Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex

The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

Influences of Horticultural Therapy and Functional Recovery Training at a Day-Care Center for the Elderly and Text Mining of Care Records by AI

Background: In Japan, due to the COVID-19 pandemic, various behavioral restrictions were implemented from March 2020, resulting in an increased number of elderly people with reduced participation in care and rehabilitation. As a result, the decline in motor and cognitive functions became more pronounced. Purpose: The study examined how activities combining passive horticultural therapy, which is always introduced, with active functional recovery training, which is used in the functional recovery training of patients with hemiplegia, influence the behavior of elder people using the facility. Methods: 36 elder people with care need 1 or 2 who regularly used the day-care facilities after the pandemic ended and who agreed to participate in the study was included. The assessment data were every three months from December 2021 to December 2023 after the COVID-19 pandemic, the MMSE and Moca-J, TMIG-Index, and GDS15. AI-based text mining was used to compare changes in visit reports before and after the introduction of the Posture Chart and Red Code, and the relationship between the language used. Results: The results of MMSE and Moca-J were both significantly higher in Group B and C than in Group A. TIMG assessment, was significantly higher in Group B and C than in Group A, and Group C was significantly higher than Group B. The GDS, an assessment of depression in old age, tended to be significantly higher in Group A than in Groups B and C. In the “Co-Occurrence Network Analysis” shown after the introduction of the latest functional recovery training equipment such as the Red Cord, its results showed a high association between the words Bathing and CARE and words such as POSTURE, Red-Code, and AI, App, which are used in functional training and rehabilitation, and their analysis. Conclusion: At day-care facilities specializing in functional recovery training and rehabilitation, a combination of horticultural therapy and the latest functional training equipment found to help maintain the physical and mental health of elderly people certified as requiring nursing care. Since this is a short-term study following behavioral restrictions, long-term research should continue to study the effects of adding functional training, handled by rehabilitation professionals, to horticultural therapy.

A hyaluronic acid granular hydrogel nerve guidance conduit promotes regeneration and functional recovery of injured sciatic nerves in rats

A hyaluronic acid granular hydrogel can promote neuronal and astrocyte colony formation and axonal extension in vitro,suggesting that the hydrogel can simulate an extracellular matrix structure to promote neural regeneration.However,in vivo experiments have not been conducted.In this study,we transplanted a hyaluronic acid granular hydrogel nerve guidance conduit to repair a 10-mm long sciatic nerve gap.The Basso,Beattie,and Bresnahan locomotor rating scale,sciatic nerve compound muscle action potential recording,Fluoro-Gold retrograde tracing,growth related protein 43/S100 immunofluorescence staining,transmission electron microscopy,gastrocnemius muscle dry/wet weight ratio,and Masson’s trichrome staining results showed that the nerve guidance conduit exhibited similar regeneration of sciatic nerve axons and myelin sheath,and recovery of the electrophysiological function and motor function as autologous nerve transplantation.The conduit results were superior to those of a bulk hydrogel or silicone tube transplant.These findings suggest that tissue-engineered nerve conduits containing hyaluronic acid granular hydrogels effectively promote the morphological and functional recovery of the injured sciatic nerve.The nerve conduits have the potential as a material for repairing peripheral nerve defects.

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice:effects of 4-aminopyridine

We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.

Ex vivo non-viral vector-mediated neurotrophin-3 gene transfer to olfactory ensheathing glia: effects on axonal regeneration and functional recovery after implantation in rats with spinal cord injury

