Rat Sciatic Nerve Injury Model Research Articles

3D Printed Conductive Multiscale Nerve Guidance Conduit with Hierarchical Fibers for Peripheral Nerve Regeneration.

Nerve guidance conduits (NGCs) have become a promising alternative for peripheral nerve regeneration; however, the outcome of nerve regeneration and functional recovery is greatly affected by the physical, chemical, and electrical properties of NGCs. In this study, a conductive multiscale filled NGC (MF-NGC) consisting of electrospun poly(lactide-co-caprolactone) (PCL)/collagen nanofibers as the sheath, reduced graphene oxide /PCL microfibers as the backbone, and PCL microfibers as the internal structure for peripheral nerve regeneration is developed. The printed MF-NGCs presented good permeability, mechanical stability, and electrical conductivity, which further promoted the elongation and growth of Schwann cells and neurite outgrowth of PC12 neuronal cells. Animal studies using a rat sciatic nerve injury model reveal that the MF-NGCs promote neovascularization and M2 transition through the rapid recruitment of vascular cells and macrophages. Histological and functional assessments of the regenerated nerves confirm that the conductive MF-NGCs significantly enhance peripheral nerve regeneration, as indicated by improved axon myelination, muscle weight increase, and sciatic nerve function index. This study demonstrates the feasibility of using 3D-printed conductive MF-NGCs with hierarchically oriented fibers as functional conduits that can significantly enhance peripheral nerve regeneration.

Engineered neural tissue made using hydrogels derived from decellularised tissues for the regeneration of peripheral nerves.

Engineered neural tissue (EngNT) promotes in vivo axonal regeneration. Decellularised materials (dECM) are complex biologic scaffolds that can improve the cellular environment and also encourage positive tissue remodelling in vivo. We hypothesised that we could incorporate a hydrogel derived from a decellularised tissue (dECMh) into EngNT, thereby providing an alternative to the currently used purified collagen I hydrogel for the first time. Decellularisation was carried out on bone (B-ECM), liver (LIV-ECM), and small intestinal (SIS-ECM) tissues and the resultant dECM was biochemically and mechanically characterised. dECMh differed in mechanical and biochemical properties that likely had an effect on Schwann cell behaviour observed in metabolic activity and contraction profiles. Cellular alignment was observed in tethered moulds within the B-ECM and SIS-ECM derived hydrogels only. No difference was observed in dorsal root ganglia (DRG) neurite extension between the dECMh groups and collagen I groups when applied as a coverslip coating, however, when DRG were seeded atop EngNT constructs, only the B-ECM derived EngNT performed similarly to collagen I derived EngNT. B-ECM EngNT further exhibited similar axonal regeneration to collagen I EngNT in a 10 mm gap rat sciatic nerve injury model after 4 weeks. Our results have shown that various dECMh can be utilised to produce EngNT that can promote neurite extension in vitro and axonal regeneration in vivo. STATEMENT OF SIGNIFICANCE: Nerve autografts are undesirable due to the sacrifice of a patient's own nerve tissue to repair injuries. Engineered neural tissue (EngNT) is a type of living artificial tissue that has been developed to overcome this. To date, only a collagen hydrogel has been shown to be effective in the production and utilisation of EngNT in animal models. Hydrogels may be made from decellularised extracellular matrix derived from many tissues. In this study we showed that hydrogels from various tissues may be used to create EngNT and one was shown to comparable to the currently used collagen based EngNT in a rat sciatic nerve injry model.

METTL3-Mediated N6-Methyladenosine Modification of lncRNA D26496 Suppresses the Proliferation and Migration of Schwann Cells after Sciatic Nerve Injury.

