing thermal nanomaterials are outlined, and future prospects in the field are presented with the aim of offering new opportunities and avenues for the utilization of thermal nanomaterials in tissue regeneration.

Digital nerve reconstruction with a new composite silk fibroin nerve conduit.

Peripheral nerve injuries often require bridging when direct repair is not feasible. Nerve autografts are the gold standard, but they can lead to donor site morbidity. Silk fibroin-based nerve conduits, like the novel SILKBridge, offer a promising alternative. This pilot study evaluates the mid-term outcomes of the first in-human digital nerve reconstruction using the SILKBridge, focusing on sensory recovery, complication rates, patient-reported outcomes, and biological integration. This study included four patients with digital nerve defects reconstructed using the SILKBridge. Clinical assessments included two-point discrimination, Semmes-Weinstein monofilament testing, and pain evaluation using the Numeric Rating Scale. Sonographic assessments were also performed to evaluate the conduit's biointegration and potential complications. At a mean follow-up of 32 months, all patients demonstrated satisfactory sensory recovery and reported minimal to no pain. Sonographic assessments confirmed effective biointegration with no signs of inflammation or scarring. The mid-term evaluation of the first in-human digital nerve reconstruction with the SILKBridge revealed safety, efficiency, and favorable biocompatibility properties. Further studies with larger cohorts are needed to validate these findings and compare them with other nerve repair methods.

Design and In Vivo Testing of an Anatomic 3D-Printed Peripheral Nerve Conduit in a Rat Sciatic Nerve Model.

Background: Three-dimensional (3D) printer technology has seen a surge in use in medicine, particularly in orthopedics. A recent area of research is its use in peripheral nerve repair, which often requires a graft or conduit to bridge segmental defects. Currently, nerve gaps are bridged using autografts, allografts, or synthetic conduits. Purpose: We sought to improve upon the current design of simple hollow, cylindrical conduits that often result in poor nerve regeneration. Previous attempts were made at reducing axonal dispersion with the use of multichanneled conduits. To our knowledge, none has attempted to mimic and test the anatomical topography of the nerve. Methods: Using serial histology sections, 3D reconstruction software, and computer-aided design, a scaffold was created based on the fascicular topography of a rat sciatic nerve. A 3D printer produced both cylindrical conduits and topography-based scaffolds. These were implanted in 12 Lewis rats: 6 rats with the topographical scaffold and 6 rats with the cylindrical conduit. Each rodent's uninjured contralateral limb was used as a control for comparison of functional and histologic outcomes. Walking track analysis was performed, and the Sciatic Functional Index (SFI) was calculated with the Image J software. After 6 weeks, rats were sacrificed and analyses performed on the regenerated nerve tissue. Primary outcomes measured included nerve (fiber) density, nerve fiber width, total number of nerve fibers, G-ratio (ratio of axon width to total fiber width), and percent debris. Secondary outcomes measured included electrophysiology studies of electromyography (EMG) latency and EMG amplitude and isometric force output by the gastrocnemius and tibialis anterior. Results: There were no differences observed between the cylindrical conduit and topographical scaffold in terms of histological outcomes, muscle force, EMG, or SFI. Conclusion: This study of regeneration of the sciatic nerve in a rat model suggests the feasibility of 3D-printed topographical scaffolds. More research is required to quantify the functional outcomes of this technology for peripheral nerve regeneration.

Preferential motor reinnervation is modulated by both repair site and distal nerve environments

