Rat Sciatic Nerve Research Articles

Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair.

The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three-dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c-Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid-derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC-based transplantation approaches for promoting peripheral nerve regeneration.

Dexamethasone and granulocyte colony-stimulating factor alter the representation of cellular patterns and neurotisation of regenerative neuroma

Aim. To evaluate the changes in the total cellularity (Nuc) of the rat sciatic nerve regenerative neuroma (RegN) and its representation of CD90, CD44, CD146, and CD133 positive cells, as well as its neurotization under the conditions of dexamethasone (Dex) and granulocyte colony-stimulating factor (GCSF). Materials and methods. After injections of dexamethasone and granulocyte colony-stimulating factor in the regenerative neuroma of 168 male Wistar rats, CD90, CD44, CD146 and CD133 positive cells were detected immunohistochemically in the regenerative neuroma. Its total cellularity and neurotization were determined and statistical processing of the obtained data was performed. Results. It was found that dexamethasone and granulocyte colony-stimulating factor change the representation of cellular patterns and neurotization of regenerative neuroma. Conclusions. The amount of neurotization of the regeneration neuroma directly depends on the specific amount of Schwann cells in its composition. Dex and GCSF, despite different mechanisms of action, lead to an increase in the content of neuroleumocytes in RegN.

Enhancement of nerve regeneration through schwann cell-mediated healing in a 3D printed polyacrylonitrile conduit incorporating hydrogel and graphene quantum dots: a study on rat sciatic nerve injury model

Despite recent technological advancements, effective healing from sciatic nerve damage remains inadequate. Cell-based therapies offer a promising alternative to autograft restoration for peripheral nerve injuries, and 3D printing techniques can be used to manufacture conduits with controlled diameter and size. In this study, we investigated the potential of Wharton’s jelly-derived mesenchymal stem cells (WJMSCs) differentiated into schwann cells, using a polyacrylonitrile (PAN) conduit filled with fibrin hydrogel and graphene quantum dots (GQDs) to promote nerve regeneration in a rat sciatic nerve injury model. We investigated the potential of WJMSCs, extracted from the umbilical cord, to differentiate into schwann cells and promote nerve regeneration in a rat sciatic nerve injury model. WJMSCs were 3D cultured and differentiated into schwann cells within fibrin gel for two weeks. A 3 mm defect was created in the sciatic nerve of the rat model, which was then regenerated using a conduit/fibrin, conduit covered with schwann cells in fibrin/GQDs, GQDs in fibrin, and a control group without any treatment (n = 6/group). At 10 weeks after transplantation, motor and sensory functions and histological improvement were assessed. The WJMSCs were extracted, identified, and differentiated. The differentiated cells expressed typical schwann cell markers, S100 and P75. In vivo investigations established the durability and efficacy of the conduit to resist the pressures over two months of implantation. Histological measurements showed conduit efficiency, schwann cell infiltration, and association within the fibrin gel and lumen. Rats treated with the composite hydrogel-filled PAN conduit with GQDs showed significantly higher sensorial recovery than the other groups. Histological results showed that this group had significantly more axon numbers and remyelination than others. Our findings suggest that the conduit/schwann approach has the potential to improve nerve regeneration in peripheral nerve injuries, with future therapeutic implications.

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis.