Previous reports showed that LncRNA D26496 was downregulated and N6-methyladenosine (m6A) methyltransferase METTL3 was upregulated in sciatic nerve injury (SNI). YTH-Domain Family Member 2 (YTHDF2) regulated RNA degradation through recognizing m6A sites. However, whether METTL3-mediated m6A of D26496 plays a role in development of SNI is unknown. Therefore, in this study, we established a rat SNI model and a H2O2-induced Schwann cell injury model to investigate the role of D26496 in modulating SNI and how the expression of D26496 was regulated during this process. D26496 expression was downregulated in both models. Rats with SNI displayed severe oxidative stress, manifested as increased MDA production and decreased SOD and GSH activity. Moreover, overexpression of D26496 alleviated H2O2-induced Schwann cell injury likely by promoting cell proliferation and migration and suppressing cell apoptosis and oxidative stress. Mechanism studies found that METTL3 expression was upregulated after SNI, and silencing METTL3 reduced the D26496 m6A level, but upregulated D26496 expression. Subsequent studies found that YTHDF2 was upregulated after SNI, and abundant m6A modified D26496 in the precipitated protein-RNA complexes by anti-YTHDF2 antibody, whereas silencing YTHDF2 promoted D26496 expression but had no effect on m6A levels of D29496. Silencing D26496 reversed the protective effect of knocking down METTL3 or knocking down YTHDF2 on H2O2-induced cell damage. In vivo, D26496 overexpression alleviated SNI-induced neuropathic pain and oxidative stress. In conclusion, our results suggested that D26496 m6A modification mediated by METTL3 and recognition of D26496 m6A sites by YTHDF2 induced D26496 degradation, thereby participating in the progression of SNI.

Spatio-temporally deciphering peripheral nerve regeneration in vivo after extracellular vesicle therapy under NIR-II fluorescence imaging.

Extracellular vesicles (EVs) show potential as a therapeutic tool for peripheral nerve injury (PNI), promoting neurological regeneration. However, there are limited data on the in vivo spatio-temporal trafficking and biodistribution of EVs. In this study, we introduce a new non-invasive near-infrared fluorescence imaging strategy based on glucose-conjugated quantum dot (QDs-Glu) labeling to target and track EVs in a sciatic nerve injury rat model in real-time. Our results demonstrate that the injected EVs migrated from the uninjured site to the injured site of the nerve, with an increase in fluorescence signals detected from 4 to 7 days post-injection, indicating the release of contents from the EVs with therapeutic effects. Immunofluorescence and behavioral tests revealed that the EV therapy promoted nerve regeneration and functional recovery at 28 days post-injection. We also found a relationship between functional recovery and the NIR-II fluorescence intensity change pattern, providing novel evidence for the therapeutic effects of EV therapy using real-time NIR-II imaging at the live animal level. This approach initiates a new path for monitoring EVs in treating PNI under in vivo NIR-II imaging, enhancing our understanding of the efficacy of EV therapy on peripheral nerve regeneration and its mechanisms.

Intramuscular Nanofat Injection Promotes Inflammation-Induced Gastrocnemius Regeneration in a Syngeneic Rat Sciatic Nerve Injury Model.

Mechanical emulsification of adipose tissue to concentrate protein and stromal cell components (ie, nanofat) has gained considerable interest in clinical practice. Although the regenerative potential of nanofat has largely been used in aesthetic applications, these effects have considerable potential in reconstruction as well. Here, the authors investigated the therapeutic properties of nanofat injected directly into the denervated gastrocnemius after a sciatic nerve injury in Lewis rats. Muscle denervation was induced by transecting and immediately repairing the sciatic nerve. Inguinal and subcutaneous adipose was harvested from donor rodents, processed into nanofat, and then injected intramuscularly into the gastrocnemius. Gait analysis was performed weekly. Rodents were euthanized at 9 and 12 weeks, after which tetanic contraction force was measured, and gene expression, histology, and cytokine multiplexing were performed. Intramuscular injection of nanofat significantly increased maximum tetanic force generation at 9 and 12 weeks. The forces of the nanofat-injected gastrocnemii were better correlated to their contralateral gastrocnemii relative to controls. Muscle repair-associated inflammatory gene expressions were significantly up-regulated in nanofat-injected gastrocnemii. Cytokines interleukin (IL)-1β, IL-18, vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor, and tissue inhibitor of metalloproteinase-1 were significantly higher in nanofat-injected gastrocnemii relative to control gastrocnemii, and the tetanic force was linearly and significantly correlated to IL-1β and IL-18 and their interacting effects. Intramuscular injection of emulsified adipose tissue (nanofat) significantly increased gastrocnemii contraction force after sciatic nerve injury, with prolonged reconstructive inflammation by means of CD68, inducible nitric oxide synthase, IL-1β, and IL-18 all being potential mechanisms for this recovery. This application could potentially increase the therapeutic breadth of nanofat to include muscular recovery after nerve injury. The authors' study investigates a clinically translatable therapy to mitigate muscle atrophy after nerve injury.

