A hydrogen generator composed of poly (lactic-co-glycolic acid) nanofibre membrane loaded iron nanoparticles for infectious diabetic wound repair.

Diabetic wound, which is chronic skin disease, poses a significant challenge in clinical practice because of persistent inflammation and impaired angiogenesis. Recently, hydrogen has emerged as a novel therapeutic agent due to its superior antioxidant and anti-inflammatory properties. In this study, we engineered a poly (lactic-co-glycolic acid) (PLGA) electrospun nanofibre membrane loaded with citric acid (CA) and iron (Fe) nanoparticles, referred to as Fe@PLGA + CA. Our in vitro assays demonstrated that the Fe@PLGA + CA membrane continuously generated and released hydrogen molecules via a chemical reaction between Fe and CA in an acidic microenvironment created by CA. We also discovered that hydrogen can ameliorate fibroblast migration disorders by reducing the levels of matrix metalloproteinase 9 (MMP9). Furthermore, we confirmed that hydrogen can scavenge or biochemically neutralise accumulated reactive oxygen species (ROS), inhibit pro-inflammatory responses, and induce anti-inflammatory reactions. This, in turn, promotes vessel formation, wound-healing and accelerates skin regeneration. These findings open new possibilities for using elemental iron in skin dressings and bring us one step closer to implementing hydrogen-releasing biomedical materials in clinical practice.

Tumor-derived microvesicles for cancer therapy.

Extracellular vesicles (EVs) are vesicles with lipid bilayer structures shed from the plasma membrane of cells. Microvesicles (MVs) are a subset of EVs containing proteins, lipids, nucleic acids, and other metabolites. MVs can be produced under specific cell stimulation conditions and isolated by modern separation technology. Due to their tumor homing and large volume, tumor cell-derived microvesicles (TMVs) have attracted interest recently and become excellent delivery carriers for therapeutic vaccines, imaging agents or antitumor drugs. However, preparing sufficient and high-purity TMVs and conducting clinical transformation has become a challenge in this field. In this review, the recent research achievements in the generation, isolation, characterization, modification, and application of TMVs in cancer therapy are reviewed, and the challenges facing therapeutic applications are also highlighted.

Engineered tumor microvesicles modified by SP94 peptide for arsenic trioxide targeting drug delivery in liver cancer therapy.

Liver cancer is among the leading cause of cancer related death worldwide. There is growing interest in using traditional Chinese medicines such as arsenic trioxide (ATO) to treat liver cancer. ATO have attracted attention due to its wide range of anti-cancer activities. However, the current ATO formulations are associated with drawbacks such as short half-life, lack of targeting ability towards solid tumors and apparent toxic side effects. Tumor microvesicles (TMVs) has shown encouraging results for the delivery of drugs to solid tumor. In this work, we designed ATO loaded TMVs further modified by SP94 peptide as liver cancer specific ligand (ATO@SP94-TMVs). This drug delivery system utilized SP94 peptide that selectively targets liver cancer cells while TMVs increase the accumulation of ATO at tumor site and activate immune response owing to the associated antigens. ATO@SP94-TMVs exhibited high encapsulation efficiency and tumor microenvironment triggered enhanced release of ATO in vitro. Cytotoxicity and uptake studies revealed remarkable inhibition and specific targeting of H22 cells. In addition, excellent immune response was detected in vitro, enhancing anti-tumor efficacy. Furthermore, a tumor inhibition rate of about 53.23 % was observed in H22 bearing tumor model. Overall, these results confirm that ATO@SP94-TMVs can be a promising nano drug delivery system for the future liver cancer therapy and improve its clinical applications.

Progress of cell membrane-derived biomimetic nanovesicles for cancer phototherapy.

In recent years, considerable attention has been given to phototherapy, including photothermal and photodynamic therapy to kill tumor cells by producing heat or reactive oxygen species (ROS). It has the high merits of noninvasiveness and limited drug resistance. To fully utilize this therapy, an extraordinary nanovehicle is required to target phototherapeutic agents in the tumor cells. Nanovesicles embody an ideal strategy for drug delivery applications. Cell membrane-derived biomimetic nanovesicles represent a developing type of nanocarrier. Combining this technique with cancer phototherapy could enable a novel strategy. Herein, efforts are made to describe a comprehensive overview of cell membrane-derived biomimetic nanovesicles for cancer phototherapy. The description in this review is mainly based on representative examples of exosome-derived biomimetic nanomedicine research, ranging from their comparison with traditional nanocarriers to extensive applications in cancer phototherapy. Additionally, the challenges and future prospectives for translating these for clinical application are discussed.

