Severe Peripheral Nerve Injury Research Articles

Dual growth factor methacrylic alginate microgels combined with chitosan-based conduits facilitate peripheral nerve repair

Treating severe peripheral nerve injuries is difficult. Nerve repair with conduit small gap tubulization is a treatment option but still needs to be improved. This study aimed to assess the use of microgels containing growth factors, along with chitosan-based conduits, for repairing nerves. Using the water–oil emulsion technique, microgels of methacrylic alginate (AlgMA) that contained vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) were prepared. The effects on rat Schwann cells (RSC96) and human umbilical vein endothelial cells (HUVECs) were evaluated. Chitosan-based conduits were fabricated and used in conjunction with microgels containing two growth factors to treat complete neurotmesis in rats. The results showed that the utilization of dual growth factor microgels improved the migration and decreased the apoptosis of RSC96 cells while promoting the growth and formation of tubes in HUVECs. The utilization of dual growth factor microgels and chitosan-based conduits resulted in notable advancements in the regeneration and myelination of nerve fibers, recovery of neurons, alleviation of muscle atrophy and recovery of neuromotor function and nerve conduction. In conclusion, the use of dual growth factor AlgMA microgels in combination with chitosan-based conduits has the potential to significantly improve the effectiveness of nerve repair.

Environment-Friendly Preparation and Characterization of Multilayered Conductive PVP/Col/CS Composite Doped with Nanoparticles as Potential Nerve Guide Conduits.

Tissue engineering constitutes the most promising method of severe peripheral nerve injuries treatment and is considered as an alternative to autografts. To provide appropriate conditions during recovery special biomaterials called nerve guide conduits are required. An ideal candidate for this purpose should not only be biocompatible and protect newly forming tissue but also promote the recovery process. In this article a novel, multilayered biomaterial based on polyvinylpyrrolidone, collagen and chitosan of gradient structure modified with conductive nanoparticles is presented. Products were obtained by the combination of electrospinning and electrospraying techniques. Nerve guide conduits were subjected to FT-IR analysis, morphology and elemental composition study using SEM/EDS as well as biodegradation. Furthermore, their effect on 1321N1 human cell line was investigated by long-term cell culture. Lack of cytotoxicity was confirmed by XTT assay and morphology study. Obtained results confirmed a high potential of newly developed biomaterials in the field of nerve tissue regeneration with a special focus on injured nerves recovery.

PENINGKATAN KUALITAS HIDUP PASIEN BRACHIALIS PLEXUS INJURY MELALUI PENDAMPINGAN KEWIRAUSAHAAN

Brachial Plexus Injury is a severe peripheral nerve injury that affects the upper extremities, resulting in functional damage and physical disability. Patients with this condition will experience functional limitations in the upper limbs due to a decrease in joint range of motion and muscle strength, thereby affecting productivity. The aim of this research is to determine the improvement in the quality of life of Brachial Plexus Injury Patients through Entrepreneurship Assistance in the Brachial Plexus Injury community. Research Method: This research uses a quantitative descriptive research design. The research was conducted in the Brachialis Plexus Injury community with a sample size of 25 patients using probability sampling techniques with simple random sampling. The instruments used were questionnaires about entrepreneurial intentions, entrepreneurial personality, family support and quality of life. The analysis test used is the multiple linear regression assumption test. Research Results: There is an influence of entrepreneurial mentoring including family support, entrepreneurial intentions, entrepreneurial personality on the quality of life. The F count results are 17.045 with a significance of 0.000. It is known that the G table value is 3.08 because the calculated F value > F table means HO is rejected and Ha is accepted, meaning that there is a significant influence between entrepreneurial assistance on the quality of life of patients with Brachial Plexus Injury conditions. There is a correlation between the variables Family support (X1), Entrepreneurial Personality (X2), Entrepreneurial intentions, with a significance value of 0.000. This means that the significance value of the three variables is smaller than 0.05 or in other words 0.000 > 0.05. So it can be concluded that there is a correlation. To see the level of closeness of the relationship, it can be seen from the R Square of 0.709, which is strongly correlated (according to the rules, if the value is 0.61 to 0.80, it is in the strong correlation category). Conclusion: There is an influence of entrepreneurial assistance including family support, entrepreneurial intentions, entrepreneurial personality on quality of life

Multifunctional Biodegradable Conductive Hydrogel Regulating Microenvironment for Stem Cell Therapy Enhances the Nerve Tissue Repair.