Objective Combine olfactory ensheathing glia （OEG） implantation with ex vivo non-viral vector-based neurotrophin- 3 （NT-3） gene therapy in attempting to enhance regeneration after thoracic spinal cord injury （SCI）. Methods Primary OEG were transfected with cationic liposome-mediated recombinant plasmid pcDNA3.1 （＋）-NT3 and subsequently implanted into adult Wistar rats directly after the thoracic spinal cord （T9） contusion by the New York University impactor. The animals in 3 different groups received 4x 1050EG transfected with pcDNA3.1 （＋）-NT3 or pcDNA3.1 （＋） plasmids, or the OEGs without any plasmid transfection, respectively; the fourth group was untreated group, in which no OEG was implanted. Results NT-3 production was seen increased both ex vivo and in vivo in pcDNA3.1 （＋）-NT3 transfected OEGs. Three months after implantation of NT-3-transfected OEGs, behavioral analysis revealed that the hindlimb function of SCI rats was improved. All spinal cords were filled with regenerated neurofilament-positive axons. Retrograde tracing revealed enhanced regenerative axonal sprouting. Conclusion Non-viral vector-mediated genetic engineering of OEG was safe and more effective in producing NT- 3 and promoting axonal outgrowth followed by enhancing SCI recovery in rats.

Adipose-derived mesenchymal stem cells accelerate nerve regeneration and functional recovery in a rat model of recurrent laryngeal nerve injury

Medialization thyroplasty or injection laryngoplasty for unilateral vocal fold paralysis cannot restore mobility of the vocal fold. Recent studies have shown that transplantation of mesenchymal stem cells is effective in the repair of nerve injuries. This study investigated wheth- er adipose-derived stem celt transplantation could repair recurrent laryngeal nerve injury. Rat models of recurrent laryngeal nerve injury were established by crushing with micro forceps. Adipose-derived mesenchymal stem cells （ADSCs; 8 ×105） or differentiated Schwann-like adipose-derived mesenchymal stem cells （dADSCs; 8×105） or extracellular matrix were injected at the site of injury. At 2, 4 and 6 weeks post-surgery, a higher density of myelinated nerve fiber, thicker myelin sheath, improved vocal fold movement, better recovery of nerve conduction capacity and reduced thyroarytenoid muscle atrophy were found in ADSCs and dADSCs groups compared with the extracellu- lar matrix group. The effects were more pronounced in the ADSCs group than in the dADSCs group. These experimental results indicated that ADSCs transplantation could be an early interventional strategy to promote regeneration after recurrent laryngeal nerve injury.

Locking compression plate+T-type steel plate for postoperative weight bearing and functional recovery in complex tibial plateau fractures

Complex tibial plateau fractures can seriously affect quality of life and physical and mental health of patients.The anatomical relationship between the proximal tibial bone and soft tissue is complex,resulting in different types of tibial plateau fractures.Violent trauma can lead to displaced fracture,serious soft tissue injury,and potentially,dislocation of the knee joint.Therefore,tibial plateau fractures are extremely unstable.AIM To assess the use of locking compression plate(LCP)+T-type steel plate for postoperative weight bearing and functional recovery of complex tibial plateau fractures.METHODS Ninety-seven patients with complex tibial plateau fractures who underwent surgery at our hospital were selected for retrospective study.Forty-nine patients had been treated with LCP+T-type steel plate limited internal fixation(study group),and 48 patients with bilateral ordinary steel plate support(control group).The operation process index,postoperative rehabilitation related index,Rasmussen score of the knee joint,tibial plateau varus angle(TPA),tibial plateau retroversion angle(PA),and surgical complications of the two groups were compared.RESULTS The operation time and intraoperative bone graft volume in the study group were lower than those in the control group(P<0.05).There were no significant differences in surgical bleeding,anterior external incision length,postoperative drainage,hospital stay duration,and fracture healing time between the groups(P>0.05).There was no significant difference in the TPA and PA angle between the groups immediately and 18 mo after surgery(P>0.05).At 12 mo after surgery,the Rasmussen scale score was higher in the study group than in the control group(P<0.05).There was no significant difference in the Rasmussen scale score at 18 mo after surgery,and the radiology score at 12 and 18 mo after surgery,between the two groups(P>0.05).The postoperative complication rate in the study group(3.77%)was lower than that in the control group(15.09%;P<0.05).CONCLUSION LCP+T-type steel plate internal fixation has advantages in terms of minimizing trauma and enabling early postoperative functional exercise,promoting functional recovery and lower limb weight-bearing,and reducing postoperative complications.