A novel fluorinated polyethyleneimine with microRNA-942-5p-sponges polyplex gene delivery system for non-small-cell lung cancer therapy.

Gene delivery for non-small-cell lung cancer treatment has been a challenge due to low nucleic acid binding ability, cell-wall barrier, and high cytotoxicity. Cationic polymers, such as the traditional "golden standard" polyethyleneimine (PEI) 25 kDa have emerged as a promising carrier for non-coding RNA delivery. However, the high cytotoxicity associated with its high molecular weight has limited its application in gene delivery. To address this limitation, herein, we designed a novel delivery system using fluorine-modified polyethyleneimine (PEI) 1.8 kDa for microRNA-942-5p-sponges non-coding RNA delivery. Compared to PEI 25 kDa, this novel gene delivery system demonstrated an approximately six-fold enhancement in endocytosis capability and maintain a higher cell viability. In vivo studies also showed good biosafety and anti-tumor effects, attribute to the positive charge of PEI and the hydrophobic and oleophobic properties of the fluorine-modified group. This study provides an effective gene delivery system for non-small-cell lung cancer treatment.

PEG-grafted arsenic trioxide-loaded mesoporous silica nanoparticles endowed with pH-triggered delivery for liver cancer therapy.

Liver cancer (LC), one of the most common malignant primary tumors, presents a poor prognosis, high morbidity rate, and poor clinical outcomes. Despite conventional treatments have been applied prior to the deterioration, their clinical benefits were still limited. Arsenic trioxide (ATO), a toxic Chinese medicine, has been proven to efficiently inhibit the growth of LC both in vitro and in vivo. However, its therapeutic effects are hindered by poor pharmacokinetics and dose-limited toxicity. In this study, we developed a pH-responsive nanoplatform (PEG-MSN@ATO) consisting of mesoporous silica nanoparticles (MSN) that were modified with amino groups, loaded with ATO, and grafted with PEG to achieve the pH-triggered release and regulate CD8+ T cells and Treg cells in the tumor microenvironment (TME). PEG-MSN@ATO were characterized by uniform size, good loading efficiency, pH-responsive release features, decreased macrophage uptake, and enhanced dendritic cell activation in vitro. Furthermore, in vivo studies demonstrated that PEG-MSN@ATO enhanced the antitumor efficacy by inducing apoptosis and ROS production, inhibiting tumor cell proliferation and metastasis, and activating antitumor immunity within the TME. PEG-MSN@ATO also reduced the system toxicity of ATO by controlling the pH-trigger release in the tumor site. These results indicate that the PEG-MSN@ATO represents a promising drug delivery platform for reducing toxicity and enhancing the therapeutic efficacy of ATO against LC.

Reliable Diagnostic Tests and Thresholds for Preoperative Diagnosis of Non-Inflammatory Arthritis Periprosthetic Joint Infection: A Meta-analysis and Systematic Review.

OBJECTIVE: The current diagnostic criteria for periprosthetic joint infection (PJI) are diverse and controversial, leading to delayed diagnosis. This study aimed to evaluate and unify their diagnostic accuracy and the threshold selection of serum and synovial routine tests for PJI at an early stage. METHODS: We searched the MEDLINE and Embase databases for retrospective or prospective studies which reported preoperative-available assays (serum, synovial, or culture tests) for the diagnosis of chronic PJI among inflammatory arthritis (IA) or non-IA populations from January 1, 2000 to June 30, 2022. Threshold effective analysis was performed on synovial polymorphonuclear neutrophils (PMN%), synovial white blood cell (WBC), serum C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) to find the relevant cut-offs. RESULTS: Two hundred and sixteen studies and information from 45,316 individuals were included in the final analysis. Synovial laboratory-based α-defensin and calprotectin had the best comprehensive sensitivity (0.91 [0.86-0.94], 0.95 [0.88-0.98]) and specificity (0.96 [0.94-0.97], 0.95 [0.89-0.98]) values. According to the threshold effect analysis, the recommended cut-offs are 70% (sensitivity 0.89 [0.85-0.92], specificity 0.90 [0.87-0.93]), 4100/µL (sensitivity 0.90 [0.87-0.93], specificity 0.97 [0.93-0.98]), 13.5 mg/L (sensitivity 0.84 [0.78-0.89], specificity 0.83 [0.73-0.89]), and 30 mm/h (sensitivity 0.79 [0.74-0.83], specificity 0.78 [0.72-0.83]) for synovial PMN%, synovial WBC, serum CRP, and ESR, respectively, and tests seem to be more reliable among non-IA patients. CONCLUSIONS: The laboratory-based synovial α-defensin and synovial calprotectin are the two best independent preoperative diagnostic tests for PJI. A cut off of 70% for synovial PMN% and tighter cut-offs for synovial WBC and serum CRP could have a better diagnostic accuracy for non-IA patients with chronic PJI.

