Peripheral nerve regeneration (PNR) represents a substantial challenge in the medical field, primarily due to the limited regenerative capacity of the peripheral nerve system (PNS). Current research efforts are focused on developing advanced medical polymer materials to enhance nerve recovery. Despite significant progress, several critical issues remain unresolved, including biocompatibility, stability, mechanical strength, controlled degradation rates, and sustained release of therapeutic agents. This study examines the utilization of hyaluronic acid hydrogels, doped with mecobalamin (MeCbl) and conductive poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), in combination with exogenous electrical stimulation (ES) for PNR of rats. The strategy utilizes the MeCbl hydrogel to create a regenerative microenvironment and provide nutritional support for nerve cells, while PEDOT:PSS facilitates enhanced electrical signal conduction. ES has been shown to promote PNR and functional recovery, thereby demonstrating considerable potential. This study aims to comprehensively analyze the synergistic effects and potential value of this combined therapeutic approach, providing novel insights and pathways for the effective PNR.

Due to the complex regenerative microenvironment after peripheral nerve injury (PNI), developing a piezoelectric/conductive composite nerve guidance conduit (NGC) for repairing nerve defects remains a great challenge. The conductivity and piezoelectricity have been separately demonstrated to enhance the repair of PNI, yet there is a paucity of studies investigating the synergistic effects of both functions. Herein, a piezoelectric/conductive nerve conduit composed of chitosan (CS), reduced graphene oxide (rGO), and poly-L-lactic acid (PLLA) was fabricated, which provided the conductivity, mechanical support and piezoelectricity. Tensile strength, conductivity, antibacterial activity, and cell viability of piezoelectric/conductive composite NGCs were evaluated. Piezoelectric/conductive composite NGCs exhibited electrical signal output capability and conductive performance. Moreover, rGO significantly promoted cell proliferation and adhesion. Overall, the piezoelectric/conductive CS/rGO/PLLA nerve conduit shows great promise as a potential treatment of PNI.

 In the treatment of peripheral nerve injuries with nerve defects, second-generation collagen-based conduits, such as Renerve® (Nipro, Osaka, Japan), have shown the potential for promoting nerve regeneration. However, there is concern related to the weak material properties. No previous studies have addressed the strength of the bridging model using collagen conduits. This study aimed to investigate the tensile strength and failure patterns in nerve defect models bridged with Renerve® conduits through biomechanical research.

 Using fresh chicken sciatic nerves, we examined the maximum failure load of four groups: bridging models using Renerve® with one suture (group A), with two sutures (group B), with three sutures (group C), and end-to-end neurorrhaphy models with two sutures (group N). Each group had eight specimens. We also evaluated failure patterns of the specimens.

 Group N showed a significantly higher maximum failure load (0.96 ± 0.13 N) compared to groups A (0.23 ± 0.06 N, p < 0.0001), B (0.29 ± 0.05 N, p < 0.0001), and C (0.40 ± 0.10 N, p < 0.0001). Regarding failure patterns, all specimens in group A showed nerve-end dislocation from the conduit. Two specimens in group B and three specimens in group C failed due to circumferential cracks in the conduit. Six specimens in group B and five specimens in group C exhibited cutting out of sutures from the conduit.

 This study suggests that the number of sutures in synthetic collagen nerve conduits has little effect on the maximum failure load. To take advantage of its biomaterial benefits, a period of postoperative range of motion restriction may be required.