Exercise promotes motor functional recovery in rats with corticospinal tract injury:anti-apoptosis mechanism

Studies have shown that exercise interventions can improve functional recovery after spinal cord injury, but the mechanism of action remains unclear. To investigate the mechanism, we estab-lished a unilateral corticospinal tract injury model in rats by pyramidotomy, and used a single pellet reaching task and horizontal ladder walking task as exercise interventions postoperatively. Functional recovery of forelimbs and forepaws in the rat models was noticeably enhanced after the exercises. Furthermore, TUNEL staining revealed signiifcantly fewer apoptotic cells in the spinal cord of exercised rats, and western blot analysis showed that spinal cord expression of the apopto-sis-related protein caspase-3 was signiifcantly lower, and the expression of Bcl-2 was signiifcantly higher, while the expression of Bax was not signiifantly changed after exercise, compared with the non-exercised group. Expression of these proteins decreased with time after injury, towards the levels observed in sham-operated rats, however at 4 weeks postoperatively, caspase-3 expression remained signiifcantly greater than in sham-operated rats. The present ifndings indicate that a re-duction in apoptosis is one of the mechanisms underlying the improvement of functional recovery by exercise interventions after corticospinal tract injury.

Inhibition of LncRNA Vof-16 expression promotes nerve regeneration and functional recovery after spinal cord injury

Our previous RNA sequencing study showed that the long non-coding RNA ischemia-related factor Vof-16(lncRNA Vof-16)was upregulated after spinal cord injury,but its precise role in spinal cord injury remains unclear.Bioinformatics predictions have indicated that lncRNA Vof-16 may participate in the pathophysiological processes of inflammation and apoptosis.PC12 cells were transfected with a pHBLV-U6-MCS-CMV-ZsGreen-PGK-PURO vector to express an lncRNA Vof-16 knockdown lentivirus and a pHLV-CMVIE-ZsGree-Puro vector to express an lncRNA Vof-16 overexpression lentivirus.The overexpression of lncRNA Vof-16 inhibited PC12 cell survival,proliferation,migration,and neurite extension,whereas lncRNA Vof-16 knockdown lentiviral vector resulted in the opposite effects in PC12 cells.Western blot assay results showed that the overexpression of lncRNA Vof-16 increased the protein expression levels of interleukin 6,tumor necrosis factor-α,and Caspase-3 and decreased Bcl-2 expression levels in PC12 cells.Furthermore,we established rat models of spinal cord injury using the complete transection at T10.Spinal cord injury model rats were injected with the lncRNA Vof-16 knockdown or overexpression lentiviral vectors immediately after injury.At 7 days after spinal cord injury,rats treated with lncRNA Vof-16 knockdown displayed increased neuronal survival and enhanced axonal extension.At 8 weeks after spinal cord injury,rats treated with the lncRNA Vof-16 knockdown lentiviral vector displayed improved neurological function in the hind limb.Notably,lncRNA Vof-16 knockdown injection increased Bcl-2 expression and decreased tumor necrosis factor-αand Caspase-3 expression in treated animals.Rats treated with the lncRNA Vof-16 overexpression lentiviral vector displayed opposite trends.These findings suggested that lncRNA Vof-16 is associated with the regulation of inflammation and apoptosis.The inhibition of lncRNA Vof-16 may be useful for promoting nerve regeneration and functional recovery after spinal cord injury.The experiments were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University,China.

Epigallocatechin-3-gallate treatment to promote neuroprotection and functional recovery after nervous system injury

Traumatic spinal cord injury （SCI） causes motor paralysis, sensory anesthesia and autonomic dysfunction below the le- sion site and additionally some SCI patients refer neuropathic pain together with these signs and symptoms. Clinical and experimental studies have revealed the main pathological changes of injured spinal cord implicated in all these signs and symptoms, including neuropathic pain. After few hours of traumatic SCI, it is usual to observe broken blood brain barrier with plasma and blood cells extravasation, cell necrosis, disruption of ascending and descending spinal cord pathways and increased potassium and glutamate. Glutamate contributes to excitotoxicity of neurons whereas potassium facilitates ectopic depolarization of survival neurons and activation of resident microglia.