To restore function after nerve injury, axons must regenerate from the injury site to the periphery, then reinnervate appropriate end organs when they arrive. Only 10 % of adults who suffer nerve injury will regain normal function, often because axons regenerate to functionally inappropriate targets (Brushart, 2011). The peripheral destination of these axons is largely determined by the pathways they enter at the site of nerve repair. To improve clinical outcomes, it is thus critical to improve the accuracy of axon pathfinding. In rodents, motor axons regenerating in mixed nerve preferentially reinnervate pathways leading to muscle, a process termed preferential motor reinnervation (PMR). Previous experiments have shown that PMR can be enhanced by predegenerating nerve grafts to enhance growth factor production and remove inhibitory factors (Abdullah et al., 2013). The current experiments explore the relative contributions of motor pathways, sensory pathways, and the repair environment to this enhancement. Sensory and/or motor pathways within rat femoral nerve grafts were predegenerated for 3 weeks to optimize growth factor production (Brushart et al., 2013) or for 12 weeks to deplete it. Optimizing the environment within previously motor Schwann cell tubes promoted PMR, regardless of whether adjacent sensory pathways were optimized or chronically denervated. However, this positive effect was abolished when sensory pathways were undergoing acute Wallerian degeneration immediately after nerve repair. The repair environment thus precluded motor axon pathfinding in spite of an optimized distal motor pathway. When sensory pathways were optimized and motor pathways were chronically denervated, not only was PMR abolished, but motoneurons failed to respond to the greater volume of growth factors in the sensory nerve. Small sensory neurons, however, selectively reinnervated cutaneous nerve under these conditions. These experiments thus strengthen the concept that, in adult rats, sensory and motor pathways have unique identities capable of influencing both sensory and motor axon regeneration. Furthermore, they demonstrate that, in the rat, delaying nerve repair for 3 weeks to enhance growth factor production and clear the products of acute Wallerian degeneration can enhance regeneration specificity without the need for exogenous treatments.

Enhancing vaginal reconstruction through 3D bioprinted scaffolds using a novel vECM-GelMA-SF bioink.

Overcoming the low cell survival rates and insufficient neovascularization associated with tissue engineering of the vagina is crucial for advancing the vaginal reconstruction. In this research, we have developed a unique bioink composed of porcine vaginal extracellular matrix (vECM), gelatin methacrylamide (GelMA), and silk fibroin (SF) to facilitate the bioprinting of a vaginal scaffold. The vECM-GelMA-SF bioink effectively replicates the in vivo microenvironment, supporting the in vitro cultivation of 3D bioprinted vaginal scaffolds. It promotes stem cell viability and enhances neovascularization by harnessing the mechanical properties of GelMA/SF and the tissue specificity of vECM. In vivo orthotopic studies have demonstrated that the use of 3D bioprinted vaginal scaffolds significantly improves the functionality of reconstructed vaginas, promoting angiogenesis, rapid epithelialization, muscle regeneration, glycogen secretion, and nerve repair. The reconstructed vaginal tissues in the 3D cell-loaded scaffold group closely resemble natural vaginal tissues. Differential proteomics analysis has provided insights into the genetic functions and biological pathways involved in vaginal reconstruction. Our study successfully optimized the composition of the vECM-GelMA-SF bioink, achieving a balance between biocompatibility and printability. This bioink is suitable for constructing 3D bioprinted vaginal scaffolds of various dimensions, transplantable in situ in animal models with different degrees of vaginal absence. The bioink may find applications in clinical settings, improving the overall effectiveness and safety of in vivo vaginal reconstruction procedures.

Automated production of nerve repair constructs containing endothelial cell tube-like structures

Engineered neural tissue (EngNT) is a stabilised aligned cellular hydrogel that offers a potential alternative to the nerve autograft for the treatment of severe peripheral nerve injury. This work aimed to automate the production of EngNT, to improve the feasibility of scalable manufacture for clinical translation. Endothelial cells were used as the cellular component of the EngNT, with the formation of endothelial cell tube-like structures mimicking the polarised vascular structures formed early on in the natural regenerative process. Gel aspiration-ejection for the production of EngNT was automated by integrating a syringe pump with a robotic positioning system, using software coded in Python to control both devices. Having established the production method and tested mechanical properties, the EngNT containing human umbilical vein endothelial cells (EngNT-HUVEC) was characterised in terms of viability and alignment, compatibility with neurite outgrowth from rat dorsal root ganglion neurons and formation of endothelial cell networksin vitro. EngNT-HUVEC manufactured using the automated system contained viable and aligned endothelial cells, which developed into a network of multinucleated endothelial cell tube-like structures inside the constructs and an outer layer of endothelialisation. The EngNT-HUVEC constructs were made in various sizes within minutes. Constructs provided support and guidance to regenerating neuritesin vitro. This work automated the formation of EngNT, facilitating high throughput manufacture at scale. The formation of endothelial cell tube-like structures within stabilised hydrogels provides an engineered tissue with potential for use in nerve repair.