Electrical stimulation displayed tremendous potential in promoting nerve regeneration. However, the current electrical stimulation therapy required complex traversing wires and external power sources, which significantly limited its practical application. Herein, a self-powered nerve scaffold based on primary battery principle was gradient printed by laser additive manufacturing technique. Specifically, poly-L-lactide (PLLA) containing Ag2O and Zn nanoparticles was prepared as the positive and negative electrode of the scaffold respectively, and PLLA/PPy was prepared as the middle conductive segment. In simulated body fluid, the negative electrode underwent oxidation to lose electrons and become positively charged. The lost electrons were transferred to the positive segment in a directed and orderly manner via the middle conductive segment, causing the positive electrode to be enriched electrons and become negatively charged. Subsequently, two segments can generate a potential difference to form an electric field, further generating current. Not merely, the redox process can release Ag+ and Zn2+ to endow the scaffold with antibacterial properties. Results showed that the scaffold could generate a current of up to 17.2 μA, which promoted a 14-fold increase in calcium ion influx and increased the mRNA expression of neuronal markers MAP2 by 24-fold. Moreover, the antibacterial rates of the scaffold against E. coli and S. aureus could reach 92.6 % and 91.9 %, respectively.

Peripheral nerve injury disrupts the function of the peripheral nervous system, leading to sensory, motor, and autonomic deficits. While peripheral nerves possess an intrinsic regenerative capacity, complete sensory and motor recovery remains challenging due to the unpredictable nature of the healing process, which is influenced by the extent of the injury, age, and timely intervention. Recent advances in microsurgical techniques, imaging technologies, and a deeper understanding of nerve microanatomy have enhanced functional outcomes in nerve repair. Nerve injury initiates complex pathophysiological responses, including Wallerian degeneration, macrophage activation, Schwann cell dedifferentiation, and axonal sprouting. Complete nerve disruptions require surgical intervention to restore nerve continuity and function. Direct nerve repair is the gold standard for clean transections with minimal nerve gaps. However, in cases with larger nerve gaps or when direct repair is not feasible, alternatives such as autologous nerve grafting, vascularized nerve grafts, nerve conduits, allografts, and nerve transfers may be employed. Autologous nerve grafts provide excellent biocompatibility but are limited by donor site morbidity and availability. Vascularized grafts are used for large nerve gaps and poorly vascularized recipient beds, while nerve conduits serve as a promising solution for smaller gaps. Nerve transfers are utilized when neither direct repair nor grafting is possible, often involving re-routing intact regional nerves to restore function. Nerve conduits play a pivotal role in nerve regeneration by bridging nerve gaps, with significant advancements made in material composition and design. Emerging trends in nerve regeneration include the use of 3D bioprinting for personalized conduits, gene therapy for targeted growth factor delivery, and nanotechnology for nanofiber-based conduits and stem cell therapy. Advancements in molecular sciences have provided critical insights into the cellular and biochemical mechanisms underlying nerve repair, leading to targeted therapies that enhance axonal regeneration, remyelination, and functional recovery in peripheral nerve injuries. This review explores the current strategies for the therapeutic management of peripheral nerve injuries, highlighting their indications, benefits, and limitations, while emphasizing the need for tailored approaches based on injury severity and patient factors.

Peripheral nerve injuries with extensive defects are often challenging to treat. Although second-generation collagen nerve conduit is a promising alternative to autologous nerve grafts, there are concerns about the limited early postoperative range of motion due to the conduit's weak material properties. This biomechanical study demonstrates the potential weakness of conventional suturing techniques in a nerve defect model using a collagen nerve conduit. We also investigated the effectiveness of a novel suturing technique, the suspension bridge method (SBM), which directly connects nerves using sutures without relying on the conduit strength.

We used fresh chicken cadaver sciatic nerves to compare the maximum tensile strength of SBM using 2 sutures (group A) against traditional suturing methods using 2 and 3 sutures (groups B and C, respectively), and end-to-end neurorrhaphy with 2 sutures (group D). We also evaluated the mechanical properties by analyzing the stress-strain curves.

Group A exhibited a significantly higher maximum failure load (1.32 ± 0.56 N) than group B (0.29 ± 0.05 N, p < 0.001) and group C (0.40 ± 0.10 N, p < 0.001), but not significantly higher than that of group D (0.96 ± 0.13 N, p = 0.056). The stress-strain curve showed steeper slopes in groups A and D than in groups B and C.

