Repair Of Peripheral Nerve Injury Research Articles

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

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

MSC-derived mitochondria promote axonal regeneration via Atf3 gene up-regulation by ROS induced DNA double strand breaks at transcription initiation region

BackgroundThe repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as a promising therapy for cellular injury, with reported applications in central nerve injury. However, its potential therapeutic effect on peripheral nerve injury remains unclear.MethodsWe established a mouse sciatic nerve crush injury model. Mitochondria extracted from MSCs were intraneurally injected into the injured sciatic nerves. Axonal regeneration was observed through whole-mount nerve imaging. The dorsal root ganglions (DRGs) corresponding to the injured nerve were harvested to test the gene expression, reactive oxygen species (ROS) levels, as well as the degree and location of DNA double strand breaks (DSBs).ResultsThe in vivo experiments showed that the mitochondrial injection therapy effectively promoted axon regeneration in injured sciatic nerves. Four days after injection of fluorescently labeled mitochondria into the injured nerves, fluorescently labeled mitochondria were detected in the corresponding DRGs. RNA-seq and qPCR results showed that the mitochondrial injection therapy enhanced the expression of Atf3 and other regeneration-associated genes in DRG neurons. Knocking down of Atf3 in DRGs by siRNA could diminish the therapeutic effect of mitochondrial injection. Subsequent experiments showed that mitochondrial injection therapy could increase the levels of ROS and DSBs in injury-associated DRG neurons, with this increase being correlated with Atf3 expression. ChIP and Co-IP experiments revealed an elevation of DSB levels within the transcription initiation region of the Atf3 gene following mitochondrial injection therapy, while also demonstrating a spatial proximity between mitochondria-induced DSBs and CTCF binding sites.ConclusionThese findings suggest that MSC-derived mitochondria injected into the injured nerves can be retrogradely transferred to DRG neuron somas via axoplasmic transport, and increase the DSBs at the transcription initiation regions of the Atf3 gene through ROS accumulation, which rapidly release the CTCF-mediated topological constraints on chromatin interactions. This process may enhance spatial interactions between the Atf3 promoter and enhancer, ultimately promoting Atf3 expression. The up-regulation of Atf3 induced by mitochondria further promotes the expression of downstream regeneration-associated genes and facilitates axon regeneration.

Oxidized sodium alginate hydrogel-mouse nerve growth factor sustained release system promotes repair of peripheral nerve injury

In recent years, mouse nerve growth factor (mNGF) has emerged as an important biological regulator to repair peripheral nerve injury, but its systemic application is restricted by low efficiency and large dosage requirement. These limitations prompted us to search for biomaterials that can be locally loaded. Oxidized sodium alginate hydrogel (OSA) exhibits good biocompatibility and physicochemical properties, and can be loaded with drugs to construct a sustained-release system that can act locally on nerve injury. Here, we constructed a sustained-release system of OSA-mouse nerve growth factor (mNGF), and investigated the loading and release of the drug through Fourier transform infrared spectroscopy and drug release curves. In vitro and in vivo experiments showed that OSA-mNGF significantly promoted the biological activities of RSC-96 cells and facilitated the recovery from sciatic nerve crush injury in rats. This observation may be attributed to the additive effect of OSA on promoting Schwann cell biological activities or its synergistic effect of cross-activating phosphoinositide 3-kinase (PI3K) through extracellular signal regulated kinase (ERK) signaling. Although the specific mechanism of OSA action needs to be explored in the future, the current results provide a valuable preliminary research basis for the clinical application of the OSA-mNGF sustained-release system for nerve repair.