Graphdiyne-Related Materials in Biomedical Applications and Their Potential in Peripheral Nerve Tissue Engineering.

Graphdiyne (GDY) is a new member of the family of carbon-based nanomaterials with hybridized carbon atoms of sp and sp2, including α, ß, γ, and (6,6,12)-GDY, which differ in their percentage of acetylene bonds. The unique structure of GDY provides many attractive features, such as uniformly distributed pores, highly π-conjugated structure, high thermal stability, low toxicity, biodegradability, large specific surface area, tunable electrical conductivity, and remarkable thermal conductivity. Therefore, GDY is widely used in energy storage, catalysis, and energy fields, in addition to biomedical fields, such as biosensing, cancer therapy, drug delivery, radiation protection, and tissue engineering. In this review, we first discuss the synthesis of GDY with different shapes, including nanotubes, nanowires, nanowalls, and nanosheets. Second, we present the research progress in the biomedical field in recent years, along with the biodegradability and biocompatibility of GDY based on the existing literature. Subsequently, we present recent research results on the use of nanomaterials in peripheral nerve regeneration (PNR). Based on the wide application of nanomaterials in PNR and the remarkable properties of GDY, we predict the prospects and current challenges of GDY-based materials for PNR.

Novel Fluorinated Spermine and Small Molecule PEI to Deliver Anti-PD-L1 and Anti-VEGF siRNA for Highly Efficient Tumor Therapy.

Small interfering RNA (siRNA) can specifically silence disease gene expression. This project investigated the overexpression of programmed death receptor ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) on the surface of tumor cells. However, the main obstacle to the development of gene therapy drugs is the lack of an efficient delivery vector, which should be able to overcome multiple delivery barriers and protect siRNA to enter the target cells. Therefore, a novel fluorine-modified endogenous molecular carrier TFSPEI was constructed by linking fluorinated groups with hydrophobic and hydrophilic characteristics on the surface of PEI and spermine. The results showed that lower toxicity, higher endocytosis, and silencing efficiency were achieved. We found that the inhibition of VEGF targets can indirectly activate the immune response to promote the tumor-killing and invasion effects of T cells. The combined delivery of anti-VEGF siRNA and anti-PD-L1 siRNA could inhibit the expression of corresponding proteins, restore the anti-tumor function of T cells and inhibit the growth of neovascularization, and obtained significant anti-tumor effects. Therefore, this safe and efficient fluorinated spermine and small molecule PEI-based anti-PD-L1 and anti-VEGF siRNA delivery system is expected to provide a new strategy for gene therapy of tumors.

Clinical progress and advanced research of red blood cells based drug delivery system.

Red blood cells (RBCs) are biocompatible carriers that can be employed to deliver different bioactive substances. In the past few decades, many strategies have been developed to encapsulate or attach drugs to RBCs. Osmotic-based encapsulation methods have been industrialized recently, and some encapsulated RBC formulations have reached the clinical stage for treating tumors and neurological diseases. Inspired by the intrinsic properties of intact RBCs, some advanced delivery strategies have also been proposed. These delivery systems combine RBCs with other novel systems to further exploit and expand the application of RBCs. This review summarizes the clinical progress of drugs encapsulated into intact RBCs, focusing on the loading and clinical trials. It also introduces the latest advanced research based on developing prospects and limitations of intact RBCs drug delivery system (DDS), hoping to provide a reference for related research fields and further application potential of intact RBCs based drug delivery system.