Our results indicate that SBM offers an improved maximum failure load and better resistance to tension compared to traditional methods. This technique may be an effective alternative to conventional suturing methods using collagen nerve conduits.

Peripheral nerve injuries are clinical conditions that often result in functional deficits, compromising patient quality of life. Given the relevance of these injuries, new treatment strategies are constantly being investigated. Although mesenchymal stem cells already demonstrate therapeutic potential due to their paracrine action, the transdifferentiation of these cells into Schwann-like cells (SLCs) represents a significant advancement in nerve injury therapy. Recent studies indicate that SLCs can mimic the functions of Schwann cells, with promising results in animal models. However, challenges remain, such as the diversity of transdifferentiation protocols and the scalability of these therapies for clinical applications. A recent study by Zou et al provided a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells in the treatment of peripheral nerve injuries. Therefore, we would like to discuss and explore the use of SLCs derived from bone marrow-derived mesenchymal stem cells in more detail as a promising alternative in the field of nerve regeneration.

Despite advancements in surgical treatments, impairments persist after peripheral nerve injuries, prompting a shift in research toward the microenvironment of injured axons. Platelet-rich plasma (PRP), rich in growth factors and derived from autologous blood, emerges as a potential candidate to accelerate nerve healing.

This study investigated the role of PRP in enhancing peripheral nerve regeneration using a rat sciatic nerve model (n = 8) in female Wistar rats.

A transected sciatic nerve model was created, with both hindlimbs repaired through end-to-end neurorrhaphy. PRP, prepared from the blood of a healthy Wistar rat, was applied to one hindlimb. Functional recovery was assessed using sciatic indices. At the 20-week time point, histological evaluations were performed to compare PRP-treated hindlimbs with control ones. Statistical analysis was conducted to compare the results between the two groups using three different calculations for specific parameters.

Walking track-based sciatic functional index (SFI) showed an improvement of 66.0%, 47.8%, and 71.6% (p < 0.05). Video analysis-based SFI revealed a 36.7% and 27.3% improvement (p < 0.05). Static sciatic index calculations indicated an improvement of 19.4% for vertical standing and 26.7% for standing on all four limbs (p < 0.001). Histopathological analysis showed a reduction in inflammation, a decrease in fibrosis, and the absence of macrophages in the sciatic nerves of the experimental group. Muscle specimens from the PRP-treated group exhibited fewer macrophages and significantly less fibrosis (p < 0.05). Overall, PRP treatment significantly improved all functional indices.

This study demonstrated PRP's utility in promoting peripheral nerve regeneration, highlighting its potential for both fundamental research and clinical applications.

Peripheral nerve injuries pose a significant clinical challenge due to the complex biological processes involved in nerve repair and their limited regenerative capacity. Despite advances in surgical techniques, conventional treatments, such as nerve autografts, are faced with limitations like donor site morbidity and inconsistent functional outcomes. As such, there is a growing interest in new, novel, and innovative strategies to enhance nerve regeneration. Tissue engineering/regenerative medicine and its use of biomaterials is an emerging example of an innovative strategy. Within the realm of tissue engineering, functionalized hydrogels have gained considerable attention due to their ability to mimic the extracellular matrix, support cell growth and differentiation, and even deliver bioactive molecules that can promote nerve repair. These hydrogels can be engineered to incorporate growth factors, bioactive peptides, and stem cells, creating a conducive microenvironment for cellular growth and axonal regeneration. Recent advancements in materials as well as cell biology have led to the development of sophisticated hydrogel systems, that not only provide structural support, but also actively modulate inflammation, promote cell recruitment, and stimulate neurogenesis. This review explores the potential of functionalized hydrogels for peripheral nerve repair, highlighting their composition, biofunctionalization, and mechanisms of action. A comprehensive analysis of preclinical studies provides insights into the efficacy of these hydrogels in promoting axonal growth, neuronal survival, nerve regeneration, and, ultimately, functional recovery. Thus, this review aims to illuminate the promise of functionalized hydrogels as a transformative tool in the field of peripheral nerve regeneration, bridging the gap between biological complexity and clinical feasibility.