Preparation of PLCL/ECM nerve conduits by electrostatic spinning technique and evaluation in vitro and in vivo

Objective. Artificial nerve scaffolds composed of polymers have attracted great attention as an alternative for autologous nerve grafts recently. Due to their poor bioactivity, satisfactory nerve repair could not be achieved. To solve this problem, we introduced extracellular matrix (ECM) to optimize the materials. Approach. In this study, the ECM extracted from porcine nerves was mixed with Poly(L-Lactide-co-ϵ-caprolactone) (PLCL), and the innovative PLCL/ECM nerve repair conduits were prepared by electrostatic spinning technology. The novel conduits were characterized by scanning electron microscopy (SEM), tensile properties, and suture retention strength test for micromorphology and mechanical strength. The biosafety and biocompatibility of PLCL/ECM nerve conduits were evaluated by cytotoxicity assay with Mouse fibroblast cells and cell adhesion assay with RSC 96 cells, and the effects of PLCL/ECM nerve conduits on the gene expression in Schwann cells was analyzed by real-time polymerase chain reaction (RT-PCR). Moreover, a 10 mm rat (Male Wistar rat) sciatic defect was bridged with a PLCL/ECM nerve conduit, and nerve regeneration was evaluated by walking track, mid-shank circumference, electrophysiology, and histomorphology analyses. Main results. The results showed that PLCL/ECM conduits have similar microstructure and mechanical strength compared with PLCL conduits. The cytotoxicity assay demonstrates better biosafety and biocompatibility of PLCL/ECM nerve conduits. And the cell adhesion assay further verifies that the addition of ECM is more beneficial to cell adhesion and proliferation. RT-PCR showed that the PLCL/ECM nerve conduit was more favorable to the gene expression of functional proteins of Schwann cells. The in vivo results indicated that PLCL/ECM nerve conduits possess excellent biocompatibility and exhibit a superior capacity to promote peripheral nerve repair. Significance. The addition of ECM significantly improved the biocompatibility and bioactivity of PLCL, while the PLCL/ECM nerve conduit gained the appropriate mechanical strength from PLCL, which has great potential for clinical repair of peripheral nerve injuries.

Fas ligand regulate nerve injury and repair by affecting AKT, β-catenin, and NF-κB pathways

ObjectiveTo investigate the regulatory effect of Fas-L on the repair and regeneration of peripheral extension injury in rats. MethodsThis study aimed to explore the effects of Fas-L on apoptosis and axonal regeneration of dorsal root ganglion (DRG) cells in rat peripheral nerve repair and regeneration by using several relevant experimental techniques from the injured nerve animal model, cell biology, and molecular biology. ResultsThe expression level of Fas-L in DRG tissues was significantly down-regulated after sciatic nerve injury. Interference with Fas-L can significantly promote the regeneration of DRG neuronal axons and inhibit apoptosis, while the overexpression of Fas-L is contrary to it. Moreover, Fas-L may play a role in the regulation of DRG function and the repair and regeneration of peripheral nerves in Sprague Dawley (SD) rats by affecting several signaling pathways, such as p-AKT/AKT, β-catenin, and NF-κB. ConclusionFas-L may have a certain effect on the repair and regeneration of peripheral nerve injury in SD rats, which may provide an experimental basis and a new theoretical basis for the functional reconstruction of peripheral nerves. Significance statementThe expression level of Fas-L in DRG tissues was significantly down-regulated after sciatic nerve injury. Fas-L can significantly promote the regeneration of DRG neuronal axons and inhibit apoptosis. Fas-L may play a role in the regulation of DRG function and the repair and regeneration of peripheral nerves in SD rats by affecting several signaling pathways, such as p-AKT/AKT, β-catenin, and NF-κB. Fas-L may have a certain effect on the repair and regeneration of peripheral nerve injury in SD rats, which may provide an experimental basis and a new theoretical basis for the functional reconstruction of peripheral nerves.