Combination of Adult Mesenchymal Stem Cell Therapy and Immunomodulation with Dimethyl Fumarate Following Spinal Cord Ventral Root Repair.

Spinal cord injury results in significant motor and sensory loss. In the experimental ventral root avulsion (VRA) model, the ventral (motor) roots are disconnected from the spinal cord surface, disrupting contact between spinal motoneurons and muscle fibers. Axotomized motoneurons typically degenerate within two to three weeks after avulsion, the situation being exacerbated by an increased glial response and chronic inflammation. Nevertheless, root reimplantation has been observed to stimulate regenerative potential in some motoneurons, serving as a model for CNS/PNS regeneration. We hypothesized that a combination of neuroprotective and immunomodulatory therapies is capable of enhancing regenerative responses following nerve root injury and repair. A heterologous fibrin biopolymer (HFB) was used for surgical repair; dimethyl fumarate (DMF) was used for neuroprotection and immunomodulation; and adipose tissue-derived mesenchymal stem cells (AT-MSCs) were used as a source of trophic factors and cytokines that may further enhance neuronal survival. Thus, adult female Lewis rats underwent unilateral VRA of the L4-L6 roots, followed by reimplantation with HFB, AT-MSCs transplantation, and daily DMF treatment for four weeks, with a 12-week postoperative survival period. An evaluation of the results focused on light microscopy, qRT-PCR, and the Catwalk motor function recovery system. Data were analyzed using one-way or two-way ANOVA (p < 0.05). The results indicate that the combined therapy resulted in a reduced glial response and a 70% improvement in behavioral motor recovery. Overall, the data support the potential of combined regenerative approaches after spinal cord root injury.

Advanced techniques and innovations in peripheral nerve repair: a comprehensive review for clinical and experimental reference.

Peripheral nerve injury, resulting from various physical and chemical causes, has a high incidence and significant functional impact. This injury, affecting both sensory and motor functions, can severely diminish quality of life and cause mental health issues. Consequently, it is a major focus of current research. Recent advancements in peripheral nerve repair technology, including the application of new techniques and materials, have expanded the options for nerve repair methods. A comprehensive article that combines the pathological process of peripheral nerve repair with these methods is needed to advance research in this field. This review aims to provide a comprehensive overview of various techniques for repairing peripheral nerve injuries. Beginning with the histopathology of nerve injury, it evaluates these techniques in detail to offer clinical guidance. This review summarizes the advantages and disadvantages of various peripheral nerve repair methods, including photobiological modulation therapy, suture repair, nerve graft repair, vein graft catheter repair, muscle graft repair, laser welding repair, nerve catheter repair, nerve sliding repair technology, growth factor-assisted repair, stem cell therapy, and exosome therapy. Additionally, it explores future directions in the treatment of peripheral nerve injuries, providing valuable references for experimental research and clinical treatment.

Portable Absorbable Electrical Stimulation System for Enhanced Peripheral Nerve Repair

AbstractPeripheral nerve injury significantly impairs sensory and motor functions, leading to diminished quality of life. Traditional treatments like nerve suturing and grafting often have limited efficacy and require long recovery. Recent advances in electrical stimulation technology show promise in speeding nerve repair, but current devices usually require lengthy surgeries, risking secondary nerve injury from prolonged nerve exposure during electrode installation and removal. This study introduces a portable, absorbable electrical stimulation system (PAESS) that integrates a battery‐free, wirelessly powered flexible printed circuit board chip with a biodegradable organic electrode. PAESS enables multiple self‐administered nerve stimulation without the need for electrode installation or removal. Using animal models, its electrical performance, biocompatibility, and efficacy in nerve repair are evaluated. The findings indicate a considerable enhancement in the recovery of nerve function, as demonstrated by improved electrophysiological measurements, decreased muscle atrophy, and positive histological results. Transcriptomic analysis indicates that the PAESS initiates the nerve regeneration process. This research presents an innovative platform for electrical stimulation, laying the groundwork for exploring electrical parameters and their mechanisms. This may deepen understanding of nerve regeneration and foster innovation in therapies.