Developing nerve grafts with intact mesostructures, superior conductivity, minimal immunogenicity, and improved tissue integration is essential for the treatment and restoration of neurological dysfunctions. A key factor is promoting directed axon growth into the grafts. To achieve this, biohybrid nerves are developed using decellularized rat sciatic nerve modified by in situ polymerization of poly(3,4-ethylenedioxythiophene) (PEDOT). Nine biohybrid nerves are compared with varying polymerization conditions and cycles, selecting the best candidate through material characterization. These results show that a 1:1 ratio of FeCl3 oxidant to ethylenedioxythiophene (EDOT) monomer, cycled twice, provides superior conductivity (>0.2 mS cm-1), mechanical alignment, intact mesostructures, and high compatibility with cells and blood. To test the biohybrid nerve's effectiveness in promoting motor axon growth, human Spinal Cord Spheroids (hSCSs) derived from HUES 3 Hb9:GFP cells are used, with motor axons labeled with green fluorescent protein (GFP). Seeding hSCS onto one end of the conduit allows motor axon outgrowth into the biohybrid nerve. The construct effectively promotes directed motor axon growth, which improves significantly after seeding the grafts with Schwann cells. This study presents a promising approach for reconstructing axonal tracts in humans.

Peripheral nerve injury occurs in a relatively large proportion of trauma patients, in whom it generally results in severe functional impairment and permanent disability. At present, however, there are no effective treatments available. Studies have shown that Schwann cells play an indispensable role in removing myelin debris and guiding axonal regeneration, and transplantation using autologous Schwann cells has shown good efficacy for patients with peripheral nerve injury. In recent years, Schwann cell autologous transplantation therapy has become an area of intensive research and is anticipated to provide a new strategy for the clinical treatment of peripheral nerve injury. In this article, we review the rationale for selecting Schwann cell autotransplantation therapy and the latest progress in key aspects of cell transplantation and clinical efficacy, and also summarize the future directions of research on this therapy. All of the above provide a strong basis for the further improvement and clinical promotion of this therapy.

High-frequency US provides excellent visualization of superficial structures and lesions, is a preferred diagnostic modality for anatomic characterization of neck abnormalities, and has a central role in clinical decision making. Recent technological advancements have led to the development of transducers that surpass 20 MHz, elevating high-frequency US to a highly valuable diagnostic tool with broader clinical use and enabling greater spatial resolution in the assessment of skin and superficial nerves and muscles. The authors focus on evolving applications of high-frequency US in neck imaging, emphasizing practical insights and strategies in skin and neuromuscular applications. ©RSNA, 2024 Supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Autologous nerve transplantation (ANT) is currently considered the gold standard for treating long-distance peripheral nerve defects. However, several challenges associated with ANT, such as limited availability of donors, donor site injury, mismatched nerve diameters, and local neuroma formation, remain unresolved. To address these issues comprehensively, we have developed porous poly(lactic-co-glycolic acid) (PLGA) electrospinning fiber nerve guide conduits (NGCs) that are optimized in terms of alignment and conductive coating to facilitate peripheral nerve regeneration (PNR) under electrical stimulation (ES). The physicochemical and biological properties of aligned porous PLGA fibers and poly(3,4-ethylenedioxythiophene):polystyrene sodium sulfonate (PEDOT:PSS) coatings were characterized through assessments of electrical conductivity, surface morphology, mechanical properties, hydrophilicity, and cell proliferation. Material degradation experiments demonstrated the biocompatibility in vivo of electrospinning fiber films with conductive coatings. The conductive NGCs combined with ES effectively facilitated nerve regeneration. The designed porous aligned NGCs with conductive coatings exhibited suitable physicochemical properties and excellent biocompatibility, thereby significantly enhancing PNR when combined with ES. This combination of porous aligned NGCs with conductive coatings and ES holds great promise for applications in the field of PNR.

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.

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.