The nerve guidance conduits incorporated with stem cells, which can differentiate into the Schwann cells (SCs) to facilitate myelination, shows great promise for repairing the severe peripheral nerve injury. The innovation of advanced hydrogel materials encapsulating stem cells, is highly demanded for generating supportive scaffolds and adaptive microenvironment for nerve regeneration. Herein, this work demonstrates a novel strategy in regulating regenerative microenvironment for peripheral nerve repair with a biodegradable conductive hydrogel scaffold, which can offer multifunctional capabilities in immune regulation, enhancing angiogenesis, driving SCs differentiation, and promoting axon regrowth. The biodegradable conductive hydrogel is constructed by incorporation of polydopamine-modified silicon phosphorus (SiP@PDA) nanosheets into a mixture of methacryloyl gelatin and decellularized extracellular matrix (GelMA/ECM). The biomimetic electrical microenvironment performs an efficacious strategy to facilitate macrophage polarization toward a pro-healing phenotype (M2), meanwhile the conductive hydrogel supports vascularization in regenerated tissue through sustained Si element release. Furthermore, the MSCs 3D-cultured in GelMA/ECM-SiP@PDA conductive hydrogel exhibits significantly increased expression of genes associated with SC-like cell differentiation, thus facilitating the myelination and axonal regeneration. Collectively, both the in vitro and in vivo studies demonstrates that the rationally designed biodegradable multifunctional hydrogel significantly enhances nerve tissues repair.

Examination Approaches to Brachial Plexus Injury for Neurosurgical Residents.

Brachial plexus injury is a severe peripheral nerve injury that affects the upper extremities and causes functional damage and disability. A detailed and accurate clinical examination is required to accurately localise the site of injury. This video manuscript aims to provide guidelines for the structured assessment of a patient with brachial plexus injury, specifically tailored to Malaysian medical students and trainees. A video demonstrating the examination of the brachial plexus was made. This video, created at the School of Medical Sciences at Universiti Sains Malaysia (USM), demonstrates the proper examination technique for brachial plexus. We hope that this video will help students and young doctors evaluate patients with brachial plexus injury and reach accurate localisation of the injury.

Barriers to Surgical Intervention and Factors Influencing Motor Outcomes in Patients with Severe Peripheral Nerve Injury: A Province Wide Cohort Study.

Despite the importance of timing of nerve surgery after peripheral nerve injury, optimal timing of intervention has not been clearly delineated. The goal of this study is to explore factors that may have a significant impact on clinical outcomes of severe peripheral nerve injury that requires reconstruction with nerve transfer or graft. Adult patients who underwent peripheral nerve transfer or grafting in Alberta were reviewed. Clustered multivariable logistic regression analysis was used to examine the association of time to surgery, type of nerve repair, and patient characteristics on strength outcomes. Cox proportional hazard regression analysis model was used to examine factors correlated with increased time to surgery. Of the 163 patients identified, the median time to surgery was 212 days. For every week of delay, the adjusted odds of achieving Medical Research Council strength grade ≥ 3 decreases by 3%. An increase in preinjury comorbidities was associated with longer overall time to surgery (aHR 0.84, 95% CI 0.74-0.95). Referrals made by surgeons were associated with a shorter time to surgery compared to general practitioners (aHR 1.87, 95% CI 1.14-3.06). In patients treated with nerve transfer, the adjusted odds of achieving antigravity strength was 388% compared to nerve grafting; while the adjusted odds decreased by 65% if the injury sustained had a pre-ganglionic injury component. Mitigating delays in surgical intervention is crucial to optimizing outcomes. The nature of initial nerve injury and surgical reconstructive techniques are additional important factors that impact postoperative outcomes.

Dynamic alternations of interhemispheric functional connectivity in brachial plexus avulsion injury patients with nerve transfer: a resting state fMRI study.