Recent Advances in Cell Membrane-Derived Biomimetic Nanotechnology for Cancer Immunotherapy.

Immunotherapy will significantly impact the standard of care in cancer treatment. Recent advances in nanotechnology can improve the efficacy of cancer immunotherapy. However, concerns regarding efficiency of cancer nanomedicine, complex tumor microenvironment, patient heterogeneity, and systemic immunotoxicity drive interest in more novel approaches to be developed. For this purpose, biomimetic nanoparticles are developed to make innovative changes in the delivery and biodistribution of immunotherapeutics. Biomimetic nanoparticles have several advantages that can advance the clinical efficacy of cancer immunotherapy. Thus there is a greater push toward the utilization of biomimetic nanotechnology for developing effective cancer immunotherapeutics that demonstrate increased specificity and potency. The recent works and state-of-the-art strategies for anti-tumor immunotherapeutics are highlighted here, and particular emphasis has been given to the applications of cell-derived biomimetic nanotechnology for cancer immunotherapy.

Freeze-Drying Formulations Increased the Adenovirus and Poxvirus Vaccine Storage Times and Antigen Stabilities.

Successful vaccines induce specific immune responses and protect against various viral and bacterial infections. Noninactivated vaccines, especially viral vector vaccines such as adenovirus and poxvirus vaccines, dominate the vaccine market because their viral particles are able to replicate and proliferate in vivo and produce lasting immunity in a manner similar to natural infection. One challenge of human and livestock vaccination is vaccine stability related to the antigenicity and infectivity. Freeze-drying is the typical method to maintain virus vaccine stability, while cold chain transportation is required for temperatures about 2 °C-8 °C. The financial and technological resource requirements hinder vaccine distribution in underdeveloped areas. In this study, we developed a freeze-drying formula consisting of bovine serum albumin (BSA), L-glutamic acid (L-Glu), polyethylene glycol (PEG), and dextran (DEX) to improve the thermal stability and activity of viral vaccines, including vaccinia recombinant vaccine (rTTV-OVA) and adenovirus vaccine (Ad5-ENV). We compared a panel of five different formulations (PEG: DEX: BSA: L-GLU = 50:9:0:0(#1), 50:5:4:0(#2), 50:10:9:0(#3), 50:0:0:9(#4), and 50:1:0:8(#5), respectively) and optimized the freeze-drying formula for rTTV-OVA and Ad5-ENV. We found that the freeze-drying formulations #2 and #3 could maintain rTTV-OVA infectivity at temperatures of 4 °C and 25 °C and that rTTV-OVA immunogenicity was retained during lyophilization. However, formulations #4 and #5 maintained Ad5-ENV infectivity under the same conditions, and Ad5-ENV immunogenicity had maximum retention with freeze-drying formulation #4. In summary, we developed new freeze-drying formulations that increased virus vaccine storage times and retained immunogenicity at an ambient temperature.

Tumor-Microenvironment- Responsive Size-Shrinkable Drug-Delivery Nanosystems for Deepened Penetration Into Tumors.

Over the years, the manipulation and clinical application of drug-delivery nanosystems for cancer diseases have attracted a rapid growth of academic research interests, and some nanodrugs have been approved for clinic application. Although encouraging achievements have been made, the potency of nanomedicines in cancer treatment is far from satisfaction, and one significant reason is the inefficient penetration of nanoparticles into solid tumors. Particle size is one of the most significant features that influence diffusion ability of the drug-delivery system in tumors. Size-shrinkable drug-delivery nanosystems possess a size-switchable property that can achieve passive targeting via the enhanced permeability and retention (EPR) effect and transform into ultrasmall particles in tumors for deep penetration into tumors. The tumor microenvironment is characterized by acidic pH, hypoxia, upregulated levels of enzymes, and a redox environment. In this review, we summarize and analyze the current research progresses and challenges in tumor microenvironment responsive size-shrinkable drug-delivery nanosystems. We further expect to present some meaningful proposals and enlightenments on promoting deep penetration into tumors of nanoparticles.