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis. Peripheral nerve injuries often result in long-lasting functional deficits, prompting the need for effective interventions. MitoTEMPO (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride) is a mitochondria-targeted antioxidant that has shown protective and therapeutic effects against pathologies associated with reactive oxygen species. This study explores the utilization of MitoTEMPO as a therapeutic and protective agent for sciatic nerve crush injuries. By employing advanced mathematical approaches, the study seeks to comprehensively analyze nerve conduction parameters, nerve excitability, and the distribution of nerve conduction velocities to gauge the potential. Forty Wistar-Albino rats were randomly divided into following groups: (I) SHAM-animals subjected to sham operation and treated intraperitoneally (i.p.) with vehicle (bidistilled water) for 14 days; (II) CI (crush injury)-animals subjected to CI and treated with vehicle 14 days; (III) MiP-animals subjected to 7 days i.p. MitoTEMPO treatment before CI (0.7 mg/kg/day dissolved in vehicle) and, only vehicle for 7 days after CI, protective MitoTEMPO; and (IV) MiT-animals i.p. treated with only vehicle for 7 days before CI and 7 days with MitoTEMPO (0.7 mg/kg/day dissolved in vehicle) after CI, therapeutic MitoTEMPO. Nerve excitability parameters were measured, including rheobase and chronaxie, along with compound action potential (CAP) recordings. Advanced mathematical analyses were applied to CAP recordings to determine nerve conduction velocities and distribution patterns. The study revealed significant differences in nerve excitability parameters between groups. Nerve conduction velocity was notably reduced in the MiP and CI groups, whereas CAP area values were diminished in the MiP and CI groups compared to the MiT group. Furthermore, CAP velocity was lower in the MiP and CI groups, and maximum depolarization values were markedly lower in the MiP and CI groups compared to the SHAM group. The distribution of nerve conduction velocities indicated alterations in the composition of nerve fiber groups following crush injuries. In conclusion, postoperative MitoTEMPO administration demonstrated promising results in mitigating the detrimental effects of nerve crush injuries.

Oxidation-treated carbon nanotube yarns accelerate neurite outgrowth and induce axonal regeneration in peripheral nerve defect

Carbon nanotubes (CNTs) have the potential to promote peripheral nerve regeneration, although with limited capacity and foreign body reaction. This study investigated whether CNTs hydrophilized by oxidation can improve peripheral nerve regeneration and reduce foreign body reactions and inflammation. Three different artificial nerve conduit models were created using CNTs treated with ozone (O group), strong acid (SA group), and untreated (P group). They were implanted into a rat sciatic nerve defect model and evaluated after 8 and 16 weeks. At 16 weeks, the SA group showed significant recovery in functional and electrophysiological evaluations compared with the others. At 8 weeks, histological examination revealed a significant increase in the density of regenerated neurofilament and decreased foreign body giant cells in the SA group compared with the others. Oxidation-treated CNTs improved biocompatibility, induced nerve regeneration, and inhibited foreign-body reactions.

Selective peripheral nerve recording using simulated human median nerve activity and convolutional neural networks

BackgroundIt is difficult to create intuitive methods of controlling prosthetic limbs, often resulting in abandonment. Peripheral nerve interfaces can be used to convert motor intent into commands to a prosthesis. The Extraneural Spatiotemporal Compound Action Potentials Extraction Network (ESCAPE-NET) is a convolutional neural network (CNN) that has previously been demonstrated to be effective at discriminating neural sources in rat sciatic nerves. ESCAPE-NET was designed to operate using data from multi-channel nerve cuff arrays, and use the resulting spatiotemporal signatures to classify individual naturally evoked compound action potentials (nCAPs) based on differing source fascicles. The applicability of this approach to larger and more complex nerves is not well understood. To support future translation to humans, the objective of this study was to characterize the performance of this approach in a computational model of the human median nerve.MethodsUsing a cross-sectional immunohistochemistry image of a human median nerve, a finite-element model was generated and used to simulate extraneural recordings. ESCAPE-NET was used to classify nCAPs based on source location, for varying numbers of sources and noise levels. The performance of ESCAPE-NET was also compared to ResNet-50 and MobileNet-V2 in the context of classifying human nerve cuff data.ResultsClassification accuracy was found to be inversely related to the number of nCAP sources in ESCAPE-NET (3-class: 97.8% ± 0.1%; 10-class: 89.3% ± 5.4% in low-noise conditions, 3-class: 70.3% ± 0.1%; 10-class: 52.5% ± 0.3% in high-noise conditions). ESCAPE-NET overall outperformed both MobileNet-V2 (3-class: 96.5% ± 1.1%; 10-class: 84.9% ± 1.7% in low-noise conditions, 3-class: 86.0% ± 0.6%; 10-class: 41.4% ± 0.9% in high-noise conditions) and ResNet-50 (3-class: 71.2% ± 18.6%; 10-class: 40.1% ± 22.5% in low-noise conditions, 3-class: 81.3% ± 4.4%; 10-class: 31.9% ± 4.4% in high-noise conditions).ConclusionAll three networks were found to learn to differentiate nCAPs from different sources, as evidenced by performance levels well above chance in all cases. ESCAPE-NET was found to have the most robust performance, despite decreasing performance as the number of classes increased, and as noise was varied. These results provide valuable translational guidelines for designing neural interfaces for human use.