Transgenic Schwann cells overexpressing POU6F1 promote sciatic nerve regeneration within acellular nerve allografts

Objective. Acellular nerve allograft (ANA) is an effective surgical approach used to bridge the sciatic nerve gap. The molecular regulators of post-surgical recovery are not well-known. Here, we explored the effect of transgenic Schwann cells (SCs) overexpressing POU domain class 6, transcription factor 1 (POU6F1) on sciatic nerve regeneration within ANAs. We explored the functions of POU6F1 in nerve regeneration by using a cell model of H2O2-induced SCs injury and transplanting SCs overexpressing POU6F1 into ANA to repair sciatic nerve gaps. Approach. Using RNA-seq, Protein–Protein Interaction network analysis, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway analysis, we identified a highly and differentially expressed transcription factor, POU6F1, following ANA treatment of sciatic nerve gap. Expressing a high degree of connectivity, POU6F1 was predicted to play a role in peripheral nervous system myelination. Main results. To test the role of POU6F1 in nerve regeneration after ANA, we infected SCs with adeno-associated virus—POU6F1, demonstrating that POU6F1 overexpression promotes proliferation, anti-apoptosis, and migration of SCs in vitro. We also found that POU6F1 significantly upregulated JNK1/2 and c-Jun phosphorylation and that selective JNK1/2 inhibition attenuated the effects of POU6F1 on proliferation, survival, migration, and JNK1/2 and c-Jun phosphorylation. The direct interaction of POU6F1 and activated JNK1/2 was subsequently confirmed by co-immunoprecipitation. In rat sciatic nerve injury model with a 10 mm gap, we confirmed the pattern of POU6F1 upregulation and co-localization with transplanted SCs. ANAs loaded with POU6F1-overexpressing SCs demonstrated the enhanced survival of transplanted SCs, axonal regeneration, myelination, and functional motor recovery compared to the ANA group loaded by SCs-only in line with in vitro findings. Significance. This study identifies POU6F1 as a novel regulator of post-injury sciatic nerve repair, acting through JNK/c-Jun signaling in SCs to optimize therapeutic outcomes in the ANA surgical approach.

Human Adipose-Derived Stem Cells Delay Muscular Atrophy after Peripheral Nerve Injury in Rats.

Given that denervation atrophy often occurs in muscle after peripheral nerve injury, the effects of injections of human adipose-derived stem cells (hADSCs) and platelet-rich plasma (PRP) into muscle after peripheral nerve injury were examined. hADSCs were isolated from human subcutaneous fat tissue, and PRP was prepared from rat whole blood before injection into a rat sciatic nerve injury model. Muscle atrophy was evaluated by quantitating the gross musculature and muscle fiber area and walking footprint analysis. At 4 weeks post-surgery, there were significant differences in the sciatic functional index between experimental (injected with hADSCs, PRP, or combined hADSCs + PRP) and non-operated groups (p < 0.0001), but no significant differences were observed between the different treatment groups (p > 0.05). Post hoc Bonferroni tests also showed significant differences in the wet muscle weight ratios of hADSC, PRP, and combined groups compared to PBS group. The gastrocnemius muscle fiber area was larger in hADSC group and the combined group compared to PBS group at 4 weeks post-surgery. The injection of hADSCs delays muscular atrophy after sciatic nerve injury in rats; thus, hADSCs are a promising alternative for regenerating atrophied muscle.

The effect of poly(lactic-co-glycolic acid) conduit loading insulin-like growth factor 1 modified by a collagen-binding domain on peripheral nerve injury in rats.

Peripheral nerve injury (PNI) exists widely and seriously affects patients' daily lives. However, the effect of nerve repair is still limited, and only 50% of patients can recover useful functions. To overcome these obstacles, collagen-coated poly(lactic-co-glycolic acid) (PLGA) conduits loaded with CBD-IGF-1 were designed and tested in vitro and in vivo. The physical characterization of the conduit was tested by scanning electron microscopy, and the static water contact angle, release rate, and nerve regeneration ability of the conduit were verified in a rat sciatic nerve injury model. The results showed that the PLGA/col/CBD-IGF-1 conduit had a rough surface and good hydrophilicity. CBD-IGF-1 could be released slowly from the PLGA/col/CBD-IGF-1 conduit. In the in vivo experiment, gait analysis and electrophysiological evaluation showed that the sciatic functional index and electrophysiological parameters were best in the group treated with the PLGA/col/CBD-IGF-1 conduit. The pathological examination results for the sciatic nerve and gastrocnemius muscle in the group treated with the PLGA/col/CBD-IGF-1 conduit were better than those in the other three groups. In short, this study demonstrated the beneficial effects of CBD-IGF-1 in nerve regeneration. The PLGA/col/CBD-IGF-1 conduit has therapeutic potential for use in the treatment of PNI.