Brachial plexus avulsion injury (BPAI) is a severe peripheral nerve injury that leads to functional reorganization of the brain. However, the interhemispheric coordination following contralateral cervical 7 nerve transfer remains unclear. In this study, 69 BPAI patients underwent resting-state functional magnetic resonance imaging examination to assess the voxel-mirrored homotopic connectivity (VMHC), which reveals the interhemispheric functional connection. The motor function of the affected upper extremity was measured using the Fugl-Meyer Assessment of Upper Extremity (FMA-UE) scale. The VMHC analysis showed significant differences between the bilateral precentral gyrus, supplementary motor area (SMA), middle frontal gyrus (MFG), and insula. Compared to the preoperative group, the VMHC of the precentral gyrus significantly increased in the postoperative short-term group (PO-ST group) but decreased in the postoperative long-term group (PO-LT group). Additionally, the VMHC of the SMA significantly increased in the PO-LT group. Furthermore, the VMHC of the precentral gyrus in the PO-ST group and the SMA in the PO-LT group were positively correlated with the FMA-UE scores. These findings highlight a positive relationship between motor recovery and increased functional connectivity of precentral gyrus and SMA, which provide possible therapeutic targets for future neuromodulation interventions to improve rehabilitation outcomes for BPAI patients.

Development and preclinical evaluation of bioactive nerve conduits for peripheral nerve regeneration: A comparative study.

In severe peripheral nerve injuries, nerve conduits (NCs) are good alternatives to autografts/allografts; however, the results the available devices guarantee for are still not fully satisfactory. Herein, differently bioactivated NCs based on the new polymer oxidized polyvinyl alcohol (OxPVA) are compared in a rat model of sciatic nerve neurotmesis (gap: 5mm; end point: 6 weeks). Thirty Sprague Dawley rats are randomized to 6 groups: Reverse Autograft (RA); Reaxon®; OxPVA; OxPVA+EAK (self-assembling peptide, mechanical incorporation); OxPVA+EAK-YIGSR (mechanical incorporation); OxPVA+Nerve Growth Factor (NGF) (adsorption). Preliminarily, all OxPVA-based devices are comparable with Reaxon® in Sciatic Functional Index score and gait analysis; moreover, all conduits sustain nerve regeneration (S100, β-tubulin) without showing substantial inflammation (CD3, F4/80) evidences. Following morphometric analyses, OxPVA confirms its potential in PNI repair (comparable with Reaxon®) whereas OxPVA+EAK-YIGSR stands out for its myelinated axons total number and density, revealing promising in injury recovery and for future application in clinical practice.

Phototherapy (photobiomodulation) for peripheral nerve and muscle injury

Severe peripheral nerve and muscle injuries are a highly prevalent condition for both civilians and military personnel caused by traffic accidents, work injuries, acts of violence, as well as combat events.
 Peripheral nerve injury is a substantial problem that annually affects more than several millions of people all over the world. For most patients who suffer from severe peripheral nerve injuries spontaneous recovery may eventually occur, but it is slow and frequently incomplete. Effective posttraumatic nerve repair and decrease or prevention of corresponding muscle atrophy remain a great challenge to restorative medicine. A certain clinical interest began to appear in the potential therapeutic value of laser phototherapy (new name – laser photobiomodulation) for regeneration enhancement of injured peripheral nerve as well as for restoration or prevention of denervated muscle atrophy. Although a pioneering report regarding the effects of laser phototherapy on the regeneration of traumatically injured peripheral nerves was published in the late 1970s,1 it is only since the end of past century - early 2000s that scientific interest in this therapeutic approach for neural rehabilitation has appeared, leading to publication of several studies that have shown positive effects of phototherapy on peripheral nerve regeneration.2 [...]

Chitin Conduits with Different Inner Diameters at Both Ends Combined with Dual Growth Factor Hydrogels Promote Nerve Transposition Repair in Rats.