Vascularized versus Free Nerve Grafts: An Experimental Study on Rats.

Vascularized nerve grafts (VNGs) have been proposed as a superior alternative to free nerve grafts (FNGs) for complex nerve defects. A greater regenerative potential has been suggested by clinical and experimental studies, but conclusive evidence is still lacking. In this experimental study, 10 adult male Wistar rats received a non-vascularized orthotopic sciatic nerve graft on their right side, and a vascularized orthotopic sciatic nerve graft nerve on their left side. Functional outcome following nerve regeneration was evaluated through electrodiagnostic studies, target muscles weight and histomorphology, and data of VNGs and FNGs were compared. The results of this study showed a significant difference in the motor unit number of Gastrocnemius Medialis (GM) estimated by MUNE in the VNG side compared to the FNG side. No other significant differences in axonal regeneration and muscle reinnervation were evident at either electrodiagnostic, histomorphology studies or muscle weight. This experimental model showed slight differences in nerve regeneration between VNGs and FNGs, but cannot support a high clinical advantage for VNGs. The results of this study show that VNGs are not strongly superior to FNGs in the rat model, even in avascular beds. Clinical advantages of VNGs are likely to be limited to extensive and thick nerve defects and can only be assessed on experimental model with bigger animals. Also, we showed that the MUNE technique provided a reliable and reproducible evaluation of functional outcomes in the rat sciatic nerve and defined a reproducible protocol for functional evaluation of muscle reinnervation.

Fascicle-Selective Ultrasound-Powered Bidirectional Wireless Peripheral Nerve Interface IC.

This paper presents an innovative, minimally invasive, battery-free, wireless, peripheral nervous system (PNS) neural interface, which seamlessly integrates a millimeter-scale, fascicle-selective integrated circuit (IC) with extraneural recording and stimulating channels. The system also incorporates a wearable interrogator equipped with integrated machine-learning capabilities. This PNS interface is specifically tailored for adaptive neuromodulation therapy, targeting individuals with paralysis, amputation, or chronic medical conditions. By employing a neural pathway classifier and temporal interference stimulation, the proposed interface achieves precise deep fascicle selectivity for recording and stimulation without the need for nerve penetration or compression. Ultrasonic energy harvesters facilitate wireless power harvesting and data reception, enhancing the usability of the system. Key circuit performance metrics encompass a 2.2 μVrms input-referred noise, 14-bit ENOB, and a 173 dB Schreier figure of merit (FOM) for the neural analog-to-digital converter (ADC). Additionally, the ultra-low-power radio-frequency (RF) transmitter boasts a remarkable 1.38 pJ/bit energy efficiency. In vivo experiments conducted on rat sciatic nerves provide compelling evidence of the interface's ability to selectively stimulate and record neural fascicles. The proposed PNS neural interface offers alternative treatment options for diagnosing and treating neurological disorders, as well as restoring or repairing neural functions, improving the quality of life for patients with neurological and sensory deficits.

Bredigite-Based Bioactive Nerve Guidance Conduit for Pro-Healing Macrophage Polarization and Peripheral Nerve Regeneration.