Engineered PVDF/PLCL/PEDOT Dual Electroactive Nerve Conduit to Mediate Peripheral Nerve Regeneration by Modulating the Immune Microenvironment

AbstractElectroactive materials are increasingly recognized for their efficacy in promoting the repair of peripheral nerve injury. However, the mechanism by which electroactive materials promote peripheral nerve regeneration by modulating the immune microenvironment remains incompletely explored. In this study, a PVDF/PLCL/PEDOT artificial peripheral nerve conduit with dual electroactivity by integrating piezoelectric properties and electrical conductivity is constructed. The electroactive conduit exhibited excellent spontaneous electrical and conductive properties, superior suture resistance and anti‐twisting properties. Detailed in vitro cell experiments and in vivo animal experiments are conducted, revealing that the electroactive nerve conduit can effectively promote rat sciatic nerve regeneration while facilitating reconstruction of both nerve conduction function and motor function. Furthermore, the underlying mechanism in depth is investigated and found that the electroactive material can regulate the immune microenvironment by activating the PI3K/AKT‐Nrf2 signaling pathway, thereby promoting macrophage polarization toward M2 anti‐inflammatory phenotype. This subsequently facilitated Schwann cell recruitment and myelin formation through mediation of the macrophage paracrine system. Importantly, blocking immune signaling pathways diminished the effectiveness of the electroactive nerve conduit in promoting nerve repair. The work elucidated how electroactive materials modulate immune microenvironment to positively impact peripheral nerve repair, highlighting the critical role of immune modulation in peripheral nerve repair.

Surface Modification of Nerve Guide Conduits with ECM Coatings and Investigating Their Impact on Schwann Cell Response.

In this study, layer-by-layer coatings composed of heparin and collagen are proposed as an extracellular mimetic environment on nerve guide conduits (NGC) to modulate the behavior of Schwann cells (hSCs). The authors evaluated the stability, degradation over time, and bioactivity of six bilayers of heparin/collagen layer-by-layer coatings, denoted as (HEP/COL)6 . The stability study reveals that (HEP/COL)6 is stable after incubating the coatings in cell media for up to 21 days. The impact of (HEP/COL)6 on hSCs viability, protein expression, and migration is evaluated. These assays show that hSCs cultured in (HEP/COL)6 have enhanced protein expression and migration. This condition increases the expression of neurotrophic and immunomodulatory factors up to 1.5-fold compared to controls, and hSCs migrated 1.34 times faster than in the uncoated surfaces. Finally, (HEP/COL)6 is also applied to a commercial collagen-based NGC, NeuraGen, and hSC viability and adhesion are studied after 6 days of culture. The morphology of NeuraGen is not altered by the presence of (HEP/COL)6 and a nearly 170% increase of the cell viability is observed in the condition where NeuraGen is used with (HEP/COL)6 . Additionally, cell adhesion on the coated samples is successfully demonstrated. This work demonstrates the reparative enhancing potential of extracellular mimetic coatings.

Artificial intelligence-assisted repair of peripheral nerve injury: a new research hotspot and associated challenges.

Artificial intelligence can be indirectly applied to the repair of peripheral nerve injury. Specifically, it can be used to analyze and process data regarding peripheral nerve injury and repair, while study findings on peripheral nerve injury and repair can provide valuable data to enrich artificial intelligence algorithms. To investigate advances in the use of artificial intelligence in the diagnosis, rehabilitation, and scientific examination of peripheral nerve injury, we used CiteSpace and VOSviewer software to analyze the relevant literature included in the Web of Science from 1994-2023. We identified the following research hotspots in peripheral nerve injury and repair: (1) diagnosis, classification, and prognostic assessment of peripheral nerve injury using neuroimaging and artificial intelligence techniques, such as corneal confocal microscopy and coherent anti-Stokes Raman spectroscopy; (2) motion control and rehabilitation following peripheral nerve injury using artificial neural networks and machine learning algorithms, such as wearable devices and assisted wheelchair systems; (3) improving the accuracy and effectiveness of peripheral nerve electrical stimulation therapy using artificial intelligence techniques combined with deep learning, such as implantable peripheral nerve interfaces; (4) the application of artificial intelligence technology to brain-machine interfaces for disabled patients and those with reduced mobility, enabling them to control devices such as networked hand prostheses; (5) artificial intelligence robots that can replace doctors in certain procedures during surgery or rehabilitation, thereby reducing surgical risk and complications, and facilitating postoperative recovery. Although artificial intelligence has shown many benefits and potential applications in peripheral nerve injury and repair, there are some limitations to this technology, such as the consequences of missing or imbalanced data, low data accuracy and reproducibility, and ethical issues (e.g., privacy, data security, research transparency). Future research should address the issue of data collection, as large-scale, high-quality clinical datasets are required to establish effective artificial intelligence models. Multimodal data processing is also necessary, along with interdisciplinary collaboration, medical-industrial integration, and multicenter, large-sample clinical studies.

