Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

Clinical Outcome of Internal Fixation and Fusion in the Treatment of Spinal Fractures by Paraspinal Muscular Space Approach

Objective:To explore the clinical effect of internal fixation and fusion with the paraspinal muscle gap approach in the treatment of spinal fracture patients.Methods:104 spinal fracture patients admitted to Central Hospital of TCM from October 2022 to April 2024 were selected as the study subjects and were randomly divided into the control group(n=52)and the observation group(n=52)according to the random number table method.The control group was treated with the conventional approach of internal fixation surgery,and the observation group was treated with the paraspinal muscular interspace approach of internal fixation fusion.The two groups’general data,surgical indexes,pain,lumbar spine function,and postoperative complications were observed.Results:The baseline data of the two groups of patients were not statistically significant(all P>0.05)while the intraoperative bleeding,the first postoperative time getting up from bed,and the length of hospital stay of the patients in the observation group were shorter than that of the control group(all P=0.000<0.001),and the duration of the operation was longer than that of the control group(t=2.644,P=0.010<0.05);at 3 months postoperatively,the VAS scores of the patients in the observation group were significantly lower than those in the control group(t=10.768,P=0.000<0.001),and the JOA score was higher than that of the control group(t=6.498,P=0.000<0.001);the total complication rate of patients in the observation group(3/5.77%)was significantly lower than that of the control group(12/23.08%)(χ^(2)=6.310,P=0.012<0.05).Conclusion:In the treatment of spinal fracture patients,compared with the conventional approach to internal fixation surgery,the paraspinal muscular gap approach to internal fixation and fusion treatment is less traumatic,postoperative lumbar spine function recovery is faster,and can reduce the incidence of postoperative complications.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Comparison of the modified Wiltse’s approach with spinal minimally invasive system and traditional approach for the therapy of thoracolumbar fracture

Thoracolumbar fractures are usually treated by open posterior pedicle screw fixation.However,this procedure involves massive paraspinal muscle stripping,inflicting surgical trauma,and prolonged X-ray exposure.In this study,we observed 127 patients with single-segment injury thoracolumbar fractures.Thirty-six patients were treated by the modified Wiltse’s paraspinal approach with minimally invasive channel system,while 91 patients were treated via traditional posterior approach.Operation time,intraoperative blood loss,intraoperative fluoroscopy frequency,screw placement accuracy,visual analogue scale score,and Cobb’s angle of two groups were compared.The X-ray exposure times were notably reduced(4.2±1.6) in the new approach group(P<0.05).The pedicle screw placement accuracy and Cobb’s angle after surgery were similar in the two groups.We conclude that modified Wiltse’s paraspinal approach w ith spinal minimally invasive channel system surgery can significantly reduce the X-ray exposure times and is an alternative therapy for the thoracolumbar fracture.

Bilateral sequential femoral neck stress fractures in young adult with HIV infection on antiretroviral therapy: A case report

BACKGROUND Femoral neck stress fractures are rarely encountered among young adults and are often associated with either repetitive excessive loading or underlying bone pathology.Preliminary research has indicated human immunodeficiency virus(HIV)/antiretroviral therapy(ART)as predisposing agents to osteopenia and osteoporosis related complications.We report a case of HIV/ART induced insufficiency fracture in a resource limited setting in Central India.Our aim is to increase awareness and promote screening of HIV/ART related osteopenia and osteoporosis in order to prevent catastrophic orthopaedic complications.CASE SUMMARY A 35-year-old HIV positive male presented with a stress fracture of left femoral neck.The patient was on ART and reported no comorbidities.He went on to be successfully managed surgically.However,during work-up osteopenia of the contralateral proximal femur was recognised using Singh’s Index.Six months post-op the patient presented with right-sided femoral-neck stress fracture.At this stage the patient was nonconcordant with ART and denied surgical fixation.CONCLUSION In the absence of co-morbidities,several mechanisms of HIV/antiretroviral therapy may have played a role in predisposing our patient towards such a presentation.We recommend routine screening all HIV-infected patients for osteopenia,especially in younger individuals.In low resource settings and district hospitals,pelvis radiograph&Singh’s index can be used for screening.

