Peripheral Nerve Regeneration Research Articles

Experimental study on promotion of peripheral nerve regeneration by selenium-methylselenocysteine

To investigate the feasibility of selenium-methylselenocysteine (SMC) to promote peripheral nerve regeneration and its mechanism of action. Rat Schwann cells RSC96 cells were randomly divided into 5 groups, which were group A (without any treatment, control group), group B (adding 100 μmol/L H 2O 2), group C (adding 100 μmol/L H 2O 2+100 μmol/L SMC), group D (adding 100 μmol/L H 2O 2+200 μmol/L SMC), group E (adding 100 μmol/L H 2O 2+400 μmol/L SMC); the effect of SMC on cell proliferation was detected by MTT method, and the level of oxidative stress was detected by immunofluorescence for free radicals [reactive oxygen species (ROS)] after determining the appropriate dose group. Thirty-six 4-week-old male Sprague Dawley rats were randomly divided into 3 groups, namely, the sham operation group (Sham group), the sciatic nerve injury group (PNI group), and the SMC treatment group (SMC group), with 12 rats in each group; the rats in the PNI group were fed with food and water normally after modelling operation, and the rats in the SMC group were added 0.75 mg/kg SMC to the drinking water every day. At 4 weeks after operation, the sciatic nerves of rats in each group were sampled for neuroelectrophysiological detection of highest potential of compound muscle action potential (CMAP). The levels of inflammatory factors [interleukin 17 (IL-17), IL-6, IL-10 and oxidative stress factors catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA)] were detected by ELISA assay. The luxol fast blue (LFB) staining was used to observe the myelin density, fluorescence intensity of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) was observed by immunofluorescence staining, and myelin morphology was observed by transmission electron microscopy with measurement of axon diameter. Western blot was used to detect the protein expressions of p38 mitogen-activated protein kinases (p38MAPK), phosphorylated p38MAPK (p-p38MAPK), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2). MTT assay showed that the addition of SMC significantly promoted the proliferation of RSC96 cells, and the low concentration could achieve an effective effect, so the treatment method of group C was selected for the subsequent experiments; ROS immunofluorescence test showed that group B showed a significant increase in the intensity of ROS fluorescence compared with that of group A, and group C showed a significant decrease in the intensity of ROS fluorescence compared with that of group B ( P<0.05). Neuroelectrophysiological tests showed that the highest potential of CMAP in SMC group was significantly higher than that in PNI and Sham groups ( P<0.05). ELISA assay showed that the levels of IL-6, IL-17, and MDA in PNI group were significantly higher than those in Sham group, and the levels of IL-10, SOD, and CAT were significantly lower; the levels of IL-6, IL-17, and MDA in SMC group were significantly lower than those in PNI group, and the levels of IL-10, SOD, and CAT were significantly higher ( P<0.05). LFB staining and transmission electron microscopy showed that the myelin density and the diameter of axons in the SMC group were significantly higher than those of the PNI group and the Sham group ( P<0.05). Immunofluorescence staining showed that the fluorescence intensity of GFAP and MBP in the SMC group were significantly stronger than those in the PNI group and Sham group ( P<0.05). Western blot showed that the relative expressions of Nrf2 and HO-1 proteins in the SMC group were significantly higher than those in the PNI group and Sham group, and the ratio of p-p38MAPK/p38MAPK proteins was significantly higher in the PNI group than that in the SMC group and Sham group ( P<0.05). SMC may inhibit oxidative stress and inflammation after nerve injury by up-regulating the Nrf2/HO-1 pathway, and then inhibit the phosphorylation of p38MAPK pathway to promote the proliferation of Schwann cells, which ultimately promotes the formation of myelin sheaths and accelerates the regeneration of peripheral nerves.

Ultrasound-Responsive Aligned Piezoelectric Nanofibers Derived Hydrogel Conduits for Peripheral Nerve Regeneration.