Functional recovery of injured sciatic nerve by intraperitoneal injection of multiwalled carbon nanotubes

Some evidence suggests that multiwalled carbon nanotubes can promote neuronal differentiation and growth. The present study investigated the effect of functional multiwalled carbon nanotubes （MWCNTs） on functional recovery of injured sciatic nerves in mice. The results revealed that MWCNTs accelerated the recovery of functional index scores of injured sciatic nerves in mice. Moreover, the medullary sheath was significantly thicker in the injured sciatic nerve following MWCNTs administration. These effects were dose-dependent.

Reorganization of spinal neural circuitry and functional recovery after spinal cord injury

The ability of the adult central nervous system to reorganize its circuits over time is the key to understand the functional improvement in subjects with spinal cord injury （SCI）. Adaptive changes within spared neuronal circuits may occur at cortical, brainstem, or spinal cord level, both above and below a spinal lesion （Bareyre et al., 2004）. At each level the reorganization is a very dynamic process, and its degree is highly variable, depending on several factors, including the age of the subject when SCI has occurred and the rehabilitative therapy. The use of electrophysiological techniques to assess these functional changes in neural networks is of great interest, because invasive methodologies as employed in preclinical models can obviously not be used in clinical studies.

Extrinsic inhibitors in axon sprouting and functional recovery after spinal cord injury

The limited axonal growth after central nervous system （CNS） injury such as spinal cord injury presents a major challenge in promoting repair and recovery. The literature in axonal repair has focused mostly on frank regeneration of injured axons. Here, we argue that sprouting of uninjured axons, an innate repair mech- anism of the CNS, might be more amenable to modulation in order to promote functional repair. Extrinsic inhibitors of axonal growth modulate axon sprouting after injury and may serve as the first group of therapeutic targets to promote functional repair.

Promoting functional recovery by inhibition of repulsive guidance molecule-a after spinal cord injury

Spinal cord injury（SCI）leads to permanent disability with motor and sensory dysfunctions.The mature mammalian central nervous system（CNS）possesses a limited capacity to regenerate/regrow after injury.

The proteome of distal nerves: implication in delayed repair and poor functional recovery

Chronic denervation is one of the key factors that affect nerve regeneration.Chronic axotomy deteriorates the distal nerve stump,causes protein changes,and renders the microenvironment less permissive for regeneration.Some of these factors/proteins have been individually studied.To better delineate the comprehensive protein expression profiles and identify proteins that contribute to or are associated with this detrimental effect,we carried out a proteomic analysis of the distal nerve using an established delayed rat sciatic nerve repair model.Four rats that received immediate repair after sciatic nerve transection served as control,whereas four rats in the experimental group(chronic denervation)had their sciatic nerve repaired after a 12-week delay.All the rats were sacrificed after 16 weeks to harvest the distal nerves for extracting proteins.Twenty-five micrograms of protein from each sample were fractionated in SDS-PAGE gels.NanoLC-MS/MS analysis was applied to the gels.Protein expression levels of nerves on the surgery side were compared to those on the contralateral side.Any protein with a P value of less than 0.05 and a fold change of 4 or higher was deemed differentially expressed.All the differentially expressed proteins in both groups were further stratified according to the biological processes.A PubMed search was also conducted to identify the differentially expressed proteins that have been reported to be either beneficial or detrimental to nerve regeneration.Ingenuity Pathway Analysis(IPA)software was used for pathway analysis.The results showed that 709 differentially expressed proteins were identified in the delayed repair group,with a bigger proportion of immune and inflammatory process-related proteins and a smaller proportion of proteins related to axon regeneration and lipid metabolism in comparison to the control group where 478 differentially expressed proteins were identified.The experimental group also had more beneficial proteins that were downregulated and more detrimental proteins that were upregulated.IPA revealed that protective pathways such as LXR/RXR,acute phase response,RAC,ERK/MAPK,CNTF,IL-6,and FGF signaling were inhibited in the delayed repair group,whereas three detrimental pathways,including the complement system,PTEN,and apoptosis signaling,were activated.An available database of the adult rodent sciatic nerve was used to assign protein changes to specific cell types.The poor regeneration seen in the delayed repair group could be associated with the down-regulation of beneficial proteins and up-regulation of detrimental proteins.The proteins and pathways identified in this study may offer clues for future studies to identify therapeutic targets.