Structural and functional healing of peripheral nerves damaged by trauma or chronic disease remain major clinical challenges, requiring the development of an effective nerve guidance conduit (NGC). The present study investigates a NGC fabrication strategy based on bredigite (BRT, Ca7MgSi4O16) bioceramic for the treatment of peripheral nerve injury. Here, BRT bioceramic shows good biocompatibility and sustainable release of Ca2+, Mg2+, and Si4+ ions. Both BRT extracts and BRT-incorporating electrospun membranes promote the proliferation and myelination potential of RSC96 cells, as well as accelerate vascular formation by human umbilical vein endothelial cells. Notably, BRT facilitates RAW 264.7 cell polarization to the pro-healing phenotype under LPS-induced inflammatory stimulation. More importantly, the macrophages activated by BRT in turn promote RSC96 cell migration and remyelination. In a rat sciatic nerve defect model, improved electrophysiological performance and alleviated gastrocnemius muscle atrophy are observed at 12 weeks post-implantation. Further experiments verify that BRT-loaded NGC facilitates axonal regrowth and revascularization with high M2-like macrophage infiltration. These findings support the beneficial effects of BRT for creating a pro-healing immune microenvironment and orchestrating multicellular processes associated with functional nerve regeneration, indicating the potential of rationally engineered bioceramics as safe, effective, and economical materials for peripheral nerve repair.

Quantitative evaluation of rat sciatic nerve degeneration using high-frequency ultrasound

In this study, we evaluated the utility of using high-frequency ultrasound to non-invasively track the degenerative process in a rat model of peripheral nerve injury. Primary analyses explored spatial and temporal changes in quantitative backscatter coefficient (BSC) spectrum-based outcomes and B-mode textural outcomes, using gray level co-occurrence matrices (GLCMs), during the progressive transition from acute to chronic injury. As secondary analyses, correlations among GLCM and BSC spectrum-based parameters were evaluated, and immunohistochemistry were used to suggest a structural basis for ultrasound outcomes. Both mean BSC spectrum-based and mean GLCM-based measures exhibited significant spatial differences across presurgical and 1-month/2-month time points, distal stumps enclosed proximity to the injury site being particularly affected. The two sets of parameters sensitively detected peripheral nerve degeneration at 1-month and 2-month post-injury, with area under the receiver operating charactersitic curve > 0.8 for most parameters. The results also indicated that the many BSC spectrum-based and GLCM-based parameters significantly correlate with each other, and suggested a common structural basis for a diverse set of quantitative ultrasound parameters. The findings of this study suggest that BSC spectrum-based and GLCM-based analysis are promising non-invasive techniques for diagnosing peripheral nerve degeneration.

Electrical stimulation via repeated biphasic conducting materials for peripheral nerve regeneration

Improved materials for peripheral nerve repair are needed for the advancement of new surgical techniques in fields spanning from oncology to trauma. In this study, we developed bioresorbable materials capable of producing repeated electric field gradients spaced 600 μm apart to assess the impact on neuronal cell growth, and migration. Electrically conductive, biphasic composites comprised of poly (glycerol) sebacate acrylate (PGSA) alone, and doped with poly (pyrrole) (PPy), were prepared to create alternating segments with high and low electrically conductivity. Conductivity measurements demonstrated that 0.05% PPy added to PSA achieved an optimal value of 1.25 × 10−4 S/cm, for subsequent electrical stimulation. Tensile testing and degradation of PPy doped and undoped PGSA determined that 35–40% acrylation of PGSA matched nerve mechanical properties. Both fibroblast and neuronal cells thrived when cultured upon the composite. Biphasic PGSA/PPy sheets seeded with neuronal cells stimulated for with 3 V, 20 Hz demonstrated a 5x cell increase with 1 day of stimulation and up to a 10x cell increase with 3 days stimulation compared to non-stimulated composites. Tubular conduits composed of repeated high and low conductivity materials suitable for implantation in the rat sciatic nerve model for nerve repair were evaluated in vivo and were superior to silicone conduits. These results suggest that biphasic conducting conduits capable of maintaining mechanical properties without inducing compression injuries while generating repeated electric fields are a promising tool for acceleration of peripheral nerve repair to previously untreatable patients.Graphical

Hybrid Electrically Conductive Hydrogels with Local Nerve Growth Factor Release Facilitate Peripheral Nerve Regeneration.