Nerve guidance conduits (NGCs) have been considered as promising treatment strategy and frontier trend for peripheral nerve regeneration; while their therapeutic outcomes are limited by the lack of controllable drug delivery and available physicochemical cues. Herein, we propose novel aligned piezoelectric nanofibers derived hydrogel NGCs with ultrasound (US)-triggered electrical stimulation (ES) and controllable drug release for repairing peripheral nerve injury. The inner layer of the NGCs was the barium titanate piezoelectric nanoparticles (BTNPs)-doped polyvinylidene fluoride-trifluoroethylene [BTNPs/P(VDF-TrFE)] electrospinning nanofibers with improved piezoelectricity and aligned orientation. The outer side of the NGCs was the thermoresponsive poly(N-isopropylacrylamide) (pNIPAM) hybrid hydrogel with bioactive drug encapsulation. Such NGCs could not only induce neuronal oriented extension and promote neurite outgrowth with US-triggered wireless ES, but also realize the controllable nerve growth factor (NGF) release with the hydrogel shrinkage under US-triggered heating. Thus, the NGC could positively accelerate the functional recovery and nerve axonal regeneration of rat models with long sciatic nerve defects. We believe that the proposed US-responsive aligned piezoelectric nanofibers derived hydrogel NGCs will find important applications in clinic neural tissue engineering. This article is protected by copyright. All rights reserved.

Autophagy-targeting modulation to promote peripheral nerve regeneration

Abstract Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy- inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

EZH2-dependent myelination following sciatic nerve injury

Abstract Demyelination and remyelination have been major focal points in the study of peripheral nerve regeneration following peripheral nerve injury. Notably, the gene regulatory network of regenerated myelin differs from that of native myelin. Silencing of enhancer of zeste homolog 2 (EZH2) hinders the differentiation, maturation, and myelination of Schwann cells in vitro. To further determine the role of EZH2 in myelination and recovery post-peripheral nerve injury, conditional knockout mice lacking Ezh2 in Schwann cells (Ezh2fl/fl;Dhh-Cre and Ezh2fl/fl;Mpz-Cre) were generated. Our results show that a significant proportion of axons in the sciatic nerve of Ezh2-depleted mice remain unmyelinated. This highlights the crucial role of Ezh2 in initiating Schwann cell myelination. Furthermore, we observed that 21 days after inducing a sciatic nerve crush injury in these mice, most axons had remyelinated at the injury site in the control nerve, while Ezh2fl/fl;Mpz-Cre mice had significantly fewer remyelinated axons compared with their wild-type littermates. This suggests that the absence of Ezh2 in Schwann cells impairs myelin formation and remyelination. In conclusion, EZH2 has emerged as a pivotal regulatory factor in the process of demyelination and myelin regeneration following peripheral nerve injury. Modulating EZH2 activity during these processes may offer a promising therapeutic target for the treatment of peripheral nerve injuries.

Electrical aligned polyurethane nerve guidance conduit modulates macrophage polarization and facilitates immunoregulatory peripheral nerve regeneration

Biomaterials can modulate the local immune microenvironments to promote peripheral nerve regeneration. Inspired by the spatial orderly distribution and endogenous electric field of nerve fibers, we aimed to investigate the synergistic effects of electrical and topological cues on immune microenvironments of peripheral nerve regeneration. Nerve guidance conduits (NGCs) with aligned electrospun nanofibers were fabricated using a polyurethane copolymer containing a conductive aniline trimer and degradable L-lysine (PUAT). In vitro experiments showed that the aligned PUAT (A-PUAT) membranes promoted the recruitment of macrophages and induced their polarization towards the pro-healing M2 phenotype, which subsequently facilitated the migration and myelination of Schwann cells. Furthermore, NGCs fabricated from A-PUAT increased the proportion of pro-healing macrophages and improved peripheral nerve regeneration in a rat model of sciatic nerve injury. In conclusion, this study demonstrated the potential application of NGCs in peripheral nerve regeneration from an immunomodulatory perspective and revealed A-PUAT as a clinically-actionable strategy for peripheral nerve injury.

Grape seed-derived procyanidins decreases neuropathic pain and nerve regeneration by suppression of toll-like receptor 4-myeloid differentiation factor-88 signaling.

Background: Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Methods: Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Result: Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Conclusion: Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.

Prophylactic Regenerative Peripheral Nerve Interface (RPNI) Surgery in Pediatric Lower Limb Amputation Patients.