Effectiveness and postoperative rehabilitation of one-stage combined anterior-posterior surgery for severe thoracolumbar fractures with spinal cord injury

BACKGROUND Thoracolumbar fractures are generally combined with spinal cord injury to varying degrees,which may cause deterioration of the patients’condition and increase the difficulty of clinical treatment.At present,anterior or combined anterior-posterior surgery is preferred for severe thoracolumbar fractures.AIM To investigate the effectiveness and postoperative rehabilitation of one-stage combined anterior-posterior surgery for severe thoracolumbar fractures with spinal cord injury.METHODS One-hundred-and-twenty patients who received surgery for severe thoracolumbar fractures with spinal cord injury at our hospital from February 2018 to February 2020 were randomly enrolled.They were randomly divided into group 1(one-stage combined anterior-posterior surgery,n=60)and group 2(onestage anterior-approach surgery,n=60).Treatment efficacy was compared between the two groups.RESULTS Blood loss was greater and the operation time was longer in group 1 than in group 2,and the differences were statistically significant(P<0.05).Incision length,intraoperative X-rays,and length of hospital stay were not significantly different between the two groups(P>0.05).Preoperative function of the affected vertebrae was not significantly different between the two groups(P>0.05).In each group,the patients showed significant improvement after surgery.The anterior vertebral height ratio and the posterior vertebral height ratio in group 1 after surgery were significantly higher than those in group 2.The Cobb angle after surgery was significantly lower in group 1 than in group 2(P<0.05).The canal-occupying ratio of the affected vertebrae was not significantly different between the two groups(P>0.05).Before surgery,there was no significant difference in the quality of life scores between the two groups(P>0.05).The above indicators were significantly improved after surgery compared with before surgery in each group.In addition,these indicators were markedly better in group 1 than in group 2 after surgery(P<0.05 for each).CONCLUSION One-stage combined anterior-posterior surgery effectively improves the function of the affected vertebrae and the life quality of patients with severe thoracolumbar fractures and spinal cord injury.This surgical approach is worthy of popularization in clinical use.

Research of the Clinical Effect of Kyphoplasty in the Treatment of Multiple Senile Osteoporotic Spinal Fractures

Objective:To evaluate the clinical effect of kyphoplasty in the treatment of multiple osteoporotic vertebral fractures in the elderly.Methods:The duration of the study was selected from January 2018 to December 2020,and 38 patients with multiple osteoporotic spinal fractures were selected for study evaluation.All patients were treated with kyphoplasty.The clinical indicators of the two groups were compared and analyzed.Results:The total effective rate was 94.7%and the complication rate was 5.3%.The height of midline,anterior and posterior vertebral body,Cobb angle,VAS score,ODI score and ADL score of 38 patients before and after treatment were compared,which were significantly better than those before treatment(P<0.05).Conclusion:The clinical effect of kyphoplasty in the treatment of elderly patients with multiple osteoporosis is significant,which can be promoted in all levels of medical institutions.

Complement-dependent neuroinflammation in spinal cord injury:from pathology to therapeutic implications

Spinal cord injury remains a major cause of disability in young adults,and beyond acute decompression and rehabilitation,there are no pharmacological treatments to limit the progression of injury and optimize recovery in this population.Following the thorough investigation of the complement system in triggering and propagating cerebral neuroinflammation,a similar role for complement in spinal neuroinflammation is a focus of ongoing research.In this work,we survey the current literature investigating the role of complement in spinal cord injury including the sources of complement proteins,triggers of complement activation,and role of effector functions in the pathology.We study relevant data demonstrating the different triggers of complement activation after spinal cord injury including direct binding to cellular debris,and or activation via antibody binding to damage-associated molecular patterns.Several effector functions of complement have been implicated in spinal cord injury,and we critically evaluate recent studies on the dual role of complement anaphylatoxins in spinal cord injury while emphasizing the lack of pathophysiological understanding of the role of opsonins in spinal cord injury.Following this pathophysiological review,we systematically review the different translational approaches used in preclinical models of spinal cord injury and discuss the challenges for future translation into human subjects.This review emphasizes the need for future studies to dissect the roles of different complement pathways in the pathology of spinal cord injury,to evaluate the phases of involvement of opsonins and anaphylatoxins,and to study the role of complement in white matter degeneration and regeneration using translational strategies to supplement genetic models.

Metabolic reprogramming: a new option for the treatment of spinal cord injury

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

Study on the Application Effect of Enhanced Recovery After Surgery (ERAS) in Patients Undergoing Spinal Fracture Surgery

Objective:To study the application effect of the Enhanced Recovery After Surgery(ERAS)model in patients undergoing spinal fracture surgery.Methods:A randomized controlled trial was designed,and 86 patients undergoing spinal fracture surgery were randomly divided into the ERAS group and the conventional care group.Postoperative recovery outcomes of the two groups were compared.Results:The ERAS group showed better outcomes in terms of postoperative pain scores,activities of daily living,length of hospital stay,and adherence to rehabilitation training compared to the conventional care group,with shorter hospital stays and lower medical expenses(P<0.05).Conclusion:The ERAS model significantly improves the postoperative recovery quality of patients undergoing spinal fracture surgery,reduces hospital stay and medical costs,and increases patient satisfaction.