It is challenging to treat peripheral nerve injury (PNI) clinically. As the gold standard for peripheral nerve repair, autologous nerve grafting remains a critical limitation, including tissue availability, donor-site morbidity, immune rejection, etc. Recently, conductive hydrogels (CHs) have shown potential applications in neural bioengineering due to their good conductivity, biocompatibility, and low immunogenicity. Herein, a hybrid electrically conductive hydrogel composed of acrylic acid derivatives, gelatin, and heparin with sustained nerve growth factor (NGF) release property was developed. The rat sciatic nerve injury (SNI) model (10 mm long segment defect) was used to investigate the efficacy of these hydrogel conduits in facilitating peripheral nerve repair. The results showed that the hydrogel conduits had excellent conductivity, mechanical properties, and biocompatibility. In addition, NGF immobilized in the hydrogel conduits had good sustained release characteristics. Finally, functional recovery and electrophysiological evaluations, together with histological analysis, indicated that the hydrogel conduits immobilizing NGF had superior effects on motor recovery, axon growth, and remyelination, thereby significantly accelerating the repairing of the sciatic nerve. This study demonstrated that hybrid electrically conductive hydrogels with local NGF release could be effectively used for PNI repair.

Graphene oxide-doped chiral dextro-hydrogel promotes peripheral nerve repair through M2 polarization of macrophages

Dextro-chirality is reported to specifically promote the proliferation and survival of neural cells. However, applying this unique performance to nerve repair remains a great challenge. Graphite oxide (GO)-phenylalanine derivative hydrogel system was constructed through doping 5% GO into self-assembly dextro- or levo-hydrogels (named as dextro and levo group, respectively), which exhibited identical physical and chemical properties, cyto-compatibility, and mirror-symmetrical chirality. In vivo experiments using rat sciatic nerve repair models showed that the functional recovery and histological restoration of regenerating nerves in the dextro group were significantly improved, approaching that of autograft implantation. The doped GO promoted M2 polarization of macrophages, increasing the expression of platelet-derived growth factor BB chain and vascular endothelial growth factor, thereby improving angiogenesis in regenerating nerves. A mechanism is proposed for the facilitated nerve repair through the synergistic effect of GO and dextro-hydrogel, involving dextro-chirality selection of neural cells and GO-induced M2 polarization, which promotes microvascular regeneration and myelination. This study showcases the immense potential of chirality in addressing neurological issues by providing a compelling demonstration of the development of effective therapies that leverage the unique matrix chirality selection of nerve cells to promote peripheral nerve regeneration.

Nerve Regeneration with a Scaffold Incorporating an Absorbable Zinc-2% Iron Alloy Filament to Improve Axonal Guidance.

Peripheral nerve damage that results in lost segments requires surgery, but currently available hollow scaffolds have limitations that could be overcome by adding internal guidance support. A novel solution is to use filaments of absorbable metals to supply physical support and guidance for nerve regeneration that then safely disappear from the body. Previously, we showed that thin filaments of magnesium metal (Mg) would support nerve regeneration. Here, we tested another absorbable metal, zinc (Zn), using a proprietary zinc alloy with 2% iron (Zn-2%Fe) that was designed to overcome the limitations of both Mg and pure Zn metal. Non-critical-sized gaps in adult rat sciatic nerves were repaired with silicone conduits plus single filaments of Zn-2%Fe, Mg, or no metal, with autografts as controls. After seventeen weeks, all groups showed equal recovery of function and axonal density at the distal end of the conduit. The Zn alloy group showed some improvements in early rat health and recovery of function. The alloy had a greater local accumulation of degradation products and inflammatory cells than Mg; however, both metals had an equally thin capsule (no difference in tissue irritation) and no toxicity or inflammation in neighboring nerve tissues. Therefore, Zn-2%Fe, like Mg, is biocompatible and has great potential for use in nervous tissue regeneration and repair.

Synaptamide modulates glial and neurotransmitter activity in the spinal cord during neuropathic pain

N-docosahexaenoylethanolamine, or synaptamide, is an endogenous metabolite of docosahexaenoic acid that is known for synaptogenic and neurogenic effects. In our previous studies we have shown that synaptamide attenuates neuropathic pain, facilitates remyelination, and reduces neuroinflammation after the chronic constriction injury (CCI) of the sciatic nerve in rats. In the current study, we show that daily synaptamide administration (4 mg/kg/day) within 14 days post-surgery: (1) decreases micro- and astroglia activity in the dorsal and ventral horns of the lumbar spinal cord; (2) modulates pro-inflammatory (IL1β, IL6) and anti-inflammatory (IL4, IL10) cytokine level in the serum and spinal cord; (3) leads to a rise in synaptamide and anandamide concentration in the spinal cord; (4) enhances IL10, CD206 and N-acylethanolamine-hydrolyzing acid amidase synthesis in macrophage cell culture following LPS-induced inflammation. Thus, the ability of synaptamide to modulate glial and cytokine activity indicates its potential for implementation in the treatment peripheral nerve injury.