CZL-80,a novel caspase-1 inhibitor,pro⁃motes functional recovery after progressive ischemic stroke

OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activated caspase-1 has thus been considered a promising target for stroke therapy.However,it remains not fully understood how caspase-1 ag⁃gravates progressive functional impairment.We previously identified a novel caspase-1 inhibitor CZL-80,the present study is to explore whether CZL-80 protects against progressive ischemic stroke.METHODS Male C57/BL6 mice and cas⁃pase-1-/-mice were subjected to photothrombotic(PT)-induced cerebral ischemia.CZL-80 was in⁃traperitoneally injected daily during 1-7 d,1-4 d,4-7 d after PT.The grid-walking task and the cyl⁃inder task were used to determine the motor function.RESULTS Mice developed primary and the secondary neurological dysfunction at 1 d and 4-7 d after PT onset.The activation of cas⁃pase-1 peaked at 7 d after ischemic stroke and caspase-1 was mainly derived from activated microglia.Treatment with CZL-80(30 mg·kg-1)during 1-7 d significantly improved motor func⁃tion.Administration of CZL-80 during 1-4 d could not ameliorate motor function loss while administration during 4-7 d after PT onset signifi⁃cantly reduced foot faults and forelimb symme⁃try.Remarkably,treatment with CZL-80 during 4-7 d showed no significant difference in efficacy compared with the its administration during 1-7 d,which indicated a key therapeutic window.More⁃over,the neuroprotective effect of CZL-80 during 4-7 d was available at least until 43 d after isch⁃emic stroke,indicating CZL-80 can improve the long-term neurological function after cerebral ischemia.Furthermore,administration of CZL-80(30 mg·kg-1)during 4-7 d after PT onset in cas⁃pase-1-/-mice failed to improve the motor func⁃tion,which suggested that the neuroprotective effect of CZL-80 was caspase-1-dependent.The results showed that CZL-80 did not inhibit the expression of GSDMD and failed to reduce neu⁃ronal loss after ischemia.These results indicated the effect of CZL-80 was not attributable to inhib⁃it pyroptosis.We further found that CZL-80 signif⁃icantly reduced the number of activated microglia in the peri-infarct brain cortex after ischemic stroke,which might be involved in its neuropro⁃tective effect.CONCLUSION CZL-80,a novel caspase-1 inhibitor,improved motor function after progressive ischemic stroke in mice.The effective therapeutic window of CZL-80 would be 4-7 d after ischemia,when the secondary neuro⁃logical dysfunction occurred.Therefore,the inter⁃vention by targeting caspase-1 in this window phase provides a novel strategy for the function⁃al recovery of stroke survivors.

Propriospinal interneurons in the spotlight for anatomical and functional recovery after spinal cord injury

Spinal cord injury（SCI）with consecutive paralysis below the lesion level is a severe disorder affecting the patient for the rest of his or her life.So far,there is no known fundamental intervention strategy for efficiently helping those patients regain their motor abilities,despite intense research in this area.Thus,effective treatment for those patients is still an open question. A spinal cord injury is accompanied by a prima- ry, severe and irreversible neuronal cell death in the trauma region, fol- lowed by a secondary extensive cell necrosis in the lesion surrounding areas. Nevertheless, recent studies indicate that regeneration after spinal cord injury could be possible if three substantial steps are fulfilled： （1） reduction of the inhibitory environment at the SCI lesion site, （2） iden- tification of a neural substrate to establish new spinal circuits, and （3） support of these circuits to form permanent, functional motor, sensory, or autonomic connections （Dru and Hoh, 2015）.

Anatomical changes in the somatosensory system after large sensory loss predict strategies to promote functional recovery after spinal cord injury

Among cases of spinal cord injury are injuries involving the dorsal column in the cervical spinal cord that interrupt the major cutaneous afferents from the hand to the cuneate nucleus（Cu）in the brainstem.Deprivation of touch and proprioceptive inputs consequently impair skilled hand use.