Microglia:a promising therapeutic target in spinal cord injury

Microglia are present throughout the central nervous system and are vital in neural repair,nutrition,phagocytosis,immunological regulation,and maintaining neuronal function.In a healthy spinal cord,microglia are accountable for immune surveillance,however,when a spinal cord injury occurs,the microenvironment drastically changes,leading to glial scars and failed axonal regeneration.In this context,microglia vary their gene and protein expression during activation,and proliferation in reaction to the injury,influencing injury responses both favorably and unfavorably.A dynamic and multifaceted injury response is mediated by microglia,which interact directly with neurons,astrocytes,oligodendrocytes,and neural stem/progenitor cells.Despite a clear understanding of their essential nature and origin,the mechanisms of action and new functions of microglia in spinal cord injury require extensive research.This review summarizes current studies on microglial genesis,physiological function,and pathological state,highlights their crucial roles in spinal cord injury,and proposes microglia as a therapeutic target.

Insights into spinal muscular atrophy from molecular biomarkers

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomarker research is currently receiving more attention,and new candidate biomarkers are constantly being discovered.This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons.We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy,which are classified as either specific or non-specific biomarkers.This review provides new insights into the pathogenesis of spinal muscular atrophy,the mechanism of biomarkers in response to drug-modified therapies,the selection of biomarker candidates,and would promote the development of future research.Furthermore,the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.

Analgesic Effect of Combined Spinal-Epidural Anesthesia and its Effect on TNF-α and CRP Levels in Elderly Patients with Hip Fracture During Surgical Treatment

Objective:To observe the analgesic effect of combined spinal and epidural anesthesia on older patients undergoing hip fracture surgery.Method:One hundred and twenty elderly hip fracture surgery patients treated in our hospital from January 2021 to December 2022 were selected and randomly divided into two groups,with 60 cases in the experimental group and 60 in the control group.The experimental group was given combined spinal-epidural anesthesia intervention measures,while the control group was given epidural anesthesia intervention measures.The analgesic effect,tumor necrosis factor-alpha(TNF-α),C-reactive protein(CRP)levels,and other observation indicators were analyzed after anesthesia intervention.Result:After the intervention,the analgesic effect and the evaluation results of the subjects in the experimental group were better than those in the control group(P<0.05);the obtained values of TNF-αand CRP levels in the experimental group were higher than those of the control group(P<0.05).Conclusion:The combined spinal-epidural anesthesia intervention demonstrated positive outcomes.The analgesic effect of patients during surgery and their inflammatory factor levels improved,which makes this intervention worthy of clinical application and promotion.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Radiographic measurement of morphological abnormalities in thoracolumbar burst fractures: relationship with spinal cord lesion

Objective:To investigate the relationship between morphological abnormalities and spinal cord deficit in thoracolumbar burst fractures. Methods: Seventy-eight patients with thoracolumbar burst fractures were retrospectively reviewed to calculate the stenotic ratio of spinal canal based on the midsagittal diameters and the hyphosis angle according to Cobb. The ASIA scoring of motor function of lower extremities was recorded . Results: The differences (P > 0.05) of the stenotic ratio of spinal canal and the kyphosis angle were not significant between patients without neurological deficit, with incomplete and complete lesions. No significant correlation(P > 0.05) between the stenotic ratio of spinal canal and the kyphosis angle, and ASIA scoring was noted. Conclusion:The severity of spinal cord injuries in thoracolumbar burst fractures is not predicted according to the percentage of canal stenosis or the degree of kyphesis induced by thoracolumbar burst fractures.

Teriparatide anabolic therapy as potential treatment of type Ⅱ dens non-union fractures

Odontoid fractures account for 5% to 15% of all cervical spine injuries and 1% to 2% of all spine fractures. Type Ⅱ fractures are the most common fracture pattern in elderly patients. Treatment(rigid and non-rigid immobilization, anterior screw fixation of the odontoid and posterior C1-C2 fusion) remains controversial and represents a unique challenge for the treating surgeon. The aims of treatment in the elderly is to quickly restore pre-injury function while decreasing morbidity and mortality associated with inactivity, immobilization with rigid collar and prolonged hospitalization. Conservative treatment of type Ⅱ odontoid fractures is associated with relatively high rates of non-union and in a few cases delayed instability. Options for treatment of symptomatic non-unions include surgical fixation or prolonged rigid immobilization. In this report we present the case of a 73-year-old woman with post-traumatic odontoid nonunion successfully treated with Teriparatide systemic anabolic therapy. Complete fusion and resolution of the symptoms was achieved 12 wk after the onset of the treatment. Several animal and clinical studies have confirmed the potential role of Teriparatide in enhancing fracture healing. Our case suggests that Teriparatide may have a role in improving fusion rates of C2 fractures in elderly patients.