To evaluate the prophylactic effect of Regenerative Peripheral Nerve Interface (RPNI) surgery on pediatric post-amputation pain. Chronic post-amputation pain is a debilitating and refractory sequela of limb amputation affecting up to 83% of pediatric patients with limb loss, resulting in disability and decreased quality of life. We postulate that prophylactic RPNI surgery performed during amputation may decrease the incidence of symptomatic neuroma and development of phantom limb pain, as well as limit analgesic use among pediatric patients with limb loss. Retrospective chart review was performed on pediatric patients between the ages of 8 and 21 years who underwent major lower limb amputation with and without RPNI surgery. Documented neuroma and phantom limb pain scores as well as analgesic use was recorded. Narcotic use was converted to milligrams morphine equivalents per day (MME/day) while overall analgesic use was converted to Medication Quantification Scale version III (MQSIII) scores. Analysis was performed using Stata. Forty-four pediatric patients were identified; 25 RPNI patients and 19 controls. Seventy-nine percent of control patients developed chronic post-amputation pain versus 21% of RPNI patients (P<0.001). Among the patients who developed post-amputation pain, 20% of controls developed clinical neuroma pain, compared to 0% of RPNI patients (P<0.001). Additionally, RPNI patients demonstrated a significant decrease in pain score (P=0.007) and narcotic usage (P<0.01), compared to controls. Overall analgesic use did not vary significantly between groups. Prophylactic RPNI surgery shows promise for pediatric patients undergoing major lower limb amputation by preventing both symptomatic neuromas and possibly the development of phantom limb pain.

Regulating Schwann Cell Growth by Nanosecond Pulsed Electric Field for Peripheral Nerve Regeneration In Vitro.

Schwann cells (SCs) are myelinating cells of the peripheral nervous system, playing a crucial role in peripheral nerve regeneration. Nanosecond Pulse Electric Field (nsPEF) is an emerging method applicable in nerve electrical stimulation that has been demonstrated to be effective in stimulating cell proliferation and other biological processes. Aiming to assess whether SCs undergo significant changes under nsPEF and help explore the potential for new peripheral nerve regeneration methods, cultured RSC96 cells were subjected to nsPEF stimulation at 5 kV and 10 kV, followed by continued cultivation for 3-4 days. Subsequently, some relevant factors expressed by SCs were assessed to demonstrate the successful stimulation, including the specific marker protein, neurotrophic factor, transcription factor, and myelination regulator. The representative results showed that nsPEF significantly enhanced the proliferation and migration of SCs and the ability to synthesize relevant factors that contribute positively to the regeneration of peripheral nerves. Simultaneously, lower expression of GFAP indicated the benign prognosis of peripheral nerve injuries. All these outcomes show that nsPEF has great potential as an efficient treatment method for peripheral nerve injuries by stimulating SCs.

Physical cues of scaffolds promote peripheral nerve regeneration

The effective treatment of long-gap peripheral nerve injury (PNI) remains a challenge in clinical settings. The autograft, the gold standard for the long-gap PNI therapy, has several limitations, including a limited supply of donor nerve, size mismatch between the donor and recipient sites, functional loss at the donor site, neuroma formation, and the requirement for two operations. With the increasing abundance of biocompatible materials with adjustable structures and properties, tissue engineering provides a promising avenue for bridging peripheral nerve gaps and addressing the above issues of autograft. The physical cues provided by tissue engineering scaffolds, essential for regulating the neural cell fate and microenvironments, have received considerable research attention. This review elaborates on three major physical cues of tissue engineering scaffolds for peripheral nerve regeneration: topological structure, mechanical support, and electrical stimulation. These three aspects are analogs to Lego bricks, wherein different combinations result in diverse functions. Innovative and more effective bricks, along with multi-level and all-around integration, are expected to provide new advances in tissue engineering for peripheral nerve generation.

Progress of electrical stimulation to promote peripheral nerve regeneration

This study reviews the latest progress on the research of electrical stimulation（ES） in peripheral nerve regeneration, summarizes the parameters in preclinical experiments and discusses the effect on nerve regeneration. A detailed description is given in the study of conditioning electrical stimulation and nerve conduit scaffolding technology combined with ES, which have been hotly researched in recent years.

OTULIN of exosomes derived from Schwann cells promotes peripheral nerve injury repair by regulating macrophage polarization via deubiquitination of ERBB2

A significant public health burden is peripheral nerve damage (PNI), which is frequently brought on by trauma. Macrophages were essential to the effective regeneration of nerves and restoration of function. It is still not entirely understood how macrophages and Schwann cells interact after damage during remyelination. Here, we established an inflammatory model in bone marrow-derived macrophages (BMDMs) and a rat sciatic nerve damage model to investigate the possible relationship between lipopolysaccharides (LPS)-induced exosomes derived from Schwann cells (LPS SCs-Exos) and peripheral nerve repair. The pro-inflammatory macrophage was changed into a pro-regeneration macrophage by LPS SC-Exos. Notably, it was discovered that SC-Exos had a substantial enrichment of OTULIN. OTULIN was a key mediator in the regulatory effects of LPS SC-Exos by deubiquitinating ERBB2 and preventing its degradation. The local injection of SC-Exos into the nerve damage site led in a faster functional recovery, axon regeneration and remyelination, and an increased M2 macrophage polarization, whereas OTULIN knockdown reversed these effects in vivo. Our results indicate that LPS SC-Exos may offer a therapeutic avenue for peripheral nerve regeneration by promoting macrophage polarization toward an M2 phenotype through the shuttling of OTULIN and deubiquitination of ERBB2.