Reduced Graphene Oxide Fibers Combined with Electrical Stimulation Promote Peripheral Nerve Regeneration.

The treatment of long-gap peripheral nerve injury (PNI) is still a substantial clinical problem. Graphene-based scaffolds possess extracellular matrix (ECM) characteristic and can conduct electrical signals, therefore have been investigated for repairing PNI. Combined with electrical stimulation (ES), a well performance should be expected. We aimed to determine the effects of reduced graphene oxide fibers (rGOFs) combined with ES on PNI repair in vivo. rGOFs were prepared by one-step dimensionally confined hydrothermal strategy (DCH). Surface characteristics, chemical compositions, electrical and mechanical properties of the samples were characterized. The biocompatibility of the rGOFs were systematically explored both in vitro and in vivo. Total of 54 Sprague-Dawley (SD) rats were randomized into 6 experimental groups: a silicone conduit (S), S+ES, S+rGOFs-filled conduit (SGC), SGC+ES, nerve autograft, and sham groups for a 10-mm sciatic defect. Functional and histological recovery of the regenerated sciatic nerve at 12 weeks after surgery in each group of SD rats were evaluated. rGOFs exhibited aligned micro- and nano-channels with excellent mechanical and electrical properties. They are biocompatible in vitro and in vivo. All 6 groups exhibited PNI repair outcomes in view of neurological and morphological recovery. The SGC+ES group achieved similar therapeutic effects as nerve autograft group (P > 0.05), significantly outperformed other treatment groups. Immunohistochemical analysis showed that the expression of proteins related to axonalregeneration and angiogenesis were relatively higher in the SGC+ES. The rGOFs had good biocompatibility combined with excellent electrical and mechanical properties. Combined with ES, the rGOFs provided superior motor nerve recovery for a 10-mm nerve gap in a murine acute transection injury model, indicating its excellent repairing ability. That the similar therapeutic effects as autologous nerve transplantation make us believe this method is a promising way to treat peripheral nerve defects, which is expected to guide clinical practice in the future.

Peripheral nerve injury repair by electrical stimulation combined with graphene-based scaffolds.

Peripheral nerve injury (PNI) is a common clinical problem, which due to poor recovery often leads to limb dysfunction and sensory abnormalities in patients. Tissue-engineered nerve guidance conduits (NGCs) that are designed and fabricated from different materials are the potential alternative to nerve autografts. However, translation of these NGCs from lab to commercial scale has not been well achieved. Complete functional recovery with the aid of NGCs in PNI becomes a topic of general interest in tissue engineering and regeneration medicine. Electrical stimulation (ES) has been widely used for many years as an effective physical method to promote nerve repair in both pre-clinical and clinical settings. Similarly, ES of conductive and electroactive materials with a broad range of electrical properties has been shown to facilitate the guidance of axons and enhance the regeneration. Graphene and its derivatives possess unique physicochemical and biological properties, which make them a promising outlook for the development of synthetic scaffolds or NGCs for PNI repair, especially in combination with ES. Considering the discussion regarding ES for the treatment of PNI must continue into further detail, herein, we focus on the role of ES in PNI repair and the molecular mechanism behind the ES therapy for PNI, providing a summary of recent advances in context of graphene-based scaffolds (GBSs) in combination with ES. Future perspectives and some challenges faced in developing GBSs are also highlighted with the aim of promoting their clinical applications.