Natural proteins-derived asymmetric porous conduit for peripheral nerve regeneration

Artificial nerve guidance conduits (NGCs) have been developed by using various biomaterials for bridging relatively long nerve defects. Though integrating neurotrophic factors with these NGCs could improve the nerve repair effects, their uncontrolled degradation and roundly random administration still restrict complete nerve regeneration. Herein, a novel silk fibroin (SF)-derived NGC with internal-facing inverse opal structures is presented, achieving the local neurotrophic factor delivery and effective nerve regeneration. The resultant NGC is confirmed with excellent biocompatibility and suitable biodegradability, as well as satisfactory mechanical performance to bridge nerve defects. Significantly, benefiting from an asymmetric structure with inverse opal porous nanostructures inside walls and hybrid hydrogel outside walls, such NGC can spatially restrict the distribution of loading factors, thus enhancing the curative efficacy. By implanting in a sciatic nerve injury rat model with a long segment defect, it is demonstrated that the drug-loaded conduit presented a similar performance to autograft, which can facilitate axons growth and remyelination, thereby promoting nerve regeneration. These results indicate a great potential of such a novel design for peripheral nerve repair applications.

Effect of glutaraldehyde-crosslinked cartilage acellular matrix film on anti-adhesion and nerve regeneration in a rat sciatic nerve injury model.

Decellularized extra-cellular matrix (ECM) has been studied as an alternative to anti-adhesive biomaterials and cartilage acellular matrix (CAM) has been shown to inhibit postoperative adhesion in several organs. This study aimed to evaluate the suitability of glutaraldehyde (GA) crosslinked CAM-films as anti-adhesion barriers for peripheral nerve injury. The films were successfully fabricated and showed improved physical properties such as mechanical strength, swelling ratio, and lengthened degradation period while maintaining the microstructure and chemical composition after GA crosslinking. In the in vitro study of CAM-film, the dsDNA content met the recommended limit of decellularization and more than 70% of the major ECM components were preserved after decellularization. The adhesion and proliferation of seeded human umbilical vein endothelial cells and fibroblasts were significantly lower in CAM-film than in control, but similar with Seprafilm. However, the CAM-film extract did not show cytotoxicity. In the in vivo study, the peri-neural fibrosis was thicker, adhesion score higher, and peri-neural collagen fibers more abundant in the control group than in the CAM-film group. The total number of myelinated axons was significantly higher in the CAM-film group than in the control group. The inflammatory marker decreased with time in the CAM-film group compared to that in the control group, whereas the nerve regenerative marker expression was maintained. Moreover, the ankle angles at contracture and toe-off were higher in the CAM film-treated rats than in the control rats. GA-crosslinked CAM films may be used during peripheral nerve surgery to prevent peri-neural adhesion and enhance nerve functional recovery.

Effects and molecular mechanisms of Achyranthes bidentata polypeptide k on proliferation of Schwann cells.