Microsurgical nerve repair

Substantial nerve lesions almost always lead to persistent functional deficits, even with ideal treatment. Nerve lesions commonly occur in young patients, are often part of complex injuries, and are repeatedly diagnosed and treated with delay. Functional outcome crucially depends on early and adequate treatment. The aim of surgical treatment is aprecise and tension-free microsurgical restoration of nerve continuity in avital and healthy tissue environment. Adequate microsurgical treatment with differentiated postoperative treatment can result in an excellent clinical outcome, even after adelayed diagnosis.

Calcium bridges built by mitochondria-associated endoplasmic reticulum membranes: potential targets for neural repair in neurological diseases.

The exchange of information and materials between organelles plays a crucial role in regulating cellular physiological functions and metabolic levels. Mitochondria-associated endoplasmic reticulum membranes serve as physical contact channels between the endoplasmic reticulum membrane and the mitochondrial outer membrane, formed by various proteins and protein complexes. This microstructural domain mediates several specialized functions, including calcium (Ca2+) signaling, autophagy, mitochondrial morphology, oxidative stress response, and apoptosis. Notably, the dysregulation of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes is a critical factor in the pathogenesis of neurological diseases. Certain proteins or protein complexes within these membranes directly or indirectly regulate the distance between the endoplasmic reticulum and mitochondria, as well as the transduction of Ca2+ signaling. Conversely, Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes influences other mitochondria-associated endoplasmic reticulum membrane-associated functions. These functions can vary significantly across different neurological diseases-such as ischemic stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease-and their respective stages of progression. Targeted modulation of these disease-related pathways and functional proteins can enhance neurological function and promote the regeneration and repair of damaged neurons. Therefore, mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling plays a pivotal role in the pathological progression of neurological diseases and represents a significant potential therapeutic target. This review focuses on the effects of protein complexes in mitochondria-associated endoplasmic reticulum membranes and the distinct roles of mitochondria-associated endoplasmic reticulum membranes-mediated Ca2+ signaling in neurological diseases, specifically highlighting the early protective effects and neuronal damage that can result from prolonged mitochondrial Ca2+ overload or deficiency. This article provides a comprehensive analysis of the various mechanisms of Ca2+ signaling mediated by mitochondria-associated endoplasmic reticulum membranes in neurological diseases, contributing to the exploration of potential therapeutic targets for promoting neuroprotection and nerve repair.

Wnt 3a-Modified Scaffolds Improve Nerve Regeneration by Boosting Schwann Cell Function.

A pivotal approach in engineering artificial peripheral nerve sheaths encompasses the augmentation of the regenerative microenvironment via the manipulation of Schwann cells (SCs). Our investigation employed single-cell sequencing analysis to elucidate the potential functions of Schwann cells and the Wnt pathway in facilitating peripheral nerve regeneration. In vitro studies showed that activating the Wnt signaling pathway promotes the transition to repair SCs, boosting their growth, movement, and immune functions. To better understand the peripheral nerve regeneration environment, we created a polymer scaffold using ammonization and electrospinning. The Wnt3a protein was incorporated into the polycaprolactone (PCL) electrospun fiber surface. In a rat sciatic nerve defect model, the Wnt3a-modified scaffold showed better nerve repair outcomes than traditional electrospun scaffolds. After a week, the test group showed better immune regulation and angiogenesis, with a significant increase in axon growth rate observed after 3 weeks. Three-month-long animal experiments revealed notable improvements in neuroelectrophysiology, reduced organ atrophy, and enhanced sciatic nerve recovery. In this nerve defect model, Wnt3a-modified neural scaffolds achieved repair effects.

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

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