Mitochondrial transplantation attenuates traumatic neuropathic pain, neuroinflammation, and apoptosis in rats with nerve root ligation.

Traumatic neuropathic pain (TNP) is caused by traumatic damage to the somatosensory system and induces the presentation of allodynia and hyperalgesia. Mitochondrial dysfunction, neuroinflammation, and apoptosis are hallmarks in the pathogenesis of TNP. Recently, mitochondria-based therapy has emerged as a potential therapeutic intervention for diseases related to mitochondrial dysfunction. However, the therapeutic effectiveness of mitochondrial transplantation (MT) on TNP has rarely been investigated. Here, we validated the efficacy of MT in treating TNP. Both in vivo and in vitro TNP models by conducting an L5 spinal nerve ligation in rats and exposing the primary dorsal root ganglion (DRG) neurons to capsaicin, respectively, were applied in this study. The MT was operated by administrating 100 µg of soleus-derived allogeneic mitochondria into the ipsilateral L5 DRG in vivo and the culture medium in vitro. Results showed that the viable transplanted mitochondria migrated into the rats' spinal cord and sciatic nerve. MT alleviated the nerve ligation-induced mechanical and thermal pain hypersensitivity. The nerve ligation-induced glial activation and the expression of pro-inflammatory cytokines and apoptotic markers in the spinal cord were also repressed by MT. Consistently, exogenous mitochondria reversed the capsaicin-induced reduction of mitochondrial membrane potential and expression of pro-inflammatory cytokines and apoptotic markers in the primary DRG neurons in vitro. Our findings suggest that MT mitigates the spinal nerve ligation-induced apoptosis and neuroinflammation, potentially playing a role in providing neuroprotection against TNP.

Epothilone B loaded in acellular nerve allograft enhanced sciatic nerve regeneration in rats.

Epothilone B (EpoB) is a microtubule-stabilizing agent with neuroprotective properties. This study examines the regenerative properties of ANA supplemented with EpoB on a sciatic nerve deficit in male Wistar rats. For this purpose, the 10mm nerve gap was filled with acellular nerve allografts (ANAs) containing EpoB at 0.1, 1, and 10nM concentrations. The sensorimotor recovery was evaluated up to 16 weeks after the operation. Real-time PCR, histomorphometry analysis, and electrophysiological evaluation were also used to evaluate the process of nerve regeneration. ANA/EpoB (0.1nM) significantly improved sensorimotor recovery in rats compared to ANA, ANA/EpoB (1nM), and ANA/EpoB (10nM) groups. This led to reduced muscle atrophy, improved sciatic functional index, and thermal paw withdrawal reflex latency, indicating nerve regeneration and target organ reinnervation. The electrophysiological and histomorphometry findings also confirmed the ANA/EpoB regenerative properties (0.1nM). EpoB only enhanced ANA regenerative properties at 0.1nM, with no therapeutic effects at higher concentrations. Totally, we concluded that ANA loaded with 0.1nM EpoB can effectively reconstruct the transected sciatic nerve in rats, likely by enhancing axonal sprouting and extension.