BackgroundAchyranthes bidentata polypeptide k (ABPPk) is an active ingredient separated from the Achyranthes bidentata polypeptides (ABPP) in traditional Chinese medicine. In the present study, we investigated the promoting effects and molecular mechanisms of ABPPk on the proliferation of Schwann cells (SCs).MethodsPrimary SCs were cultured with ABPPk or nerve growth factor (NGF) in vitro, and cell viability, cell cycle, EdU assay, and the expressions of proliferating cell nuclear antigen (PCNA) and Ki67 were analyzed. In addition, RNA-seq was used for bioinformatics analysis at different time points. PCNA was detected at different time points in a rat sciatic nerve injury model to further determining the role of ABPPk in sciatic nerve injury repair.ResultsWe found that ABPPk could effectively promote the proliferation of SCs, while ABPPk and NGF had different molecular mechanisms for their proliferation at different time points. Weighted gene co-expression network analysis (WGCNA) showed that ABPPk was mainly involved in the positive regulation of cell proliferation and epigenetic regulation of cell proliferation, while the main cell proliferation-related modules that NGF participated in were attenuation of negative regulation of cell proliferation and positive regulation of cell cycle. There were significant differences in the genes involved in different modules between the two groups, and ABPPk differed from NGF in the biological process of SC migration, differentiation, movement, and development in terms of action time and key genes. Functional enrichment analysis revealed ABPPk had more advantages and participation in the axon extension and vascular system areas. Furthermore, ABPPk significantly promoted the proliferation of SCs in vivo.ConclusionsThrough in vitro and in vivo studies, we identified the promoting effects of ABPPk on the proliferation of SCs. Using high-throughput sequencing technology, our work more comprehensively revealed the characteristics and mechanism of ABPPk on SCs. These results further enrich an understanding of the positive function and molecular mechanism of ABPPk in peripheral nerve regeneration and are conducive to the discovery of new therapeutic targets for peripheral nerve regeneration.

Long Non-coding RNA MSTRG.24008.1 Regulates the Regeneration of the Sciatic Nerve via the miR-331-3p-NLRP3/MAL Axis.

Peripheral nerve injury (PNI) is a common clinical problem, which can cause severe disability and dramatically affect a patient’s quality of life. Neural regeneration after PNI is a complex biological process that involves a variety of signaling pathways and genes. Emerging studies demonstrated that long non-coding RNAs (lncRNAs) were abnormally expressed after PNI and played pivotal roles in peripheral nerve regeneration. Based on the rat sciatic nerve injury model, we found that the expression levels of several lncRNAs were increased significantly in the sciatic nerve after injury. Software prediction prompted us to focus on one up-regulated lncRNA, MSTRG.24008.1. Dual-luciferase reporter assay, RNA pull-down assay and RNA interference approach verified that MSTRG.24008.1 regulated neuroregeneration via the miR-331-3p/nucleotide-binding oligomerization domain-like pyrin domain containing 3 (NLRP3)/myelin and lymphocyte protein (MAL) axis in vitro. Subsequently, we performed gastrocnemius muscle gravity and sciatic functional index experiments to evaluate the recovery of injured sciatic nerves after MSTRG.24008.1 siRNA interference in vivo. In conclusion, knockdown of MSTRG.24008.1 promotes the regeneration of the sciatic nerve via the miR-331-3p/NLRP3/MAL axis, which may provide a new strategy to evaluate and repair injured peripheral nerves clinically.

Magnetic Assembly of a Multifunctional Guidance Conduit for Peripheral Nerve Repair

AbstractNerve growth conduits are designed to support and promote axon regeneration following nerve injuries. Multifunctionalized conduits with combined physical and chemical cues, are a promising avenue aimed at overcoming current therapeutic barriers. However, the efficacious assembly of conduits that promote neuronal growth remains a challenge. Here, a biomimetic regenerative gel is developed, that integrates physical and chemical cues in a biocompatible “one pot reaction” strategy. The collagen gel is enriched with magnetic nanoparticles coated with nerve growth factor (NGF). Then, through a remote magnetic actuation, highly aligned fibrillar gel structure embedded with anisotropically distributed coated nanoparticles, combining multiple regenerating strategies, is obtained. The effects of the multifunctional gels are examined in vitro, and in vivo in a 10‐mm rat sciatic nerve injury model. The magneto‐based therapeutic conduits demonstrate oriented and directed axonal growth, and improve nerve regeneration in vivo. The study of multifunctional guidance scaffolds that can be implemented efficiently and remotely provides the foundation to a novel therapeutic approach to overcome current medical obstacles for nerve injuries.

Efficacy of Silicone Conduit in the Rat Sciatic Nerve Repair Model: Journey of a Thousand Miles.

