From single to combinatorial therapies in spinal cord injuries for structural and functional restoration

Spinal cord injury results in paralysis, sensory disturbances, sphincter dysfunction, and multiple systemic secondary conditions, most arising from autonomic dysregulation. All this produces profound negative psychosocial implications for affected people, their families, and their communities;the financial costs can be challenging for their families and health institutions. Treatments aimed at restoring the spinal cord after spinal cord injury, which have been tested in animal models or clinical trials, generally seek to counteract one or more of the secondary mechanisms of injury to limit the extent of the initial damage. Most published works on structural/functional restoration in acute and chronic spinal cord injury stages use a single type of treatment: a drug or trophic factor, transplant of a cell type, and implantation of a biomaterial. Despite the significant benefits reported in animal models, when translating these successful therapeutic strategies to humans, the result in clinical trials has been considered of little relevance because the improvement, when present, is usually insufficient. Until now, most studies designed to promote neuroprotection or regeneration at different stages after spinal cord injury have used single treatments. Considering the occurrence of various secondary mechanisms of injury in the acute and sub-acute phases of spinal cord injury, it is reasonable to speculate that more than one therapeutic agent could be required to promote structural and functional restoration of the damaged spinal cord. Treatments that combine several therapeutic agents, targeting different mechanisms of injury, which, when used as a single therapy, have shown some benefits, allow us to assume that they will have synergistic beneficial effects. Thus, this narrative review article aims to summarize current trends in the use of strategies that combine therapeutic agents administered simultaneously or sequentially, seeking structural and functional restoration of the injured spinal cord.

Timing of surgical repair of bile duct injuries after laparoscopic cholecystectomy: A systematic review

BACKGROUND The surgical management of bile duct injuries(BDIs)after laparoscopic cholecystectomy(LC)is challenging and the optimal timing of surgery remains unclear.The primary aim of this study was to systematically evaluate the evidence behind the timing of BDI repair after LC in the literature.AIM To assess timing of surgical repair of BDI and postoperative complications.METHODS The MEDLINE,EMBASE,and The Cochrane Library databases were systematically screened up to August 2021.Risk of bias was assessed via the Newcastle Ottawa scale.The primary outcomes of this review included the timing of BDI repair and postoperative complications.RESULTS A total of 439 abstracts were screened,and 24 studies were included with 15609 patients included in this review.Of the 5229 BDIs reported,4934(94%)were classified as major injury.Timing of bile duct repair was immediate(14%,n=705),early(28%,n=1367),delayed(28%,n=1367),or late(26%,n=1286).Standardization of definition for timing of repair was remarkably poor among studies.Definitions for immediate repair ranged from<24 h to 6 wk after LC while early repair ranged from<24 h to 12 wk.Likewise,delayed(>24 h to>12 wk after LC)and late repair(>6 wk after LC)showed a broad overlap.CONCLUSION The lack of standardization among studies precludes any conclusive recommendation on optimal timing of BDI repair after LC.This finding indicates an urgent need for a standardized reporting system of BDI repair.

Neural regeneration after peripheral nerve injury repair is a system remodelling process of interaction between nerves and terminal effector

In China, there are approximately 20 million people suffering from peripheral nerve injury and this number is increasing at a rate of 2 million per year. These patients cannot live or work independently and are a heavy responsibility on both family and society because of extreme disability and dysfunction caused by peripheral nerve injury （PNI）. Thus, repair of PNI has become a major public health issue in China.

Repairing peripheral nerve injury using tissue engineering techniques

Each year approximately 360,000 people in the United States suffer a peripheral nerve injury （PNI）, which is a leading source of lifelong disability （Kelsey et al., 1997; Noble et al., 1998）. The most frequent cause of PNIs is motor vehicle accidents, while gunshot wounds, stabbings, and birth trauma are also common factors. Patients suffering from disabilities as a result of their PNIs are also burdensome to the healthcare system, with aver- age hospital stays of 28 days each year （Kelsey et al., 1997; Noble et al., 1998）.

Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats.