Antibacterial and antibiofilm effects of flufenamic acid against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are one of the most serious surgery complications, and their prevention is of utmost importance. Flufenamic acid is a non-steroid anti-inflammatory drug approved for clinical use to relieve inflammation and pain in rheumatoid arthritis patients. In this study, we explored the antibacterial efficacy of flufenamic acid and the mechanisms underlying this effect. By using minimal inhibitory concentration (MIC), time-kill, resistance induction assays, and the antibiotic synergy test, we demonstrated that flufenamic acid inhibited the growth of methicillin-resistant staphylococci and did not induce resistance when it was used at the MIC. Furthermore, flufenamic acid acted synergistically with the beta-lactam antibiotic oxacillin and did not show significant toxicity toward mammalian cells. The biofilm inhibition assay revealed that flufenamic acid could prevent biofilm formation on medical implants and destroy the ultrastructure of the bacterial cell wall. RNA sequencing and quantitative RT-PCR indicated that flufenamic acid inhibited the expression of genes associated with peptidoglycan biosynthesis, beta-lactam resistance, quorum sensing, and biofilm formation. Furthermore, flufenamic acid efficiently ameliorated a local infection caused by MRSA in mice. In conclusion, flufenamic acid may be a potent therapeutic compound against MRSA infections and a promising candidate for antimicrobial coating of implants and surgical devices.

Mechano-Informed Biomimetic Polymer Scaffolds by Incorporating Self-Powered Zinc Oxide Nanogenerators Enhance Motor Recovery and Neural Function.

Piezoelectric materials can produce electrical power from the mechanical stimulation and thus, they may accelerate electroactive tissue healing as a promising treatment for traumatic peripheral nerve injuries. In this study, a piezoelectric zinc oxide nanogenerator scaffold is manufactured by 3D injectable multilayer biofabrication. The piezoelectric polymeric scaffold displays desirable mechanical and physical characteristics, such as aligned porosity, high elasticity, scaffold stiffness, surface energy, and excellent shear behavior. In addition, its biocompatibility supplies Schwann cells with an adhesive, proliferative, and angiogenic interface, as is reflected by higher expression of functional proteins including nerve growth factor (NGF) and vascular endothelial growth factor (VEGF). In vivo mechanical stimuli by treadmill practice contribute to the comprehensive reparative therapy. The piezoelectric conduit accelerates nerve conducting velocity, promotes axonal remyelination, and restores motor function by recovering endplate muscles. Moreover, the piezoelectric nanogenerator scaffold creates biomimetic electrically conductive microenvironment without causing noticeable toxicity to functioning organs and improves peripheral nerve restoration by the multifunctional characteristics. Therefore, the mechano-informed biomimetic piezoelectric scaffold may have enormous potential in the neuroengineering for regenerative medicine.

A fluorinated low-molecular-weight PEI/HIF-1α shRNA polyplex system for hemangioma therapy.

Hemangioma, one of the most common angiogenic diseases in infants and children, is characterized by the abnormal and aggressive proliferation of vascular endothelial cells. Advanced therapeutic strategies like RNA interference can inhibit the expression of target proteins at the translational level, but they are rarely used in hemangioma treatment owing to the lack of safe carriers. In this study, we showed for the first time that RNAi technology targeting HIF-1α (hypoxia-inducible factor-1 alpha) could benefit hemangioma therapy effectively. Heptafluorobutyric anhydride (HFAA) was used to modify low-molecular-weight PEI (PEI1.8k), and a novel fluorinated polycation carrier named fluorinated PEI (FPEI) was synthesized. Furthermore, HIF-1α-shRNA-pDNA was condensed by FPEI to fabricate FPEI polyplexes. Compared with PEI25k polyplexes, which are usually the gold standard used in gene delivery, FPEI polyplexes showed lower cytotoxicity and higher serum stability, transfection efficiency and gene silencing efficiency both in vitro and in vivo. In addition, we confirmed that FPEI polyplexes could efficiently inhibit the formation of new capillaries and tumor growth in vivo, which may provide a practicable strategy for clinical hemangioma treatment in the future.

Enhancement of sciatic nerve regeneration with dual delivery of vascular endothelial growth factor and nerve growth factor genes.