A lot of options have been tried for bridging the two ends of the injured nerves. Researchers have used decellularized nerve grafts, artificial materials and even nerve growth factors to augment functional recovery. These materials are either costly or inaccessible in developing world. The study aimed to evaluate the efficacy of the silicone conduit in a rat sciatic nerve injury model. 24 healthy Sprague-Dawley (SD) rats (250-300 grams; 8-10 weeks) were used and right sciatic nerve was exposed; transected and re-anastomosed by two different methods in 16 rats. In control group, n = 8 (Group I) the sciatic nerve was untouched; Group II (reverse nerve anastomosis, n = 8): 1-centimeter of nerve was cut and re-anastomosed by using 10-0 monofilament suture; Group III (silicone conduit, n = 8) 1-centimeter nerve segment was cut, replaced by silicone conduit and supplemented by fibrin glue]. Evaluation of nerve recovery was done functionally (pain threshold and sciatic functional index) over 3 months and histologically and electron microscopically. Functional results showed a trend of clinical improvement in Group III and II but recovery was poor and never reached up to normal. Histopathological and electron microscopic results showed an incomplete axonal regeneration in Groups II and III. Psychological analyses showed that no outwards signs of stress were present and none of the rats showed paw biting and teeth chattering. The silicone conduit graft may be an economical and effective alternative to presently available interposition grafts, however for short segments only.

Elastin-like Proteins to Support Peripheral Nerve Regeneration in Guidance Conduits.

Synthetic nerve guidance conduits (NGCs) offer an alternative to harvested nerve grafts for treating peripheral nerve injury (PNI). NGCs have been made from both naturally derived and synthesized materials. While naturally derived materials typically have an increased capacity for bioactivity, synthesized materials have better material control, including tunability and reproducibility. Protein engineering is an alternative strategy that can bridge the benefits of these two classes of materials by designing cell-responsive materials that are also systematically tunable and consistent. Here, we tested a recombinantly derived elastin-like protein (ELP) hydrogel as an intraluminal filler in a rat sciatic nerve injury model. We demonstrated that ELPs enhance the probability of forming a tissue bridge between the proximal and distal nerve stumps compared to an empty silicone conduit across the length of a 10 mm nerve gap. These tissue bridges have evidence of myelinated axons, and electrophysiology demonstrated that regenerated axons innervated distal muscle groups. Animals implanted with an ELP-filled conduit had statistically higher functional control at 6 weeks than those that had received an empty silicone conduit, as evaluated by the sciatic functional index. Taken together, our data support the conclusion that ELPs support peripheral nerve regeneration in acute complete transection injuries when used as an intraluminal filler. These results support the further study of protein engineered recombinant ELP hydrogels as a reproducible, off-the-shelf alternative for regeneration of peripheral nerves.

Mechanical, topographicaland chemical cues combined with physical therapy for peripheral nerve injuries.

Aim: The aim of this paper is to evaluate biomaterial cues combined with physical therapy (PT) on functional recovery in a rat sciatic nerve injury model. Materials & methods: Nerve growth conduits were filled with longitudinally aligned hyaluronic acid fibers and microspheres containing neurotrophic factor (growth factor[GF]). All animals received behavior and functional testing throughout the study, which concluded with measurement of compound muscle action potentials and contractile force of the gastrocnemius muscle. Results & conclusion: Including GF improved recovery of gross motor function and increased sensory pain sensation. During the 4weeks that animals participated in PT, these groups showed higher static sciatic index scores. Including GF and PT has the potential to improve clinical outcomes following peripheral nerve injury.

Electroacupuncture Promoted Nerve Repair After Peripheral Nerve Injury by Regulating miR-1b and Its Target Brain-Derived Neurotrophic Factor.

Growing evidence indicates that electroacupuncture (EA) has a definite effect on the treatment of peripheral nerve injury (PNI), but its mechanism is not completely clear. MicroRNAs (miRNAs) are involved in the regulation of a variety of biological processes, and EA may enhance PNI repair by regulating miRNAs. In this study, the rat sciatic nerve injury model was treated with EA for 4 weeks. Acupoints Huantiao (GB30) and Zusanli (ST36) were stimulated by EA 20 min once a day, 6 days a week for 4 weeks. We found that EA treatment downregulated the expression of miR-1b in the local injured nerve. In vitro experiments showed that overexpression of miR-1b inhibited the expression of brain-derived neurotrophic factor (BDNF) in rat Schwann cell (SC) line, while BDNF knockdown inhibited the proliferation, migration, and promoted apoptosis of SCs. Subsequently, the rat model of sciatic nerve injury was treated by EA treatment and injection of agomir-1b or antagomir-1b. The nerve conduction velocity ratio (NCV), sciatic functional index (SFI), and S100 immunofluorescence staining were examined and showed that compared with the model group, NCV, SFI, proliferation of SC, and expression of BDNF in the injured nerves of rats treated with EA or EA + anti-miR-1b were elevated, while EA + miR-1b was reduced, indicating that EA promoted sciatic nerve function recovery and SC proliferation through downregulating miR-1b. To summarize, EA may promote the proliferation, migration of SC, and nerve repair after PNI by regulating miR-1b, which targets BDNF.