Acetyl-11-keto-beta-boswellic acid promotes sciatic nerve repair after injury: molecular mechanism

Previous studies showed that acetyl-11-keto-beta-boswellic acid(AKBA),the active ingredient in the natural Chinese medicine Boswellia,can stimulate sciatic nerve injury repair via promoting Schwann cell proliferation.However,the underlying molecular mechanism remains poorly understood.In this study,we performed genomic sequencing in a rat model of sciatic nerve crush injury after gastric AKBA administration for 30 days.We found that the phagosome pathway was related to AKBA treatment,and brain-derived neurotrophic factor expression in the neurotrophic factor signaling pathway was also highly up-regulated.We further investigated gene and protein expression changes in the phagosome pathway and neurotrophic factor signaling pathway.Myeloperoxidase expression in the phagosome pathway was markedly decreased,and brain-derived neurotrophic factor,nerve growth factor,and nerve growth factor receptor expression levels in the neurotrophic factor signaling pathway were greatly increased.Additionally,expression levels of the inflammatory factors CD68,interleukin-1β,pro-interleukin-1β,and tumor necrosis factor-αwere also decreased.Myelin basic protein-andβ3-tubulin-positive expression as well as the axon diameter-to-total nerve diameter ratio in the injured sciatic nerve were also increased.These findings suggest that,at the molecular level,AKBA can increase neurotrophic factor expression through inhibiting myeloperoxidase expression and reducing inflammatory reactions,which could promote myelin sheath and axon regeneration in the injured sciatic nerve.

Delayed peripheral nerve repair: methods, including surgical ‘cross-bridging' to promote nerve regeneration

Despite the capacity of Schwann cells to support peripheral nerve regeneration, functional recovery after nerve injuries is frequently poor, especially for proximal injuries that require regenerating axons to grow over long distances to reinnervate distal targets. Nerve transfers, where small fascicles from an adjacent intact nerve are coapted to the nerve stump of a nearby denervated muscle, allow for functional return but at the expense of reduced numbers of innervating nerves. A 1-hour period of 20 Hz electrical nerve stimulation via electrodes proximal to an injury site accelerates axon outgrowth to hasten target reinnervation in rats and humans, even after delayed surgery. A novel strategy of enticing donor axons from an otherwise intact nerve to grow through small nerve grafts（cross-bridges） into a denervated nerve stump, promotes improved axon regeneration after delayed nerve repair. The efficacy of this technique has been demonstrated in a rat model and is now in clinical use in patients undergoing cross-face nerve grafting for facial paralysis. In conclusion, brief electrical stimulation, combined with the surgical technique of promoting the regeneration of some donor axons to ‘protect＇ chronically denervated Schwa nn cells, improves nerve regeneration and, in turn, functional outcomes in the management of peripheral nerve injuries.

Self-assembling peptide nanofibrous hydrogel as a promising strategy in nerve repair after traumatic injury in the nervous system

Following injury in central nervous system（CNS）,there are pathological changes in the injured region,which include neuronal death,axonal damage and demyelination,inflammatory response and activation of glial cells.The proliferation of a large number of astrocytes results in the formation of glial scar.

Optimising repetitive transcranial magnetic stimulation for neural circuit repair following traumatic brain injury

While it is well-known that neuronal activity promotes plasticity and connectivity, the success of activity-based neural rehabilitation programs remains extremely limited in human clinical experience because they cannot adequately control neuronal excitability and activity within the injured brain in order to induce repair. However, it is possible to non-invasively modulate brain plasticity using brain stimu- lation techniques such as repetitive transcranial （rTMS） and transcranial direct current stimulation （tDCS） techniques, which show promise for repairing injured neural circuits （Henrich-Noack et al., 2013; Lefaucher et al., 2014）. Yet we are far from having full control of these techniques to repair the brain following neurotrauma and need more fundamen- tal research （Ellaway et al., 2014; Lefaucher et al., 2014）. In this perspective we discuss the mechanisms by which rTMS may facilitate neurorehabilitation and propose experimental techniques with which magnetic stimulation may be investi- gated in order to optimise its treatment potential.

Who is who after spinal cord injury and repair? Can the brain stem descending motor pathways take control of skilled hand motor function?