Severe peripheral nerve injuries, such as deficits over long distances or proximal nerve trunk injuries, pose complex reconstruction challenges that often result in unfavorable outcomes. Innovative techniques, such as nerve transposition repair with conduit suturing, can be employed to successfully treat severe peripheral nerve damage. However, cylindrical nerve guides are typically unsuitable for nerve transposition repair. Furthermore, angiogenic and neurotrophic factors are necessary to stimulate the emergence of axonal lateral sprouts, proximal growth, and the rehabilitation of neuron structures and functions. In the current study, we used chitosan to make chitin conduits with different inner diameters at both ends, combined with gelatin methacrylate hydrogels that can continuously release dual growth factors, namely, the vascular endothelial growth factor (VEGF) and the nerve growth factor (NGF), and evaluated its impact on nerve transposition repair in rats. At 16 weeks after the operation, our findings showed that the conduit combined with the dual growth factor hydrogel significantly improved the restoration of both motor and conduction functions of the nerve. In addition, histological analysis showed significant recovery of nerve fibers, target muscles, and neurons. In conclusion, the combination of chitin conduits with different inner diameters and dual growth factor hydrogels can significantly improve the effect of nerve transposition repair, which has important potential clinical value.

A Novel 3D‐Printed/Porous Conduit with Tunable Properties to Enhance Nerve Regeneration Over the Limiting Gap Length

AbstractEngineered grafts constitute an alternative to autologous transplant for repairing severe peripheral nerve injuries. However, current clinically available solutions have substantial limitations and are not suited for the repair of long nerve defects. A novel design of nerve conduit is presented here, which consists of a chitosan porous matrix embedding a 3D‐printed poly‐ε‐caprolactone mesh. These materials are selected due to their high biocompatibility, safe degradability, and ability to support the nerve regeneration process. The proposed design allows high control over geometrical features, pores morphology, compression resistance, and bending stiffness, yielding tunable and easy‐to‐manipulate grafts. The conduits are tested in chronic animal experiments, aiming to repair a 15‐mm long gap in the sciatic nerve of rats, and the results are compared with an autograft. Electrophysiological and nociception tests performed monthly during a 4‐month follow‐up show that these conduits allow a good degree of muscle functional recovery. Histological analyses show abundant cellularization in the wall and in the lumen of the conduits and regenerated axons within all rats treated with these grafts. It is suggested that the proposed conduits have the potential to repair nerves over the limiting gap length and can be proposed as strategy to overcome the limitations of autograft.

Commentary: Decellularized Graft for Repairing Severe Peripheral Nerve Injuries in Sheep.

Commentary: Decellularized Graft for Repairing Severe Peripheral Nerve Injuries in Sheep.

Decellularized Graft for Repairing Severe Peripheral Nerve Injuries in Sheep.

Peripheral nerve injuries resulting in a nerve defect require surgical repair. The gold standard of autograft (AG) has several limitations, and therefore, new alternatives must be developed. The main objective of this study was to assess nerve regeneration through a long gap nerve injury (50 mm) in the peroneal nerve of sheep with a decellularized nerve allograft (DCA). A 5-cm long nerve gap was made in the peroneal nerve of sheep and repaired using an AG or using a DCA. Functional tests were performed once a month and electrophysiology and echography evaluations at 6.5 and 9 months postsurgery. Nerve grafts were harvested at 9 months for immunohistochemical and morphological analyses. The decellularization protocol completely eliminated the cells while preserving the extracellular matrix of the nerve. No significant differences were observed in functional tests of locomotion and pain response. Reinnervation of the tibialis anterior muscles occurred in all animals, with some delay in the DCA group compared with the AG group. Histology showed a preserved fascicular structure in both AG and DCA; however, the number of axons distal to the nerve graft was higher in AG than in DCA. The decellularized graft assayed supported effective axonal regeneration when used to repair a 5-cm long gap in the sheep. As expected, a delay in functional recovery was observed compared with the AG because of the lack of Schwann cells.

Regulation of nerve cells using conductive nanofibrous scaffolds for controlled release of Lycium barbarum polysaccharides and nerve growth factor.