Fabrication of a conduit for future peripheral nerve regeneration using decellularized plant tissue modified with polyaniline/graphene oxide nanosheet

Fabrication of a conduit for future peripheral nerve regeneration using decellularized plant tissue modified with polyaniline/graphene oxide nanosheet

D78. Does Targeted Muscle Reinnervation (TMR) And Regenerative Peripheral Nerve Interface (RPNI) Improve Post-amputation Pain? A Systematic Review and Meta-analysis

D78. Does Targeted Muscle Reinnervation (TMR) And Regenerative Peripheral Nerve Interface (RPNI) Improve Post-amputation Pain? A Systematic Review and Meta-analysis

Postoperatively Noninvasive Optogenetic Stimulation via Upconversion Nanoparticles Enhancing Sciatic Nerve Repair.

The efficacy of electrical stimulation facilitating peripheral nerve regeneration is evidenced extensively, while the associated secondary damage resulting from repeated electrode invasion and indiscriminate stimulation is inevitable. Here, we present an optogenetics strategy that utilizes upconversion nanoparticles (UCNPs) to convert deeply penetrating near-infrared excitation into blue emission, which activates an adeno-associated virus-encoding ChR2 photoresponsive ion channel on cell membranes. The induced Ca2+ flux, similar to the ion flux in the electrical stimulation approach, efficiently regulates viability and proliferation, secretion of nerve growth factor, and neural function of RSC96 cells. Furthermore, deep near-infrared excitation is harnessed to stimulate autologous Schwann cells in situ via a UCNP-composited scaffold, which enhances nerve sprouting and myelination, consequently promoting functional recovery, electrophysiological restoration, and reinnervation of damaged nerves. This developed postoperatively noninvasive optogenetics strategy presents a novel, minimally traumatic, and enduring therapeutic stimulus to effectively promote peripheral nerve repair.

Regenerative peripheral nerve interfaces (RPNIs): an overview of innovative surgical approaches

Complications following amputation can be devastating for patients, including debilitating neuropathic pain, the inability to perform activities of daily living (ADLs) or gain meaningful employment. While prosthesis use allows patients to restore independence and reintegrate into daily activities, patients often abandon these devices. Despite the immense advancements in prosthetic technology, there is still a need for an interface that can provide a natural experience with accurate and reliable long-term control. The Regenerative Peripheral Nerve Interface (RPNI) is a simple surgical technique that offers real-time control of myoelectric prosthetic devices to restore extremity function. This stable, biological nerve interface successfully amplifies efferent motor action potentials, provides sensory feedback, and offers a more functional prosthetic device experience. Based on the principles of RPNI, novel surgical approaches have been developed to expand its applications and improve outcomes. This review article summarizes the utilization of the RPNI and its recent modifications of different neural interfaces in the setting of major limb amputation and musculoskeletal injuries.

Conductive and alignment-optimized porous fiber conduits with electrical stimulation for peripheral nerve regeneration

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.

Core/shell nanofibrous conduit containing natural surfactant enhanced axonal regrowth guiding for peripheral nerve regeneration

This study illustrated the impact of Saponins in electrospun nanofibers on nerve regeneration and compared them with Tween 80, which is commonly used as a synthetic surfactant. The study explores the effect of Saponins, natural emulsifiers known for their effectiveness in forming and stabilizing emulsions. Surfactant choice is crucial due to its effects on fluid stability, influenced by parameters like polymer concentration, homogenization rate, and surfactant type/amount. This study explored PCL as the core and PVA as the shell.Core/shell scaffolds displayed favorable wettability (contact angle: 67.0° ± 1.3) and improved mechanical properties (wet state tensile strength: PVA 1.1 ± 0.2 MPa, PVA/PCL-Saponin 2.0 ± 0.5 MPa). The MTT viability assay demonstrated higher viability of PC12 cells on Saponin-containing nanofibers (85.0 % ± 0.1) compared to Tween 80 (69.0 % ± 0.1) after 24 h. Subcutaneous implantation in rats showed no significant inflammation after one week. Eventually, in the animal model, the conduit containing Saponin was more effective than Tween 80 in repairing the rat's sciatic nerve within six weeks, as evidenced by NF-200 counts and histological studies. Overall, the study indicates that PVA/PCL-Saponin nanofibers, without requiring Saponin surfactant removal, show high quality and effectiveness for tissue engineering and medical purposes.