BACKGROUND: Peripheral nerve injury is one common clinical disease worldwide, in which sciatic nerve is anatomically the most challenging to regenerate given its length and large cross-sectional area. For the present, autologous nerve grafting remains to be the most ideal strategy when treating with sciatic nerve injury. However, this method sacrifices healthy nerves and requires highly intensive surgery, still calling for other advanced alternatives for nerve grafting. RESULTS: In this study, we utilized previously well-established gene delivery system to dually deliver plasmid DNA (pDNA) encoding vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), exploring therapeutics for sciatic nerve injury. Low-molecular-weight branched polyethylenimine (bPEI) was constructed as the backbone structure of gene vectors, and it was further crosslinked to synthesize degradable polycations via the conjugation of dialdehydes. Potential synergistic effect between VEGF and NGF proteins were observed on rat sciatic nerve crush injury model in this study. CONCLUSIONS: We concluded that dual delivery of plasmid VEGF and NGF as gene therapy could enhance sciatic nerve regeneration.

(-)-Epigallocatechin gallate-loaded polycaprolactone scaffolds fabricated using a 3D integrated moulding method alleviate immune stress and induce neurogenesis.

OBJECTIVES: In peripheral neuropathy, the underlying mechanisms of nerve and muscle degeneration include chronic inflammation and oxidative stress in fibrotic tissues. (-)-Epigallocatechin gallate (EGCG) is a major, active component in green tea and may scavenge free radical oxygen and attenuate inflammation. Conservative treatments such as steroid injection only deal with early, asymptomatic, peripheral neuropathy. In contrast, neurolysis and nerve conduit implantation work effectively for treating advanced stages. MATERIALS AND METHODS: An EGCG-loaded polycaprolactone (PCL) porous scaffold was fabricated using an integrated moulding method. We evaluated proliferative, oxidative and inflammatory activity of rat Schwann cells (RSCs) and rat skeletal muscle cells (RSMCs) cultured on different scaffolds in vitro. In a rat radiation injury model, we assessed the morphological, electrophysiological and functional performance of regenerated sciatic nerves and gastrocnemius muscles, as well as oxidative stress and inflammation state. RESULTS: RSCs and RSMCs exhibited higher proliferative, anti-oxidant and anti-inflammatory states in an EGCG/PCL scaffold. In vivo studies showed improved nerve and muscle recovery in the EGCG/PCL group, with increased nerve myelination and muscle fibre proliferation and reduced macrophage infiltration, lipid peroxidation, inflammation and oxidative stress indicators. CONCLUSIONS: The EGCG-modified PCL porous nerve scaffold alleviates cellular oxidative stress and repairs peripheral nerve and muscle structure in rats. It attenuates oxidative stress and inflammation in vivo and may provide further insights into peripheral nerve repair in the future.

Concentrically Integrative Bioassembly of a Three-Dimensional Black Phosphorus Nanoscaffold for Restoring Neurogenesis, Angiogenesis, and Immune Homeostasis.

Black phosphorus is well known for its excellent electromechanical properties. Although it has previously been used for therapeutic drug delivery in cancer, it has never been applied as an electroactive polymer for post-trauma tissue regeneration (e.g., in cardiac muscles and neurons). The major concern currently preventing such applications is its controversial biosafety profile in vivo. Here, we demonstrate the production of a concentrically integrative layer-by-layer bioassembled black phosphorus nanoscaffold. This scaffold has remarkable electrical conductivity, permitting smooth release into the surrounding microenvironment. We confirmed that, under mild oxidative stress, our black phosphorus nanoscaffold induced angiogenesis and neurogenesis and stimulated calcium-dependent axon regrowth and remyelination. Long-term in vivo implantation of this nanoscaffold during severe neurological defect regeneration induced negligible toxicity levels. These results provide new insight into the regenerative capability of manufactured 3D scaffolds using neuroengineered 2D black phosphorus nanomaterials.

Advances in electrical and magnetic stimulation on nerve regeneration.

Central and peripheral nerve injuries pose a great threat to people. Complications such as inflammation, muscle atrophy, traumatic neuromas and delayed reinnervation can bring huge challenges to clinical practices and barriers to complete nerve regrowth. Physical interventions such as electrical and magnetic stimulation show satisfactory results with varying parameters for acute and chronic nerve damages. The biological basis of electrical and magnetic stimulation mainly relies on protein synthesis, ion channel regulation and growth factor secretion. This review focuses on the various paradigms used in different models of electrical and magnetic stimulation and their regenerative potentials and underlying mechanisms in nerve injuries. The combination of physical stimulation and conductive biomaterial scaffolds displays an infinite potentiality in translational application in nerve regeneration.