Currently, more and more patients suffer from peripheral nerve injury due to trauma, tumor and other causes worldwide. Biomaterial-based nerve conduits are increasingly recognized as a potential alternative to nerve autografts for the treatment of peripheral nerve injury. However, an ideal nerve conduit must offer topological guidance and biochemical and electrical signal transduction mechanisms. In this work, aligned conductive nanofibrous scaffolds comprising polylactic-co-glycolic acid and multiwalled carbon nanotubes (MWCNTs) were fabricated via coaxial electrospinning, and nerve growth factor (NGF) and Lycium barbarum polysaccharides (LBP) purified from the wolfberry were loaded on the core and shell layers of the nanofibers, respectively. LBP were confirmed to accelerate long-distance axon regeneration after severe peripheral nerve injury. In addition, the synergistic promotion of LBP and NGF on nerve cell proliferation and neurite outgrowth was demonstrated. MWCNTs were introduced into the aligned fibers to further increase the electrical conductivity, which promoted the directional growth and neurite extension of neurons in vitro. Further, the combination of conductive fibrous scaffolds with electrical stimulation that mimics endogenous electric fields significantly promoted the differentiation of PC12 cells and the axon outgrowth of neurons. Based on robust cell-induced behaviors, conductive composite fibers with optimized fiber alignment may be used for the promotion of nerve recovery.

Repair of Long Peripheral Nerve Defects in Sheep: A Translational Model for Nerve Regeneration.

Despite advances in microsurgery, full functional recovery of severe peripheral nerve injuries is not commonly attained. The sheep appears as a good preclinical model since it presents nerves with similar characteristics to humans. In this study, we induced 5 or 7 cm resection in the peroneal nerve and repaired with an autograft. Functional evaluation was performed monthly. Electromyographic and ultrasound tests were performed at 6.5 and 9 months postoperation (mpo). No significant differences were found between groups with respect to functional tests, although slow improvements were seen from 5 mpo. Electrophysiological tests showed compound muscle action potentials (CMAP) of small amplitude at 6.5 mpo that increased at 9 mpo, although they were significantly lower than the contralateral side. Ultrasound tests showed significantly reduced size of tibialis anterior (TA) muscle at 6.5 mpo and partially recovered size at 9 mpo. Histological evaluation of the grafts showed good axonal regeneration in all except one sheep from autograft 7 cm (AG7) group, while distal to the graft there was a higher number of axons than in control nerves. The results indicate that sheep nerve repair is a useful model for investigating long-gap peripheral nerve injuries.

Repair of Long Nerve Defects with a New Decellularized Nerve Graft in Rats and in Sheep.

Decellularized nerve allografts (DC) are an alternative to autografts (AG) for repairing severe peripheral nerve injuries. We have assessed a new DC provided by VERIGRAFT. The decellularization procedure completely removed cellularity while preserving the extracellular matrix. We first assessed the DC in a 15 mm gap in the sciatic nerve of rats, showing slightly delayed but effective regeneration. Then, we assayed the DC in a 70 mm gap in the peroneal nerve of sheep compared with AG. Evaluation of nerve regeneration and functional recovery was performed by clinical, electrophysiology and ultrasound tests. No significant differences were found in functional recovery between groups of sheep. Histology showed a preserved fascicular structure in the AG while in the DC grafts regenerated axons were grouped in small units. In conclusion, the DC was permissive for axonal regeneration and allowed to repair a 70 mm long gap in the sheep nerve.

Transection injury differentially alters the proteome of the human sural nerve.

Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury. In a unique study design, we collected closely matched samples of naïve and injured sural nerve. Naïve and injured (two weeks after injury) samples were analyzed using mass spectrometry and immunoassays. We found significantly altered levels following the nerve injury. Mass spectrometry revealed that injury samples had 568 proteins significantly upregulated and 471 significantly downregulated compared to naïve samples (q-value ≤ 0.05 and Z ≥ |2| (log2)). We used Gene Ontology (GO) pathway overrepresentation analysis to highlight groups of proteins that were significantly upregulated or downregulated with injury-induced degeneration and regeneration. Significant protein changes in key pathways were identified including growth factor levels, Schwann cell de-differentiation, myelination downregulation, epithelial-mesenchymal transition (EMT), and axonal regeneration pathways. The proteomes of the uninjured nerve compared to the degenerating/regenerating nerve may reveal biomarkers to aid in the development of repair strategies such as infusing supplemental trophic factors and in monitoring neural tissue regeneration.