Enhanced peripheral nerve regeneration by mechano-electrical stimulation

To address limitations in current approaches for treating large peripheral nerve defects, the presented study evaluated the feasibility of functional material-mediated physical stimuli on peripheral nerve regeneration. Electrospun piezoelectric poly(vinylidene fluoride-trifluoroethylene) nanofibers were utilized to deliver mechanical actuation-activated electrical stimulation to nerve cells/tissues in a non-invasive manner. Using morphologically and piezoelectrically optimized nanofibers for neurite extension and Schwann cell maturation based on in vitro experiments, piezoelectric nerve conduits were synthesized and implanted in a rat sciatic nerve transection model to bridge a critical-sized sciatic nerve defect (15 mm). A therapeutic shockwave system was utilized to periodically activate the piezoelectric effect of the implanted nerve conduit on demand. The piezoelectric nerve conduit-mediated mechano-electrical stimulation (MES) induced enhanced peripheral nerve regeneration, resulting in full axon reconnection with myelin regeneration from the proximal to the distal ends over the critical-sized nerve gap. In comparison, a control group, in which the implanted piezoelectric conduits were not activated in vivo, failed to exhibit such nerve regeneration. In addition, at both proximal and distal ends of the implanted conduits, a decreased number of damaged myelination (ovoids), an increased number of myelinated nerves, and a larger axonal diameter were observed under the MES condition as compared to the control condition. Furthermore, unlike the control group, the MES condition exhibited a superior functional nerve recovery, assessed by walking track analysis and polarization-sensitive optical coherence tomography, demonstrating the significant potential of the piezoelectric conduit-based physical stimulation approach for the treatment of peripheral nerve injury.

Functional outcomes of nerve allografts augmented with mesenchymal stem cells and surgical angiogenesis in a rat sciatic nerve defect model

Motor function recovery following acellular nerve allograft (ANA) repair remains inferior to autologous nerve reconstruction. We investigated the functional recovery of ANAs after combined mesenchymal stem cell (MSC) delivery and surgical angiogenesis in a rat sciatic nerve defect model. In 100 Lewis rats, unilateral sciatic nerve defects were reconstructed with (I) autografts, (II) ANAs, (III) ANAs wrapped with a superficial inferior epigastric artery fascial (SIEF) flap, combined with either (IV) undifferentiated MSCs or (V) Schwann cell-like differentiated MSCs. The tibialis anterior muscle area was evaluated during the survival period using ultrasonography. Functional recovery, histomorphometry, and immunofluorescence were assessed at 12 and 16 weeks. At 12 weeks, the addition of surgical angiogenesis and MSCs improved ankle contractures. The SIEF flap also significantly improved compound muscle action potential (CMAP) outcomes compared with ANAs. Autografts outperformed all groups in muscle force and weight. At 16 weeks, ankle contractures of ANAs remained inferior to autografts and SIEF, whereas the CMAP amplitude was comparable between groups. The muscle force of autografts remained superior to all other groups, and the muscle weight of ANAs remained inferior to autografts. No differences were found in histomorphometry outcomes between SIEF groups and ANAs. Vascularity, determined by CD34 staining, was significantly higher in SIEF groups compared with ANAs. The combination of surgical angiogenesis and MSCs did not result in a synergistic improvement in functional outcomes. In a short nerve gap model, the adipofascial flap may provide sufficient MSCs to ANAs without additional ex vivo MSC seeding.

Nanocrystals Slow-Releasing Ropivacaine and Doxorubicin to Synergistically Suppress Tumor Recurrence and Relieve Postoperative Pain.

Although surgical resection provides a straightforward and effective treatment for most malignant solid tumors, tumor recurrence and acute postoperative pain continue to be two big problems associated with this treatment. To resolve these problems, a nanocrystal composite slow-releasing ropivacaine and doxorubicin was fabricated in this study. Briefly, a self-assembling peptide was used to form nanoparticle complexes with the two drugs, based on which homogeneous nanocrystals were obtained by adjusting the pH. In cultured human melanoma cells, the nanocrystals exhibited improved antitumor activity due to a synergistic effect and enhanced cellular uptake of the two drugs. On the other hand, the nanocrystals could slowly release ropivacaine in vitro and in vivo, generating long-acting analgesia on the rat sciatic nerve block model and incisional pain model. On a nude mouse tumor resection model, the nanocrystals simultaneously suppressed the recurrence of solid tumor and relieved postoperative pain, indicating a potential postoperative treatment for tumor resection patients. This nanocrystal system also suggested a promising and facile strategy for developing multifunctional formulations combining different drugs, which could achieve better therapeutic outcomes in a synergistic and sustained manner.