Over the last years,anatomical,electrophysiological and genetic studies have carefully dissected the pathways connecting the brain and the spinal cord.Lawrence and Kuypers（1968）described the organization of the descending motor pathways in the non-human primate spinal cord.Although there are some differences between species regarding the precise anatomical location of each spinal pathway and the selective connectivity onto spinal interneurons and motoneurons, the pattern of organization described is con- served among the mammalian spinal cord （Courtine et al., 2007）. Based on their description, the major descending motor pathways are grouped depending on their anatomical origin and their termi- nal distribution pattern in the spinal grey matter. The motor cortex projects corticospinal axons to the spinal cord, which mostly run in the contralateral cord and innervate the mid and dorsal grey matter neurons.

A 16-channel high-voltage reconfigurable and flexible-controlled implantable wireless closed-loop system for SCI repair

An adaptive closed-loop system for spinal cord injury(SCI) repair is designed. It integrates stimulation and recording on 16 pairs of electrodes. Two switches(SAS3 T16/SAS1 T16 X2) fabricated in high-voltage 0.8 μm process with online re-configurable function are proposed. These two switches are combined with commercial off-the-shelf(COTS) electronics to implement the closed-loop implantable system in compact module. The system includes amplifier for recording neural signals, high-voltage stimulator, power transmission device, central processing module and flexible implantable electrodes. Two customized switches route any electrode to amplifier or stimulator, and nerve stimulation and signal recording are performed through lead wire-driven channels. The entire system is able to operate at up to 28 V, and is a biocompatible package with a volume of 42 mm×35 mm×8 mm. This system solves several problems encountered in implantable devices: low flexibility, negative influence of stimulus artifacts on neural detection and low integration of electrodes.

Stem cell transplantation for repair of sciatic nerve injury

Three articles regarding transplantation of umbilical cord mesenchmal stem cells alone or in combination with Schwann cells and feridex and polylysine complex-labeled bone marrow stromal cell transplantation （MRI tracing） for repair of sciatic nerve injury were reported in Neural Regeneration

Tissue-engineered nerve for repair of sciatic nerve injury

Three articles regarding the use of nerve fragments bridging regeneration chambers, three-dimensional bionic nerve conduits and multiwalled carbon nanotubes for repair of sciatic nerve injury were reported in Neural Regeneration Research. We hope that our readers find these papers useful to their research.

Glial kon/NG2 gene network for central nervous system repair

The glial regenerative response to central nervous system（CNS） injury,although limited,can be harnessed to promote regeneration and repair.Injury provokes the proliferation of ensheathing glial cells,which can differentiate to remyelinate axons,and partially restore function.This response is evolutionarily conserved,strongly implying an underlying genetic mechanism.In mammals,it is elicited by NG2 glia,but most often newly generated cells fail to differentiate.Thus an important goal had been to find out how to promote glial differentiation following the proliferative response.A gene network involving Notch and prospero（pros） controls the balance between glial proliferation and differentiation in flies and mice,and promotes CNS repair at least in fruit-flies.A key missing link had been how to relate the function of NG2 to this gene network.Recent findings by Losada-Perez et al.,published in JCB,demonstrated that the Drosophila NG2 homologue kon-tiki（kon） is functionally linked to Notch and pros in glia.By engaging in two feedback loops with Notch and Pros,in response to injury,Kon can regulate both glial cell number and glial shape homeostasis,essential for repair.Drosophila offers powerful genetics to unravel the control of stem and progenitor cells for regeneration and repair.

Acupuncture promotes repair of cerebral ischemic injury

Three articles conceming the molecular biology and proteomics study of the mechanism underlying the effects of acupuncture on the repair of cerebral ischemic injury were published in the Neural Regeneration Research. We hope that our readers find these papers useful to their research.