Exercise facilitates regeneration after severe nerve transection and further modulates neural plasticity

Patients with severe traumatic peripheral nerve injury (PNI) always suffer from incomplete recovery and poor functional outcome. Physical exercise-based rehabilitation, as a non-invasive interventional strategy, has been widely acknowledged to improve PNI recovery by promoting nerve regeneration and relieving pain. However, effects of exercise on chronic plastic changes following severe traumatic PNIs have been limitedly discussed. In this study, we created a long-gap sciatic nerve transection followed by autograft bridging in rats and tested the therapeutic functions of treadmill running with low intensity and late initiation. We demonstrated that treadmill running effectively facilitated nerve regeneration and prevented muscle atrophy and thus improved sensorimotor functions and walking performance. Furthermore, exercise could reduce inflammation at the injured nerve as well as prevent the overexpression of TRPV1, a pain sensor, in primary afferent sensory neurons. In the central nervous system, we found that PNI induced transcriptive changes at the ipsilateral lumber spinal dorsal horn, and exercise could reverse the differential expression for genes involved in the Notch signaling pathway. In addition, through neural imaging techniques, we found volumetric, microstructural, metabolite, and neuronal activity changes in supraspinal regions of interest (i.e., somatosensory cortex, motor cortex, hippocampus, etc.) after the PNI, some of which could be reversed through treadmill running. In summary, treadmill running with late initiation could promote recovery from long-gap nerve transection, and while it could reverse maladaptive plasticity after the PNI, exercise may also ameliorate comorbidities, such as chronic pain, mental depression, and anxiety in the long term.

Clinically relevant small-molecule promotes nerve repair and visual function recovery

Adult mammalian injured axons regenerate over short-distance in the peripheral nervous system (PNS) while the axons in the central nervous system (CNS) are unable to regrow after injury. Here, we demonstrated that Lycium barbarum polysaccharides (LBP), purified from Wolfberry, accelerated long-distance axon regeneration after severe peripheral nerve injury (PNI) and optic nerve crush (ONC). LBP not only promoted intrinsic growth capacity of injured neurons and function recovery after severe PNI, but also induced robust retinal ganglion cell (RGC) survival and axon regeneration after ONC. By using LBP gene expression profile signatures to query a Connectivity map database, we identified a Food and Drug Administration (FDA)-approved small-molecule glycopyrrolate, which promoted PNS axon regeneration, RGC survival and sustained CNS axon regeneration, increased neural firing in the superior colliculus, and enhanced visual target re-innervations by regenerating RGC axons leading to a partial restoration of visual function after ONC. Our study provides insights into repurposing of FDA-approved small molecule for nerve repair and function recovery.

Transcription and proteome changes involved in re-innervation muscle following nerve crush in rats

Severe peripheral nerve injury leads to the irreparable disruption of nerve fibers. This leads to disruption of synapses with the designated muscle, which consequently go through progressive atrophy and damage of muscle function. The molecular mechanism that underlies the re-innervation process has yet to be evaluated using proteomics or transcriptomics. In the present study, multi-dimensional data were therefore integrated with transcriptome and proteome profiles in order to investigate the mechanism of re-innervation in muscles. Two simulated nerve injury muscle models in the rat tibial nerve were compared: the nerve was either cut (denervated, DN group) or crushed but with the nerve sheath intact (re-innervated, RN group). The control group had a preserved and intact tibial nerve. At 4 weeks, the RN group showed better tibial nerve function and recovery of muscle atrophy compared to the DN group. As the high expression of Myh3, Postn, Col6a1 and Cfi, the RN group demonstrated superior re-innervation as well. Both differentially expressed genes (DEGs) and proteins (DEPs) were enriched in the peroxisome proliferator-activated receptors (PPARs) signaling pathway, as well as the energy metabolism. This study provides basic information regarding DEGs and DEPs during re-innervation-induced muscle atrophy. Furthermore, the crucial genes and proteins can be detected as possible treatment targets in the future.