Differentiated mesenchymal stem cells-derived exosomes immobilized in decellularized sciatic nerve hydrogels for peripheral nerve repair

Peripheral nerve injury (PNI) and the limitations of current treatments often result in incomplete sensory and motor function recovery, which significantly impact the patient's quality of life. While exosomes (Exo) derived from stem cells and Schwann cells have shown promise on promoting PNI repair following systemic administration or intraneural injection, achieving effective local and sustained Exo delivery holds promise to treat local PNI and remains challenging. In this study, we developed Exo-loaded decellularized porcine nerve hydrogels (DNH) for PNI repair. We successfully isolated Exo from differentiated human adipose-derived mesenchymal stem cells (hADMSC) with a Schwann cell-like phenotype (denoted as dExo). These dExo were further combined with polyethylenimine (PEI), and DNH to create polyplex hydrogels (dExo-loaded pDNH). At a PEI content of 0.1%, pDNH showed cytocompatibility for hADMSCs and supported neurite outgrowth of dorsal root ganglions. The sustained release of dExos from dExo-loaded pDNH persisted for at least 21 days both in vitro and in vivo. When applied around injured nerves in a mouse sciatic nerve crush injury model, the dExo-loaded pDNH group significantly improved sensory and motor function recovery and enhanced remyelination compared to dExo and pDNH only groups, highlighting the synergistic regenerative effects. Interestingly, we observed a negative correlation between the number of colony-stimulating factor-1 receptor (CSF-1R) positive cells and the extent of PNI regeneration at the 21-day post-surgery stage. Subsequent in vitro experiments demonstrated the potential involvement of the CSF-1/CSF-1R axis in Schwann cells and macrophage interaction, with dExo effectively downregulating CSF-1/CSF-1R signaling.

Electrospun Composite PLLA-PPSB Nanofiber Nerve Conduits for Peripheral Nerve Defects Repair and Regeneration.

Peripheral nerve injury (PNI) is a common clinical problem and regenerating peripheral nerve defects remain a significant challenge. Poly(polyol sebacate) (PPS) polymers are developed as promising materials for biomedical applications due to their biodegradability, biocompatibility, elastomeric properties, and ease of production. However, the application of PPS-based biomaterials in nerve tissue engineering, especially in PNI repair, is limited. In this study, PPS-based composite nanofibers poly(l-lactic acid)-poly(polycaprolactone triol-co-sebacic acid-co-N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid sodium salt) (PLLA-PPSB) are aimed to construct through electrospinning and assess their in vitro biocompatibility with Schwann cells (SCs) and in vivo repair capabilities for peripheral nerve defects. For the first time, the biocompatibility and bioactivity of PPS-based nanomaterial are examined at the molecular, cellular, and animal levels for PNI repair. Electrospun PLLA-PPSB nanofibers display favorable physicochemical properties and biocompatibility, providing an effective interface for the proliferation, glial expression, and adhesion of SCs in vitro. In vivo experiments using a 10-mm rat sciatic nerve defect model show that PLLA-PPSB nanofiber nerve conduits enhance myelin formation, axonal regeneration, angiogenesis, and functional recovery. Transcriptome analysis and biological validation indicate that PLLA-PPSB nanofibers may promote SC proliferation by activating the PI3K/Akt signaling pathway. This suggests the promising potential of PLLA-PPSB nanomaterial for PNI repair.