Effect of mid-frequency pulse therapy combined with external fixation on bone metabolism, inflammatory response and oxidative stress in patients with osteoporotic distal radial fractures

Objective:To study the effect of mid-frequency pulse therapy combined with external fixation on bone metabolism, inflammatory response and oxidative stress in patients with osteoporotic distal radial fractures.Methods: A total of 72 patients with osteoporotic distal radial fractures who were treated in the hospital between September 2015 and January 2017 were collected and divided into control group (n=36) and observation group (n=36) according to the random number table method. Control group received routine external fixation, and observation group received mid-frequency pulse therapy combined with external fixation. The differences in serum levels of bone metabolism indexes, inflammatory factors and oxidative stress indexes were compared between two groups of patients before and after treatment.Results: Before treatment, differences in serum levels of bone metabolism indexes, inflammatory factors and oxidative stress indexes were not statistically significant between the two groups. After 1 month of treatment, serum BGP, TAC and SOD levels of both groups of patients were higher than those before treatment whileβ-CTX, AKP, TRAP, CRP, IL-1β, IL-6 and MDA levels were lower than those before treatment, and serum BGP, TAC and SOD levels of observation group were higher than those of control group whileβ-CTX, AKP, TRAP, CRP, IL-1β, IL-6 and MDA levels were lower than those of control group.Conclusion: Mid-frequency pulse therapy combined with external fixation can promote fracture healing and reduce postoperative inflammatory response and oxidative stress response in patients with osteoporotic distal radial fracture.

Spinal cord biological safety of image-guided radiation therapy versus conventional radiation therapy

Tumor models were simulated in purebred Beagles at the T9-10 levels of the spinal cord and treated with spinal image-guided radiation therapy or conventional radiation therapy with 50 or 70 Gy total radiation. Three months after radiation, neuronal injury at the T9-10 levels was observed, including reversible injury induced by spinal image-guided radiation therapy and apoptosis induced by conventional radiation therapy. The number of apoptotic cells and expression of the proapoptotic protein Fas were significantly reduced, but expression of the anti-apoptotic protein heat shock protein 70 was significantly increased after image-guided radiation therapy compared with the conventional method of the same radiation dose. Moreover, the spinal cord cell apoptotic index positively correlated with the ratio of Fas/heat shock protein 70. These findings indicate that 3 months of radiation therapy can induce a late response in the spinal cord to radiation therapy; image-guided radiation therapy is safer and results in less neuronal injury compared with conventional radiation therapy.

Establishment and validation of standardized animal models of spinal cord injury by normal external force-caused fracture dislocation

The duplication of animal models plays a key role in spinal cord injury research; however, there has been limited study into normal, external force-derived fracture dislocation. This study adopted experimental devices, designed in-house, to construct standardized ventral and dorsal spinal cord injury animal models of 6 g and 17 g falling from a height of 2, 4, and 10 cm, and 15, 30 or 50 g transversal compression on the spinal cord. The results showed that gradual increases in the degree of histopathological injury led to decreased Tarlov and Basso, Beattie and Bresnahan scores for the behavioral test, and increased Ashworth scores for the hind limb. Furthermore, there was a gradual decline in the slope test in the rats with dorsal spinal cord injury that correlated to increases in the falling substance weight or falling height. Similar alterations were observed in the ventral spinal cord injured rats, proportional to the increase in compression weight. Our experimental findings indicate that the standardized experimental rat models of dorsal and ventral spinal cord injury are stable, reliable and reproducible.

Multimodal therapy strategies based on hydrogels for the repair of spinal cord injury

Spinal cord injury(SCI)is a serious traumatic disease of the central nervous system,which can give rise to the loss of motor and sensory function.Due to its complex pathological mechanism,the treatment of this disease still faces a huge challenge.Hydrogels with good biocompatibility and biodegradability can well imitate the extracellular matrix in the microenvironment of spinal cord.Hydrogels have been regarded as promising SCI repair material in recent years and continuous studies have confirmed that hydrogel-based therapy can effectively eliminate inflammation and promote spinal cord repair and regeneration to improve SCI.In this review,hydrogel-based multimodal therapeutic strategies to repair SCI are provided,and a combination of hydrogel scaffolds and other therapeutic modalities are discussed,with particular emphasis on the repair mechanism of SCI.