The role of kinases in peripheral nerve regeneration: mechanisms and implications.

Peripheral nerve injury disease is a prevalent traumatic condition in current medical practice. Despite the present treatment approaches, encompassing surgical sutures, autologous nerve or allograft nerve transplantation, tissue engineering techniques, and others, an effective clinical treatment method still needs to be discovered. Exploring novel treatment methods to improve peripheral nerve regeneration requires more effort in investigating the cellular and molecular mechanisms involved. Many factors are associated with the regeneration of injured peripheral nerves, including the cross-sectional area of the injured nerve, the length of the nerve gap defect, and various cellular and molecular factors such as Schwann cells, inflammation factors, kinases, and growth factors. As crucial mediators of cellular communication, kinases exert regulatory control over numerous signaling cascades, thereby participating in various vital biological processes, including peripheral nerve regeneration after nerve injury. In this review, we examined diverse kinase classifications, distinct nerve injury types, and the intricate mechanisms involved in peripheral nerve regeneration. Then we stressed the significance of kinases in regulating autophagy, inflammatory response, apoptosis, cell cycle, oxidative processes, and other aspects in establishing conductive microenvironments for nerve tissue regeneration. Finally, we briefly discussed the functional roles of kinases in different types of cells involved in peripheral nerve regeneration.

Electrospun silk fibroin/polylactic acid conduit filled with proangiogenic carboxylated silk fibroin/chitosan hydrogel facilitates peripheral nerve regeneration

Angiogenesis plays a crucial role in peripheral nerve regeneration after injury. We introduce a proangiogenic hydrogel-filled nerve conduit, designed to promote peripheral nerve regeneration. The hydrogel was synthesized by chemically crosslinking carboxylated silk fibroin (cSF) and chitosan (CS), enriched with vascular endothelial growth factor (VEGF) to initiate angiogenesis. Complementarily, a nerve conduit was fabricated using coaxial electrospinning of poly-lactic acid (PLA), silk fibroin (SF), and ibuprofen (IBU) was incorporated to further support nerve regeneration. The hydrogel exhibited optimal properties including rapid gelation, uniform porosity and full biodegradation within four weeks. The nerve conduit, on the other hand, displayed enhanced mechanical strength, elasticity, and controlled biodegradability. In vitro assays demonstrated a sustained release of VEGF and IBU, which significantly enhanced cell adhesion, proliferation, migration and angiogenesis in Human umbilical vein endothelial cells (HUVEC), as well as promoted adhesion and proliferation in rat Schwann cells (RSC96). This proangiogenic hydrogel-filled nerve conduit thus emerged as a potent candidate for advancing peripheral nerve regeneration.

Constructing Nerve Guidance Conduit using dECM‐Doped Conductive Hydrogel to Promote Peripheral Nerve Regeneration

AbstractPeripheral nerve injury often leads to the loss of neurological functions due to the slow regeneration rate and inefficient functional reconstruction. Current clinical treatments using nerve guidance conduits (NGCs) still face challenges in providing a biomimetic microenvironment to promote nerve repair. Herein, decellularized extracellular matrix (dECM) is obtained from porcine Achilles tendon and crosslinked with 3‐amino‐4‐methoxybenzoic acid grafted gelatin (PAMB‐G) to obtain conductive hydrogels. Then, a novel nerve guidance conduit is developed by assembling poly(vinyl alcohol) (PVA) conduit and conductive ECM@PAMB‐G hydrogel. This bioengineered ECM@PAMB‐G/PVA conduit demonstrated excellent cytocompatibility, electrical conductivity, mechanical properties, and biodegradability. In vitro experiments confirmed that the ECM@PAMB‐G hydrogel significantly promotes the proliferation and migration of PC12 cells and primary Schwann cells, as well as the growth of dorsal root ganglion (DRG) axons. Furthermore, in vivo studies in a rat sciatic nerve model exhibited improvements in axonal regeneration, Schwann cell migration, myelin sheath formation, and functional recovery mediated by the ECM@PAMB‐G/PVA conduit. This work demonstrates the synergistic effects of extracellular matrix and electrical cues in enhancing peripheral nerve regeneration. The ECM@PAMB‐G/PVA nerve guidance conduit shows potential as an alternative to autografts for supporting peripheral nerve reconstruction.