GDNF facilitates the differentiation of ADSCs to Schwann cells and enhances nerve regeneration through GDNF/MTA1/Hes1 axis

Adipose tissue-derived stem cells (ADSCs) are a kind of stem cells with multi-directional differentiation potential, which mainly restore tissue repair function and promote cell regeneration. It can be directionally differentiated into Schwann-like cells to promote the repair of peripheral nerve injury. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the repair of nerve injury, but the underlying mechanism remains unclear, which seriously limits its further application.The study aimed to identify the molecular mechanism by which overexpression of glial cell line–derived neurotrophic factor (GDNF) facilitates the differentiation of ADSCs into Schwann cells, enhancing nerve regeneration after injury. In vitro, ADSCs overexpressing GDNF for 48 h exhibited changes in their morphology, with 80% of the cells having two or more prominences. Compared with that of ADSCs, GDNF-ADSCs exhibited increased expression of the Schwann cell marker S100, nerve damage repair-related factors.ADSC cells in normal culture and ADSC cells were overexpressing GDNF(GDNF-ADSCs) were analysed using TMT-Based Proteomic Analysis and revealed a significantly higher expression of MTA1 in GDNF-ADSCs than in control ADSCs. Hes1 expression was significantly higher in GDNF-ADSCs than in ADSCs and decreased by MTA1 silencing, along with a simultaneous decrease in the expression of S100 and nerve damage repair factors. These findings indicate that GDNF promotes the differentiation of ADSCs into Schwann cells and induces factors that accelerate peripheral nerve damage repair.

A materiobiology-inspired sericin nerve guidance conduit extensively activates regeneration-associated genes of Schwann cells for long-gap peripheral nerve repair

Peripheral nerve injury (PNI) is one of the most common causes of adult disability. Following PNI, Schwann cells (SCs) dedifferentiate, proliferate, and upregulate a variety of regeneration-associated genes (RAGs), including neurotrophic factors, ultimately promoting nerve regeneration. Even though certain reported biomaterials could upregulate one or several neurotrophic factors of SCs, none of them was able to activate these RAGs extensively. Herein, this work represents a novel manganese organic framework material (Mn-MOF) capable of effectively upregulating RAGs of SCs. In vitro cell coculture assay revealed that these Mn-MOF treated SCs enhanced the axon extension of PC12 cells, further confirming the axon regeneration-promoting activity of this framework. STAT3 and C-JUN signaling pathways were involved in Mn-MOF-induced RAGs activation. Using sericin, a well-proved biomaterial with neuroprotective properties, a Mn-MOF modified sericin conduit (MOF-SS) was prepared via π-π interactions between the cyclobenzene of framework materials and the aromatic acid of natural proteins. The microstructures and physiochemical properties of MOF-SS were comprehensively characterized, and its RAGs-activating effect on SCs was well confirmed. When applied in vivo to bridge 13-mm sciatic nerve defect, this conduit significantly promoted nerve microstructural regeneration, enhanced electrical conduction performance of regenerated nerve, improved functional recovery, and more importantly, alleviated muscle atrophy. In summary, this work represents a novel Mn-MOF modified sericin conduit capable of extensively activating RAGs of SCs, significantly promoting long-gap PNI repair.

Study on the Role and Mechanism of Exosomes Derived from Dental Pulp Stem Cells in Promoting Regeneration of Myelin Sheath in Rats with Sciatic Nerve Injury.

The prognosis of peripheral nerve injury (PNI) is usually poor, and currently, there is no effective treatment for PNI. Studies have shown that exosomes derived from mesenchymal stem cells could promote nerve regeneration by optimizing the function of endogenous Schwann cells (SCs), while the mechanism is unclear. Autophagy, a highly conserved intracellular catabolic process responsible for maintaining cellular homeostasis, has been proved to be involved in the regulation of nerve repair after injury. We explored the effect of exosomes derived from dental pulp stem cells (DPSC-Exos) on the regeneration of myelin sheath in rats with sciatic nerve injury (SNI). In vitro and in vivo experiments were performed to clarify whether the effect of DPSC-Exos is associated with autophagy of SCs and to reveal the mechanism at the molecular level. Our results showed that the SCs of SNI rats exhibited the obvious autophagic characteristics, and the increase of P53 expression was an internal factor of autophagy. Our mechanism research indicated that DPSC-Exos could deliver miR-122-5p from DPSCs into SCs and suppressed the rapamycin (RAPA)-induced autophagy in SCs by inhibiting P53 expression. Rescue experiments showed that both the use of GW4869 and overexpression of exogenous P53 in SCs could reverse the inhibitory effect of DPSCs on the autophagy in SCs from co-culture system. In short, our study indicated that DPSC-Exos could promote the regeneration of the myelin sheath through suppressing the autophagy in SCs caused by PNI via miR-122-5p/P53 pathway; this provides researchers with another option for precise repair of PNI.