Preparation of Encapsulated Resveratrol Liposome Thermosensitive Gel and Evaluation of Its Capability to Repair Sciatic Nerve Injury in Rats

The purpose of this study was to prepare a liposomal temperature-sensitive gel able to slowly release resveratrol after local intramuscular injection. The best formulation of resveratrol liposomes was based on the highest encapsulation efficiency and drug loading designed by Box-Behnken. The prepared liposomes were approximately circular, with a mean particle diameter of 161.5±0.12 nm and zeta potential of -6.9 mV. The optimized liposomes were dispersed in a polymer gel (PLGA-PEG-PLGA) for preparation of an in situ-formed gel at 35±2°C. In vitro release of the prepared liposome temperature-sensitive gel was studied and compared with ordinary drug-releasing gels, revealing a significantly longer drug release time. Finally, a rat sciatic nerve injury model was used to evaluate the pharmacological activity of the liposome temperature-sensitive gels for the repair of damaged nerves. The results indicate that the gel was able to promote recovery of damaged nerves.

Electrically Conductive Hydrogel Nerve Guidance Conduits for Peripheral Nerve Regeneration

AbstractPeripheral nerve injuries are serious conditions, and surgical treatment has critical limitations. Therefore, nerve guidance conduits (NGCs) are proposed as an alternative. In this study, multifunctional NGCs are fabricated for the regeneration of injured peripheral nerves. Graphene oxide (GO) and gelatin‐methacrylate (GelMA) are polymerized and chemically reduced to form reduced (GO/GelMA) (r(GO/GelMA)). The prepared materials present good electrical conductivity, flexibility, mechanical stability, and permeability, which are suitable for use as NGCs. In vitro studies show 2.1‐ and 1.4‐fold promotion of neuritogenesis of PC12 neuronal cells on r(GO/GelMA) compared to GelMA and unreduced GO/GelMA, respectively. Animal studies using a rat sciatic nerve injury model with a 10 mm gap between the proximal and distal regions of the defect reveal that r(GO/GelMA) NGCs significantly enhance peripheral nerve regeneration, indicated by improved muscle weight increase, electro‐conduction velocity, and sciatic nerve function index. Specifically, r(GO/GelMA) NGCs are utilized to potentiate regrowth with myelination in rat sciatic nerves followed by histological, immunohistological, and morphometrical analyses. This study successfully shows the feasibility of electrically conductive hydrogel NGCs as functional conduits for improved nerve regeneration in a preclinical study, where these NGCs can not only mimic nerve tissues but also strongly promote nerve regeneration.

Controlled local release of PPARγ agonists from biomaterials to treat peripheral nerve injury

Objective. Poor clinical outcomes following peripheral nerve injury (PNI) are partly attributable to the limited rate of neuronal regeneration. Despite numerous potential drug candidates demonstrating positive effects on nerve regeneration rate in preclinical models, no drugs are routinely used to improve restoration of function in clinical practice. A key challenge associated with clinical adoption of drug treatments in nerve injured patients is the requirement for sustained administration of doses associated with undesirable systemic sideeffects. Local controlled-release drug delivery systems could potentially address this challenge, particularly through the use of biomaterials that can be implanted at the repair site during the microsurgical repair procedure. Approach. In order to test this concept, this study used various biomaterials to deliver ibuprofen sodium or sulindac sulfide locally in a controlled manner in a rat sciatic nerve injury model. Following characterisation of release parameters in vitro, ethylene vinyl acetate tubes or polylactic-co-glycolic acid wraps, loaded with ibuprofen sodium or sulindac sulfide, were placed around directly-repaired nerve transection or nerve crush injuries in rats. Main results. Ibuprofen sodium, but not sulindac sulfide caused an increase in neurites in distal nerve segments and improvements in functional recovery in comparison to controls with no drug treatment. Significance. This study showed for the first time that local delivery of ibuprofen sodium using biomaterials improves neurite growth and functional recovery following PNI and provides the basis for future development of drug-loaded biomaterials suitable for clinical translation.