Editor's Choice—Application of tissue-engineered materials in the repair of spinal cord injury

The development of tissue-engineered technology brings hope to the treatment of spinal cord injury. Preparation of a tissue-engineered spinal cord stent with three-dimensional bionic structure has important value in the construction of tissue-engineered spinal cord and the repair of spinal cord injury. Acellular scaffolds can be produced with chemical extraction,

Research progress of stem cell-derived exosomes in injury repair

After organ and tissue injury,the proliferation and differentiation of stem cells themselves play only a small role in the repair of injury,and their repair role is mainly played through the paracrine function of stem cells.Exosomes are nano-scale vesicles that are secreted into the extracellular space in an exocytic manner,and its own function will be regulated after the target cells absorb the exosomes.Stem cell-derived exosomes communicate between cells by transmitting proteins,lipids and micro-RNAs(miRNAs).The targeting and biological properties of stem cell-derived exosomes are determined by the level of miRNAs that they carry.After the exosomes reach the target cells and undergo fusion,the gene expression of the target cells is changed by degradation and expression.In addition,the RNA and protein of stem cell-derived exosomes can also limit the development of injury through cell homing.This article will review the mechanism of stem cell-derived exosomes in wound healing,joint injury,fracture healing and cardiac injury.

Telemedicine and digital management in repair and regeneration after nerve injury and in nervous system diseases

To the editor, We read with interest the article, ＂Facilitating transparency in spinal cord injury studies using data standards and ontol- ogles＂ by Professor Vance E Lemmon, University of Miami, USA （Lemmon et al., 2014） and would like to add to the discussion on digital management in spinal cord injury. We have analyzed the advancements in the treatment of spinal cord injury, traumatic brain jury. Encouraging outcomes injury and peripheral nerve in- have been achieved in the area of regulating axon growth in vivo and in vitro. However, such a large amount of information neither provides in-depth insight for other scholars nor provides detailed therapeutic nrotocols for clinical studies.

Dynamics of glutamine synthetase expression in hepatic ischemiareperfusion injury: Implications for therapeutic interventions

BACKGROUND Hepatic ischemia-reperfusion injury(IRI)poses a great challenge in liver surgery and transplantation because of oxidative stress and inflammatory responses.The changes in glutamine synthetase(GS)expression during hepatic IRI remain unclear.AIM To investigate the dynamic expression of GS during hepatic IRI.METHODS Following hepatic ischemia for 1 h and reperfusion,liver tissue samples were collected at 0.5,6,and 24 hours postreperfusion for fixation,embedding,section-ing.Hematoxylin and eosin staining and GS staining were performed.RESULTS GS expression rapidly decreases in hepatocytes around the central vein after IRI,reaching its lowest point at 6 hours postreperfusion,and then gradually recovers.CONCLUSION GS is highly sensitive to IRI,highlighting its potential role as an indicator of liver injury states and a target for therapeutic intervention.

Acetyl-11-keto-β-boswellic acid extracted from Boswellia serrata promotes Schwann cell proliferation and sciatic nerve function recovery

Frankincense can promote blood circulation. Acetyl-11-keto-β-boswellic acid （AKBA） is a small molecule with anti-inflammatory properties that is derived from Boswellia serrata. Here, we hypothesized that it may promote regeneration of injured sciatic nerve. To address this hypothesis, we established a rat model of sciatic nerve injury using a nerve clamping method. Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection for 30 days from the 1st day after injury. Sciatic nerve function was evaluated using the sciatic functional index. Degree of muscle atrophy was measured using the triceps surae muscle Cuadros index.Neuropathological changes were observed by hematoxylin-eosin staining. Western blot analysis was used to detect expression of phospho-extracellular signal-regulated kinase 1 and 2 （p-ERK1/2） in injured nerve. S100 immunoreactivity in injured nerve was detected by immunohistochemistry. In vivo experiments showed that 3 and 6 mg/kg AKBA significantly increased sciatic nerve index, Cuadros index of triceps muscle, p-ERK1/2 expression, and S100 immunoreactivity in injured sciatic nerve of sciatic nerve injury model rats. Furthermore,for in vitro experiments, Schwann cells were treated with AKBA at 0–20 μg/mL. Proliferation of Schwann cells was detected by Cell Counting Kit-8 colorimetry assay. The results showed that 2 μg/mL AKBA is the optimal therapeutic concentration. In addition, ERK phosphorylation levels increased following 2 μg/mL AKBA treatment. In the presence of the ERK1/2 inhibitor, PD98059 （2.5 μL/mL）, the AKBA-induced increase in p-ERK1/2 protein expression was partially abrogated. In conclusion, our study shows that AKBA promotes peripheral nerve regeneration with ERK protein phosphorylation playing a key role in this process.