Physical exercise to promote regeneration after peripheral nerve injury in animal models: A systematic review.

Peripheral nerve injuries are common injuries that often have a drastic effect on patient's activities of daily living and physical function. While techniques for the surgical repair of these injuries have improved over time, rehabilitation methods following these repairs have been non-standardized and under researched. Electronic searches were conducted in Ovid/Medline and SCOPUS to identify articles that discuss rehabilitation and exercise following peripheral nerve injury in animal models and its effects on peripheral nerve regeneration and recovery of function. Thirty-eight articles met inclusion criteria; all were prospective studies in animal models. This systematic review suggests that exercise is a useful tool in returning autonomy to the individual and has beneficial effects in the recovery from peripheral nerve injury. It is beneficial to use rehabilitation exercises following the repair of peripheral nerve injuries to promote regeneration, and timing of that exercise may be just as important as the exercise prescribed. However, further studies with standardized models and outcome measures need to be conducted before translation to clinical trials.

Magnetoactive Composite Conduits Based on Poly(3-hydroxybutyrate) and Magnetite Nanoparticles for Repair of Peripheral Nerve Injury.

Peripheral nerve injury poses a threat to the mobility and sensitivity of a nerve, thereby leading to permanent function loss due to the low regenerative capacity of mature neurons. To date, the most widely clinically applied approach to bridging nerve injuries is autologous nerve grafting, which faces challenges such as donor site morbidity, donor shortages, and the necessity of a second surgery. An effective therapeutic strategy is urgently needed worldwide to overcome the current limitations. Herein, a magnetic nerve guidance conduit (NGC) based on biocompatible biodegradable poly(3-hydroxybutyrate) (PHB) and 8 wt % of magnetite nanoparticles modified by citric acid (Fe3O4-CA) was fabricated by electrospinning. The crystalline structure of NGCs was studied by X-ray diffraction, which indicated an enlarged β-phase of PHB in the composite conduit compared to a pure PHB conduit. Tensile tests revealed greater ductility of PHB/Fe3O4-CA: the composite conduit has Young's modulus of 221 ± 52 MPa and an elongation at break of 28.6 ± 2.9%, comparable to clinical materials. Saturation magnetization (σs) of Fe3O4-CA and PHB/Fe3O4-CA is 61.88 ± 0.29 and 7.44 ± 0.07 emu/g, respectively. The water contact angle of the PHB/Fe3O4-CA conduit is lower as compared to pure PHB, while surface free energy (σ) is significantly higher, which was attributed to higher surface roughness and an amorphous phase as well as possible PHB/Fe3O4-CA interface interactions. In vitro, the conduits supported the proliferation of rat mesenchymal stem cells (rMSCs) and SH-SY5Y cells in a low-frequency magnetic field (0.67 Hz, 68 mT). In vivo, the conduits were used to bridge damaged sciatic nerves in rats; pure PHB and composite PHB/Fe3O4-CA conduits did not cause acute inflammation and performed a barrier function, which promotes nerve regeneration. Thus, these conduits are promising as implants for the regeneration of peripheral nerves.

A 3D printable gelatin methacryloyl/chitosan hydrogel assembled with conductive PEDOT for neural tissue engineering

In neural tissue engineering, biomaterial scaffolds that have high conductivity and customized structures are crucial in promoting nerve regeneration. Poly(3,4-ethylenedioxythiophene) (PEDOT) has emerged as a promising conductive polymer with excellent chemical stability and biocompatibility. However, traditional three-dimensional (3D) printing of PEDOT-based conductive scaffolds faces challenges in limited printing resolution, poor solubility, and brittleness of conductive materials. Herein, digital light processing (DLP) printing was used to fabricate complex hydrogel structures using gelatin methacryloyl (GelMA) and chitosan (CS) while incorporating PEDOT nanoparticles through interfacial polymerization to create conducting pathways within a hydrogel structure. The integration of PEDOT significantly enhanced the electrical conductivity and mechanical properties of the GelMA/CS hydrogel while preserving printed details. The GelMA/CS-PEDOT hydrogel promoted cell proliferation and facilitated axon outgrowth of PC12 cells and Schwann cells during in vitro culture. Moreover, in vitro direct current electrical stimulation promoted axon elongation of PC12 cells cultured on a conductive substrate. In vivo studies used a conductive nerve conduit to repair a 10-mm rat sciatic nerve defect, validating the efficacy of GelMA/CS-PEDOT scaffold in peripheral nerve injury repair. These findings highlight the significant potential of conductive GelMA/CS-PEDOT hydrogel in the field of neural tissue engineering.

Regulating Schwann cells and endothelial cells by YIGSR functionalized porous chitosan scaffolds for nerve regeneration

Numerous artificial nerve implants for repair of peripheral nerve injury has been developed while their performance still needs to be further improved. In this study, the Tyr-Ile-Gly-Ser-Arg (YIGSR, YR) functionalized porous chitosan scaffolds were prepared by freeze-drying technique and surface biomodification for simultaneous regulation of Schwann cells (SCs) and endothelial cells (ECs), which play important role in nerve regeneration. The physicochemical properties were characterized, including morphology, composition, wettability, mechanical properties, porosity, etc. The culture of SCs and ECs were used to evaluate the pro-neural and endothelial cell growth effects of the grafts, as well as the constitutive relationship between YR-regulated SCs and ECs. Then, the mechanisms involved were explored using molecular biology experiments. The results showed that the YR-grafted chitosan scaffolds could be successfully prepared with aggregated dopamine and YR particles on the surface of the scaffolds. The scaffolds showed a uniform porous structure, YR grafting decreased the porosity of the scaffolds but increased the mechanical properties of the scaffolds, and YR displayed a relatively stable release behavior. Further on, all YR-grafted scaffolds were proven no cytotoxicity and significantly promoted the proliferation and spreading of SCs and ECs, up-regulated the gene expression of Tumor Necrosis Factor-alpha (TNF-α) and Recombinant Contactin 2 (Cntn2), and facilitated the release of growth factors such as brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF). Thus, this YR-functionalized scaffold is expected to simultaneously promote both neuronal cell growth and vascularization in peripheral nerve regeneration. This study provides a strategy for the development of biofunctionalized nerve grafts.

A responsive cascade drug delivery scaffold adapted to the therapeutic time window for peripheral nerve injury repair.

Peripheral nerve injury (PNI) is a common clinical challenge, requiring timely and orderly initiation of synergistic anti-inflammatory and reparative therapy. Although the existing cascade drug delivery system can realize sequential drug release through regulation of the chemical structure of drug carriers, it is difficult to adjust the release kinetics of each drug based on the patient's condition. Therefore, there is an urgent need to develop a cascade drug delivery system that can dynamically adjust drug release and realize personalized treatment. Herein, we developed a responsive cascade drug delivery scaffold (RCDDS) which can adapt to the therapeutic time window, in which Vitamin B12 is used in early controllable release to suppress inflammation and nerve growth factor promotes regeneration by cascade loading. The RCDDS exhibited the ability to modulate the drug release kinetics by hierarchically opening polymer chains triggered by ultrasound, enabling real-time adjustment of the anti-inflammatory and neuroregenerative therapeutic time window depending on the patient's status. In the rat sciatic nerve injury model, the RCDDS group was able to achieve neural repair effects comparable to the autograft group in terms of tissue structure and motor function recovery. The development of the RCDDS provides a useful route toward an intelligent cascade drug delivery system for personalized therapy.